(12) United States Patent (Io) Patent No.: US 9,526,824 B2 Ferrari Et Al

Home , Abanoquil, Ablukast, Aceglutamide, Adafenoxate, Adatanserin, Adrenalone

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(12) United States Patent (io) Patent No.: US 9,526,824 B2 Ferrari et al. (45) Date of Patent: Dec. 27, 2016

(54) NANOCHANNELED DEVICE AND RELATED (52) U.S. Cl. METHODS CPC ...... A61M 5/00 (2013.01); A61K 9/0097 (2013.01); A61M37/00 (2013.01); (71) Applicants:The Board of Regents of the (Continued) University of Texas System, Austin, TX (US); The Ohio State University (58) Field of Classification Search Research Foundation, Columbus, OH CPC ...... B81C 1/00444; B81C 1/00476; B81C (US) 1/00119; BO1D 67/0034; YIOS 148/05 (Continued) (72) Inventors: Mauro Ferrari, Houston, TX (US); Xuewu Liu, Sugar Land, TX (US); (56) References Cited Alessandro Grattoni, Houston, TX (US); Daniel Fine, Austin, TX (US); U.S. PATENT DOCUMENTS Randy Goodall, Austin, TX (US); Sharath Hosali, Austin, TX (US); 3,731,681 A 5/1973 Blackshear et al. Ryan Medema, Pflugerville, TX (US); 3,921,636 A 11/1975 Zaffaroni Lee Hudson, Elgin, TX (US) (Continued)

(73) Assignees: The Board of Regents of the FOREIGN PATENT DOCUMENTS University of Texas System, Austin, TX (US); The Ohio State University CN 1585627 2/2005 Research Foundation, Columbus, OH DE 10 2006 014476 7/2007 (US) (Continued)

(*) Notice: Subject to any disclaimer, the term of this OTHER PUBLICATIONS patent is extended or adjusted under 35 U.S.C. 154(b) by 784 days. "The Economic Costs of Drug Abuse in the United States," www. whitehousedrugpolicy.gov, Sep. 2001. (21) Appl. No.: 13/875,871 (Continued) (22) Filed: May 2, 2013 Primary Examiner Binh X Tran (65) Prior Publication Data (74) Attorney, Agent, or Firm Parker Highlander PLLC US 2013/0240483 Al Sep. 19, 2013 Related U.S. Application Data (57) ABSTRACT (63) Continuation of application No. 12/618,233, filed on A nanochannel delivery device and method of manufactur- Nov. 13, 2009, now Pat. No. 8,480,637. ing and use. The nanochannel delivery device comprises an (Continued) inlet, an outlet, and a nanochannel. The nanochannel may be oriented parallel to the primary plane of the nanochannel (51) Int. Cl. delivery device. The inlet and outlet may be in direct fluid C23F 1/00 (2006.01) communication with the nanochannel. A61 5/00 (2006.01) (Continued) 22 Claims, 35 Drawing Sheets

280 ~X31 270

210 US 9,526,824 B2 Page 2

Related U.S. Application Data 2010/0077515 Al * 3/2010 Espinosa ...... B81C 1/00071 850/40 2010/0170796 Al * 7/2010 Bhatia ...... BOIL 3/5027 (60) Provisional application No. 61/168,844, filed on Apr. 204/453 13, 2009, provisional application No. 61/114,687, 2010/0212762 Al * 8/2010 Den Toonder ...... BO1F 13/0059 filed on Nov. 14, 2008. 137/803 2011/0137596 Al 6/2011 Grattoni et al. (51) Int. Cl. A61K 9/00 (2006.01) FOREIGN PATENT DOCUMENTS A61M 37/00 (2006.01) EP 1 977 775 10/2008 B81C 1/00 (2006.01) WO WO 00/74751 12/2000 B82Y5100 (2011.01) WO WO 2004/036623 4/2004 A61 51142 (2006.01) WO WO 2005/079387 9/2005 (52) U.S. Cl. WO WO 2006/113860 10/2006 WO WO 2007/047539 4/2007 CPC ...... B81C 1100119 (2013.01); B82Y5100 WO WO 2007/089483 8/2007 (2013.01); A61M 5114276 (2013.01); B81B WO WO 2008/019886 9/2008 22011058 (2013.01); B81B 220310338 WO WO 2009/149362 12/2009 (2013.01); Y1OT 13718593 (2015.04); Y1 OT WO WO 2010/056986 5/2010 WO WO 2010/120817 10/2010 15611064 (2015.01) (58) Field of Classification Search USPC ...... 216/2, 39, 41, 56 OTHER PUBLICATIONS See application file for complete search history. "Under the Counter: The Diversion and Abuse of Controlled Pre- scription Drugs in the US," The National Center on Addiction and (56) References Cited Substance Abuse (CASA) at Columbia University, New York, NY, U.S. PATENT DOCUMENTS CASA, Jul. 2005. Extended European Search Report issued in European Application 4,834,704 A 5/1989 Reinicke No. 09826831, mailed Jul. 12, 2012. 4,955,861 A 9/1990 Enegren et al. Nath et al., `Buprenorphine pharmacokinetics: relative bioavail- 5,085,656 A 2/1992 Polaschegg 5,395,324 A 3/1995 Hinrichs et al. ability of sublingual tablet and liquid formulations," J. Clin. 5,651,900 A 7/1997 Keller et al. Pharmacol., 39:619-623, 1999. 5,728,396 A 3/1998 Peery et al. Report Stakeholder Workshop on a National Buprenorphine Pro- 5,769,823 A 6/1998 Otto gram Health Canada Nov. 18, 2004. 5,770,076 A 6/1998 Chu et al. Samhsa, "Overview of Findings from the 2002 National Survey on 5,798,042 A 8/1998 Chu et al. Drug Use and Health," Rockville, MD, DHHS publication, SMA 5,893,974 A 4/1999 Keller et al. 03-3774. 5,938,923 A 8/1999 Tu et al. 5,948,164 A 9/1999 Iida et al. Samhsa, "Results from the 2003 National Survey on Drug Use and 5,948,255 A 9/1999 Keller et al. Health: National Findings," Rockeville, MD, DHHS publication, 5,985,164 A 11/1999 Chu et al. SMA 3-3964. 5,985,328 A 11/1999 Chu et al. Samhsa, "The DAWN Report: oxycodaone, hydrocodone, and 6,044,981 A 4/2000 Chu et al. polydrug use," 2002. Jul. 2004 http://oas.samhsa.gov/2k4/ 6,592,519 B1 7/2003 Martinez oxycodone/oxycodone.cfm. 7,025,871 B2 4/2006 Broadley et al. Office Action issued in Chinese Application No. 200980154070.X, 7,135,144 B2 11/2006 Christel et al. 7,326,561 B2 2/2008 Goodman et al. dated Jan. 7, 2013. (English Translation). 7,413,846 B2 8/2008 Maloney et al. Office Action issued in European Application No. 09826831, dated 7,955,614 B2 6/2011 Martin et al. Jul. 11, 2013. 8,480,637 B2 7/2013 Ferrari et al. Office Action issued in U.S. Appl. No. 12/618,233, mailed Apr. 27, 8,632,510 B2 1/2014 Ferrari et al. 2012. 9,005,185 B2 4/2015 Ferrari et al. Office Action issued in U.S. Appl. No. 12/618,233, mailed Oct. 16, 2002/0087120 Al 7/2002 Rogers et al. 2012. 2002/0156462 Al 10/2002 Stultz PCT International Preliminary Report on Patentability issued in 2003/0010638 Al 1/2003 Hansford et al. 2003/0064095 Al 4/2003 Martin et al. International Application No. PCT/US2009/064376, mailed May 2004/003 82 60 Al 2/2004 Martin et al. 26, 2011. 2004/0082908 Al 4/2004 Whitehurst et al. PCT International Search Report and Written Opinion issued in 2004/0116905 Al 6/2004 Pedersen et al. International Application No. PCT/US2009/064376, mailed Aug. 2004/0260418 Al 12/2004 Staats 23, 2010. 2004/0262159 Al 12/2004 Martin et al. Christensen et al., "Tantalum oxide thin films as protective coatings 2005/0118229 Al 6/2005 Boiarski for sensors," J. Micromech. Microeng., 9:113-118, 1999. 2006/0180469 Al 8/2006 Han et al. Extended European Search Report issued in European Application 2006/0191831 Al 8/2006 Hansford et al. No. 10765046, mailed Oct. 1, 2012. 2006/0259015 Al 11/2006 Steinbach Extended European Search Report issued in European Application 2006/0270983 Al 11/2006 Lord et al. No. 11784219.5, mailed Jul. 8, 2014. 2007/0066138 Al 3/2007 Ferrari et al. 2007/0077273 Al 4/2007 Martin et al. Fine et al.,"A robust nanofiuidic membrane with tunable zero-order 2007/0286773 Al 12/2007 Schlautmann et al. release for implantable dose specific drug delivery," Lab on a Chip, 2008/0073506 Al 3/2008 Lazar 10(2): 3074-3083, 2010. 2009/0181200 Al * 7/2009 Borenstein ...... B81C 1/00119 Hammerle et al., `Biostability of micro-photodiode arrays for 428/36.9 subretinal implantation," Biomaterials, 23:797-804, 2002. 2009/02 143 92 Al 8/2009 Kameoka et al. Hess et al., "PECVD silicon carbide as a thin film packaging 2010/0003143 Al * 1/2010 Toonder ...... BO1F 13/0059 material for microfabricated neural electrodes," Mater. Res. Soc. 417/53 Symp. Proc., 1009-UO4-03, 2007. US 9,526,824 B2 Page 3

(56) References Cited PCT International Search Report and Written Opinion issued in International Application No. PCT/US2011/037094, dated Jan. 13, OTHER PUBLICATIONS 2012. PCT International Search Report and Written Opinion issued in Narayan et al., "Mechanical and biological properties of nanoporous International Application No. PCT/US2010/030937, dated Feb. 21, carbon membranes," Biomed. Mater., 3:034107, 2008. 2011. Nath et al., `Buprenorphine pharmacokinetics: relative bioavail- Report: Stakeholder Workshop on a National Buprenorphine Pro- ability of sub lingual tablet and liquid formulations," J. Clin. gram, Health Canada, Nov. 18, 2004. Pharmacol., 39:619-623, 1999. Samhsa, "Results from the 2003 National Survey on Drug Use and Nurdin et al., "Haemocompatibility evaluation of DLC-and SIC- Health: National Findings," Rockeville, MD, DHHS publication, coated surfaces," Eur Cells Mat., 5: 17-28, 2003. SMA 04-3964. Office Action issued in European Application No. 10765046, mailed Schmitt et al., "Passivation and corrosion of microelectrode arrays," Jul. 11, 2013. Electrochimica Acta, 44:3865-3883, 1999. Office Action issued in U.S. Appl. No. 13/111,368, mailed Apr. 21, Voskerician et al., `Biocompatibility and biofouling of MEMS drug 2015. delivery devices," Biomaterials, 24:1959-1967, 2003. Office Action issued in U.S. Appl. No. 13/111,368, mailed Oct. 17, Yakimova et al., "Surface functionalization and biomedical appli- 2014. cations base on SiC," JPhysics D, 40: 6435-6442, 2007. Office Action issued in U.S. Appl. No. 13/264,069, mailed Feb. 22, Zorman et al., "Silicon carbide as a material for biomedical 2013. Microsystems," DIT, Apr. 1-3, 2009. Office Action issued in U.S. Appl. No. 13/264,069, mailed Oct. 29, 2012. * cited by examiner U.S. Patent Dec. 27, 2016 Sheet 1 of 35 US 9,526,824 B2 ~C4

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FIG. 17 Nanochannel Ceiling & Floor Removal Solvent/Etchant Placeholder (substrate & capping layer) Tungsten SiO2, Si3N4, Si, SiC, SiCN, Au, BCB Warm H2O2 Ge SiO2, Si3N4, Si, SiC, SiCN, Au, BCB Warm H2O2 Cu SiO2, Si3N4, Si, SiC, SiCN Piranha Au SiO2, Si3N4, Si, SiC, SiCN, BCB Aqua Regia Cr SiO2, Si3N4, Si, SX, SiCN, BCB Chrome Etchant TN SiO2, Si3N4, Si, SX, SiCN, BCB Ammonia/Peroxide mix Al SiO2, Si3N4, Si, SX, SiCN H3PO41HNO3 Al SiO2, Si3N4, SiC, SiCN, BCB KOH Phosphosilicate glass Si3N4, W, SiC, SiCN, Si, Au, BCB Dilute HF Si02 Si3N4, W, SX, Si, SO,Au, BCB BOE Polymers Si, Si3N4, SiC, SiCN, Oxide, Metal Organic Solvents, Piranha SI3N4 SI, 5102, SIC, SICN Hot H3PO4 Si Si3N4, SiO2, SiC, SICN Hot KOH

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FIG. 31 US 9,526,824 B2 N NANOCHANNELED DEVICE AND RELATED of a single layer nanochannel delivery device or system, and METHODS allow a wide range of pre-defined porosity to achieve an arbitrary release rate using any preferred nanochannel size. CROSS-REFERENCE TO RELATED In certain embodiments, the nanochannel delivery device APPLICATIONS 5 is made of a "sandwich" of materials, composed of a thin top layer, the horizontal nanochannels, and a thicker bottom This application is a Continuation of U.S. patent appli- wafer. The thin top layer can house an array of microchan- cation Ser. No. 12/618,233, filed Nov. 13, 2009, now U.S. nels that offer an inlet or outlet for diffusing molecules. It Pat. No. 8,480,637, entitled "Nanochanneled Device and can also serve as the lid or ceiling for the nanochannels by Related Methods", U.S. Provisional Patent Application Ser. io providing the channels' top surface. The thicker bottom No. 61/114,687, filed Nov. 14, 2008, entitled "Nanochan- wafer can house an array of microchannels that offer a neled Device and Method of Use", and U.S. Provisional collateral outlet or inlet. Note that in the following, inlets are Patent Application Ser. No. 61/168,844, filed Apr. 13, 2009, indicated in the bottom wafer and outlets are indicated in the entitled "Nanochanneled Device and Method of Use", the top layer, but this is not a limit of the invention. In certain entire disclosures of which are specifically incorporated 15 embodiments, the nanochannels are fabricated by a sacrifi- herein by reference. cial layer technique that provides smooth surfaces and This invention was made with government support under precisely controlled dimensions. The nanochannels can be contract NNJ06HE06A awarded by NASA.The government formed in between the two layers and connect the outlet has certain rights in this invention. microchannels with the array of inlet microchannels formed 20 in the bottom wafer, additionally allowing thin surface BACKGROUND INFORMATION layers to be applied to both the top and the bottom surfaces independently, in order to optimize channel properties such Considerable advances have been made in the field of as surface charge, hydrophobicity, wetting and conductivity. therapeutic agent (e.g. drug) delivery technology over the Each inlet and outlet microchannel can be connected to one, last three decades, resulting in many breakthroughs in clini- 25 two, or more nanochannels. The height, width, and length of cal medicine. The creation of therapeutic agent delivery the nanochannel can be used to maintain a constant (zero- devices that are capable of delivering therapeutic agents in order) delivery. By the help of nanofabrication, a nanochan- controlled ways is still a challenge. One of the major nel length of 10 nm or less is feasible. requirements for an implantable drug delivery device is In certain embodiments, the nanochannel delivery device controlled release of therapeutic agents, ranging from small 30 is designed to yield high strength. This can be achieved by drug molecules to larger biological molecules. It is particu- a supporting structure obtained in the bottom side of the larly desirable to achieve a continuous passive drug release thick wafer. The structure can be composed by a regular profile consistent with zero order kinetics whereby the mesh of micrometric walls which create the side surfaces of concentration of drug in the bloodstream remains constant larger inlet macrochannels. Moreover, the top portion of the throughout an extended delivery period. 35 bottom wafer (in or on which nanochannels may be fabri- These devices have the potential to improve therapeutic cated) can be engineered to provide good mechanical sta- efficacy, diminish potentially life-threatening side effects, bility. improve patient compliance, minimize the intervention of The thickness of the supporting layer underneath the healthcare personnel, reduce the duration of hospital stays, nanochannels can be optimized, and can be realized by and decrease the diversion of regulated drugs to abusive 40 controlling the depth of the inlet microchannels and outlet uses. macrochannels or by selecting an SOI wafer with appropri- Nanochannel delivery devices may be used in drug deliv- ate depth of buried oxide layer. The materials and thickness ery products for the effective administration of drugs. In of top layers is also optimized for the attributes noted above. addition, nanochannel delivery devices can be used in other Certain embodiments include a nanochannel delivery applications where controlled release of a substance over 45 device comprising: an inlet microchannel; a nanochannel; time is needed. and an outlet microchannel, wherein the inlet microchannel and the outlet microchannel are in direct fluid communica- SUMMARY tion with the nanochannel. In specific embodiments, the nanochannel is oriented parallel to the primary plane of the Embodiments of this invention comprise a nanochannel 5o nanochannel delivery device. In particular embodiments, a delivery device having nanochannels within a structure flow path from the inlet microchannel to the nanochannel to configured to yield high mechanical strength and high flow the outlet microchannel requires a maximum of two changes rates. Various fabrication protocols may be used to form the in direction. nanochannel delivery device. Embodiments ofthe fabricated In specific embodiments, the inlet microchannel has a devices feature horizontal nanochannel lay-out (e.g., the 55 length, a width, and a depth; the outlet microchannel has a nanochannel is parallel to the primary plane of the device), length, a width, and a depth; and the nanochannel has a high molecule transport rate, high mechanical strength, length, a width, and a depth. In certain embodiments, the optional multilayered lay-out, amenability to select channel ratio of the nanochannel length to the inlet microchannel lining materials, and possible transparent top cover. Based length is between 0.01 and 10.0, and the ratio of the on silicon microfabrication technology, the dimensions of 6o nanochannel length to the outlet microchannel length is the nanochannel area as well as concomitant microchannel between 0.01 and 10.0. In particular embodiments, the areas can be precisely controlled, thus providing a predict- nanochannel length is greater than the inlet microchannel able, reliable, constant release rate of drug (or other) mol- length and the nanochannel length is greater than the outlet ecules over an extended time period. In certain embodi- microchannel length. In specific embodiments, the ratio of ments, the nanochannel delivery device can be used to build 65 the nanochannel length to either the inlet microchannel a multilayered nanochannel structure. Multilayered nano- length or the outlet microchannel length is between 0.2 and channel structures can extend the limit of release rate range 5.0, between 0.3 and 3.0, between 0.4 and 2.0, or between US 9,526,824 B2 3 _►, 0.5 and 1.0. In certain embodiments, the nanochannel length stantially planar body. Particular embodiments comprise an is greater than the length, width, and depth of the outlet inlet macrochannel between the inlet surface and the inlet microchannel. In particular embodiments, the inlet micro- microchannel, where the inlet macrochannel comprises channel is in direct fluid communication with the outlet boundary walls that are generally perpendicular to the inlet microchannel via a single nanochannel. 5 surface. In specific embodiments, the inlet macrochannel is Certain embodiments include a nanochannel delivery formed by deep reactive-ion etching. In particular embodi- device comprising: an inlet microchannel; a nanochannel; an ments, a primary axis of the outlet microchannel is perpen- outlet microchannel; and a fluid flow path from the inlet dicular to a plane that is parallel to the substantially planar microchannel to the outlet microchannel, where the fluid body. flow path requires a maximum of two changes in direction. 10 Certain embodiments comprise an apparatus comprising a In specific embodiments, the nanochannel is oriented par- first nanochannel delivery device inserted into a capsule. In allel to the primary plane of the nanochannel delivery particular embodiments, the first nanochannel delivery device. In particular embodiments, the inlet microchannel device is installed perpendicular to the primary axis of the and the outlet microchannel are in direct fluid communica- capsule. In particular embodiments, the capsule comprises a tion with the nanochannel. 15 septum. In certain embodiments, the septum comprises a Certain embodiments include a nanochannel delivery self-sealing material. In specific embodiments, the septum comprising: a substantially planar body comprising a first comprises silicone rubber. In certain embodiments, the sep- surface and a second surface opposing the first surface; a tum is configured to receive an injection of a therapeutic nanochannel disposed within the substantially planar body; agent. an inlet microchannel in fluid communication with the 20 Particular embodiments comprise a cap covering the nanochannel; and an outlet microchannel in fluid commu- septum. In certain embodiments, the cap comprises an nication with the nanochannel. In particular embodiments, orifice configured to guide a needle towards the septum. In the inlet microchannel extends from the nanochannel to the specific embodiments, the capsule comprises a cover first surface and wherein the outlet microchannel extends extending over the first nanochannel delivery device. In from the nanochannel to second surface. 25 particular embodiments, the cover comprises one or more Certain embodiments include a nanochannel delivery orifices. In certain embodiments, the one or more orifices are device comprising: a plurality of inlet microchannels; a sized so that they do not limit diffusion of a therapeutic agent plurality of nanochannels; and a plurality of outlet micro- from the capsule during use. In certain embodiments, the channels, where each inlet microchannel is in direct fluid cover is configured to protect the first nanochannel delivery communication with an outlet microchannel via a single so device from mechanical damage.In particular embodiments, nanochannel. In particular embodiments, the nanochannel is the cover is configured to protect the first nanochannel oriented parallel to the primary plane of the nanochannel delivery device from incursion by biological tissue struc- delivery device, and/or an inlet microchannel and an outlet tures after the capsule has been implanted in a living body. microchannel are in direct fluid communication with a In certain embodiments, the capsule comprises a first inner common nanochannel. In particular embodiments, indi- 35 reservoir. In specific embodiments, the first nanochannel vidual inlet and outlet microchannels are arranged perpen- delivery device is in fluid communication with the first inner dicular to a primary plane of the nanochannel delivery reservoir. device; the plurality of inlet microchannels form a first In specific embodiments, the capsule comprises a second array; the plurality of outlet microchannels form a second inner reservoir in fluid communication with a second nano- array; and the first array and the second array are overlap- 40 channel delivery device. In certain embodiments, the first ping so that individual inlet microchannels are distributed and second inner reservoir are not in fluid communication between individual outlet microchannels when viewed along with each other. In particular embodiments, the first and a section taken perpendicular to the primary plane. second inner reservoir are separated by a wall. In specific Certain embodiments include a nanochannel delivery embodiments, the first inner reservoir contains a first thera- device comprising: a substantially planar body including: a 45 peutic agent and the second inner reservoir comprises a length, a width, and a thickness, wherein the length and the second therapeutic agent. In particular embodiments, the width are each greater than the thickness; an inlet surface on first nanochannel delivery is configured to diffuse a first a first side of the substantially planar body, wherein the inlet therapeutic agent at a first diffusion rate and the second surface is bounded by the length and the width of the nanochannel delivery device is configured to diffuse the substantially planar body; and an outlet surface on a second 50 second therapeutic agent a second diffusion rate. side of the substantially planar body. In particular embodi- In certain embodiments the volume of the first inner ments, the outlet surface is bounded by the length and the reservoir can be modified by replacing a first removable width of the substantially planar body, and the inlet surface component of the capsule with a larger removable compo- is substantially parallel with the outlet surface. Specific nent. In particular embodiments, the first inner reservoir embodiments comprise a nanochannel disposed within the 55 comprises a coating compatible with a therapeutic sub- substantially planar body, where the nanochannel comprises stance. In specific embodiments, the capsule comprises an an inlet end and an outlet end; an inlet microchannel in fluid outer coating configured to prevent deleterious tissue encap- communication with the nanochannel; and an outlet micro- sulation. In particular embodiments, the capsule comprises a channel in fluid communication with the nanochannel, cylindrical shape. In certain embodiments, the capsule com- where the inlet microchannel and nanochannel are config- bo prises a disc shape. In certain embodiments, the capsule ured such that a first linear axis can extend between the inlet comprises a rectangular surface and an arched surface. In surface and the inlet end of the nanochannel. In particular specific embodiments, the capsule comprises a uniform embodiments, the outlet microchannel and nanochannel are cross-section. configured such that a second linear axis can extend between In certain embodiments, the capsule comprises one or the outlet surface and the outlet end of the nanochannel. In 65 more of the following materials: stainless steel, titanium, certain embodiments, a primary axis of the inlet microchan- polyetheretherkeytone, polysulfone, epoxy, silicone rubber, nel is perpendicular to a plane that is parallel to the sub- polyetherketoneketone, and thermoplastic polyurethane. In US 9,526,824 B2 5 T particular embodiments, the capsule comprises an anchor layer. In particular embodiments of the method, forming a member. In certain embodiments, the anchor member is plurality of inlet macrochannels comprises etching material configured to receive a suture. In specific embodiments, the from a back side of the first substrate, and the etching is capsule comprises a color coding to indicate a characteristic terminated at the internal oxide layer. of the capsule or the nanochannel delivery device. In par- 5 In certain embodiments the removal of the internal oxide ticular embodiments, the color coding indicates a character- layer after etching material to form the inlet microchannel istic of a therapeutic agent contained within the capsule. In and inlet macrochannels opens a pathway between the inlet specific embodiments the capsule comprises a translucent or microchannels and inlet macrochannels. In particular transparent cover extending over the first nanochannel deliv- embodiments of the method, each nanochannel is between ery device. io approximately one and ten nanometers deep, between Certain embodiments include a method of fabricating a approximately ten and twenty nanometers deep, between nanochannel delivery device. In particular embodiments, the approximately twenty and thirty nanometers deep, between method comprises: providing a first substrate; forming a approximately thirty and forty nanometers deep, or between plurality of nanochannels in the first substrate; forming a approximately forty and two hundred nanometers deep. plurality of inlet microchannels in the nanochannels of the 15 In certain embodiments of the method, the first sacrificial first substrate; providing a second substrate; forming a material can be subsequently removed by selective etching. plurality of outlet microchannels in the second substrate; and In particular embodiments, the first sacrificial material is coupling the second substrate to the first substrate, wherein tungsten. In specific embodiments, the second sacrificial each inlet microchannel is in direct fluid communication material can be subsequently removed by selective etching. with a nanochannel. 20 In certain embodiments of the method, the second sacrificial In particular embodiments of the method, the first sub- material is selected from the group consisting of: tungsten, strate comprises a silicon-on-insulator wafer. In certain copper, doped glass, and undoped glass. In particular embodiments, the height of each nanochannel is between embodiments, the second sacrificial material is filled into the approximately one and ten nanometers. In specific embodi- plurality of inlet microchannels so that the second sacrificial ments, the height of each nanochannel is between approxi- 25 material extends above the top of the inlet microchannels mately ten and twenty nanometers, between approximately and is planarized by chemical-mechanical planarization twenty and thirty nanometers, between approximately thirty (CMP). and fifty nanometers, between approximately fifty and one In particular embodiments of the method, the capping hundred nanometers, or between approximately one hundred layer is selected from silicon nitride, silicon oxide, silicon and two hundred nanometers. In certain embodiments the 30 carbonitride, silicon carbide, and silicon. In certain embodi- second substrate comprises a sacrificial release layer of ments, the capping layer comprises multiple depositions of indium tin oxide film on silicon. Particular embodiments materials comprising tensile and compressive stresses such further comprise depositing a glass film on the second that the net capping layer stress is tensile. In certain embodi- substrate prior to forming the plurality of inlet microchan- ments of the method, the capping layer is between approxi- nels in the second substrate. In specific embodiments, the 35 mately 0.5 and 1.0 microns thick, between approximately second substrate comprises a glass wafer and the glass wafer 1.0 and 2.0 microns thick, between approximately 2.0 and is bonded to the first substrate and the glass wafer is ground 4.0 microns thick, or between approximately 4.0 and 10.0 to reduce the thickness prior to forming the plurality of microns thick. In specific embodiments, the capping layer is outlet microchannels. greater than 10.0 microns thick. Certain embodiments include a method of fabricating a 40 Particular embodiments comprise a method offabricating nanochannel delivery device where the method comprises: a nanochannel delivery device, where the method com- providing first substrate; forming a plurality of nanochannels prises: providing a first substrate; forming a plurality of on the first substrate; filling in the plurality of nanochannels nanochannels on a first side of the first substrate; filling in with a first sacrificial material; forming a plurality of inlet the plurality of nanochannels with a sacrificial material; microchannels in the first substrate; filling in the plurality of 45 coupling an initial capping layer to the first side of the first inlet microchannels with a second sacrificial material; form- substrate; forming a plurality of inlet microchannels in the ing a capping layer that covers the plurality of nanochannels; capping layer; preparing a second substrate with a bonding forming a plurality of outlet microchannels in the capping layer; coupling the second substrate to a second side of the layer; removing the first sacrificial material from the plu- first substrate; removing a first portion of the second sub- rality of nanochannels; and removing the second sacrificial 50 strate; providing an additional capping layer to the second material from the plurality of inlet microchannels. substrate; forming a plurality of outlet microchannels in the In particular embodiments of the method, an inlet micro- second substrate; and removing the sacrificial material to channel is arranged perpendicular to a primary plane of the open the plurality of nanochannels. first substrate. In specific embodiments, an outlet micro- In certain embodiments of the method, the second sub- channel is arranged perpendicular to a primary plane of the 55 strate comprises a release layer, and the release layer can be first substrate. In certain embodiments of the method, an selectively removed to cause separation of the second sub- inlet microchannel is in direct fluid communication with a strate from the first substrate. In particular embodiments of nanochannel. In particular embodiments, an outlet micro- the method, an outlet microchannel is in direct fluid com- channel is in direct fluid communication with a nanochan- munication with the a nanochannel. In certain embodiments, nel. 60 the first substrate comprises a silicon-on-insulator wafer In certain embodiments of the method, the first substrate comprising an internal oxide layer. In specific embodiments, comprises a silicon-on-insulator wafer comprising an inter- forming the plurality of inlet microchannels comprises etch- nal oxide layer. In particular embodiments, the inlet and ing material from the capping layer, and the etching is outlet microchannels are patterned using a photolithography terminated at the internal oxide layer. process. In certain embodiments, forming the plurality of 65 In certain embodiments, forming a plurality of inlet inlet microchannels comprises etching material from the first macrochannels comprises etching material from a back side substrate, and the etching is terminated at the internal oxide of the first substrate, and the etching is terminated at the US 9,526,824 B2 7 8 internal oxide layer. In particular embodiments, the removal ing the substance to the person via the nanochannel delivery of the internal oxide layer after etching material to form the device comprises subcutaneously inserting the nanochannel inlet microchannel and inlet macrochannels opens a pathway delivery device into the person. between the inlet microchannels and inlet macrochannels. In the following, the term "coupled" is defined as con- In certain embodiments, each nanochannel is formed 5 nected, although not necessarily directly, and not necessarily between approximately one and ten nanometers deep, mechanically. between approximately ten and twenty nanometers deep, The use of the word "a" or "an" when used in conjunction between approximately twenty and thirty nanometers deep, with the term "comprising" in the claims and/or the speci- between approximately thirty and forty nanometers deep, or fication may mean "one," but it is also consistent with the between approximately forty and two hundred nanometers 10 meaning of "one or more" or "at least one." The term deep. "about" means, in general, the stated value plus or minus In particular embodiments, the sacrificial material can be 5%. The use of the term "or" in the claims is used to mean subsequently removed by selective etching. In specific "and/or" unless explicitly indicated to refer to alternatives embodiments, the sacrificial material is tungsten. In certain only or the alternative are mutually exclusive, although the embodiments, the initial capping layer is silicon nitride 15 disclosure supports a definition that refers to only alterna- deposited by plasma enhanced chemical vapor deposition. In tives and "and/or." certain embodiments of the method, the initial capping layer The terms "comprise"(and any form of comprise, such as is between approximately 0.01 and 0.5 microns thick, "comprises" and "comprising"), "have" (and any form of between approximately 0.5 and 1.0 microns thick, between have, such as "has" and "having"), "include"(and any form approximately 1.0 and 2.0 microns thick, between approxi- 20 of include, such as "includes" and "including") and "con- mately 2.0 and 4.0 microns thick, or between approximately tain" (and any form of contain, such as "contains" and 4.0 and 10.0 microns thick. In specific embodiments of the "containing") are open-ended linking verbs. As a result, a method, the initial capping layer is greater than 10.0 microns method or device that "comprises," "has," "includes" or thick. In certain embodiments of the method, the initial "contains" one or more steps or elements, possesses those capping layer is selected from silicon nitride, silicon oxide, 25 one or more steps or elements, but is not limited to possess- silicon carbonitride, silicon carbide, and silicon. In particu- ing only those one or more elements. Likewise, a step of a lar embodiments, the initial capping layer comprises mul- method or an element of a device that "comprises," "has," tiple depositions of materials comprising tensile and com- "includes" or "contains" one or more features, possesses pressive stresses such that the net capping layer stress is those one or more features, but is not limited to possessing tensile. In certain embodiments of the method, the bonding 30 only those one or more features. Furthermore, a device or layer is selected from the group consisting of benzocy- structure that is configured in a certain way is configured in clobutene, silicon oxide, copper, doped glass, gold and gold at least that way, but may also be configured in ways that are alloys. not listed. In certain embodiments, the method of coupling the The term "inlet microchannel" is defined as a microchan- second substrate to the first substrate is selected from the 35 nel through which a molecule travels prior to entering a group consisting of anodic bonding, fusion bonding, and nanochannel in a nanochanneled delivery device. then nocompression bonding. The term "outlet microchannel" is defined as a micro- Particular embodiments include a nanochannel delivery channel through which a molecule travels immediately prior device comprising: a plurality of inlet microchannels, where to exiting a nanochanneled delivery device. each of the inlet microchannels has a length, a width, and a 40 The term "nanochannel" is defined as a channel with a depth, and where the inlet microchannel length is greater cross-section having at least one dimension (e.g. height, than the inlet microchannel width and depth; a plurality of width, diameter, etc.) that is less than 200 mu. outlet microchannels, where each of the outlet microchan- The term "macrochannel" is defined as a channel with a nels has a length, a width, and a depth; and a plurality of cross-section having a maximum dimension (e.g. height, nanochannels in fluid communication with the plurality of 45 width, diameter, etc.) that is greater than about 10 µm. inlet microchannels and outlet microchannels. In certain Other objects, features and advantages of the present embodiments, the plurality of inlet microchannels are invention will become apparent from the following detailed arranged so that the inlet microchannel width and depth description. It should be understood, however, that the define a first plane that is parallel to the primary plane of the detailed description and the specific examples, while indi- nanochannel delivery device; and the plurality of outlet 50 cating specific embodiments of the invention, are given by micro channels are arranged so that the outlet micro channel way of illustration only, since various changes and modifi- width and depth define a second plane that is parallel to the cations within the spirit and scope of the invention will be primary plane of the nanochannel delivery device. apparent to those skilled in the art from this detailed descrip- Particular embodiments include a method of treating a tion. condition of a person, the method comprising: providing a 55 nanochannel delivery device as described herein; providing BRIEF DESCRIPTION OF THE FIGURES a reservoir in fluid communication with the nanochannel delivery device; providing a substance in the reservoir, FIGS. 1A-1J are schematic views of a manufacturing where the substance is configured to treat the condition; and process according to an exemplary embodiment. administering the substance to the person via the nanochan- 60 FIGS. 2A-2E are perspective views of a first portion of a nel delivery device. In particular embodiments of the nanochannel delivery device during the manufacturing pro- method, the substance is selected from the group consisting cess. of: leuprolide, letrozole, laptinib, buprenorphine, interferon, FIGS. 3A-3F are perspective views of a second portion of and zidovudine. In certain embodiments, the condition is a nanochannel delivery device during the manufacturing selected from the group consisting of: prostate cancer, breast 65 process. cancer, opiate dependencey, giant cell angioblastoma and FIG. 3G is a partial perspective view of a nanochannel HIV. In particular embodiments of the method, administer- delivery device with representative dimensions labeled. US 9,526,824 B2 9 10 FIG. 4A-4L are schematic views of a manufacturing FIG. 30 is a perspective view of a capsule according to an process according to an exemplary embodiment. exemplary embodiment in an installed location. FIGS. 5A-5H are schematic cross-section views of a FIG. 31 is a perspective view and a section view of a nanochannel delivery device during the manufacturing pro- capsule according to an exemplary embodiment. cess according to an exemplary embodiment. 5 FIGS. 6A-6J are schematic views of a manufacturing DETAILED DESCRIPTION OF ILLUSTRATIVE process according to an exemplary embodiment. EMBODIMENTS FIG. 7 is a cross-sectional side view of a schematic of an exemplary embodiment of a nanochannel delivery device. Protocol 1: Bonded Capping Layer FIGS. 8A-8I are schematic views of a manufacturing 10 FIGS. la-1j, 2A-2E, and 3A-3G provide illustrations of process according to an exemplary embodiment. steps performed in an exemplary first method of manufac- FIGS. 8J-8P are orthogonal and perspective views of turing a nanochannel delivery device. Specific dimensions exemplary embodiments during various stages of the manu- are provided for purposes of illustration only, and it is facturing process. 15 understood that other exemplary embodiments may com- FIG. 9 is a perspective view of a nanochannel delivery prise different dimensions. device according to an exemplary embodiment. In one exemplary embodiment manufactured according to FIG. 10 is a cross-sectional side view of a schematic of an this protocol, the top layer is a cover of a 5µm thick exemplary embodiment of a nanochannel delivery device. evaporated glass layer and the bottom wafer is a 4 inch SOI FIG. 11 is a scanning electron microscope image of a 20 wafer with a 30 µm device layer, and a 500 µm bulk layer, portion of a nanochannel delivery device according to an so that the supporting layer under the nanochannels has 30 exemplary embodiment. µm thickness. In this exemplary structure, the inlet and FIG. 12 is an optical image of a bonded wafer of a outlet microchannels are 5µm by 5µm, and the in-plane nanochannel delivery device according to an exemplary dimension of each nanochannel is 5µm by 5µm. The space embodiment. 25 between adjacent openings (e.g., the distance between adja- FIG. 13 is an optical image of a front surface of a cent nanochannels) is 2µm. The inlet macrochannel under nanochannel delivery device according to an exemplary the support network is approximately 200 µm by 200 µm up embodiment after polishing. through the 500 µm thick bulk layer. FIG. 14 is a scanning electron microscope image of a A general overview of this method of manufacturing will portion of a nanochannel delivery device according to an 30 first be presented, followed by a more detailed discussion of exemplary embodiment. the features comprised in the nanochannel delivery device. FIG. 15 is an optical image of a portion of a nanochannel In this embodiment, fabrication of the nanochannel delivery delivery device according to an exemplary embodiment after device does not utilize chemical mechanical polishing polishing. (CMP), and the microfabrication protocol comprises the FIG. 16 is scanning electron microscope image of a 35 following steps. Starting with a SOI (silicon on insulator) portion of a nanochannel delivery device according to an wafer (see FIG. 2A), a hard mask layer such as silicon exemplary embodiment. nitride film or LTO (low temperature oxidation) film that FIG. 17 is scanning electron microscope image of a will protect underneath silicon during thermal oxidation portion of a nanochannel delivery device according to an process is deposited. If silicon nitride is used, a silicon exemplary embodiment. 4o dioxide pad layer may be deposited before nitride deposi- FIG. 18 is a table of materials that may be used in tion. As an alternative, the bottom substrate can also be a exemplary embodiments of manufacturing processes. silicon wafer instead of SOI if the etching process rates are FIG. 19 is an exploded perspective view of a capsule and well characterized. In this case, the etching depth is con- a nanochannel delivery device according to an exemplary trolled by timing. embodiment. 45 The nanochannel areas can then be patterned on the mask FIG. 20 is an assembled perspective view of the embodi- layer using photolithography process. (see FIGS. 1(a) and ment of FIG. 19. 213), and the mask materials on nanochannel areas are FIG. 21 is an assembled perspective view of a capsule selectively removed but do not affect underneath silicon. A according to an exemplary embodiment. combination of dry etching, and short time wet etching may FIG. 22 is an exploded perspective view of the embodi- 5o be applied for this purpose. Then a silicon dioxide film (with ment of FIG. 21. a thickness that is well-controlled) can be deposited on bare FIG. 23 is an exploded perspective view of a capsule and silicon area by thermal oxidation. In this embodiment, the a nanochannel delivery device according to an exemplary thickness of the oxidation layer is used to define the height embodiment. of nanochannels, and the mask layer is stripped. FIG. 24 is an exploded perspective view of a capsule and 55 A mask layer suitable for deep silicon etching can then be a nanochannel delivery device according to an exemplary deposited. The mask layer should be able to be patterned, embodiment. and have a high selectivity to silicon during deep silicon FIG. 25 is an assembled perspective view of a capsule etching process. Depending on the technique for deep sili- according to an exemplary embodiment. con etching, a layer of silicon oxide, photoresist, or metal FIG. 26 is an exploded perspective view of the embodi- 60 film may be used. ment of FIG. 25. In this embodiment, the inlet microchannels are patterned FIG. 27 is an assembled perspective view of a capsule on the mask layer, and the inlet microchannels are etched according to an exemplary embodiment. down to the oxide layer of the SOI wafer by deep RIE FIG. 28 is an exploded perspective view of the embodi- (Reactive Ion Etch) or ICP (Inductive Coupled Plasma) ment of FIG. 27. 65 technique, as shown FIGS. 1(b) and 2C. If a silicon wafer is FIG. 29 is a perspective view of a capsule according to an used, the etching depth is determined by etching rate and exemplary embodiment. time. US 9,526,824 B2 11 12 The inlet macrochannels (the large openings from the microchannels 30 are formed to allow passage of material back)are laid out and etched to the oxide layer of SOI wafer, through the substrate 20 and top layer 15. At this stage, the as shown in FIGS. 1(c) and 2D, and the exposed oxide areas lower portion 40 of nanochannel delivery device 100 is are cleaned by HE solution. (see FIGS. 1(d) and 2E). To complete. fabricate the top cover of the nanochannel delivery devices 5 Referring now to FIGS. 3A-3F, the fabrication of the in this embodiment, starting with a support wafer (e.g., a upper portion 45 of nanochannel delivery device 100 begins silicon wafer), a sacrificial layer is deposited. (see FIGS. with a sacrificial layer 50 deposited on a support substrate 1(e), 1(f) and 3A). This sacrificial layer (e.g., indium tin 55. In addition, an additional layer 60 (e.g., spin-on-glass, oxide (ITO)), is selected so that it can be removed in a sputtered glass, e-beam evaporated glass, ITO-glass sand- solution that is safe for silicon and top cover materials. io wich, silicon, polymer, etc.) may be used in processes The top cover of the nanochannel delivery devices is utilizing a lift-off technique, as shown in FIG. 3B. Exit deposited on the sacrificial layer (see FIGS. 1(g) and 313), microchannels 70 are formed in sacrificial layer (and addi- and the outlets are patterned on the structure, as shown in tional layer 60, if utilized) as shown in FIG. 3C. FIGS. 1(h) and 3C). As an alternative, a lift-off technique At this stage, upper portion 45 is ready to be bonded to may be applied for the cases of sputtered glass or e-beam 15 lower portion 40 of nanochannel delivery device 100. It is evaporated glass. The materials may be any suitable mate- understood, the designations "upper" and "lower" are used rial, e.g. spin-on-glass, sputtered glass, e-beam evaporated only for purposes of clarification in the description of the glass, ITO-glass sandwich, silicon, polymer, etc. The mate- figures, and do not dictate the relationship of components rials may include glass and glass materials known to those during use of the device. As shown in FIGS. 3D and 3E, skilled in the art to bond to silicon by specific means, e.g., 20 upper portion 45 and lower portion 40 are bonded together anodic bonding or fusion bonding. The materials should be (through, e.g., anodic bonding or Si Si direct bonding or able to bond to silicon by certain means. For instance of intermediate layer aided bonding). Support substrate 55 is glass, anodic bonding can be applied. A spin-on-glass layer removed from upper portion 45, and nanochannel delivery may also applicable. Depending on the surface quality, a device 100 is completed, as shown in FIGS. 3F and 3G. The planarization process may be needed. 25 embodiment shown in FIG. 3G comprises optional tapered The structure wafer and the top cover are bonded together surfaces in the transitions between outlet microchannels 70 by a technique such as anodic bonding or Si Si direct and nanochannels 25, as well as between nanochannels 25 bonding or intermediate layer aided bonding, as shown in and inlet microchannels 30. FIGS. 1(c), 3D, and 3E, and the support wafer of top cover As shown in FIG. 3G, nanochannels 25 lie in a plane is removed (as shown in FIGS. 1(j) and 3F). Finally, the 30 parallel to the primary plane of nanochannel delivery device individual nanochannel delivery devices are obtained by 100 (e.g., the plane defined by the larger dimensions [in this dicing the wafer, and cleaning. example, L and W] of nanochannel delivery device 100). In another exemplary embodiment manufactured accord- Such a configuration allows for the length of nanochannel 25 ing to this protocol, while keeping the bottom silicon sub- (e.g., approximately the distance between adjacent outlet 70 strate is the same 4 inch SOI wafer with a 30 µm device layer 35 and inlet 30) and the height and width of the nanochannel to and a 500 µm bulk layer as that mentioned in above be varied without varying the length L, width W, and embodiment, the top layer is a 10 µm thick glass film. The thickness T of nanochannel delivery device 100. The thick- 10 um thick glass film is manufactured by thinning a thicker ness T of nanochannel delivery device 100 can therefore be glass layer. To make this thin film, a 100 um to 500 um thick based on other criteria (such as mechanical integrity) rather glass wafer is bonded to the structural silicon substrate. A 40 than the need to control the flow of a substance being planarization technique such as backgrinding, or lapping, or delivered via nanochannel delivery device 100. CMP, or chemical etching, or dry etching is then applied to The embodiments shown in FIGS. 3A-3G also provide for thin the glass layer until the designed thickness such 10 um each outlet 70 to be in fluid communication with any inlet 30 is reached. The outlets are then patterned on the thinned via a single nanochannel 25. Such a configuration can glass film, and etched down to the underneath silicon surface 45 provide for greater control over the diffusion of a substance to open the outlets. In this exemplary structure, the inlet and being delivered via nanochannel delivery device 100. For outlet microchannels are 5µm by 5µm, and the in-plane example, the diffusion rate through nanochannel delivery dimension of each nanochannel is 5µm by 5µm. The space device 100 is more closely related to the dimensions of between adjacent openings (e.g., the distance between adja- nanochannel 25, as compared to configurations that have cent nanochannels) is 2µm. The inlet macrochannel under 5o numerous nanochannels in fluid communication with a the support network is 200 µm by 200 µm up through the 500 single extended inlet. In such configurations, the inlet(rather µm thick bulk layer. than the nanochannel) may become a restriction on flow and Referring specifically now to FIGS. 2A-2E and 3A-3F, a limit the ability to control the flow by varying the dimen- more detailed view of the features of nanochannel delivery sions of the nanochannel. device 100 is provided. Referring initially to FIG. 2A, an 55 As shown in the detailed view of FIG. 3G (not to scale), SOI wafer 10 comprises a top layer 15 over a substrate 20 nanochannel 25 comprises a length nL, a width nW and a and separated by an oxide layer 35. As shown in FIG. 213, height nH. Outlet microchannel 70 comprises a length oL, a a series of nanochannels 25 are formed using a pattern mask width oW, and a height oH. In addition, inlet microchannel in top layer 15. One or more inlet microchannels 30 is 30 comprises a length iL, a width iW and a height iH. As formed using a pattern mask in each nanochannel 25, as 60 shown in FIG. 3G,the "length" of each channel is measured shown in FIG. 2C, exposing an oxide layer 35 between the along the path that a molecule would travel as it moves from substrate 20 and the top layer 15. For purposes of clarity not inlet microchannel 30, through nanochannel 25, and out all features, for example inlet microchannels 30, are labeled through outlet microchannel 70. In certain embodiments in the figures. oL=4 um,oW -5 um, off-5 um while nH=50 mu,nW=4 um, As shown in FIG. 2D, a portion of substrate 20 is removed 65 and nL-5 um and oL=30 um, oW-5 um, off-5 um. using a pattern mask from below the oxide layer 35. Oxide In certain embodiments, the ratio of oL/nL or iL/nL can be layer 35 is then removed (as shown in FIG. 2E), and inlet 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, US 9,526,824 B2 13 14 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, lift off technique may be applied for certain cases.(See FIG. 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(ij)). The materials may include, for example, spin-on- 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, glass, sputtered glass, e-beam evaporated glass, ITO-glass 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, sandwich, silicon, etc. The materials should be able to bond 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, 5 to silicon by some means. For instance, a transparent glass 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, layer can be deposited by e-beam evaporation. A spin-on- 20, 30, 40 50, 60, 70, 80, 90, or 100. glass layer may also usable. Depending on the surface Protocol 2: Multilayered Structure with Bonded Capping quality, a planarization may be needed. The structure wafer Layer from the previous step and the top cover can be bonded In a second embodiment, a multilayered nanochannel io together by a technique such as anodic bonding or Si Si structure can be fabricated by modifying the above-de- direct bonding or intermediate layer aid bonding.(See FIG. scribed protocol 1. This embodiment comprises the follow- 4(k)). The support wafer of top cover can be removed (See ing steps. Starting with a SOI (silicon on insulator) silicon FIG. 4(1)), and the devices obtained by dicing the wafer and wafer, a silicon dioxide layer (with a thickness that is cleaning. well-controlled) is deposited by thermal oxidation. The 15 Protocol 3: Monolithically Fabricated Capping Layer thickness of the oxidation layer can be used to define the As a third embodiment, a nanochannel structure can be height of nanochannels. As an alternative, the bottom sub- fabricated monolithically (e.g., without bonding) and strate can also be silicon wafer instead of SOI if the etching optionally utilizing CMP in the process. This exemplary process rates are well characterized. The nanochannel areas microfabrication protocol comprises the following steps as can be patterned on the oxide layer using photolithography 20 shown in FIGS. 5A-5H. process. Specific dimensions are provided for purposes of illus- The silicon oxide on non-nanochannel areas can be selec- tration only, and it is understood that other exemplary tively removed but not affect the oxide on nanochannel area. embodiments may comprise different dimensions. In this (See FIG. 4(a)). A polysilicon structure layer can be depos- embodiment, the top layer is approximately 2µm of deposited on the top of oxide nanochannel spacing layer.(see FIG. 25 ited silicon nitride. This embodiment also comprises a 4(b)). A second defined thickness oxide layer can be depos- bottom wafer that is a 8 inch SOI wafer with a 30 µm device ited again, and the nanochannel areas can be patterned on the layer, and a 725 µm bulk layer, so that the supporting layer oxide layer using photolithography process. The silicon under the nanochannels has 30 µm thickness. In this exem- oxide on non-nanochannel areas can be selectively removed plary structure, the openings for the inlet and outlet micro- but do not affect the oxide on nanochannel area. (See FIG. 30 channels are 3µm by 5µm, and the in-plane dimension of 4(c)). This process finishes the second layer of nanochan- each nanochannel is 3µm by 5µm. The space between nels. The previous two steps can be repeated to achieve adjacent microchannel openings is 2µm. As in previously- desired number of layers. described embodiments, the inlet macrochannel under the As an alternative to the previous steps, the silicon oxide support network is approximately 200 µm by 200 µm up nanochannel spacing layer and multilayer structure layer 35 through the 725 µm thick bulk layer. may also use other materials. For example, an aluminum Starting with an SOI (silicon on insulator) wafer 210, a film as nanochannel spacing layer, and evaporated glass film nanochannel spacing layer 220 (with a thickness that is well as multilayer structure layers. controlled, for example, ±5% over the relevant portion of A first mask layer suitable for deep silicon etching can be SOI wafer 210) is deposited. The thickness of spacing layer deposited. The mask layer should be able to be patterned, 40 220 can be used to define the height of the nanochannels. and have high selectivity to silicon during deep silicon This spacing layer 220 is a sacrificial layer, and the material etching process. Depending on the technique for deep sili- will be removed in a subsequent step, so the silicon surface con etching, a layer of silicon oxide, photoresist, or metal immediately under it is the "floor" of the eventually formed film may be used. nanochannels. The spacing material should have a high wet The inlet microchannels are patterned on the first mask 45 etch selectivity to other materials in the nanochannel deliv- layer, and a second mask layer is deposited on the top of first ery device (nDD). As an example, a thin film of tungsten, mask layer. The inlet microchannels are patterned on the germanium, or silicon oxide can be used for the nanochannel both first and second mask layers. The outlet microchannels spacing layer 220. are etched down to a certain depth close to oxide layer of the As shown in FIG. 5A, a capping layer 230 is deposited SOI wafer, and the second mask layer is stripped to expose 50 over the nanochannel spacing layer 220. Capping layer 230 the first mask layer. The outlet microchannel is etched will ultimately be the "ceiling" of the nanochannels. Silicon through multiple layers of the nanochannel spacing layer nitride, silicon oxide, silicon carbide, or other material and structure layer. A combination of wet etching and DRIE which has a high etch selectivity to the material for spacing may be applied. This will also etch the inlet down to the layer 220 may be used for capping layer 230. insulator layer of SOI wafer. (See FIG. 4(i)). If a silicon 55 A mask layer (not shown) suitable for deep reactive-ion wafer is used, the etching depth is determined by etching etching (DRIE) is deposited, and the inlet microchannels rate and time. Then the inlet macrochannels on the back are 240 are patterned on the mask layer using photolithography. laid out and etched to the oxide layer of SOI wafer (see FIG. As shown in FIG. 513, the DRIE process(es) etch micro- 4(e)), and the oxide on the exposed areas is cleaned. (See channels 240 through the capping layer 230 and spacing FIG. 4(f)). 60 layer 220 and silicon down to the buried oxide layer 250 of To fabricate the top cover of the nanochannel delivery SOI wafer 210. The mask layer can then be removed. devices, starting with a support wafer (e.g., a silicon wafer), As shown in FIG. 5C, inlet microchannels 240 are filled a sacrificial layer is deposited. (See FIG. 4(h)). This sacri- with a fill material 260 that can be polished by CMP or ficial layer is selected so that it can be removed in a solution etched. Non-limiting examples of fill material 260 include that is safe for silicon and top cover materials. The top cover 65 copper, tungsten, polysilicon, or phosphosilicate glass, each of the nanochannel delivery device is deposited on the deposited by techniques known in the art. Fill material 260 supporting wafer and the inlet microchannels are etched. A should have a wet etch with high selectivity to silicon and US 9,526,824 B2 15 16 the material of capping layer 230. In this exemplary embodi- of dry etching, and short time wet etching may be applied for ment, fill material 260 only needs to fill in the top of inlet this purpose. A silicon dioxide film (with a well-controlled microchannels 240. A CMP or etch back process can be used thickness) is deposited on the bare silicon area by thermal to remove the excess fill material 260 that extends above or oxidation. The thickness of the oxidation layer defines the outside of inlet microchannels 240. The surface of the 5 height of nanochannels, and the mask layer and oxide is remaining fill material 260 should be above the level of stripped. spacing layer 220. A mask layer suitable for potassium hydroxide (KOH) Referring now to FIG. 5D, additional material may be wet etching is deposited, such as silicon nitride. A new mask deposited onto capping layer 230. The areas of capping layer is designed to lay-out both inlet microchannels and outlet 230 and spacing layer 220 above and between the inlet io microchannels on the same layer, and the nanochannel microchannels 240 can be patterned using a photolithogra- length is defined by the spacing between adjacent inlet and phy process. The spacing layer 220 and capping layer 230 outlet microchannels. The mask layer is patterned using the outside of the inlet nanochannels 240 (e.g., regions 221 and new mask by standard photolithography process. The mask 231) can be etched to or slightly below the silicon surface. materials on open areas are selectively removed. Then a Referring now to FIG. 5E, a final capping layer 270 is 15 KOH wet etching is applied to form openings with the slope deposited over the entire surface of wafer 210 to provide wall, and the mask layer is stripped. (See FIG. 6(b)). structural rigidity and seal the sidewalls of the nanochannel A mask layer suitable for deep silicon etching can be areas. Using a photolithography process, outlet microchan- deposited. The mask layer should be able to be patterned, nels 280 can be patterned and etched through capping layers and have a high selectivity to silicon during deep silicon 230, 270 and optionally through spacing layer 220 into 20 etching process. Depending on the technique for deep sili- silicon 210 for additional process latitude. As shown in FIG. con etching, a layer of silicon oxide, photoresist, metal film, 5F, a protective layer 275 is deposited over capping layer or other suitable material may be used. 270 and outlet microchannels 280. The outlet microchannels are patterned on the mask layer Referring now to FIG. 5G, wafer 210 can then be inverted and the outlet micro channels are etched down to the oxide and large openings for inlet macrochannels 245 on the back 25 layer of the SOI wafer by a suitable technique, for example of wafer 210 can be formed by DRIE down to the buried a deep RIE or ICP technique. (See FIG. 6(c)). If a silicon oxide layer 250 of wafer 210. As shown in FIG. 5H, wafer is used, the etching depth can be determined by sacrificial and protective layers used during processing (e.g. etching rate and time. spacing layer 220, fill material 260, capping layer 270, and The inlet macrochannels from the back are laid out and portions of oxide layer 250) are removed by appropriate 30 etched to the oxide layer of the SOI wafer, and the exposed processes known in the art. As shown in FIG. 5H, when oxide areas are cleaned by HF solution. (See FIG. 6(d)). To spacing layer 220 is removed, nanochannels 205 are formed. fabricate the top cover of the nanochannel delivery devices, The wafers can then be diced to get individual nanochannel starting with a support wafer (e.g., silicon wafer), a sacri- delivery devices. ficial layer is deposited. (See FIG. 6(e, ff). This sacrificial As illustrated in this embodiment, nanochannels 205 are 35 layer (e.g. ITO), is selected so that it can be removed in a in direct fluid communication with inlet microchannels 240 solution that is safe for silicon and top cover materials. and outlet microchannels 280. Specifically, inlet microchan- The top cover of the nanochannel delivery devices is nels 240 and nanochannels 205 are directly connected so deposited on the sacrificial layer. (See FIG. 6(g)), and the that a fluid exiting an inlet microchannel will immediately outlets are patterned on the structure.(See FIG. 6(h)). As an enter the nanochannel without flowing through an intenne- 4o alternative, a lift-off technique may be applied for the cases diate body. of sputtered glass or e-beam evaporated glass. In certain As a variant of this protocol, and in analogy to protocol embodiments, the materials may be spin-on-glass, sputtered 2 above, a multilayered structure can be built by repeated glass, e-beam evaporated glass, ITO-glass sandwich, silicon, application of the monolithic top layer process. A plurality polymer, etc. The materials should be able to bond to silicon of capping layer 230 and spacing layer 220 pairs can be 45 by certain means. For instance of glass, anodic bonding can deposited. The inlet microchannels can be etched through all be applied. A spin-on-glass layer may also applicable. layers down to the buried oxide and filled with fill material Depending on the surface quality, a planarization process 260 and polished as above. The final capping layer 270 can may be needed. be applied and outlet microchannels 280 etched as above. The structure wafer from step (6)and the top cover can be Protocol 4: Varying the Length of Nanochannels 5o bonded together by a technique such as anodic bonding or In certain embodiments, Protocol 1 can be modified to Si Si direct bonding or intermediate layer aided bonding. make a nanochannel delivery device with different a nano- (See FIG. 6(i)). The support wafer of top cover is removed channel length while keep other features unchanged. An (See FIG. 6(j)), and the devices are obtained by dicing the exemplary microfabrication protocol comprises the follow- wafer, and cleaning. ing steps. 55 Ifthe preferred length of nanochannel is less than 500 mu, Starting with a SOI (silicon on insulator) wafer, a hard a nanofabrication technique such as e-beam or nanoimprint mask layer such as silicon nitride film or LTO (low tem- may be applied. Isotropic silicon etching technique may also perature oxidation) film that will protect the underneath be applied. A schematic structure view of a short nanochan- silicon during thermal oxidation process is deposited. If nel delivery device is shown in FIG. 7. As shown in FIG. 7, silicon nitride is used, a silicon dioxide pad layer may be 60 inlet microchannel 340 has a portion 341 that is flared or deposited before nitride deposition. As an alternative, the tapered proximal to nanochannel 305. Similarly, outlet bottom substrate can also be silicon wafer instead of SOI if microchannel 380 has a portion 381 that is flared or tapered the etching process rates are well characterized. proximal to nanochannel 305. Nanochannel 305 is therefore The nanochannel areas can be patterned on the mask layer shortened as a result of portions 341 and 381. using photolithography process. (See FIG. 6(a)), and the 65 Protocol 5: Hybrid Monolithic-Bonded Capping Layer mask materials on nanochannel areas are selectively As a fifth embodiment, a nanochannel structure can be removed but do not affect underneath silicon. A combination fabricated without the use of a CMP process, while utilizing US 9,526,824 B2 17 18 bonding as a non-critical step in the capping layer fabrica- mechanical thinning, a chemical etch, or a combination of tion. This exemplary microfabrication protocol comprises both. In the case of the optionally added "release layer" 421, the following steps as seen in FIGS. 8A-8P. the release layer can be selectively removed to cause sepa- Referring initially to FIG. 8A, starting with an SOI ration of the silicon capping wafer 411 from substrate wafer (silicon on insulator) substrate wafer 410, a nanochannel 5 410. spacing layer 420 (with a thickness that is well-controlled, Referring now to FIG. 8G, using a photolithography for example, ±5% over the relevant portion of SOI substrate process, outlet microchannels 480 can be patterned and wafer 410) is deposited. The thickness of spacing layer 420 etched through optional release layer 421, bonding layer can be used to define the height of the nanochannels. This 441, capping material 431, capping layer 430, and optionally spacing layer 420 is a sacrificial layer, and the material will io through spacing layer 420 into the silicon for additional be removed in a subsequent step, so the silicon surface process latitude. immediately under it is the "floor" of the eventually formed Referring now to FIG. 8H, a protective capping layer 470 nanochannels. The spacing material should have a high wet is deposited over the surface of substrate wafer 410. Wafer etch selectivity to all other materials in the nanochannel 410 (with layer 421 and bonding layer 441 from wafer 411) delivery device. As an example, a thin film of tungsten, 15 is then inverted and inlet macrochannels 445 on the back of germanium, or silicon oxide can be used for nanochannel wafer 410 can be formed by DRIE down to the buried oxide spacing layer 420. layer 450 of wafer 410. A capping layer 430 is deposited over nanochannel spac- Referring now to FIG. 8I, sacrificial layers (e.g. spacing ing layer 420. Capping layer 430 will ultimately be the layer 420, capping layer 470, and portions of oxide layer "ceiling" of the nanochannels. Silicon nitride, silicon oxide, 20 450) are removed by appropriate processes known in the art. silicon carbide, or other material which has a high wet etch As shown in FIG. 8I, when spacing layer 420 is removed, selectivity to the material for spacing layer 420 may be used nanochannels 405 are formed. As illustrated in this embodi- for capping layer 430. The nanochannel areas can be pat- ment, nanochannels 405 are in direct fluid communication terned on spacing layer 420 and capping layer 430 using a with inlet microchannels 440 and outlet microchannels 480. photolithography process. As shown in FIG. 813, spacing 25 Referring now to FIG. 87, a top view of the entire wafer layer 420 and capping layer 430 on non-nanochannel areas 410 is illustrated. As shown in this view, wafer 410 (prior to 432 and 433 are etched to or slightly below the silicon dicing) comprises several nanochannel delivery devices 400 surface of silicon wafer 410. (only one of which is identified in the figure). Wafer 410 can Referring now to FIG. 8C, additional capping material be diced to separate the individual nanochannel delivery 431 is deposited, and optionally planarized by CMP to 3o devices 400 from each other. A detailed view of an indi- provide a flat surface. Inlet microchannels 440 are patterned vidual nanochannel delivery device 400 with exemplary on the mask layer (not shown) using photolithography. The dimensions is illustrated in FIG. 8K.In this view, a plurality DRIE process(es) etch inlet microchannels 440 through the of inlet macrochannels 445 are visible on one side of capping layer 430 and spacing layer 420 and silicon down to nanochannel delivery device 400. This exemplary embodi- a buried oxide layer 450 of SOI substrate wafer 410. The 35 ment of nanochannel delivery device 400 is approximately mask layer is removed and additional appropriate surface 6.0 mm square, and the inlet macrochannels form a gener- layers useful for bonding can be deposited on this surface, ally circular shape approximately 3.6 mm in diameter. It is as needed. understood that while wafer 410 of Protocol 5 is illustrated Referring now to FIG. 8D, on another silicon substrate in FIG. 87, other protocols will also yield wafers that (e.g. a capping wafer 411), a layer 421 (comprising, for 40 comprise multiple nanochannel delivery devices, and can be example, silicon nitride or silicon oxide) can be deposited. diced or separated into the individual devices. It is also On top of layer 421, a bonding layer 441 is deposited. The understood that other exemplary embodiments may com- material for bonding layer 441 can be chosen so as to adhere prise different dimensions than those shown in FIG. 8K. In well to the material on the surface of wafer 410 (e.g. capping some embodiments, the wafer 410 may remain whole, material 431). The material for bonding layer 441 can also 45 effectively forming a nanochannel delivery device with be designed so that any surface particles can be absorbed dimensions similar to that of a silicon wafer, for example, into bonding layer 441 to prevent any delamination between approximately 500 to 750 micrometers in thickness and 100, capping wafer 410 and substrate wafer 411 after bonding. 150, 200, 300, 450, or 675 mm in diameter. Alternatively, a highly clean process before and during For example,referring to FIGS.8L and 8M a nanochannel bonding can be used without this requirement. Exemplary 5o delivery device 500 is shown comprising a body 501 that is materials for bonding layer 441 include polymeric materials, substantially planar and has a rectangular shape with a silicon oxide, and copper. Before the application of bonding thickness "T", a length "L" that is 4 mm and a width "W" layer 441, optionally, a material with a very high etch rate, that is 3 mm.The thickness "T" may be varied, but in certain "the release layer" 421, can also be applied with an addi- embodiments is approximately 550-700 µm, and is less than tional silicon nitride or silicon oxide layer (not shown) on 55 either length L or width W. Length L and width W define the top of this release layer. Layer 421 can comprise a material primary plane of nanochannel delivery device 500. As with a high selectivity to other materials in the nanochannel shown in the figures, body 501 has an inlet surface 502 on delivery device. one side and an outlet surface 503 on the opposite side. Inlet Referring now to FIG. 8E, capping wafer 411 and sub- surface 502 and outlet surface 503 are generally parallel to strate wafer 410 are then bonded onto each other. In certain 60 each other and parallel to the primary plane of nanochannel embodiments, the bonding can be polymer-silicon nitride delivery device 500. Visible in FIG. 8M are a plurality of bond, such as Benzocyclobutene (BCB)-silicon nitride, cop- inlet macrochannels 545 (only one of which is identified in per-copper then nocompression bond or oxide-to-oxide the figure). FIG. 8N provides a perspective view of a partial fusion bond, each with appropriate pre- and post-bond cross-section of nanochannel delivery device 500 taken treatments known to those skilled in the art. 65 along line 8N-8N in FIG.8M. The portion illustrated in FIG. Referring now to FIG. 8F, the silicon portion of capping 8N comprises a single inlet macrochannel 545 and multiple wafer 411 is then removed through a suitable process, e.g. inlet microchannels 540 and outlet microchannels 580. As US 9,526,824 B2 19 20 shown in FIGS. 8L-8N, inlet microchannels 540 and outlet a nanochannel delivery device according to Protocol 1 microchannels 580 are formed so that individual inlet and (described above). This example is provided for illustration outlet microchannels are perpendicular to the primary plane purposes only and is not intended to limit the scope of the of nanochannel delivery device 500 (e.g., the length of the invention described herein. microchannels is measured along a line that is perpendicular 5 Processing begins with a double polished 4" SOI wafer to the primary plane of the device). In addition, the plurality (available from Silicon Quest). The wafer comprises a of inlet microchannels 540 and outlet microchannels 580 device layer that is 30 um thick, <100> orientation P-type, form overlapping arrays so that individual inlet microchan- Boron doped, and a 1-10 Ohm-cm surface resistivity, a nels 580 are distributed between individual outlet micro- buried oxide layer that is 0.4 um thick and a handle layer that channels 580, and vice versa. Referring now to FIG. 8 As io is 500 um thick, P-type, Boron doped, and 1-10 Ohm-cm shown in the detailed view of FIG. 80, each nanochannel 505 is in direct fluid communication with an inlet micro- surface resistivity. The wafer was cleaned in a fresh Piranha channel 540 and an outlet microchannel 580. solution (3:1 98% sulfuric acid: 30% hydrogen peroxide, Referring now to FIG. 8P, a detailed section view of a over 100 C)for 10 min, and spun dried. A 50 nm pad oxide section of nanochannel delivery device 500 is illustrated. In layer was then thermally grown on the surface. Then a 100 this view, three inlet nanochannels 540 are visible, along 15 nm low-stress nitride was deposited on the pad oxide layer with a pair of outlet microchannels 580 and a pair of by low-pressure chemical vapor deposition(LPCVD). The 5 nanochannels 505. As shown, nanochannel 505 comprises um wide nanochannel patterns were transferred from the an inlet end 506 and an outlet end 507. In this embodiment, photo mask onto the silicon nitride layer by standard pho- a first linear axis 508 extends between inlet end 506 and inlet tolithography using an EVG 620 aligner. The exposed surface 502. Also visible in FIG. 8P, a second linear axis 509 20 nitride area was removed by CF4 RIE. extends between outlet end 507 and outlet surface 503. After the photoresist was stripped, the pad oxide was Also shown in FIG. 8P, inlet microchannel 540 comprises cleaned by dipping in 1:10 HE water solution. Then the a primary axis 512 and outlet microchannel 580 comprises wafer was placed in a thermal oxide furnace to grow a primary axis 511. As shown in this embodiment, primary sacrificial oxide. The thickness of this sacrificial oxide axis 511 and primary axis 512 are perpendicular to a plane 25 determined the height of nanochannels, i.e. height of 513 that is parallel to a substantially planar body 550 of nanochannel-0.46*Thickness of Oxide. In this example, a nanochannel delivery device 500. In FIG. 8P, only a portion 39 nm oxide was grown for 18 nm nanochannels. Then the of substantially planar body 550 is shown. A complete view nitride and oxide were removed in dilute HE solution. A 3 of substantially planar body 550 is visible in FIGS. 8L and um thick low temperature oxide (LTO) layer was then 8M. 3o deposited on the surface by LPCVD. Then the backside of Referring now to FIG. 9, specific dimensions for an exemplary embodiment of a nanochannel delivery device wafer was protected by 3 um spun-on Futurrex negative manufactured according to the above protocol are provided. photoresist. The LTO on front side was removed in a It is understood that these dimensions are illustrative of the buffered oxide etch (BOE) solution, and the wafer was specific embodiment shown, and that other embodiments cleaned in piranha solution. may incorporate different dimensions. 35 A 500 nm LTO film was deposited on the wafer using Referring now to FIG. 10, a partial cross-section of LPCVD. The 5 umx5 um inlet microchannel patterns were nanochannel delivery device 500 illustrates the diffusion transferred to the LTO film on the device side of wafer using path 575 for a molecule passing through nanochannel deliv- standard lithography on an EVG 620 aligner, and LTO were ery device 500. It is understood that nanochannel delivery etched using CF4 RIE. Then the 200 umx200 um inlet device 500 may be oriented in any direction during use. As 40 macrochannel patterns were transferred onto the backside of shown in FIG. 10, flow path 105 requires a maximum of two the wafer, and RIE was done. changes in direction between the point where the molecule After cleaning out the photoresist, deep silicon etching of enters nanochannel delivery device 500 and the point at inlet microchannels was done using an Oerlikon DSE etcher. which the molecule exits nanochannel delivery device 500. The etching was stopped on the buried oxide layer. The For example, the molecule enters nanochannel delivery 45 wafer was flipped over, and attached onto a handle wafer device 500 and is initially located within inlet macrochannel using thermal grease (Al Technology). The 190 umx190 um 545. The molecule then enters inlet microchannel 540. In the inlet macrochannels were then etched on the Oerlikon DSE embodiment shown,flow path 575 turns at a 90 degree angle etcher, and stopped on the oxide layer. FIG. 11 shows a SEM to the right as the molecule enters the nanochannel 505 that image of deep etched 190 um openings. The wafer was is in direct fluid communication with inlet microchannel 5o detached from the handle wafer, and cleaned. The wafer was 540. After the molecule exits the nanochannel 505, the flow dipped in BOE for 5 min to open the buried oxide layer, and path turns again (this time, a 90 degree turn to the left) as it spun dried. Then mask LTO films on both sides of wafer enters the outlet microchannel 580, which is also in direct were removed in HE water solution. fluid communication with the nanochannel 505. Therefore, A 500 um thick double side polished Pyrex 7740 glass flow path 575 requires a maximum of two changes in 55 wafer was bonded onto the silicon substrate as a nanochan- direction as the molecule diffuses through nanochannel nel cap by anodic bonding using an EVG 520 bonder. The delivery device 500. While a molecule may undergo more anodic binding was performed at 800 volts, and 325° C. for than two changes in direction as it passes through nano- 10 min. FIG. 12 shows an optical image ofthe bonded wafer. channel delivery device 500, it is only required to make two The bonded wafer pair was adhered on a wafer holder using changes in direction. 60 wax, and backlapping was applied to thin the glass down to 30 um, and then CMP polished to a final thickness of 5-10 Example um (by Valley Design Corp). FIG. 13 shows an optical image of the front surface after Protocol 1: Bonded Capping Layer polishing. The contrast indicates that nanochannels are open. 65 The 5 umx5 um outlet microchannels were formed by The following example is provided as an illustration of CF4/Ar RIE using Ni film as mask layer. To do so, a copper one non-limiting embodiment of a method of manufacturing seed layer was firstly deposited on the glass surface. The 5 US 9,526,824 B2 21 22 umx5 um outlet microchannel patterns were transferred to channels. The excess copper overburden is then polished the copper film using standard lithography on an EVG 620 away using a pad/slurry combination, under moderate pres- aligner, and were wet etched. Then Ni was electroplated sure/speed (2-4 psi, 30-90 rpm) process. In this same pro- onto the patterned copper film. The CF4/Ar RIE was used to cess, the TiN in the non-microchannel area (field) is also etch the inlet microchannels into the glass film to reach the 5 completely removed. Finally, the inlet microchannel process silicon surface. After stripping the mask layer, the wafer was is hardened with a short bake anneal at 150-250 C,for about cleaned, and diced using DAD321 Dicing Saw (Disco). The 30 minutes, and the surface is cleaned. FIG. 15 presents a top fabricated devices are 6 mmx6 mm overall dimension. There view of the device after filling with copper. are 161 in total 190 umx190 um openings arranged in a 3.6 A thin silicon nitride ("SiN2") layer of about 50 nm is mm diameter circle. Each such opening is connected to 501 io deposited by PECVD to cap the copper. The nanochannel in total 5 umx5 um inlet channels, and the inlet channels are lines are then exposed in resist (1.3 um) using photolithog- connected to nanochannel and outlet channels. raphy and the silicon nitride (S1NI as well as SiN2) layers are etched, along with the tungsten nanochannel material, Example with the etch proceeding a few tens of nanometers into the 15 silicon. Protocol 3: Monolithically Fabricated Capping A thicker, tensile silicon nitride ("SiN3") is then depos- Layer ited, of a thickness of about 1-1.5 um. The tensile stress of this layer is chosen so as to make the overall dielectric stack The following example is provided as an illustration of slightly tensile by about 20 MPa. The outlet microchannels one non-limiting embodiment of a method of manufacturing 20 are then exposed on a resist layer (of nominal thickness 2 a nanochannel delivery device according to Protocol 3 um) and a further etch of all silicon nitride layers (S1NI, (described above). This example is provided for illustration SiN2, SiN3) along with the W nanochannel layer are etched purposes only and is not intended to limit the scope of the so that the bottom of the outlet microchannels end in the invention described herein. device silicon. The resist is stripped after this stage. FIG. 16 Processing begins with a double-side polished Silicon On 25 presents a cross-section of a device at this stage of process- Insulator (SOI) wafer using a 690 um thick base wafer with ing. a top silicon layer thickness of 30 um and a buried oxide An appropriate protection layer is applied to the surface thickness of 2 um. This wafer is cleaned with a piranha Ti/TiN (250/300A), Tungsten (5000 A) followed by Phos- solution (3:1 98% Sulfuric acid:30% Hydrogen peroxide, pho silicate Glass (PSG)of thickness of 1 um, which can be over 100 C)to remove any organic and metal contamination. 30 used as both an HE protectant as well as a surface protectant. A smooth (typically <5 A rms), uniform (typically <2% The wafer is then turned upside down and a thick resist (10 non-uniformity,) tungsten metal layer is sputtered on this um) is spun on. Using the front side alignment marks, wafer, using a physical vapor deposition(PVD) process at a macrochannels are exposed on the backside. The macro- temperature of 100 C. The thickness of this tungsten layer is channels are etched all the way through the wafer (about 700 selected to be the height of the nanochannel layer, for 35 um)using a Bosch DRIE process. This process lands on the example 5 mu. buried oxide, which forms an effective etch stop. FIG. 17 The nanochannel space layer is then covered by a plasma presents a cross-section of a test device at this stage of enhanced chemical vapor deposition (PECVD) silicon processing. This buried oxide is then removed by a plasma nitride ("S1NI") with low stress (380 C, appropriate stoi- etch. chiometry), with a target thickness of 500 mu and a non- 40 A series of wet etches are done to remove all the sacrificial uniformity of less than 2%. Positive resist is then spun on, materials. A short buffered HE etch, for about 5 minutes, is with a thickness of 2 um. The inlet microchannels are done to remove any residual oxide (of the buried oxide), as exposed in this resist, with the sizes varying from 1 um to well as to remove the PSG layer. The wafers are then over 5 um, as needed. Using this resist, the applied silicon wet-etched in an SC-1 solution (hot Ammonium hydrox- nitride is etched through, along with tungsten, using a 45 ide hydrogen peroxide mixture) for about 10 minutes to conventional C4F8 etch chemistry with appropriate plasma remove the TiN barrier at the top surface as well as at the powers, and other reactive and inert gases. bottom of the inlet microchannels. The wafers are subjected The etch in this process is timed to be deep enough that to a piranha etch for about 20 minutes to remove the copper it goes through the tungsten layer also, which takes a few in the inlet microchannels. This is followed by another SC-1 minutes. Another etch is performed, still using the resist as 50 etch to remove all the TiN from the sidewalls of the inlet the mask, to etch a deep via in the silicon that is deep enough microchannels. Finally, the Tungsten is removed from the to go into the buried oxide. A 5 dep/5 etch per cycle Bosch nanochannels by placing the wafers in wafer hydrogen etch is used in this step since the etch automatically termi- peroxide for 2 hours, followed by a rinse with DI water. The nates at, and is highly selective to, the buried oxide. A small wafers are then cleaned with Iso-Propyl Alcohol (IPA) to overetch of 10-20% of the most critical structure is provided 55 displace the water with IPA, and the wafers are allowed to to compensate for the non-uniformity of the process. The dry. remaining resist is then removed using an oxygen plasma Material Selection and the wafers are additionally cleaned of all polymer Regardless of the protocol used to manufacture the nano- residues using an appropriate wet chemistry FIG. 14 pres- channel delivery device, the materials used during the manu- ents an example of a device at this stage of process. 60 facturing process should be selected to successfully remove The next module consists of filling or capping these inlet sacrificial materials while leaving the non-sacrificial mate- microchannels. This can be accomplished by plugging the rials. As shown in FIG. 18, the selection of a nanochannel inlets with copper. A TiN barrier layer is deposited by "placeholder" (e.g., the sacrificial material used to fill the sputter, with a thickness of 300 A. A copper seed layer, with space of the nanochannel) and nanochannel "ceiling" and a nominal thickness of about 4000 A is deposited through a 65 "floor" materials (e.g., the substrate and capping layers) PVD sputter process. A low current (2 A, 10-15 minutes) should be coordinated with the selection of a solvent or electroplating process is used to fill or plug the inlet micro- etchant. Examples of suitable solvents and etchants that can US 9,526,824 B2 23 24 be used to remove sacrificial materials while leaving the faces that are not angled in a manner (when capsule 600 is substrate and capping layers are shown in FIG. 18. It is installed) which could trap air bubbles. understood that other combinations of materials may be Referring now to FIGS. 21 and 22, capsule 700 is similar utilized as well. to the previously-described capsule 600. However, in this Post Wafer Processing 5 embodiment capsule 700 is fitted with a septum 760 on the During post wafer processing, each wafer is attached to a end of cylindrical body 720 that is distal from end portion tape-ring with an adhesive tape. A UV release tape is 630. Septum 760 comprises a self-sealing material (e.g., preferred since it has better adhesion. Since both surfaces of silicone rubber) that permits injection of a therapeutic agent the wafer have critical device structures, UV tape is attached into inner volume 750 of cylindrical body 720. In certain 10 embodiments, a therapeutic agent can be injected with a to both top and bottom surfaces. The wafers are then diced hypodermic needle just prior to implantation of capsule 700. into individual die and cleaned. The tapeframe is then Referring now to FIG. 23, a capsule 800 comprises exposed to a UV light source to decrease the adhesion of the components equivalent to previously-described embodi- tape to the surface. The dice are individually picked and ments. However, this embodiment comprises a cap 825 that placed into a bare-die holder using an automated pick and 15 covers septum 860. Cap 825 may comprise an orifice (not place sorter tool. The tape on the top surface of the die is visible in the perspective view of FIG. 21) configured to subsequently peeled off manually. The dice are then indi- guide a needle or other device used to penetrate septum 860 vidually placed in a final clean container and cleaned with and inject a therapeutic agent into inner volume 850 of acetone with a final rinse of IPA to promote channel drying. cylindrical body 820. A die is attached by epoxy or other fixing method to a 20 Referring now to FIG. 24, a capsule 900 comprises a capsule mating surface. cylindrical body 922 coupled to a separate end component Capsule Configurations 935 and a cap 925. In this embodiment, cylindrical body 922 Referring now to FIGS. 19 and 20, nanochannel delivery can be replaced with another cylindrical body having a device 500 may form part of a larger assembly, e.g., a different length in order to vary the internal volume of capsule 600 that may be used to administer drugs or other 25 capsule 900 (and the amount of therapeutic agent that therapeutic agents to a patient. FIG. 19 shows a detailed capsule 900 can contain). Similar to previous embodiments, view of one end of capsule 600 in an exploded view, while end component 935 comprises an end portion 930 config- FIG. 20 illustrates an assembled view of capsule 600. It is ured to receive cap 910. End component 935 also comprises understood that in other embodiments, nanochannel delivery a recessed portion 940 configured to receive nanochannel device 500 may be used in other applications where it is 30 delivery device 500. desired to precisely control the diffusion or passage of small Referring now to FIGS. 25 and 26, a capsule 1000 amounts of any substance. comprises a disc-shaped body 1020 with a cap 1010 com- In the embodiment shown in FIGS. 19 and 20, capsule prising a series of exit ports 1015. In this embodiment, 600 comprises a generally cylindrical body 620 having an disc-shaped body 1020 comprises a septum 1060 through end portion 630 configured to receive a first cap 610 and a 35 which a therapeutic agent may be injected. As shown in the second cap 625. In this embodiment, nanochannel delivery exploded view of FIG. 26, supports 1050 can be used to hold device 500 is installed in a plane that is perpendicular to the nanochannel delivery device 500 proximal to exit ports primary axis of capsule 600 (e.g., an axis that is parallel to 1015. In this manner, a therapeutic agent contained within the length of cylindrical body 620 and concentric with capsule 1000 is forced to pass through nanochannel delivery cylindrical body 620). End portion 630 also comprises a 40 device 500 proximal before exiting capsule 1000. recessed portion 640 configured to receive nanochannel In the embodiment shown in FIGS. 27 and 28, a capsule delivery device 500. In certain embodiments, a glue or other 1100 comprises a rectangular planar surface 1121 and an boding agent may be used to secure nanochannel delivery arched surface 1120. Capsule 1100 also comprises a closed device 500 in recessed portion 640. When assembled, nano- end 1125 and a septum 1160 that can be inserted into an open channel delivery device 500 can be inserted into recessed 45 end 1161. In the embodiment shown, septum 1160 covers portion 640, and first cap 610 may be fitted onto end portion the entire open end 1161. In other embodiments, a septum 630. may cover part of an open end, and a cap may cover the During use, drugs (or any other substance administered remaining portions. Similar to previously-described via capsule 600) can pass from cylindrical body 620 to embodiments, septum 1160 is self-sealing and can be punc- nanochannel delivery device via an inner volume 650 con- 50 tured with a needle to insert a therapeutic agent. Capsule tained within cylindrical body 620. After diffusing through 1100 also comprises a first recessed portion 1140 configured nanochannel delivery device 500 and into first cap 610, the to receive nanochannel delivery device 500, and a second administered substances can exit cap 610 via exit ports 615. recessed portion 1130 configured to receive a cap 1110 In exemplary embodiments, the dimensions of exit ports 615 comprising exit ports 1115. An aperture 1135 extends (and other aspects of capsule 610, such as inner volume 650 55 through recessed portion 1140 into an inner volume 1150 and cap 610) are large enough so that these features do not bounded by rectangular planar surface 1121, arched surface restrict the diffusion of the administered substance from 1120, closed end 1125 and septum 1160. In this embodiment, capsule 600. As a result, the diffusion of the administered a therapeutic agent can be contained within inner volume substance can be more precisely controlled by selecting the 1150 and dispensed through aperture 1135, nanochannel dimensions of nanochannel delivery device 500, particularly 60 delivery device 500, and exit ports 1115. the dimensions of nanochannels 505. Cap 610 may also Referring now to FIG. 29, another embodiment of a provide dimensional rigidity and protect nanochannel deliv- capsule 1200 is generally equivalent to capsule 1100, but ery device 500 from mechanical damage and the incursion comprises features that accommodate two nanochannel of biological tissue structures after implantation. delivery devices (not shown). In this embodiment, capsule In certain embodiments, inner volume 650 is configured 65 1200 comprises a rectangular planar surface 1221, arched to minimize capture points for air bubbles. For example, surface 1220, closed end 1225 and septum 1260. Capsule inner volume 650 may comprise radiused corners and sur- 1200 also comprises a pair of first recessed portion 1240 US 9,526,824 B2

w1i each configured to receive nanochannel delivery device (not 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, shown), and a second pair of recessed portions 1230 each 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, configured to receive a cap with exit ports (not shown). Each 100 mm. In other embodiments, the capsule may have a recessed portion 1240 comprises an aperture 1235 that width greater than 100 mm. provides fluid communication between inner volume 1250 5 In specific embodiments, a capsule may have a length of and the environment surrounding capsule 1200. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, In certain embodiments, inner volume 1250 comprises 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, separate, internal reservoirs in which each reservoir is in 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, fluid communication with a single aperture 1235. The inter- 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, nal reservoirs may be separated by inner walls within io 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, aperture 1235. In such embodiments, each reservoir may be 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, filled with a separate therapeutic agent. Each nanochannel 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, device can be configured to provide the preferred dosage of 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, each individual therapeutic agent. 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, Referring now to FIG. 30, another embodiment of a 15 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, capsule 1300 is shown in an installed position so that it 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, partially extends beneath an epidermal surface 1301 of a 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, patient into which capsule 1300 has been inserted. Capsule 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 1300 comprises multiple covers 1310 with exit ports 1315. 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, Beneath each cover 1310, a nanochannel delivery device is 20 196, 197, 198, 199 or 200 mm. In other embodiments, the inserted over an aperture that is in fluid communication with capsule may have a length greater than 200 mm. an inner volume of capsule 1300 (similar to the embodi- It is noted that the various embodiments of capsules ments described in FIGS. 27-29). The inner volume of described in this disclosure comprise a cross-section that is capsule 1300 may be divided into separate compartments so nominally constant along the length of the capsule. Such an that each nanochannel delivery device can be used to 25 optional configuration can facilitate sliding removal from a administer a specific and distinct therapeutic agent. Capsule surgical site within the body without damage to surrounding 1300 also comprises an anchor member 1305 configured to tissue. serve as a point at which a suture (not shown) can be In exemplary embodiments a capsule may comprise suit- attached to capsule 1300 when it is installed. Anchor mem- able materials such as stainless steel, titanium, polyethere- ber 1305 may also be coupled to a string or other device (not 30 therkeytone, polysulfone, and other plastics and metals. In shown) used to remove or retrieve capsule 1300. certain embodiments, a capsule may comprise coating(s) on Referring now to FIG. 31, another embodiment of a the interior to provide an optimal environment for a thera- capsule 1400 is shown. This capsule is a minimal covering peutic substance and/or coating(s) on the exterior to prevent of the back and sides of the nanochannel device, such that deleterious tissue encapsulation. In specific embodiments, the "reservoir" for a contained drug is limited to the volume 35 the capsule may comprise color coding to indicate the model of the macrochannels on the back of the chip (e.g., the of the capsule or a particular characteristic (e.g., the thera- nanochannel delivery device), which is about 4.5 mm3 for peutic agent, rate of administering the agent, the capacity of the embodiment shown in FIG.8K. This embodiment can be the capsule, etc.). In certain embodiments, a capsule may made particularly small, for example 2 mmx2 mmx0.5 mm, comprise a translucent or transparent portion or component and is, therefore, especially suited for implantation with very 40 (e.g. a cap) to facilitate observation of the quantity of high potency drugs into sensitive locations, e.g., glaucoma therapeutic agent contained within the capsule. For example, medication into the inner portion of the eye. a translucent or transparent cap covering the nanochannel Exemplary embodiments ofthe previously-described cap- delivery device can allow a person to confirm the capsule is sules can be sized so that the capsule may be implanted full by orienting the capsule so that the nanochannel delivery subcutaneously. In specific embodiments, the capsule may 45 device is positioned towards the top of the capsule. A needle have a diameter of 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, (or other loading device) can then penetrate the septum and 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, the therapeutic agent can be injected into the capsule. When 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, liquid appears on the top of the nanochannel delivery device 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, (as viewed through the cap), the person filling the capsule 10.0, 11.0, 12.0, 13.0, 14.0, 15.0, 16.0, 17.0, 18.0, 19.0 or 50 will have an indication that the capsule is full. 20.0 mm.In other embodiments, the capsule may be greater In exemplary embodiments, a capsule may be used to than 20.0 mm in diameter. administer one or more of the following substances: adren- In certain embodiments, the capsule may have a thickness ergic agent; adrenocortical steroid; adrenocortical suppres- of 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, sant aldosterone; alkylating agent; antagonist; amino acid; 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, 55 anabolic; analeptic; analgesic; anesthetic; anorexogenic; 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, anti-acne agent; anti-adrenergic; anti-allergic; anti-alopecia 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, agent; anti-amebic; anti-anemic; anti-anginal; antiangio- 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, genic, anti-anxiety; anti-arthritic; anti-asthmatic; anti-ath- 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, erosclerotic; antibacterial; antibiotic; anticancer; anticholin- 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, 60 ergic; anticoagulant anticonvulsant; antidepressant; 9.8, 9.9 or 10.0 mm.In other embodiments, the capsule may antidiabetic; antidiarrheal; antidiuretic; anti-dyskinetic; anti- have a thickness greater than 10.0 mm. emetic; anti-epileptic; antifibrinolytic; antifungal; anti-hem- In specific embodiments, a capsule may have a width of orrhagic; antihistamine; anti-hypercalcemic, anti-hypercho- 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, lesterolaemic; anti-hyperlipidaemic; anti-hypertensive; anti- 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 65 hypertriglyceridemic; anti-hypotensive; anti-infective; anti- 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, inflammatory; anti-ischemic; antimicrobial; antimigraine; 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, antimitotic; antimycotic; anti-nauseant; anti-neoplastic; US 9,526,824 B2 27 28 anti-neutropenic; anti-obesity agent; anti-osteoporotic, anti- diol, Estrogen, Eszopiclone, etanercept, Ethembutol hydro- parasitic; antiproliferative; antipsychotic; antiretroviral; chloride, Ethosuximide, ethynl estradiol, etonogestrel, anti-resorptives; anti-rheumatic; anti-seborrheic; antisecre- etoricoxib, etravirine, Exenatide, Ezetimibe, Ezetimibe, tory; antispasmodic; antisclerotic; antithrombotic; antitu- Factor VII, famotidine, Famotidine, Fenofibrate, Fenofi- mor; anti-ulcerative; antiviral; appetite suppressant; bispho- 5 brate, Fentanyl, Fentanyl citrate, Ferrous sulfate, Fexofena- sphonate; blood glucose regulator; bronchodilator; dine, fexofenadine hydrochloride, Filgrastim, Finasteride, cardiovascular agent; central nervous system agent; contra- fluconazole, Fluoxetine hydrochloride, Fluticasone, Fluvas- ceptive; cholinergic; concentration aid; depressant; diagnos- tatin, folic acid, Follitropin alfa, Follitropin beta, For- tic aid; diuretic; DNA-containing agent, dopaminergic moterol, Fosinopril sodium, Gabapentin, Gabapentin, Gem- agent; estrogen receptor agonise fertility agent; fibrinolytic; io citabine, glargine insulin, Glatiramer, glimepride, Goserelin, fluorescent agent; free oxygen radical scavenger; gastric histrelin acetate, Human growth hormone, Hydralazine acid supressant; gastrointestinal motility effector; glucocor- hydrochloride, Hydrocodone bitartrate, Hydroxyurea, ticoid; glutamatergic agent; hair growth stimulant; hemo- Hydroxyzine hydrochloride, Ibandronate, Imatinib, Imiglu- static; histamine H2 receptor antagonist; hormone; hypoc- cerase, Imipenem, imiquimod, Indinavir sulfate, infliximab, holesterolemic; hypoglycemic; hypolipidemic; hypotensive; 15 Interferon beta-la, Ipratropium, Irbesartan, Irinotecan, Iso- imaging agent; immunizing agent; immunomodulator; niazid, Isosorbide moninitrate, ixabepilone, ketamine, keto- immunostimulane immunosuppressant; interleukin, kera- conazole, Ketorolac, Lactobionate, Lamivudine, Lamivu- tolytic; LHRH agonist; mood regulator; mucolytic; mydri- dine, Lamotrigine, lanreotide acetate, Lansoprazole, atic; nasal decongestant; neuromuscular blocking agent; lapatinib, laropiprane Latanoprose Letrozole, Leuprolide, neuroprotective; NMDA antagonist; non-hormonal sterol 20 Levalbuterol, Levamisole hydrochloride, Levetiracetam, derivative; nootropic agent; parasympathomimetic agent; levocetirizine dihydrochloride, levodopa, Levofloxacin, plasminogen activator; platelet activating factor antagonist; levonorgestrel, Levothyroxine, levothyroxine sodium, Lido- platelet aggregation inhibitor; platinum-containing agent, caine, Linezolid, Lisdexamfetamine Dimesylate, Lisinopril, psychotropic; radioactive agent; raf antagonist, RNA-con- Lispro insulin, Lopinavir, Loratadine, lorazepam, Losartan taining agent, scabicide; sclerosing agent; sedative; seda- 25 potassium, maraviroc, Marinol, meclizine hydrochloride, tive-hypnotic; selective adenosine Al antagonist; selective Meloxicam, Memantine, Meropenem, metaxalone, met- estrogen receptor modulator, serotonin antagonist; serotonin formin, Metformin Hydrochloride, methadone, methoxy inhibitor; serotonin receptor antagonist; steroid; stimulant; polyethylene glycol-epoetin beta, Methylphenidate, Meth- thrombic agent; thyroid hormone; thyroid inhibitor; thyro- ylphenidate hydrochloride, Metoprolol, Metoprolol tartrate, mimetic; tranquilizer; vasoconstrictor; vasodilator; wound 30 metronidazole, Metronidazole, miglitol, Minocycline, healing agent; xanthine oxidase inhibitor; and the like; Minocycline hydrochloride, mirtazepine, Modafinil, Abacavir, Abacavir sulfate, abatacepe Acarbose, Acet- Mometasone, montelukast, Montelukast sodium, Morphine, aminophen, Aciclovir, Adalimumab, Adapalene, Alendro- Moxifloxacin, Mycophenolate mofetil, Naloxone, Naproxen nate, Alendronate sodium, Alfuzosin, aliskiren, allopurinol, sodium, natalizumab, Neostigmine bromide, Niacin, Nico- alvimopan, ambrisentan, Aminocaproic acid, Amitriptyline 35 tinamide, Nifedipine, Nifurtimox, nilotinib hydrochloride hydrochloride, amlodipine, amlodipine besylate, amoxicil- monohydrate, nitrofurantoin, Nortriptyline hydrochloride, lin, amoxicilline, Amphetamine, Anastrozole, Aripiprazole, nystatin, olanzapine, Olanzepine, Olmesartan, olmesartan annodafinil, Atazanavir, atenolol, Atomoxetine, atorvastatin medoxomil, olopatadine hydrochloride, Omalizumab, calcium, atorvastatin, Atropine sulfate, Azelastine, azithro- Omega-3 acid ethyl esters, Omeprazole, Ondansetron, Orl- mycin, Balsalazide, Benazepril, bendamustine hydrochlo- 40 istae Oseltamivir, Oxaliplatin, Oxcarbazepine, Oxybytynin ride, Benzepril hydrochloride, bevacizumab, Bicalutamide, chloride, oxycodone hydrochloride, Paclitaxel, Palivi- Bimatoprost, Bisoprolol, Bisoprolol fumarate, Bosentan, zumab, Pantoprazole, paracetamol, Paroxetine, paroxetine Botulin toxin, Budesonide, Buformin, Buprenorphine, hydrochloride, Pegylated interferon alfa-2a, Pemetrexed, Bupropion, bupropion hydrobromide, Bupropion Hydro- Penicillamine, Penicillin V potassium, Phenformin, Pheny- chloride, Cabergoline, Calcipotriol, calcitriol, candesartan 45 loin sodium, Pioglitazone, Piperacillin, Potassium chloride, cilexetil, Capecitabine, Captopril, carbidopa, carisoprodol, Pramipexole, Pravastatin, Pravastatin sodium, prednisolone Carvedilol, Caspofungin, Cefdinir, Cefoperazone, Cefotiam, quetiapine fumerate, Pregabalin, Primaquine phosphate, cefprozil, Cefuroxime, Celecoxib, cephalaxin, Certolizumab Progesterone, Promethazine, Promethazine hydrochloride, Pegol, Cetirizine, Cetrizine hydrochloride, Cetuximab, Proponolol hydrochloride, Propoxyphene hydrochloride, Chlorpromazine hydrochloride, Chlorpheniramine maleate, 50 pseudoephedrine, Pseudophedrine hydrochloride, Pyri- ciclesonide, Cilastatin, cimetidine, Cinacalcee Ciprofloxa- dostigmine bromide, Pyridoxine hydrochloride, Quetiapine, cin, citalopram hydrobromide, Clarithromycin, Clindamy- quetiapine fumarate, Quinapril hydrochloride, Rabeprazole, cin, Clindamycin, clindamycin hydrochloride, Clomip- raloxifene, raltegravir, Ramipril, Ranitidine, Ranitidine ramine hydrochloride, Clonidine hydrochloride, hydrochloride, Recombinant factor VIII, retapamulin, clopidogrel, Clopidogrel bisulfate, Cloxacillin Sodium, Co- 55 Rimonabane Risedronate, Risedronate sodium, risperidone, Amoxiclav, Codeine phosphate, Colchicines, Colesevelam, Ritonavir, rituximab, Rivastigmine, rivastigmine tartrate, cyclobenzaprine hydrochloride, Cyclophosphamide, Rizatriptan, Ropinirole, rosiglitazone, Rosiglitazone Cyclosporine, darbepoetin alfa, Darifenacin, DCRM 197 maleate, Rosuvastatin, Rotavirus vaccine, rotigotine, Salbu- protein, Desloratadine, desloratidine, Desmopressin sulfate, tamol, Salbutamol sulfate, salmeterol, sapropterin dihydro- Desoximetasone, dexamethasone, Diclofenac, Diethylcar- 60 chloride, Sertraline, sertraline hydrochloride, Sevelamer, bamazine citrate, difluprednate, diphenhydramine, Sevoflurane, Sildenafil, sildenafil citrate, simvastatin, Sim- Dipyridamole, DL-methionine, Docetaxel, Donepezil, vastatin, Sitagliptin, Sodium valproate, Solifenacin, Soma- doripenem, Dorzolamide, Doxazosin, doxazosin mesylate, tostatin, Somatropin, Stavudine, Sulfomethoxazole, doxycydine, Drospirenone, Duloxetine, Dutasteride, eculi- Sumatriptan, Sumatriptan succinate, Tacrolimus, Tadalafil, zumab, Efavirenz, Emtricitabine, Enalapril, enalapril 65 tamoxifen citrate, Tamsulosin, tamsulosin hydrochloride, maleate, Enoxaparin Sodium, Eprosartan, Erlotinib, Eryth- Tegaserod, Telmisartan, temazepam, Temozolomide, temsi- romycin, Erythropoetin, Escitalopram, esomeprazole, estra- rolimus, Tenofovir, Terazosin Hydrochloride, Terbinafine, US 9,526,824 B2 29 30 Teriparatide, testosterone, Tetracycline hydrochloride, Tha- cin, Anagestone Acetate, anagrelide, Anakinra, ananain, lidomide, thymopentin, Timolol meleate, Tiotropium, tipra- anaritide, Anaritide Acetate, Anastrozole, Anazolene navir, Tolterodine, tolterodine tartrate, topiramate, topote- Sodium, Ancrod, andrographolide, Androstenedione, Angio- can, Tramadol, Tramodol hydrochloride, trastuzumab, tensin Amide, Anidoxime, Anileridine, Anilopam Hydro- trazodone hydrochloride, trimethoprim, Valaciclovir, Vala- 5 chloride, Aniracetam, Anirolac, Anisotropine Methylbro- cyclovir hydrochloride, Valproate semisodium, valsartan, mide, Anistreplase, Anitrazafen, anordrin, antagonist D, Vancomycin, Vardenafil, Varenicline, venlafaxine, Venlafax- antagonist G, antarelix, Antazoline Phosphate, Anthelmycin, ine hydrochloride, Verapamil Hydrochloride, vildagliptin, Anthralin, Anthramy ci antiandrogen, antiestrogen, antine- Voglibose, Voriconazole, Wafarin sodium acetylsalicylic oplaston, Antipyrine, antisense oligonucleotides, apadoline, acid, Zaleplon, Zidovudine, Ziprasidone, Zoledronate, io apafant, Apalcillin Sodium, apaxifylline, Apazone, aphidi- Zolpidem, or pharmaceutically acceptable salts thereof; colin glycinate, Apixifylline, Apomorphine Hydrochloride, 16-alpha fluoroestradiol, 17-alpha dihydroequilenin, 17-al- apraclonidine, Apraclonidine Hydrochloride, Apramycin, pha estradiol, 17-beta estradiol, 17-hydroxyprogesterone, Aprindine, Aprindine Hydrochloride, aprosulate sodium, 1-dodecpyrrolidinone, 22-oxacalcitriol, 3-isobutyl-gamma- Aprotinin, Aptazapine Maleate, aptiganel, apurinic acid, butyric acid, 6-fluoroursodeoxycholic acid, 7-methoxyta- 15 apurinic acid, aranidipine, Aranotin, Arbaprostil, arbekicin, crine, Abacavir, Abacavir sulfate, Abamectin, abanoquil, arbidol, Arbutamine Hydrochloride, Arclofenin, Ardeparin abatacept, abecarnil, abiraterone, Ablukast, Ablukast Sodium, argatroban, Arginine, Argipressin Tannate, Aril- Sodium, Acadesine, acamprosate, Acarbose, Acebutolol, done, Aripiprazole, armodafinil, arotinolol, Arpinocid, Arte- Acecamide Hydrochloride, Aceclidine, aceclofenae, flene, Artilide Fumarate, asimadoline, aspalatone, Aspara- Acedapsone, Acedapsone, Aceglutamide Aluminum, Ace- 20 ginase, Aspartic Acid, Aspartocin, asperfuran, Aspirin, mannan, Acetaminophen, Acetazolamide, Acetohexamide, aspoxicillin, Asprelin, Astemizole, Astromicin Sulfate, asu- Acetohydroxamic Acid, acetomepregenol, Acetophenazine lacrine, atamestane, Atazanavir, Atenolol, atevirdine, Atipa- Maleate, Acetosulfone Sodium, Acetylcholine Chloride, mezole, Atiprosin Maleate, Atolide, Atomoxetine, atorvas- Acetylcysteine, acetyl-L-carnitine, acetylmethadol, Aciclo- tatin, Atorvastatin Calcium, Atosiban, Atovaquone, atpenin vir, Acifran, acipimox, acitemate, Acitretin, Acivicin, Acla- 25 B, Atracurium Besylate, atrimustine, atrinositol, Atropine, rubicin, aclatonium, Acodazole Hydrochloride, aconiazide, Atropine sulfate, Auranofin, aureobasidin A, Aurothioglu- Acrisorcin, Acrivastine, Acronine, Actisomide, Actodigin, cose, Avilamycin, Avoparcin, Avridine, Axid, axinastatin 1, Acyclovir, acylfulvene, Adatanserin Hydrochloride, axinastatin 2, axinastatin 3, Azabon, Azacitidinie, Azaclor- adafenoxate, Adalimumab, Adapalene, adatanserin, adecy- zine Hydrochloride, Azaconazole, azadirachtine, Azalanstat penol, adecypenol, Adefovir, adelmidrol, ademetionine, 3o Dihydrochloride, Azaloxan Fumarate, Azanator Maleate, Adenosine, Adinazolam, Adipheinine Hydrochloride, adi- Azanidazole, Azaperone, Azaribine, Azaserine, azasetron, posin, Adozelesin, adrafinil, Adrenalone, Aiclometasone Azatadine Maleate, Azathioprine, Azathioprine Sodium, Dipropionate, airbutamine, alacepril, Alamecin, Alanine, azatoxin, azatyrosine, azelaic acid, Azelastine, azelnidipine, Alaproclate, alaptide, Albendazole, albolabrin, Albuterol, Azepindole, Azetepa, azimilide, Azithromycin, Azlocillin, Alclofenae, Alcloxa, aldecalmycin, Aldesleukin, Aldioxa, 35 Azolimine, Azosemide, Azotomycin, Aztreonam, Azu- Aletamine Hydrochloride, Alendronate, Alendronate molene Sodium, Bacampicillin Hydrochloride, baccatin III, Sodium, alendronic acid, alentemol, Alentemol Hydrobro- Bacitracin, Baclofen, bacoside A, bacoside B, bactobo- mide, Aleuronium Chloride, Alexidine, alfacalcidol, Alfen- lamine, balanol, balazipone, balhimycin, balofloxacin, bal- tanil Hydrochloride, alfuzosin, Algestone Acetomde, alglu- salazide, Bambermycins, bambuterol, Bamethan Sulfate, cerase, Aliflurane, alinastine, Alipamide, aliskiren, 4o Bamifylline Hydrochloride, Bamidazole, baohuoside 1, Bar- Allantoin, Allobarbital, Allopurinol, Alonimid, alosetron, mastine, bamidipine, Basic, Basifungin, Batanopride Alosetron Hydrochloride, Alovudine, Alpertine, alpha- Hydrochloride, batebulast, Batelapine Maleate, Batimastat, idosone, Alpidem, Alprazolam, Alprenolol Hydrochloride, beau vericin, Becanthone Hydrochloride, becaplermin, Alprenoxime Hydrochloride, Alprostadil, Alrestatin becliconazole, Beclomethasone Dipropionate, befloxatone, Sodium, Altanserin Tartrate, Alteplase, Althiazide, Altret- 45 Beinserazide, Belfosdil, Belladonna, Beloxamide, Bemese- amine, altromycin B,Alverinc Citrate, alvimopan, Alvircept tron, Bemitradine, Bemoradan, Benapryzine Hydrochloride, Sudotox, Amadinone Acetate, Amantadine Hydrochloride, Benazepril, Benazepril Hydrochloride, Benazeprilat, Benda ambamustine, Ambomycin, ambrisentan, Ambruticin, calol Mesylate, bendamustine hydrochloride, Bendazac, Ambuphylline, Ambuside, Amcinafal, Amcinonide, Amdi- Bendroflumethiazide, benflumetol, benidipine, Benorterone, nocillin, Amdinocillin Pivoxil, Amedalin Hydrochloride, 5o Benoxaprofen, Benoxaprofen, Benoxinate Hydrochloride, amelometasone, Ameltolide, Amesergide, Ametantrone Benperidol, Bentazepam, Bentiromide, Benurestat, Benz- Acetate, amezinium metilsulfate, amfebutamone, Amfenac bromarone, Benzepril hydrochloride, Benzethonium Chlo- Sodium, Amfiutizole, Amicycline, Amidephrine Mesylate, ride, Benzetimide Hydrochloride, Benzilonium Bromide, amidox, Amifloxacin, amifostine, Amilcacin, Amiloride Benzindopyrine Hydrochloride, benzisoxazole, Benzocaine, Hydrochloride, Aminacrine Hydrochloride, Aminobenzoate 55 benzochlorins, Benzoctamine Hydrochloride, Benzodepa, Potassium, Aminobenzoate Sodium, Aminocaproic Acid, benzoidazoxan, Benzonatate, Benzoyl Peroxide, benzoyl- Aminoglutethimide, Aminohippurate Sodium, aminolevu- staurosporine, Benzquinamide, Benzthiazide, benztropine, linic acid, Aminophylline, A minorex, Aminosalicylate Benztropine Mesylate, Benzydamine Hydrochloride, Ben- sodium, Aminosalicylic acid, Amiodarone, Amiprilose zylpenicilloyl Polylysine, bepridil, Bepridil Hydrochloride, Hydrochloride, Amiquinsin Hydrochloride, amisulpride, 60 Beractant, Beraprost, Berefrine, berlafenone, bertosamil, Amitraz, Amitriptyline Hydrochloride, Amlexanox, amlo- Berythromycin, besipirdine, betaalethine, betaclamycin B, dipine, amlodipine besylate, Amobarbital Sodium, Amodia- Betamethasone, betamipron, betaxolol, Betaxolol Hydro- quine, Amodiaquine Hydrochloride, Amorolfine, Amoxap- chloride, Bethanechol Chloride, Bethanidine Sulfate, betu- ine, Amoxicillin, Amphecloral, Amphetamine, linic acid, bevacizumab, bevantolol, Bevantolol Hydrochlo- Amphetamine Sulfate, Amphomycin, Amphoterin B, Ampi- 65 ride, Bezafibrate, Bialamicol Hydrochloride, Biapenem, cillin, ampiroxieam, Ampyzine Sulfate, Amquinate, Amri- Bicalutamide, Bicifadine Hydrochloride, Biclodil Hydro- none, amrubicin, Amsacrine, Amylase, amylin, amythiami- chloride, Bidisomide, bifemelane, Bifonazole, bimakalim, US 9,526,824 B2 31 ON Bimatoprost, bimithil, Bindarit, Biniramycin, binospirone, Cefuroxime, celastrol, Celecoxib, celikalim, celiprolol, bioxalomycin, Bipenamol Hydrochloride, Biperiden, Biphe- cepacidiine A, Cephacetrile Sodium, Cephalexin, Cephalo- namine Hydrochloride, biriperone, bisantrene, bisaramil, glycin, Cephaloridine, Cephalothin Sodium, Cephapirin bisaziridinylspermine, bis-benzimid zole A, bis-benzimida- Sodium, Cephradine, cericlamine, cerivastatin, Ceruletide, zole B, bisnafide, Bisobrin Lactate, Bisoprolol, Bisoprolol 5 Ceronapril, Certolizumab Pegol, certoparin sodium, Ceta- fumarate, Bispyrithione Magsulfex, bistramide D, bistr- ben Sodium, Cetalkonium Chloride, Cetamolol Hydrochlo- amide K, bistratene A, Bithionolate Sodium, Bitolterol ride, Cethuperazone, cetiedil, cetirizine, Cetophenicol, Mesylate, Bivalirudin, Bizelesin, Bleomycin Sulfate, bold- Cetraxate Hydrochloride, Cetrizine hydrochloride, cetrore- ine, Bolandiol Dipropionate, Bolasterone, Boldenone Unde- lix, Cetuximab, Cetylpyridinium Chloride, Chenodiol, cylenate, Bolenol, Bolmantalate, bopindolol, Bosentan, io Chlophedianol Hydrochloride, Chloral Betaine, Chlorambu- Botulin toxin, Boxidine, brefeldin, breflate, Brequinar cil, Chloramphenicol, Chlordantoin, Chlordiazepoxide, Sodium, Bretazenil, Bretylium Tosylate, Brifentanil Hydro- Chlorhexidine Gluconate, chlorins, Chlormadinone Acetate, chloride, brimonidine, Brinolase, Brocresine, Brocrinat, chloroorienticin A, Chloroprocaine Hydrochloride, Chloro- Brofoxine, Bromadoline Maleate, Bromazepam, Bromchlo- propamide, Chloroquine, chloroquinoxaline sulfonamide, renone, Bromelain, bromfenac, Brominidione, Bromocrip- 15 Chlorothiazide, Chlorotrianisene, Chloroxine, Chloroxyle- tine, Bromodiphenhydramine Hydrochloride, Bromoxanide, nol, Chlorphe niramine Maleate, Chlorphenesin Carbamate, Bromperidol, Bromperidol Decanoate, Brompheniramine Chlorpheniramine maleate, Chlorpromazine, Chlorpromaz- Maleate, Broperamole, Bropirimine, Brotizolam, Bucamide ine hydrochloride, Chlorpropamide, Chlorprothixene, Chlo- Maleate, bucindolol, Buclizine Hydrochloride, Bucromar rtetracycline Bisulfate, Chlorthalidone, Chlorzoxazone, one, Budesonide, budipine, budotitane, Buformin, 20 Cholestyramine Resin, Chromonar Hydrochloride, cibenzo- Bumetanide, Bunaprolast, bunazosin, Bunolol Hydrochlo- line, cicaprost, Ciclafrine Hydrochloride, Ciclazindol, cicle- ride, Bupicomide, Bupivacaine Hydrochloride, Buprenor- sonide, cicletanine, Ciclopirox, Cicloprofen, cicloprolol, phine, Buprenorphine Hydrochloride, Bupropion, bupropion Cidofovir, Cidoxepin Hydrochloride, Cifenline, Ciglitazone, hydrobromide, Bupropion Hydrochloride, Buramate, Buser- Ciladopa Hydrochloride, cilansetron, Cilastatin, Cilastatin elin Acetate, Buspirone Hydrochloride, Busulfan, Butabar- 25 Sodium, Cilazapril, cilnidipine, Cilobamine Mesylate, cilo- bital, Butacetin, Butaclamol Hydrochloride, Butalbital, bradine, Cilofungin, cilostazol, Cimaterol, Cimetidine, Butamben, Butamirate Citrate, Butaperazine, Butaprost, cimetropium bromide, Cinacalcet, Cinalukast, Cinanserin Butedronate Tetrasodium, butenafine, Buterizine, buthion- Hydrochloride, Cinepazet Maleate, Cinflumide, Cingestol, inc sulfoximine, Butikacin, Butilfenin, Butirosin Sulfate, cinitapride, Cinnamedrine, Cinnarizine, cinolazepam, Cino- Butimrate, butixocort propionate, Butoconazole Nitrate, 30 xacin, Cinperene, Cinflomide, Cintazone, Cintriamide, Ciot Butonate, Butopamine, Butoprozine Hydrochloride, Butor- eronel, Cipamfylline, Ciprefadol Succinate, Ciprocinonide, phanol, Butoxamine Hydrochloride, Butriptyline Hydro- Ciprofibrate, Ciprofloxacin, ciprostene, Ciramadol, Cirole- chloride, Cabergoline, Cactinomycin, Cadexomer Iodine, mycin, C is platin, cisapride, cisatracurium besilate, Ciscon- Caffeine, calanolide A, Calcifediol, Calcipotriene, calcipot- azole, cis-porphyrin, cistinexine, citalopram, citalopram riol, Calcitonin, Calcitriol, Calcium Undecylenate, cal- 35 hydrobromide, Citenamide, citicoline, citreamicin alpha, phostin C, Calusterone, Cambendazole, Cammonam cladribine, Clamoxyquin Hydrochloride, Clarithromycin, Sodium, camonagrel, canary pox IL-2, candesartan, cande- clausenamide, Clavulanate Potassium, Clazolam, Clazolim- sartan cilexetil, Candicidin, candoxatril, candoxatrilat, Can- ine, clebopride, Clemastine, Clentiazem Maleate, Clidinium iglibose, Camenoate Potassium, Canrenone, capecitabine, Bromide, clinafloxacin, Clindamycin, clindamycin hydro- Capobenate Sodium, Capobenic Acid, Capreomycin Sulfate, 40 chloride, Clioquinol, Clioxanide, Cliprofen, clobazam, Clo- capromab, capsaicin, Captopril, Capuride, Car bocysteine, betasol Propionate, Clobetasone Butyrate, Clocortolone Caracemide, Carbachol, Carbadox, Carbamazepine, Carb- Acetate, Clodanolene, Clodazon Hydrochloride, clodronic amide Peroxide, Carbantel Lauryl Sulfate, Carbaspirin Cal- acid, Clofazimine, Clofibrate, Clofilium Phosphate, Cloge cium, Carbazeran, carbazomycin C, Carbenicillin Potas- stone Acetate, Clomacran Phosphate, Clomegestone sium, Carbenoxolone Sodium, Carbetimer, carbetocin, 45 Acetate, Clometherone, clomethiazole, clomifene ana- Carbidopa, Carbidopa-Levodopa, Carbinoxamine Maleate, logues, Clominorex, Clomiphene, Clomipramine Hydro- Carbiphene Hydrochloride, Carbocloral, Carbol-Fuchsin, chloride, Clonazepam, Clonidine, Clonidine hydrochloride, Carboplatin, Carboprost, carbovir, carboxamide-amino-tri- Clofibrate, Clonixeril, Clonixin, Clopamide, Clopenthixol, azo-le, carboxyamidotriazole, carboxymethylated beta-1,3- Cloperidone Hydrochloride, clopidogrel, Clopidogrel bisul- glucan, Carbuterol Hydrochloride, CaRest M3, Carfentanil 50 fate, Clopimozide, Clopipazan Mesylate, Clopirac, Clopred- Citrate, Carisoprodol, Carmantadine, Carmustine, CARN nol, Cloprostenol Sodium, Clorazepate Dipotassium, Clore- 700, Camidazole, Caroxazone, carperitide, Carphenazine thate, Clorexolone, Cloroperone Hydrochloride, Maleate, Carprofen, Carsatrin Succinate, Cartazolate, car- Clorprenaline Hydrochloride, Clorsulon, Clortemine Hydro- teolol, Carteolol Hydrochloride, Carubicin Hydrochloride, chloride, Closantel, Closiramine Aceturate, Clothiapine, carvedilol, carvotroline, Carvotroline Hydrochloride, carze- 55 Clothixamide Maleate Cloticasone Propionate, Clotrima- lesin, Caspofungin, castanospernine, caurumonam, cebar- zole, Cloxacillin Benzathine, Cloxacillin Sodium, Cloxy- acetam, cecropin B, Cedefingol, Cefaclor, Cefadroxil, Cefa- quin, Clozapine, Co-Amoxiclav, Cocaine, Coccidioidin, mandole, Cefaparole, Cefatrizine, Cefazaflur Sodium, Codeine, Codeine phosphate, Codoxime, Colchicine, Cole- Cefazolin, cefcapene pivoxil, cefdaloxime pentexil tosilate, sevelam, colestimide, Colestipol Hydrochloride, Coles- Cefdinir, cefditoren pivoxil, Cefepime, cefetamet, Cefete- 60 tolone, Colforsin, Colfosceril Palmitate, Colistimethate col, cefixime, cefluprenam, Cefinenoxime Hydrochloride, Sodium, Colistin Sulfate, collismycin A, collismycin B, Cefinetazole, cefminlox, cefodizime, Cefonicid Sodium, Colterol Mesylate, combretastatin A4, complestatin, con- Cefoperazone, Cefoperazone Sodium, Ceforanide, cefoselis, agenin, Conorphone Hydrochloride, contignasterol, contor- Cefotaxime Sodium, Cefotetan, cefotiam, Cefoxitin, cefo- trostatin, Cormethasone Acetate, Corticorelin Ovine Tnflu- zopran, cefpimizole, Cefpiramide, cefpirome, cefpodoxime 65 tate, Corticotropin, Cortisone Acetate, Cortivazol, proxetil, cefprozil, Cefroxadine, cefsulodin, Ceftazidime, Cortodoxone, cosalane, costatolide, Cosyntropin, cotinine, cefteram, ceftibuten, Ceftizoxime Sodium, ceftriaxooe, Coumadin, Coumermycin, crambescidin, Crilvastatin, cris- US 9,526,824 B2 33 M-! natol, Cromitrile Sodium, Cromolyn Sodium, Crotamiton, nate, Dimercaprol, Dimethadione, Dimethindene Maleate, cryptophycin, cucumariosid, Cuprimyxin, curacin A, curd- Dimethisterone, Dimethyl Sulfoxide, dimethylhomosper- Ian sulfate, curiosin, Cyclacillin, Cyclazocine, cyclazosin, mine, dimethylprostaglandinAl, dimiracetam, Dimoxamine Cyclindole, Cycliramine Maleate, Cyclizine, Cyclobenda- Hydrochloride, Dinoprost, Dinoprostone, Dioxadrol Hydro- zole, cyclobenzaprine, cyclobenzaprine hydrochloride, 5 chloride, dioxamycin, diphenhydramine, Diphenhydramine cyclobutA, cyclobut G, cyclocapron, Cycloguanil Pamoate, Citrate, Diphenidol, Diphenoxylate Hydrochloride, diphe- Cycloheximide, cyclopentanthraquinones, Cyclopenthiaz- nylspiromustine, Dipivefin Hydrochloride, Dipivefrin, ide, Cyclopentolate Hydrochloride, Cyclophenazine Hydro- dipliencyprone, diprafenone, dipropylnorspermine, chloride, Cyclophosphamide, cycloplatam, Cyclopropane, Dipyridamole, Dipyrithione, Dipyrone, dirithromycin, dis- Cycloserine, cyclosin, Cyclosporine, cyclothialidine, io codermolide, Disobutamide, Disofenin, Disopyramide, Dis- Cyclothiazide, cyclothiazomycin, Cyheptamide, cypemycin, oxaril, disulfuram, Ditekiren, Divalproex Sodium, Dizocil- Cyponamine Hydrochloride, Cyprazepam, Cyproheptadine pine Maleate, DL-methionine, Dobutamine, docarpamine, Hydrochloride, Cyprolidol Hydrochloride, cyproterone, Docebenone, Docetaxel, Doconazole, docosanol, dofetilide, Cyproximide, Cysteamine, Cysteine Hydrochloride, Cys- dolasetron, Donepezil, doripenem, Dorzolamide, Doxa- tine, Cytarabine, Cytarabine Hydrochloride, cytarabine 15 zosin, doxazosin mesylate, doxycydine, Drospirenone, ocfosfate, cytochalasin B, cytostatin, Dacarbazine, daclix- Duloxetine, Dutasteride, Ebastine, ebiratide, ebrotidine, imab, dactimicin, Dactinomycin, daidzein, Daledalin Tosy- ebselen, ecabapide, ecabet, ecadotril, ecdisteron, echicetin, late, dalfopristin, Dalteparin Sodium, Daltroban, Dalvasta- echistatin, Echothiophate Iodide, Eclanamine Maleate, Ecla- tin, danaparoid, Danazol, Dantrolene, daphlnodorin A, zolast, ecomustine, Econazole, ecteinascidin 722, eculi- dapiprazole, dapitant, Dapoxetine Hydrochloride, Dapsone, 20 zumab, edaravone, Edatrexate, edelfosine, Edifolone Daptomycin, darbepoetin alfa, Darglitazone Sodium, Acetate, edobacomab, Edoxudine, edrecolomab, Edropho- darifenacin, darlucin A, Darodipine, darsidomine, Daunoru- nium Chloride, edroxyprogesteone Acetate, Efavirenz, efe- bicin Hydrochloride, Dazadrol Maleate, Dazepinil Hydro- gatran, eflornithine, efonidipine, egualcen, Elantrine, ele- chloride, Dazmegrel, Dazopride Fumarate, Dazoxiben atonin, elemene, eletriptan, elgodipine, eliprodil, Hydrochloride, DCRM 197 protein, Debrisoquin Sulfate, 25 Elsamitrucin, eltenae, Elucaine, emailcalim, emedastine, Decitabine, deferiprone, deflazacort, Dehydrocholic Acid, Emetine Hydrochloride, emiglitate, Emilium Tosylate, dehydrodidemnin B, Dehydroepiandrosterone, delapril, Del- emitefur, emoctakin, Enuricitabine, Enadoline Hydrochlo- april Hydrochloride, Delavirdine Mesylate, delequamine, ride, Enailciren, enalapril, enalapril maleate, enazadrem, delfaprazine, Delmadinone Acetate, delmopinol, delphini- Encyprate, Endralazine Mesylate, Endrysone, Enflurane, din, Demecarium Bromide, Demeclocycline, Demecycline, 30 englitazone, Enilconazole, Enisoprost, Enlimomab, Enlo- Demoxepam, Denofungin, deoxypyridinoline, Depakote, platin, Enofelast, Enolicam Sodium, Enoxacin, enoxacin, deprodone, Deprostil, depsidomycin, deramciclane, derma- enoxaparin sodium, Enoxaparin Sodium, Enoximone, tan sulfate, Desciclovir, DescinoloneAcetonide, Desflurane, Enpiroline Phosphate, Enprofylline, Enpromate, entaca- Desipramine Hydrochloride, desirudin, Deslanoside, Deslo- pone, enterostatin, Enviradene, Enviroxime, Ephedrine, Epi- ratadine, deslorelin, desmopressin, Desmopressin sulfate, 35 cillin, Epimestrol, Epinephrine, Epinephryl Borate, Epipro- desogestrel, Desonide, Desoximetasone, desoxoami- pidine, Epirizole, epirubicin, Epitetracycline Hydrochloride, odarone, Desoxy-corticosterone Acetate, detajmium bitar- Epithiazide, Epoetin Alfa, Epoetin Beta, Epoprostenol, Epo- trate, Deterenol Hydrochloride, Detirelix Acetate, prostenol Sodium, epoxymexrenone, epristeride, Eprosar- Devazepide, Dexamethasone, Dexamisole, Dexbrompheni- tan, eptastigmine, equilenin, Equilin, Erbulozole, erdosteine, ramine Maleate, Dexchlorpheniramine Maleate, Dexclamol 40 Ergoloid Mesylates, Ergonovine Maleate, Ergotamine Tar- Hydrochloride, Dexetimide, Dexfenfluramine Hydrochlo- trate, Erlotinib, ersentilide, Ersofermin, erythritol, Erythrityl ride, dexifosfamide, Deximafen, dexketoprofen, dexloxiglu- Tetranitrate, Erythromycin, Erythropoetin, Escitalopram, mide, Dexmedetomidine, Dexormaplatin, Dexoxadrol Esmolol Hydrochloride, esomeprazole, Esorubicin Hydro- Hydrochloride, Dexpanthenol, Dexpemedolac, Dexpropra- chloride, Esproquin Hydrochloride, Estazolam, Estradiol, nolol Hydrochloride, Dexrazoxane, dexsotalol, dextrin 45 Estramustine, Estrazinol Hydrobromide, Estriol, Estrofu- 2-sulphate, Dextroamphetamine, Dextromethorphan, Dex- rate, Estrogen, Estrone, Estropipate, esuprone, Eszopiclone, trorphan Hydrochloride, Dextrothyroxine Sodium, dexvera- Etafedrine Hydrochloride, etanercept, Etanidazole, etan- pamil, Dezaguanine, dezinamide, dezocine, Diacetolol terol, Etarotene, Etazolate Hydrochloride, Eterobarb, etha- Hydrochloride, Diamocaine Cyclamate, Diapamide, Dia- cizin, Ethacrynate Sodium, Ethacrynic Acid, Ethambutol trizoate Meglumine, Diatrizoic Acid, Diaveridine, Diaz- 50 Hydrochloride, Ethamivan, Ethanolamine Oleate, Ethehlo- epam, Diaziquone, Diazoxide, Dibenzepin Hydrochloride, rvynol, Ethembutol hydrochloride, Ethinyl estradiol, Ethio- Dibenzothiophene, Dibucaine, Dichliorvos, Dichloral- dized Oil, Ethionamide, Ethonam Nitrate, Ethopropazine phenazone, Dichlorphenamide, Dicirenone, Diclofenac, Hydrochloride, Ethosuximide, Ethosuximide, Ethotoin, Diclofenac Sodium, Dicloxacillin, dicranin, Dicumarol, Ethoxazene Hydrochloride, Ethybenztropine, Ethyl Chlo- Dicyclomine Hydrochloride, Didanosine, didemnin B, 55 ride, Ethyl Dibunate, Ethylestrenol, Ethyndiol, Ethynerone, didox, Dienestrol, dienogest, Diethylcarbamazine Citrate, ethynl estradiol, Ethynodiol Diacetate, Etibendazole, Etido- diethylhomospermine, diethylnorspermine, Diethylpropion caine, Etidronate Disodium, Etidronic Acid, Etifenin, Etinti- Hydrochloride, Diethylstilbestrol, Difenoximide Hydro- dine Hydrochloride, etizolam, Etodolac, Etofenamate, Eto- chloride, Difenoxin, Diflorasone Diacetate, Difloxacin formin Hydrochloride, Etomidate, Etonogestrel, Hydrochloride, Difluanine Hydrochloride, Diflucortolone, 60 Etoperidone Hydrochloride, Etoposide, Etoprine, etori- Diflumidone Sodium, Diflunisal, Difluprednate, Diftalone, coxib, Etoxadrol Hydrochloride, Etozolin, etrabamine, etra- Digitalis, Digitoxin, Digoxin, Dihexyverine Hydrochloride, virine, Etretinate, Etryptamine Acetate, Eucatropine Hydro- dihydrexidine, dihydro-5-azacytidine, Dihydrocodeine chloride, Eugenol, Euprocin Hydrochloride, eveminomicin, Bitartrate, Dihydroergotamine Mesylate, Dihydroestoster- Exametazime, examorelin, Exaprolol Hydrochloride, one, Dihydrostreptomycin Sulfate, Dihydrotachysterol, 65 exemestane, Exenatide, Ezetimibe, Ezetimibe, Factor VII, Dilantin, Dilevalol Hydrochloride, Diltiazem Hydrochlo- fadrozole, faeriefungin, Famciclovir, Famotidine, Fampri- ride, Dimefadane, Dimefline Hydrochloride, Dimenhydri- dine, fantofarone, Fantridone Hydrochloride, faropenem, US 9,526,824 B2 35 kf, fasidotril, fasudil, fazarabine, fedotozine, Felbamate, fel- Gonadotropins, Goserelin, Gramicidin, Granisetron, gre- bamate, Felbinac, Felodipine, Felypressin, Fenalamide, pafioxacin, Griseofulvin, Guaiapate, Guaithylline, Gua- Fenamole, Fenbendazole, Fenbufen, Fencibutirol, Fen- nabenz, Guanabenz Acetate, Guanadrel Sulfate, Guancy- clofenac, Fenclonine, Fenclorac, Fendosal, Fenestrel, Fen- dine, Guanethidine Monosulfate, Guanfacine ethylline Hydrochloride, Fenfluramine Hydrochloride, 5 Hydrochloride, Guanisoquin Sulfate, Guanoclor Sulfate, Fengabine, Fenimide, Fenisorex, Fenmetozole Hydrochlo- Guanoctine Hydrochloride, Guanoxabenz, Guanoxan Sul- ride, Feumetramide, Fenobam, Fenoctimine Sulfate, Feno- fate, Guanoxyfen Sulfate, Gusperimus Trihydrochloride, fibrate, fenoldopam, Fenoprofen, Fenoterol, Fenpipalone, Halazepam, Halcinonide, halichondrin B, Halobetasol Pro- Fenprinast Hydrochloride, Fenprostalene, Fenquizone, fen- pionate, halofantrine, Halofantrine Hydrochloride, retinide, fenspiride, fentanyl, Fentanyl Citrate, Fentiazac, io Halofenate, Halofuginone Hydrobromide, halomon, Fenticlor, fenticonazole, Fenyripol Hydrochloride, fepradi- Halopemide, Haloperidol, halopredone, Haloprogesterone, nol, ferpifosate sodium, ferristene, ferrixan, Ferrous Sulfate, Haloprogin, Halothane, Halquinols, Hamycin, hatomamicin, Ferumoxides, ferumoxsil, Fetoxylate Hydrochloride, Fex- hatomarubigin A, hatomarubigin B, hatomarubigin C, hato- ofenadine, fexofenadine hydrochloride, Fezolamine Fumar- marubigin D, Heparin Sodium, hepsulfam, heregulin, Heta- ate, Fiacitabine, Fialuridine, fibmoxef, Fibrinogen, Fil- 15 cillin, Heterooium Bromide, Hexachlorophene:Hydrogen grastim, Filipin, Finasteride, fiorfenicol, fiorifenine, Peroxide, Hexafluorenium Bromide, hexamethylene bisac- fiosatidil, fiumecinol, fiunarizine, fiuparoxan, fiupirtine, fiu- etamide, Hexedine, Hexobendine, Hexoprenaline Sulfate, rithromycin, fiutrimazole, fiuvastatin, fiuvoxamine, Fla- Hexylresorcinol, Histamine Phosphate, Histidine, Histoplas- vodilol Maleate, flavopiridol, Flavoxate Hydrochloride, Fla- min, Histrelin, histrelin acetate, Homatropine Hydrobro- zalone, flecamide, flerobuterol, Fleroxacin, flesinoxan, 20 wide, Hoquizil Hydrochloride, Human chorionic gonado- Flestolol Sulfate, Fletazepam, flezelastine, flobufen, Floc- tropin, Human growth hormone, Hycanthone, Hydralazine tafenine, Flordipine, Flosequinan, Floxacillin, Floxuridine, Hydrochloride, Hydralazine Polistirex, Hydrochlorothiaz- fluasterone, Fluazacort, Flubanilate Hydrochloride, Fluben- ide, Hydrocodone Bitartrate, Hydrocortisone, Hydroflume- dazole, Flucindole, Flucloronide, Fluconazole, Flucytosine, thiazide, Hydromorphone Hydrochloride, Hydroxyamphet- Fludalanine, Fludarabine Phosphate, Fludazonium Chloride, 25 amine Hydrobromide, Hydroxychloroquine Sulfate, Fludeoxyglucose, Fludorex, Fludrocortisone Acetate, Flufe- Hydroxyphenamate, Hydroxyprogesterone Caproate, namic Acid, Flufenisal, Flumazenil, Flumequine, Flumeri- Hydroxyurea, Hydroxyzine Hydrochloride, Hymecromone, done, Flumethasone, Flumetramide, Flumezapine, Flumi- Hyoscyamine, hypericin, Ibafloxacin, Ibandronate, ibo- norex, Flumizole, Flumoxonide, Flunidazole, Flunisolide, gaine, Ibopam, ibudilast, Ibufenac, Ibuprofen, Ibutilide Flunitrazepam, Flunixin, fluocalcitriol, Fluocinolone so Fumarate, Icatibant Acetate, Ichthammol, Icotidine, idaru- Acetonide, Fluocinonide, Fluocortin Butyl, Fluocortolone, bicin, idoxifene, Idoxuridine, idramantone, Ifetroban, Ifos- Fluorescein, fluorodaunorunicin hydrochloride, Fluorodopa, famide, Ilepeimide, illimaquinone, ilmofosin, ilomastat, Ilo- Fluorometholone, Fluorouracil, Fluotracen Hydrochloride, nidap, iloperidone, iloprost, Imafen Hydrochloride, Fluoxetine, Fluoxetine hydrochloride, Fluoxymesterone, Imatinib, Imazodan Hydrochloride, imidapril, imidazenil, Fluperamide, Fluperolone Acetate, Fluphenazine Decano- 35 imidazoacridone, Imidecyl Iodine, Imidocarb Hydrochlo- ate, Fluprednisolone, Fluproquazone, Fluprostenol Sodium, ride, Imidoline Hydrochloride, Imidurea, Imiglucerase, Imi- Fluquazone, Fluradoline Hydrochloride, Flurandrenolide, loxan Hydrochloride, Imipenem, Imipramine Hydrochlo- Flurazepam Hydrochloride, Flurbiprofen, Fluretofen, Flu- ride, imiquimod, Impromidine Hydrochloride, Indacrinone, orocitabine, Fluorofamide, Fluorogestone Acetate, Fluoro- Indapamide, Indecamide Hydrochloride, Indeloxazine thyl, Fluoroxene, Fluspiperone, Fluspirilene, Fluticasone, 4o Hydrochloride, Indigotindisulfonate Sodium, indinavir, Fluticasone Propionate, Flutroline, Fluvastatin, Fluvastatin Indinavir sulfate, Indocyanine Green, Indolapril Hydrochlo- Sodium, Fluzinamide, Folic Acid, Follicle regulatory pro- ride, Indolidan, indometacin, Indomethacin Sodium, Indo- tein, Folliculostatin, Follitropin alfa, Follitropin beta, profen, indoramin, Indorenate Hydrochloride, Indoxole, Fomepizole, Fonazine Mesylate,forasartan, forfenimex,for- Indriline Hydrochloride, infliximab, inocoterone, inogatran, fenirmex, formestane, Formocortal, formoterol, Fosarilate, 45 inolimomab, Inositol Niacinate, Insulin, Interferon beta-la, Fosazepam, Foscamet Sodium, fosfomycin, Fosfonet Intrazole, Intriptyline Hydrochloride, iobenguane, Ioben- Sodium,fosinopril, Fosinopril sodium, Fosinoprilat, fosphe- zamic Acid, iobitridol, Iodine, iodoamiloride, iododoxoru- nyloin, Fosquidone, Fostedil, fostriecin, fotemustine, bicin, iofratol, iomeprol, iopentol, iopromide, iopyrol, iotri- Fuchsin, Fumoxicillin, Fungimycin, Furaprofen, Furazoli- side, ioxilan, ipazilide, ipenoxazone, ipidacrine, Ipodate done, Furazolium Chloride, Furegrelate Sodium, Furobufen, 50 Calcium, ipomeanol, Ipratropium, Ipratropium Bromide, Furodazole, Furosemide, Fusidate Sodium, Fusidic Acid, ipriflavone, Iprindole, Iprofenin, Ipronidazole, Iproplatin, Gabapentin, Gadobenate Dimeglumine, gadobenic acid, Iproxamine Hydrochloride, ipsapirone, irbesartan, irinote- gadobutrol, Gadodiamide, gadolinium texaphyrin, Gado- can, irloxacin, iroplact, irsogladin, Irtemazole, isalsteine, pentetate Dimegiumine, gadoteric acid, Gadoteridol, Gado- Isamoxole, isbogrel, Isepamicin, isobengazole, Isobutam- versetamide, galantamine, galdansetron, Galdansetron 55 ben, Isocarboxazid, Isoconazole, Isoetharine, isofloxythe- Hydrochloride, Gallamine Triethiodide, gallium nitrate, gal- pin, Isoflupredone Acetate, Isoflurane, Isofluorophate, iso- lopamil, galocitabine, Gamfexine, gamolenic acid, Ganci- homohalicondrin B, Isoleucine, Isomazole Hydrochloride, clovir, ganirelix, Gemcadiol, Gemcitabine, Gemeprost, Isomylamine Hydrochloride, Isoniazid, Isopropamide Gemfibrozil, Gentamicin Sulfate, Gentian Violet, gepirone, Iodide, Isopropyl Alcohol, isopropyl unoprostone, Isopro- Gestaclone, Gestodene, Gestonorone Caproate, Gestrinone, 60 terenol Hydrochloride, Isosorbide, Isosorbide Mononitrate, Gevotroline Hydrochloride, girisopam, glargine insulin, Isotiquimide, Isotretinoin, Isoxepac, Isoxicam, Isoxsuprine glaspimod, Glatiramer, glaucocalyxin A, Glemanserin, Gli- Hydrochloride, isradipine, itameline, itasetron, Itazigrel, ito- amilide, Glibornuride, Glicetanile Sodium, Glifiumide, pride, Itraconazole, Ivermectin, ixabepilone, jasplakinolide, Glimepiride, Glipizide, Gloximonam, Glucagon, glutapy- Jemefloxacin, Jesopitron, Josamycin, kahalalide F, Kala- rone, Glutethimide, Glyburide, glycopine, glycopril, Glyco- 65 fungin, Kanamycin Sulfate, ketamine, Ketanserin, Ketazo- pyrrolate, Glyhexamide, Glymidine Sodium, Glyoctamide, cine, Ketazolam, Kethoxal, Ketipramine Fumarate, Keto- Glyparamide, Gold Au-198, Gonadoctrinins, Gonadorelin, conazole, Ketoprofen, Ketorfanol, ketorolac, Ketotifen US 9,526,824 B2 37 38 Fumarate, Kitasamycin, Labetalol Hydrochloride, Laci- Mazindol, Mebendazole, Mebeverine Hydrochloride, dipine, lacidipine, lactitol, lactivicin, Lactobionate, laennec, Mebrofenin, Mebutamate, Mecamylamine Hydrochloride, lafutidine, 1-alphahydroxyvitamin D2, lamellarin-N triac- Mechlorethamine Hydrochloride, meclizine hydrochloride, etate, lamifiban, Lamivudine, Lamotrigine, lanoconazole, Meclocycline, Meclofenamate Sodium, Mecloqualone, Lanoxin, lanperisone, lanreotide, lanreotide acetate, Lanso- 5 Meclorisone Dibutyrate, Medazepam Hydrochloride, prazole, lapatinib, laropiprant, latanoprost, lateritin, lauro- Medorinone, Medrogestone, Medroxalol, Medroxyproges- capram, Lauryl Isoquinolinium Bromide, Lavoltidine Suc- terone, Medrysone, Meelizine Hydrochloride, Mefenamic cinate, lazabemide, Lecimibide, leinamycin, lemildipine, Acid, Mefenidil, Mefenorex Hydrochloride, Mefexamide, leminoprazole, lenercept, Leniquinsin, lenograstim, Lenper- Mefloquine Hydrochloride, Mefruside, Megalomicin Potas- one, lentinan sulfate, leptin, leptolstatin, lercanidipine, Ler- io sium Phosphate, Megestrol Acetate, Meglumine, Meglutol, gotrile, lerisetron, Letimide Hydrochloride, letrazuril, letro- Melengestrol Acetate, Meloxicam, Melphalan, Memantine, zole, Leucine, leucomyzin, leuprolide, Leuprolide Acetate, Memotine Hydrochloride, Menabitan Hydrochloride, leuprorelin, Levalbuterol, Levamfetamine Succinate, Menoctone, menogaril, Menotropins, Meobentine Sulfate, levamisole, Levdobutamine Lactobionate, Leveromakalim, Mepartricin, Mepenzolate Bromide, Meperidine Hydrochlo- levetiracetam, Leveycloserine, levobetaxolol, levobunolol, 15 ride, Mephentermine Sulfate, Mephenyloin, Mephobarbital, levobupivacaine, levocabastine, levocarnitine, levocetiriz- Mepivacaine Hydrochloride, Meprobamate, Meptazinol ine, levocetirizine dhydrochloride, Levodopa, levodro- Hydrochloride, Mequidox, Meralein Sodium, merbarone, propizine, levofloxacin, Levofuraltadone, Levoleucovorin Mercaptopurine, Mercufenol Chloride, Merisoprol, Mero- Calcium, Levomethadyl Acetate, Levomethadyl Acetate penem, Mesalamine, Meseclazone, Mesoridazine, Mester- Hydrochloride, levomoprolol, Levonantradol Hydrochlo- 20 olone, Mestranol, Mesuprine Hydrochloride, Metalol ride, Levonordefrin, Levonorgestrel, Levopropoxyphene Hydrochloride, Metaproterenol Polistirex, Metaraminol Napsylate, Levopropylcillin Potassium, levormeloxifene, Bitartrate, Metaxalone, Meteneprost, meterelin, Metformin, Levorphanol Tartrate, levosimendan, levosulpiride, Levo- Methacholine Chloride, Methacycline, methadone, Meth- thyroxine, Levothyroxine Sodium, Levoxadrol Hydrochlo- adyl Acetate, Methalthiazide, Methamphetamine Hydro- ride, Lexipafant, Lexithromycin, liarozole, Libenzapril, Lid- 25 chloride, Methaqualone, Methazolamide, Methdilazine, amidine Hydrochloride, Lidocaine, Lidofenin, Lidoflazine, Methenamine, Methenolone Acetate, Methetoin, Methicillin Lifarizin, Lifibrate, Lifibrol, Linarotene, Lincomycin, Lin- Sodium, Methimazole, methioninase, Methionine, Methisa- ezolid, Linogliride, Linopirdine, linotroban, linsidomine, zone, Methixene Hydrochloride, Methocarbamol, Metho- lintitript, lintopride, Liothyronine I-125, liothyronine hexital Sodium, Methopholine, Methotrexate, Methotrime- sodium, Liotrix, lirexapride, Lisdexamfetamine Dimesylate, 30 prazine, methoxatone, methoxy polyethylene glycol-epoetin lisinopril, Lispro insulin, lissoclinamide, Lixazinone Sul- beta, Methoxyflurane, Methsuximide, Methyclothiazide, fate, lobaplatin, Lobenzarit Sodium, Lobucavir, locarmate Methyl Palmoxirate, Methylatropine Nitrate, Methylbenze- Meglumine, locarmic Acid, locetamic Acid, lodamide, thonium Chloride, Methyldopa, Methyldopate Hydrochlo- Lodelaben, lodipamide Meglumine, lodixanol, Iodoantipy- ride, Methylene Blue, Methylergonovine Maleate, methyl- rine I-131, Iodocholesterol I-131, Iodohippurate Sodium 35 histamine, methylinosine monophosphate, I-131, Iodopyracet I-125, Iodoquinol, Iodoxamate Meglu- Methylphenidate, Methylprednisolone, Methyltestosterone, mine, lodoxamide, IodoxamieAcid, Lofemizole Hydrochlo- Methynodiol Diacelate, Methysergide, Methysergide ride, Lofentanil Oxalate, Lofepramine Hydrochloride, lofe- Maleate, Metiamide, Metiapine, Metioprim, metipamide, tamine Hydrochloride I-123, Lofexidine Hydrochloride, Metipranolol, Metizoline Hydrochloride, Metkephamid loglicic Acid, loglucol, loglucomide, loglycamic Acid, logu- 40 Acetate, metoclopramide, Metocurine Iodide, Metogest, lamide, lohexyl, lombricine, Lomefloxacin, lomerizine, Metolazone, Metopimazine, Metoprine, Metoprolol, Meto- lomethin I-125, Lometraline Hydrochloride, lometrexol, prolol tartrate, Metouizine, metrifonate, Metrizamide, Lomofungin, Lomoxicam, Lomustine, Lonapalene, lonazo- Metrizoate Sodium, Metronidazole, Meturedepa, lac, lonidamine, lopamidol, lopanoic Acid, Loperamide Metyrapone, Metyrosine, Mexiletine Hydrochloride, Hydrochloride, lophendylate, Lopinavir, loprocemic Acid, 45 Mexrenoate Potassium, Mezlocillin, Mianserin Hydrochlo- lopronic Acid, lopydol, lopydone, loracarbef, Lorajmine ride, mibefradil, Mibefradil Dihydrochloride, Mibolerone, Hydrochloride, loratadine, Lorazepam, Lorbamate, Lorc- michellamine B, Miconazole, microcolinA, Midaflur, Mida- amide Hydrochloride, Loreclezole, Loreinadol, lorglumide, zolam Hydrochloride, midodrine, mifepristone, Mifobate, Lormetazepam, Lomoxicam, lornoxicam, Lortalamine, miglitol, milacemide, milameline, mildronate, Milenperone, Lorzafone, losartan, Losartan potassium, losefamic Acid, 50 Milipertine, milnacipran, Milrinone, miltefosine, Mimbane loseric Acid, losigamone, losoxantrone, losulamide Meglu- Hydrochloride, minaprine, Minaxolone, Minocromil, Mino- mine, Losulazine Hydrochloride, losumetic Acid, lotasul, cycline, Minocycline hydrochloride, Minoxidil, Mioflazine loteprednol, lotetric Acid, lothalamate Sodium, lothalamic Hydrochloride, miokamycin, mipragoside, mirfentanil, Acid, lotrolan, lotroxic Acid, lovastatin, loversol, loviride, mirimostim, Mirincamycin Hydrochloride, Mirisetron loxagiate Sodium, loxaglate Meglumine, loxaglic Acid, 55 Maleate, Mirtazapine, Misonidazole, Misoprostol, Mitindo- Loxapine, Loxoribine, loxotrizoic Acid, lubeluzole, Lucan- mide, Mitocarcin, Mitocromin, Mitogillin, mitoguazone, thone Hydrochloride, Lufironil, Lurosetron Mesylate, lurto- mitolactol, Mitomalcin, Mitomycin, mitonafide, Mitosper, tecan, lutetium, Lutrelin Acetate, luzindole, Lyapolate Mitotane, mitoxantrone, mivacurium chloride, mivazerol, Sodium, Lycetamine, lydicamycin, Lydimycin, Lynestrenol, mixanpril, Mixidine, mizolastine, mizoribine, Moclobe- Lypressin, Lysine, lysofylline, lysostaphin, Maduramicin, 60 wide, modafinil, Modaline Sulfate, Modecamide, moexipril, Mafenide, magainin 2 amide, Magnesium Salicylate, Mag- mofarotene, Mofegiline Hydrochloride, mofezolac, molgra- nesium Sulfate, magnolol, maitansine, Malethamer, mallo- mostim, Molinazone, Molindone Hydrochloride, Molsidom- toaponin, mallotochromene, Malotilate, malotilate, manga- ine, mometasone, Monatepil Maleate, Monensin, Monoc- fodipir, manidipine, maniwamycin A, Mannitol, tanoin, montelukast, Montelukast Sodium, montirelin, mannostatin A, manumycin E, manumycin F, mapinastine, 65 mopidamol, moracizine, Morantel Tartrate, Moricizine, Maprotiline, maraviroc, marimastat, Marinol, Masoprocol, Morniflumate, Morphine, Morrhuate Sodium, mosapramine, maspin, massetolide, Maytansine, Mazapertine Succiniate, mosapride, motilide, Motretinide, Moxalactam Disodium, US 9,526,824 B2 39 40 Moxazocine, Moxifloxacin, moxiraprine, Moxnidazole, Acid, Oxprenolol Hydrochloride, Oxtriphylline, Oxybu- moxonidine, Mumps Skin Test Antigen, Muzolimine, tynin Chloride, Oxychlorosene, Oxycodone, oxycodone mycaperoxide B, Mycophenolate mofetil, Mycophenolic hydrochloride, Oxymetazoline Hydrochloride, Acid, myriaporone, Nabazenil, Nabilone, Nabitan Hydro- oxymetholone, Oxymorphone Hydrochloride, Oxypertine, chloride, Naboctate Hydrochloride, Nabumetone, N-acetyl- 5 Oxyphenbutazone, Oxypurinol, Oxytetracycline, Oxytocin, dinaline, Nadide, nadifloxacin, Nadolol, nadroparin cal- ozagrel, Ozlinone, Paclitaxel, palauamine, Paldimycin, pali- cium, nafadotride, nafamostat, nafarelin, Nafcillin Sodium, navir, Palivizumab, palmitoylrhizoxin, Palmoxirate Sodium, Nafenopin, Nafimidone Hydrochloride, Naflocort, Nafom- pamaqueside, Pamatolol Sulfate, pamicogrel, Pamidronate ine Malate, Nafoxidine Hydrochloride, Nafronyl Oxalate, Disodium, pamidronic acid, Panadiplon, panamesine, Naftifine Hydrochloride, naftopidil, naglivan, nagrestip, io panaxytriol, Pancopride, Pancuronium Bromide, Nalbuphine Hydrochloride, Nalidixate Sodium, Nalidixic panipenem, pannorin, panomifene, pantethine, pantopra- Acid, nalmefene, Nalmexone Hydrochloride, naloxone, Nal- zole, Papaverine Hydrochloride, parabactin, paracetamol, trexone, Namoxyrate, Nandrolone Phenpropionate, Nant- Parachlorophenol, Paraldehyde, Paramethasone Acetate, radol Hydrochloride, Napactadine Hydrochloride, napadisi- Paranyline Hydrochloride, Parapenzolate Bromide, Pararo- late, Napamezole Hydrochloride, napaviin, Naphazoline 15 saniline Pamoate, Parbendazole, Parconazole Hydrochlo- Hydrochloride, naphterpin, Naproxen, Naproxen sodium, ride, Paregoric, Pareptide Sulfate, Pargyline Hydrochloride, Naproxol, napsagatran, Naranol Hydrochloride, Narasin, parnaparin sodium, Paromomycin Sulfate, Paroxetine, par- naratriptan, nartograstim, nasaruplase, natalizumab, oxetine hydrochloride, parthenolide, Partricin, Paulomycin, Natamycin, nateplase, Naxagolide Hydrochloride, Nebiv- pazelliptine, Pazinaclone, Pazoxide, pazufloxacin, pefloxa- olol, Nebramycin, nedaplatin, Nedocromil, Nefazodone 20 cin, pegaspargase, Pegorgotein, Pegylated interferon alfa- Hydrochloride, Neflumozide Hydrochloride, Nefopam 2a, Pelanserin Hydrochloride, peldesine, Peliomycipelretin, Hydrochloride, Nelezaprine Maleate, Nemazoline Hydro- Perinone Hydrochloride, Pemedolac, Pemerid Nitrate, chloride, nemorubicin, Neomycin Palmitate, Neostigmine Pemetrexed, pemirolast, Pemoline, Penamecillin, Penbu- Bromide, neridronic acid, Netilmicin Sulfate, Neutramycin, tolol Sulfate, Penciclovir, Penfluridol, Penicillamine, Peni- Nevirapin Nexeridine Hydrochloride, Niacin, Nibroxane, 25 cillin G Benzathine, Penicillin G Potassium, Penicillin G Nicardipine Hydrochloride, Nicergoline, Niclosamide, Nic- Procaine, Penicillin G Sodium, Penicillin V Hydrabamine, orandil, Nicotinamide, Nicotinyl Alcohol, Nifedipine, Penicillin V Benzathine, Penicillin V Potassium, Pentabam- Nifirmerone, Nifluridide, Nifuradene, Nifuraldezone, Nifu- ate, Pentaerythritol Tetranitrate, pentafuside, pentamidine, ratel, Nifuratrone, Nifurdazil, Nifurimide, Nifurpirinol, pentamorphone, Pentamustine, Pentapiperium Methylsul- Nifurquinazol, Nifurthiazole, Nifurtimox, nilotinib, nilo- 30 fate, Pentazocine, Pentetic Acid, Pentiapine Maleate, pen- tinib hydrochloride monohydrate, nilutamide, Nilvadipine, tigetide, Pentisomicin, Pentizidone Sodium, Pentobarbital, Nimazone, Nimodipine, niperotidine, niravoline, Nirida- Pentomone, Pentopril, pentosan, pentostatin, Pentoxifylline, zole, nisamycin, Nisbuterol Mesylate, raisin, Nisobamate, Pentrinitrol, pentrozole, Peplomycin Sulfate, Pepstatin, per- Nisoldipine, Nisoxetin Nisterime Acetate, Nitarsone, nita- flubron, perfofamide, Perfosfamide, pergolide, Perhexyline zoxanide, nitecapone, Nitrafudam Hydrochloride, Nitrala- 35 Maleate, perillyl alcohol, Perindopril, perindoprilat, Per- mine Hydrochloride, Nitramisole Hydrochloride, Nitraze- lapin Permethrin, perospirone, Perphenazine, Phenacemide, pam, Nitrendipine, Nitrocydine, Nitrodan, Nitrofurantoin, phenaridine, phenazinomycin, Phenazopyridine Hydrochlo- Nitrofurazone, Nitroglycerin, Nitromersol, Nitromide, ride, Phenbutazone Sodium Glycerate, Phencarbamide, Nitromifene Citrate, Nitrous Oxide, nitroxide antioxidant, Phencyclidine Hydrochloride, Phendimetrazine Tartrate, nitrullyn, Nivazol, Nivimedone Sodium, Nizatidine, 40 Phenelzine Sulfate, Phenformin, Phenmetrazine Hydrochlo- Noberastine, Nocodazole, Nogalamycin, Nolinium Bro- ride, Phenobarbital, Phenoxybenzamine Hydrochloride, mide, Nomifensine Maleate, Noracymethadol Hydrochlo- Phenprocoumon, phenaerine, phensuccinal, Phensuximide, ride, Norbolethone, Norepinephrine Bitartrate, Norethin- Phentermine, Phentermine Hydrochloride, phentolamine drone, Norethynodrel, Norfurane, Norfloxacin, mesilate, Phentoxifylline, Phenyl Aminosalicylate, pheny- Norgestimate, Norgestomet, Norgestrel, Nortriptyline 45 lacetate, Phenylalanine, phenylalanylketoconazole, Phe- Hydrochloride, Noscapine, Novobiocin Nylestriol, Nystatin, nylbutazone, Phenylephrine Hydrochloride, Phenylpropa- Obidoxime Chloride, Ocaperidone, Ocfentanil Hydrochlo- nolamine Hydrochloride, Phenylpropanolamine Polistirex, ride, Ocinaplon, Octanoic Acid, Octazamide, Octenidine Phenyramidol Hydrochloride, Phenyloin, Phenyloin Hydrochloride, Octodrine, Octreotide, Octriptyline Phos- sodium, Physostigmine, picenadol, picibanil, Picotrin phate, Ofloxacin, Ofornine, okicenone, Olanzepine, Olme- 5o Diolamine, picroliv, picumeterol, pidotimod, Pifarnine, sartan, olmesartan medoxomil, olopatadine, olopatadine Pilocarpine, pilsicamide, pimagedine, Pimetine Hydrochlo- hydrochloride, olprinone, olsalazine, Olsalazine Sodium, ride, pimilprost, Pimobendan, Pimozide, Pinacidil, Pinado- Olvanil, Omalizumab, Omega-3 acid ethyl esters, omepra- line, Pindolol, pinnenol, pinocebrin, Pinoxepin Hydrochlo- zole, onapristone, ondansetron, Ontazolast, Oocyte Opipra- ride, pioglitazone, Pipamperone, Pipazethate, pipecuronium mol Hydrochloride, oracin, Orconazole Nitrate, Orgotein, 55 bromide, Piperacetazine, Piperacillin, Piperacillin Sodium, Orlislat, Ormaplatin, Ormetoprim, Ornidazole, Orpanoxin, Piperamide Maleate, piperazinc, Pipobroman, Piposulfan, Orphenadrine Citrate, osaterone, Oseltamivir, otenzepad, Pipotiazine Palmitate, Pipoxolan Hydrochloride, Piprozolin, Oxacillin Sodium, Oxagrelate, oxaliplatin, Oxamarin Piquindone Hydrochloride, Piquizil Hydrochloride, Pirac- Hydrochloride, oxamisole, Oxamniquine, oxandrolone, etam, Pirandamine Hydrochloride, pirarubicin, Pirazmonam Oxantel Pamoate, Oxaprotiline Hydrochloride, Oxaprozin, 60 Sodium, Pirazolac, Pirbenicillin Sodium, Pirbuterol Acetate, Oxarbazole, Oxatomide, oxaunomycin, Oxazepam, oxcar- Pirenperone, Pirenzepine Hydrochloride, piretanide, Pirfeni- bazepine, Oxendolone, Oxethazaine, Oxetorone Fumarate, done, Piridicillin Sodium, Piridronate Sodium, Piriprost, Oxfendazole, Oxfenicine, Oxibendazole, oxiconazole, Oxi- piritrexim, Pirlimycin Hydrochloride, pirlindole, pirmagrel, dopamine, Oxidronic Acid, Oxifungin Hydrochloride, Pirmenol Hydrochloride, Pirnabine, Piroctone, Pirodavir, Oxilorphan, Oximonam, Oximonam Sodium, Oxiperomide, 65 pirodomast, Pirogliride Tartrate, Pirolate, Pirolazamide, oxiracetam, Oxiramide, Oxisuran, Oxmetidine Hydrochlo- Piroxantrone Hydrochloride, Piroxicam, Piroximone, Pir- ride, oxodipine, Oxogestone Phenpropionate, Oxolinic profen, Pirquinozol, Pirsidomine, Pivampicillin Hydrochlo- US 9,526,824 B2 41 ,_►N ride, Pivopril, Pizotyline, placetin A, Plicamycin, Plomes- Riboprine, ricasetron, Ridogrel, Rifabutin, Rifametane, tane, Pobilukast Edamine, Podofilox, Poisonoak Extract, Rifamexil, Rifamide, Rifampin, Rifapentine, Rifaximin, Poldine Methylsulfate, Poliglusam, Polignate Sodium,Poly- rilopirox, Riluzole, rimantadine, Rimcazole Hydrochloride, myxin B Sulfate, Polythiazide, Ponalrestat, Porfimer Rimexolone, Rimiterol Hydrobromide, Rimonabant, rimo- Sodium, Porfiromycin, Potassium Chloride, Potassium 5 progin, riodipine, Rioprostil, Ripazepam, ripisartan, Rise- Iodide, Potassium Permanganate, Povidone-Iodine, Prac- dronate, Risedronate Sodium, risedronic acid, Risocaine, tolol, Pralidoxime Chloride, Pramipexole, Pramiracetam Risotilide Hydrochloride, rispenzepine, Risperdal, Risperi- Hydrochloride, Pramoxine Hydrochloride, Pranolium Chlo- done, Ritanserin, ritipenem, Ritodrine, Ritolukast, ritonavir, ride, Pravadoline Maleate, Pravastatin, Pravastatin sodium, rituximab, rivastigmine, rivastigmine tartrate, Rizatriptan, Prazepam, Prazosin, Prazosin Hydrochloride, Prednazate, io rizatriptan benzoate, Rocastine Hydrochloride, Rocuronium Prednicarbate, Prednimustine, Prednisolone, prednisolone Bromide, Rodocaine, Roflurane, Rogletimide, rohitukine, quetiapine fumerate, Prednisone, Prednival, Pregabalin, rokitamycin, Roletamicide, Rolgamidine, Rolicyprine, Pregnenolone Succiniate, Prenalterol Hydrochloride, Pre- Rolipram, Rolitetracycline, Rolodine, Romazarit,romurtide, nylamine, Pridefine Hydrochloride, Prifelone, Prilocalne Ronidazole, Ropinirole, Ropitoin Hydrochloride, ropiva- Hydrochloride, Prilosec, Primaquine Phosphate, Primidolol, 15 caine, Ropizine, roquinimex, Rosaramicin, rosiglitazone, Primidone, Prinivil, Prinomide Tromethamine, Prinoxodan, Rosiglitazone maleate, Rosoxacin, Rosuvastatin, Rotavirus pritosufloxacin, Prizidilol Hydrochloride, Proadifen Hydro- vaccine, rotigotine, Rotoxamine, roxaitidine, Roxarsone, chloride, Probenecid, Probicromil Calcium, Probucol, Pro- roxindole, roxithromycin, rubiginone B1, ruboxyl, rufloxa- cainamide Hydrochloride, Procaine Hydrochloride, Procar- cin, rupatidine, Rutamycin, ruzadolane, Sabeluzole, safin- bazine Hydrochloride, Procaterol Hydrochloride, 20 gol, safironil, saintopin, salbutamol, Salbutamol sulfate, Prochlorperazine, Procinonide, Proclonol, Procyclidine Salcolex, Salethamide Maleate, Salicyl Alcohol, Salicylam- Hydrochloride, Prodilidine Hydrochloride, Prodolic Acid, ide, Salicylate Meglumine, Salicylic Acid, Salmeterol, Sal- Profadol Hydrochloride, Progabide, Progesterone, Proglu- nacediin, Salsalate, sameridine, sampatrilat, Sancycline, mide, Proinsulin (human), Proline, Prolintane Hydrochlo- sanfetrinem, Sanguinarium Chloride, Saperconazole, ride, Promazine Hydrochloride, Promethazine, Promethaz- 25 saprisartan, sapropterin, sapropterin dihydrochloride, saqui- ine hydrochloride, Propafenone Hydrochloride, navir, Sarafloxacin Hydrochloride, Saralasin Acetate, sar- propagermanium, Propanidid, Propantheline Bromide, cophytol A, sargramostim, Sarmoxicillin, Sarpicillin, sar- Proparacaine Hydrochloride, Propatyl Nitrate, propentofyl- pogrelate, saruplase, saterinone, satigrel, satumomab line, Propenzolate Hydrochloride, Propikacin, Propiomaz- pendetide, Scopafungin, Scopolamine Hydrobromide, ine, Propionic Acid, propionylcamitine, propiram, propiram, 30 Scrazaipine Hydrochloride, Secalciferol, Secobarbital, Seel- propiverine, Propofol, Proponolol hydrochloride, Propoxy- zone, segiline, Seglitide Acetate, Selegiline Hydrochloride, caine Hydrochloride, Propoxyphene Hydrochloride, Propra- Selenium Sulfide, Selenomethionine Se-75, Selfotel, sema- nolol Hydrochloride, Propulsid, propylbis-acri done, Propy- tilide, semduramicin, semotiadil, semustine, Sepazonium lhexedrine, Propyliodone, Propylthiouracil, Proquazone, Chloride, Seperidol Hydrochloride, Seprilose, Seproxetine Prorenoate Potassium, Proroxan Hydrochloride, Proscillari- 35 Hydrochloride, Seractide Acetate, Sergolexole Maleate, Ser- din, Prostalene, prostratin, Protamine Sulfate, protegrin, ine, Sermetacin, Sermorelin Acetate, sertaconazole, sertin- Protirelin, Protriptyline Hydrochloride, Proxazole, Prox- dole, sertraline, sertraline hydrochloride, S-ethynyluracil, azole Citrate, Proxicromil, Proxorphan Tartrate, prulifloxa- setiptiline, Setoperone, Sevelamer, sevirumab, sevoflurane, cin, pseudoephedrine, Pseudophedrine hydrochloride, Puro- sezolamide, Sibopirdine, Sibutramine Hydrochloride, Silan- mycin, Pyrabrom, Pyrantel Pamoate, Pyrazinamide, 4o drone, Sildenafil, sildenafil citrate, silipide, silteplase, Silver Pyrazofurin, pyrazoloacridine, Pyridostigmine Bromide, Nitrate, simendan, Simtrazene, Simvastatin, Sincalide, Sine- Pyridoxine hydrochloride, Pyrilamine Maleate, Pyrimeth- fungin, sinitrodil, sinnabidol, sipatrigine, sirolimus, Sisomi- amine, Pyrinoline, Pyrithione Sodium, Pyrithione Zinc, cin, Sitagliptin, Sitogluside, sizofiran, sobuzoxane, Sodium Pyrovalerone Hydrochloride, Pyroxamine Maleate, Pyrro- Amylosulfate, Sodium Iodide I-123, Sodium Nitroprusside, caine, Pyrroliphene Hydrochloride, PyrroInitrin, Pyrvinium 45 Sodium Oxybate, sodium phenylacetate, Sodium Salicylate, Pamoate, Quadazocine Mesylate, Quazepam, Quazinone, Sodium valproate, Solifenacin, solverol, Solypertine Tar- Quazodine, Quazolast, quetiapine, quetiapine fumarate, qui- trate, Somalapor, Somantadine Hydrochloride, somatome- flapon, quinagolide, Quinaldine Blue, quinapril, Quinapril din B, somatomedin C, Somatostatin, somatrem, somatro- hydrochloride, Quinazosin Hydrochloride, Quinbolone, pin, Somenopor, Somidobove, Sorbinil, Sorivudine, sotalol, Quinctolate, Quindecamine Acetate, Quindonium Bromide, 50 Soterenol Hydrochloride, Sparfioxacin, Sparfosate Sodium, Quinelorane Hydrochloride, Quinestrol, Quinfamide, sparfosic acid, Sparsomy, Sparteine Sulfate, Spectinomycin Quingestanol Acetate, Quingestrone, Quinidine Gluconate, Hydrochloride, spicamycin D, Spiperone, Spiradoline Quinelorane Hydrochloride, Quinine Sulfate, Quinpirole Mesylate, Spiramycin, Spirapril Hydrochloride, Spiraprilat, Hydrochloride, Quinterenol Sulfate, Quinuclium Bromide, Spirogermanum Hydrochloride, Spiromustine, Spironolac- Quinupristin, Quipazine Maleate, Rabeprazole, Rabeprazole 55 tone, Spiroplatin, Spiroxasone, splenopentin, spongistatin, Sodium, Racephenicol, Racepinephrine, Rafoxanide, Rali- Sprodiamide, squalamine, Stallimycin Hydrochloride, Stan- toline, raloxifene, raltegravir, raltitrexed, ramatroban, nous Pyrophosphate, Stannous Sulfur Colloid, Stanozolol, Ramipril, Ramoplann,ramosetron, ranelic acid, Ranmycin, Statolon, staurosporine, stavudine, Steflimycin, Stenbolone Rantidine, Rantidine hydrochloride, ranolazine, Rauwolfia Acetate, stepronn, Stilbazium Iodide, Stilonum Iodide, Serpentina, recainam, Recainam Hydrochloride, Reclaze- 60 stipiamide, Stiripentol, stobadine, Streptomycin Sulfate, pam, Recombinant factor VIII, regavirumab, Regramostim, Streptoncozid, Streptongrin, Streptozocin, Strontium Chlo- Relaxin, Relomycin, Remacemide Hydrochloride, Remifen- ride Sr-89, succibun, Succimer, Succinylcholine Chloride, tanl Hydrochloride, Remiprostol, Remoxipride, Repirinast, Sucralfate, Sucrosofate Potassium, Sudoxicam, Sufentanl, Repromicin, Reproterol Hydrochloride, Reserpine, resin- Sufotidine, Sulazepam, Sulbactam Pivoxil, Sulconazole feratoxin, Resorcinol, retapamulin, retelliptine demethyl- 65 Nitrate, Sulfabenz, Sulfabenzamide, Sulfacetamide, Sul- ated, reticulon, reviparin sodium, revizinone, rhenium facytine, Sulfadiazine, Sulfadoxine, Sulfalene, Sulfamera- etidronate, rhizoxin, RI retinamide, Ribaminol, Ribavirin, zine, Sulfameter, Sulfamethazine, Sulfamethizole, Sulfame- US 9,526,824 B2 43 44 thoxazole, Sulfamonomethoxine, Sulfamoxole, Sulfanilate ride, Tobramycin, Tocamide, Tocamphyl, Tofenacin Hydro- Zinc, Sulfanitran, sulfasalazine, Sulfasomizole, Sulfazamet, chloride, Tolamolol, Tolazamide, Tolazoline Hydrochloride, Sulfinalol Hydrochloride, sulfinosine, Sulfinpyrazone, Tolbutamide, Tolcapone, Tolciclate, Tolfamide, Tolgabide, Sulfisoxazole, Sulfomethoxazole, Sulfomyxin, Sulfonterol Tolimidone, Tolindate, Tolmetin, Tolnaftate, Tolpovidone, Hydrochloride, sulfoxamine, Sulinldac, Sulmarin, Sulnida- 5 Tolpyrramide, Tolrestat, Tolterodine, tolterodine tartrate, zole, Suloctidil, Sulofenur, sulopenem, Suloxifen Oxalate, Tomelukast, Tomoxetine Hydrochloride, Tonazocine Mesy- Sulpiride, Sulprostone, sultamicillin, Sulthiame, sultopride, late, Topiramate, topotecan, Topotecan Hydrochloride, sulukast, Sumarotene, sumatriptan, Sumatriptan succinate, topsentin, Topterone, Toquizine, torasemide, toremifene, Suncillin Sodium, Suproclone, Suprofen, suradista, suramin, Torsemide, Tosifen, Tosufloxacin, totipotent stem cell factor Surfomer, Suricamide Maleate, Suritozole, Suronacrine io (TSCF), Tracazolate, trafermin, Tralonide, Tramadol, Tra- Maleate, Suxemerid Sulfate, swainsonine, symakalim, madol Hydrochloride, Tramazoline Hydrochloride, tran- Symclosene, Symetine Hydrochloride, Taciamine Hydro- dolapril, Tranexamic Acid, Tranilast, Transcamide, trastu- chloride, Tacrine Hydrochloride, Tacrolimus, Tadalafil, zumab, traxanox, Trazodone Hydrochloride, Trebenzomine Talampicillin Hydrochloride, Taleranol, Talisomycin, talli- Hydrochloride, Trefentanil Hydrochloride, Treloxinate, mustine, Talmetacin, Talniflumate, Talopram Hydrochlo- 15 Trepipam Maleate, Trestolone Acetate, tretinoin, Triacetin, ride, Talosalate, Tametraline Hydrochloride, Tamoxifen, triacetyluridine, Triafungin, Triamcinolone, Triampyzine tamoxifen citrate, Tampramine Fumarate, Tamsulosin, Tam- Sulfate, Triamterene, Triazolam, Tribenoside, tricaprilin, sulosin Hydrochloride, Tandamine Hydrochloride, tan- Tricetamide, Trichlonnethiazide, trichohyalin, triciribine, dospirone, tapgen, taprostene, Tasosartan, tauromustine, Tricitrates, Triclofenol piperazine, Triclofos Sodium, trien- Taxane, Taxoid, Tazadolene Succinate, tazanolast, tazaro- 20 tine, Trifenagrel, triflavin, Triflocin, Triflubazam, Triflumi- tene, Tazifylline Hydrochloride, Tazobactam, Tazofelone, date, Trifluoperazine Hydrochloride, Trifluperidol, Triflu- Tazolol Hydrochloride, Tebufelone, Tebuquine, Teclozan, promazine, Triflupromazine Hydrochloride, Trifluridine, Tecogalan Sodium, Teecleukin, Teflurane, Tegafur, Tegas- Trihexyphenidyl Hydrochloride, Trilostane, Trimazosin erod, Tegretol, Teicoplanin, telenzepine, tellurapyrylium, Hydrochloride, trimegestone, Trimeprazine Tartrate, telmesteine, telmisartan, Teloxantrone Hydrochloride, 25 Trimethadione, Trimethaphan Camsylate, Trimethoprim, Teludipine Hydrochloride, Temafloxacin Hydrochloride, Trimetozine, Trimetrexate, Trimipramine, Trimoprostil, Tri- Tematropium Methyl sulfate, Temazepam, Temelastine, moxamine Hydrochloride, Triolein, Trioxifene Mesylate, temocapril, Temocillin, temoporfin, temozolomide, temsi- Tripamide, Tripelennamine Hydrochloride, Triprolidine rolimus, Tenidap, Teniposide, Tenofovir, tenosal, tenoxicam, Hydrochloride, Triptorelin, Trisulfapyrimidines, Troclosene tepirindole, Tepoxalin, Teprotide, terazosin, Terazosin so Potassium, troglitazone, Trolamine, Troleandomycin, trom- Hydrochloride, Terbinafine, Terbutaline Sulfate, Tercon- bodipine, trometamol, Tropanserin Hydrochloride, Tropic- azole, terfenadine, terfiavoxate, terguride, Teriparatide, Teri- amide, tropine, tropisetron, trospectomycin, trovafloxacin, paratide Acetate, terlakiren, terlipressin, terodiline, Terox- trovirdine, Tryptophan, Tuberculin, Tubocurarine Chloride, alene Hydrochloride, Teroxirone, tertatolol, Tesicam, Tubulozole Hydrochloride, tucaresol, tulobuterol, turos- Tesimide, Testolactone, Testosterone, Tetracaine, tetrachlo- 35 teride, Tybamate, tylogenin, Tyropanoate Sodium, Tyrosine, rodecaoxide, Tetracycline, Tetracycline hydrochloride, Tet- Tyrothricin, tyrphostins, ubenimex, Uldazepam, Unde- rahydrozoline Hydrochloride, Tetramisole Hydrochloride, cylenic Acid, Uracil Mustard, urapidil, Urea, Uredepa, uri- Tetrazolast Meglumine, tetrazomine, Tetrofosmin, Tetroqui- dine triphosphate, Urofollitropin, Urokinase, Ursodiol, none, Tetroxoprim, Tetrydamine, thaliblastine, Thalidomide, valaciclovir, Valacyclovir hydrochloride, Valine, Valnoct- Theofibrate, Theophylline, Thiabendazole, Thiamiprine, 4o amide, Valproate semisodium, Valproic Acid, valsartan, Thiamphenicol, Thiamylal, Thiazesim Hydrochloride, Thi- vamicamide, vanadeine, Vancomycin, vaminolol, Vapiprost azinamium Chloride, Thiethylperazine, Thiithixene, Thime- Hydrochloride, Vapreotide, Vardenafil, Varenicline, variolin rfonate Sodium, Thimerosal, thiocoraline, thiofedrine, Thio- B, Vasopressin, Vecuronium Bromide, velaresol, Velnacrine guanine, thiomarinol, Thiopental Sodium, thioperamide, Maleate, venlafaxine, Venlafaxine hydrochloride, Verado- Thioridazine, Thiotepa, Thiphenamil Hydrochloride, Thip- 45 line Hydrochloride, veramine, Verapamil Hydrochloride, hencillin Potassium, Thiram, Thozalinone, Threoxine, verdins, Verilop am Hydrochloride, Verlukast, Verofylline, Thrombin, thrombopoietin, thymalfasin, thymopentin, thy- veroxan, verteporfin, Vesnarinone, vexibinol, Vidarabine, motrinan, Thyromedan Hydrochloride, Thyroxine, Tiacri- vigabatrin, vildagliptin, Viloxazine Hydrochloride, Vinblas- last, Tiacrilast Sodium, tiagabine, Tiamenidine, tianeptine, tine Sulfate, vinburnine citrate, Vincofos, vinconate, Vin- tiapafant, Tiapamil Hydrochloride, Tiaramide Hydrochlo- 50 cristine Sulfate, Vindesine, Vindesine Sulfate, Vinepidine ride, Tiazofurin, Tibenelast Sodium, Tibolone, Tibric Acid, Sulfate, Vinglycinate Sulfate, Vinleurosine Sulfate, vinore- Ticabesone Propionate, Ticarbodine, Ticarcillin Cresyl lbine, vinpocetine, vintoperol, vinxaltine, Vinzolidine Sul- Sodium, Ticlatone, ticlopidine, Ticrynafen, tienoxolol, Tifu- fate, Viprostol, Virginiamycin, Viridofulvin, Viroxime, rac Sodium, Tigemonam Dicholine, Tigestol, Tiletamine vitaxin, Voglibose, Volazocine, voriconazole, vorozole, vox- Hydrochloride, Tilidine Hydrochloride, tilisolol, tilnoprofen 55 ergolide, Wafarin, Xamoterol, Xanomeline, Xanoxate arbamel, Tilorone Hydrochloride, Tiludronate Disodium, Sodium, Xanthinol Niacinate, xemilofiban, Xenalipin, Xen- tiludronic acid, Timefurone, Timobesone Acetate, Timolol, bucin, Xilobam, ximoprofen, Xipamide, Xorphanol Mesy- Timolol meleate, Tinabinol, Timidazole, Tinzaparin late, Xylamidine Tosylate, Xylazine Hydrochloride, Xylo- Sodium, Tioconazole, Tiodazosin, Tiodonium Chloride, Tio- metazoline Hydrochloride, xylose, yangambin, zabicipril, peridone Hydrochloride, Tiopinac, Tiospirone Hydrochlo- 60 zacopride, zafirlukast, Zalcitabine, Zaleplon, zalospirone, ride, Tiotidine, Tiotropium, tiotropium bromide, Tioxida- Zaltidine Hydrochloride, zaltoprofen, zanamivir, zankiren, zole, Tipentosin Hydrochloride, tipranavir, Tipredane, zanoterone, Zantac, Zarirlukast, zatebradine, zatosetron, Tiprenolol Hydrochloride, Tiprinast Meglumine, Tipropidil Zatosetron Maleate, zenarestat, Zenazocine Mesylate, Zeni- Hydrochloride, Tiqueside, Tiquinamide Hydrochloride, platin, Zeranol, Zidometacin, Zidovudine, zifrosilone, Zil- tirandalydigin, Tirapazamine, tirilazad, tirofiban, tiropr- 65 antel, zilascorb, zileuton, Zimeldine Hydrochloride, Zinc amide, titanocene dichloride, Tixanox, Tixocortol Pivalate, Undecylenate, Zindotrine, Zinoconazole Hydrochloride, Tizanidine Hydrochloride, Tnmethobenzamide Hydrochlo- Zinostatin, Zinterol Hydrochloride, Zinviroxime, ziprasi- US 9,526,824 B2 45 46 done, Zobolt, Zofenopril Calcium, Zofenoprilat, Zolamine inhibitors are promising chemopreventive agents for breast Hydrochloride, Zolazepam Hydrochloride, Zoledronate, cancer through inhibition of estrogen biosynthesis. In par- Zolertine Hydrochloride, zolmitriptan, zolpidem, Zomepirac ticular, research has suggested that letrozole is an ideal Sodium, Zometapine, Zoniclezole Hydrochloride, Zonis- candidate for chemoprevention for women in high risk amide, zopiclone, Zopolrestat, Zorbamyciin, Zorubicin 5 group such as BRCAI positive. However, the low efficacy Hydrochloride, zotepine, Zucapsaicin, and pharmaceutically and the side effects associated with the conventional sys- acceptable salts thereof. temic administration of letrozole are limiting factors for its long term usage. EXAMPLE 1 Breast cancer growth is highly dependent on estrogen, to and thus inhibition of estrogen is highly effective for the The capsule as described herein is used to administer prevention of breast tumor development. Recent studies leuprolide acetate for the treatment of prostate cancer. Leu- have highlighted aromatase inhibitors such as anastrozole, prolide acetate (USP 31) is a synthetic nonapeptide agonist letrozole, and exemestane, as promising molecules that can analog ofluteinizing hormone-releasing factor(LNHR). The 15 be used for chemoprevention of breast cancer. Aromatase leuprolide acetate molecule is approximately 1209 Daltons in weight and two to three nanometers in size. It is soluble mediates biosynthesis of estradiol, the most potent form of in aqueous media at a level of approximately 10 mg/mL. An estrogen, from androgens by the cytochrome P450 enzyme existing method of administering leuprolide via extended complex (Aromatase). Aromatase is present in breast tissue release is disclosed in U.S. Pat. No. 5,728,396 filed Jan. 30, and the nonsteroidal and steroidal aromatase inhibitors 1997 and incorporated herein by reference. 20 reduce circulating estrogen level to 1% to 10% of pretreat- The nanochannel delivery device chip is installed in a ment levels, respectively. Therefore, inhibition of aromatase capsule as described herein and filled with a 5 mg/mL is an important approach for reducing growth-stimulatory leuprolide acetate solution(NDC number 0703-4014-18)for effects of estrogens in estrogen-dependent breast cancer, use in the treatment of prostate cancer. The capsule is sized which constitutes approximately 60-70% of breast cancer. to approximately 2.8 mL, so that the filled capsule contains 25 Among the aromatase inhibitors, letrozole is a highly potent approximately 14 mg of leuprolide acetate. If stronger non-steroid inhibitor which inhibits approximately 99% of concentrations of leuprolide acetate solution are used, the estrogen biosynthesis. Additionally, several studies and capsule volume may be correspondingly reduced. The cap- clinical trials on chemotherapy of metastatic breast cancer sule is implanted subcutaneously in the inner portion of the indicated higher efficacy with fewer side effects of letrozole upper arm or upper leg or in the abdomen. The capsule is 30 when compared to Tamoxifen. Hence, research suggests implanted, with optional use of a tissue separator, through a letrozole as a candidate for the development of chemopre- small incision in a clinical outpatient procedure and ventive therapy for women at increased risk of breast cancer. removed two to three months later through a small incision. However, the conventional oral administration of letrozole For implant and explant, a small amount of anesthetic is showed increased risk of heart problems and osteoporosis. used, for example, a 1% lidocaine injection at the site. 35 The key for the success of chemoprevention for breast The micro- and nano-channel sizes of the nanochannel cancer relies on long term delivery of specific drugs while delivery device are chosen (for example, according to the circumventing side effects. As opposed to the inefficient oral model described in [Grattoni, A. Ferrari, M., Liu, X. Quality administration, a constant local release of chemopreventive control method for micro-nano-channels silicon devices. agent (i.e. letrozole) in breast tissue could significantly U.S. Patent Application No. 61/049,287 (April 2008)]), to 4o reduce occurrence of breast tumor as well as systemic side provide a release rate of about 120 µg/day can be obtained effects. This shows promise for improvement in patient for about 90 days in certain embodiments. quality of life. In this example, the nanochannel delivery device configu- It is believed that the implantable nanochanneled devices ration with this behavior uses a 6x6 mm chip size, with 161 according to the present disclosure will allow the constant macrochannels with openings of 190x190 µm each, and 45 and sustained local release of letrozole in breast tissues and within each macrochannel approximately 23 rows of nano- significant reduction of estrogen dependent epithelial cell channel structures, consisting of 10 each of inlet and outlet proliferation with minimum toxicities. microchannels, connected through about 20 nanochannels Prior clinical trials employed letrozole daily doses of 2.5 according to the description herein. The inlets and outlets are mg. It is believed that the constant local release of letrozole approximately 5x5 µm in cross-section, with the inlets being 50 in breast tissues (utilizing nanochanneled devices according about 30 µm long and the outlets being about 1.6 µm long, to the present disclosure) would require lower dosage if and the nanochannels are about 5µm long and 5µm wide compared to oral delivery. In first analysis it is believed that and 13 nm high. Other configurations with different dimen- a local daily release in the range 25 to 50 ug could be sions may be derived from the mathematical model that effective. yield approximately the same release rate and duration in 55 The achievement of an efficient chemopreventive therapy other examples. by the use of long-term, constant release implants for local administration of chemopreventive agents will have signifi- EXAMPLE 2 cant impact on the quality of life of women in the high risk group. It is believed that use of nanochannel delivery The capsule and nanochannel delivery device are config- 6o devices according to the present disclosure will lead to ured and implanted as described in Example 1. However, improved efficacy of therapy, as well as potential reduction instead of administering leuprolide acetate, the capsule and of drug doses and reduction of side effects through true nanochannel delivery device administer letrozole for the constant release. A reduction in the number of breast cancer treatment of breast cancer. The limited success of chemo- occurrences due to effective preventive therapy would also therapy for the treatment of breast cancer emphasizes the 65 have a positive economic impact on patients, their employ- need of novel preventive strategies to minimize the cancer ers and insurers through lowered cost of treatment, fewer occurrence. Recent studies have highlighted that aromatase medical visits, and less work time lost. US 9,526,824 B2 47 48 The development of a reliable extended release implant- described in terms of particular embodiments, it will be able technology adds a new dimension to drug delivery for apparent to those of skill in the art that variations may be breast cancer. Tumor treatment and the suppression of applied to the devices, systems and/or methods in the steps metastasis and/or tumor recurrence are natural follow-on or in the sequence of steps of the method described herein developments. Technology enhancements to the initial plat- 5 without departing from the concept, spirit and scope of the form could support variable and programmed release, invention. All such similar substitutes and modifications including remote, interactive control of the implanted apparent to those skilled in the art are deemed to be within device, further enabling capabilities to deploy multiple the spirit, scope and concept of the invention as defined by drugs simultaneously. In vivo refilling could also extend the the appended claims. functionality of the nanochannel device and also decrease 10 REFERENCES adverse events associated with explanation. As a general drug delivery method, other indications may be identified, The contents of the following references are incorporated broadening the applicability of the innovation. by reference herein: EXAMPLE 3 15 [1] Santen, R. J., Yue, W., Naftolin, F., Mor, G., Berstein, L. The potential of aromatase inhibitors in breast cancer The capsule and nanochannel delivery device are config- prevention. Endocrine-Related Cancer. 6, 235-243 ured and implanted in a patient as described in Example 1. (1999). However, instead of administering leuprolide acetate, the [2] Goss, P. E., Strasser, K. Aromatase Inhibitors in the capsule and nanochannel delivery device administer lapa- 20 Treatment and Prevention of Breast Cancer. J. Clin. tinib for the treatment of breast cancer. Oncol. 19, 881-894 (2001). [3] Chlebowski, R. T. Reducing the Risk of Breast Cancer. EXAMPLE 4 N. Engl. J. Med., 343, 191-198 (2000). [4] Dowsett, M., Jones, A., Johnston, S. R., Jacobs, S., The capsule and nanochannel delivery device are config- 25 Trunet, P., Smith, I. E. In vivo measurement of aromatase ured and implanted in a patient as described in Example I. inhibition by letrozole (CGS 20267) in postmenopausal However, instead of administering leuprolide acetate, the patients with breast cancer. Clin. Cancer Res. 1, 1511- capsule and nanochannel delivery device administer bupe- 1515 (1995). norphine for the treatment of opiate dependency. [5] Brueggemeier, R. W., Hackett, J. C., Diaz-Cruz, E. S. 30 Aromatase Inhibitors in the Treatment of Breast Cancer. EXAMPLE 5 Endocrine Reviews 26, 331-345 (2005). [6] Coates, A. S., Keshaviah, A., Thiirlimann, B., et al. Five The capsule and nanochannel delivery device are config- years of letrozole compared with tamoxifen as initial ured and implanted in a patient as described in Example 1. adjuvant therapy for postmenopausal women with endo- However, instead of administering leuprolide acetate, the 35 crine-responsive early breast cancer: update of study BIG capsule and nanochannel delivery device administer inter- 1-98. J. Clin. Oncol. 25, 486-492 (2007). feron alpha implant for giant cell angioblastoma. [7] Goss, P. E., Ingle, J. N., Martino, S., et al. Arandomized trial of letrozole in postmenopausal women after five EXAMPLE 6 years of tamoxifen therapy for early-stage breast cancer. 40 N. Engl. J. Med. 349, 1793-1802 (2003). The capsule and nanochannel delivery device are config- [8] Garreau, J. R., Delamelena, T., Walts, D., Karamlou, K., ured and implanted in a patient as described in Example 1. Johnson, N. Side effects of aromatase inhibitors versus However, instead of administering leuprolide acetate, the tamoxifen: the patients' perspective. Am. J. Surg. 192, capsule and nanochannel delivery device administer zido- 496-8 (2006). vudine in an intravaginal treatment for preventing HIV 45 [9] Luthra, R., Kinna, N., Jones, J., Tekmal, R. R. Use of being transmitted from a pregnant mother to a child. letrozole as a chemopreventive agent in aromatase over- As used herein, the term "direct fluid communication" is expressing transgenic mice. The Journal of Steroid Bio- interpreted as fluid communication between two bodies that chemistry and Molecular Biology. 86, 461-467 (2003). are directly connected, e.g. such that fluid may exit one body [10] Harper-Wynne, C., Ross, G., Sacks, N., Salter, J., and immediately enter the second body without flowing 50 Nasiri, N., Iqbal, J., A'Hern, R., Dowsett, M. Effects of through an intermediate body. For example, in the embodi- the aromatase inhibitor letrozole on normal breast epithe- ment shown in FIGS. 3A-3G, outlet 70 is in direct fluid lial cell proliferation and metabolic indices in postmeno- communication with nanochannel 25. However, outlet 70 is pausal women: a pilot study for breast cancer prevention. not in direct fluid communication with inlet 30, because fluid Cancer Epidemiol. Biomarkers Prev. 11, 614-21 (2002). must flow through an intermediate body (nanochannel 25) 55 The invention claimed is: after exiting inlet 30 and before entering outlet 70. 1. A method offabricating a nanochannel delivery device, Furthermore, as used herein, the term "inlet" is interpreted the method comprising: as a chamber or reservoir within a nanochannel delivery providing first substrate; device that initially retains a substance being delivered via forming a plurality of nanochannels on the first substrate; the nanochannel delivery device. Similarly, an "outlet" is 60 filling in the plurality of nanochannels with a first sacri- interpreted as a chamber or reservoir within a nanochannel ficial material; delivery device that retains a substance immediately prior to forming a plurality of inlet microchannels in the first the substance exiting the nanochannel delivery device. substrate; All of the devices, systems and/or methods disclosed and filling in the plurality of inlet microchannels with a claimed herein can be made and executed without undue 65 second sacrificial material; experimentation in light of the present disclosure. While the forming a capping layer that covers the plurality of devices, systems and methods of this invention have been nanochannels; US 9,526,824 B2 49 50 forming a plurality of outlet microchannels in the capping 12. The method of claim 1 wherein the capping layer is layer; selected from silicon nitride, silicon oxide, silicon carboni- removing the first sacrificial material from the plurality of tride, silicon carbide, and silicon. nanochannels; and 13. The method of claim 1, wherein the capping layer removing the second sacrificial material from the plurality 5 comprises multiple depositions of materials comprising tensile and compressive stresses such that the net capping layer of inlet microchannels. stress is tensile. 2. The method of claim 1, wherein an inlet microchannel 14. The method of claim 1, wherein the capping layer is of the plurality of inlet microchannels is arranged perpen- between approximately 0.5 and 1.0 microns thick. dicular to a primary plane of the first substrate. 15. The method of claim 1, wherein the capping layer is 3. The method of claim 1, wherein an outlet microchannel l0 between approximately 1.0 and 2.0 microns thick. of the plurality of outlet microchannels is arranged perpen- 16. The method of claim 1, wherein the capping layer is dicular to a primary plane of the first substrate. between approximately 2.0 and 4.0 microns thick. 4. The method of claim 1, wherein an inlet microchannel 17. The method of claim 1, wherein the second sacrificial of the plurality of inlet microchannels is in direct fluid material is subsequently removed by selective etching. communication with a nanochannel. 15 18. The method of claim 17, wherein the second sacrificial 5. The method of claim 1, wherein an outlet microchannel material is selected from the group consisting of: tungsten, of the plurality of outlet microchannels is in direct fluid copper, doped glass, and undoped glass. communication with a nanochannel. 19. The method of claim 1, wherein the first substrate comprises a silicon-on-insulator wafer comprising an inter- 6. The method of claim 1, wherein the inlet and outlet 20 microchannels are patterned using a photolithography pro- nal oxide layer. cess. 20. The method of claim 19, wherein forming the plurality 7. The method of claim 1, wherein each nanochannel is of inlet microchannels comprises etching material from the between approximately one and ten nanometers deep. first substrate, and wherein the etching is terminated at the 8. The method of claim 1, wherein each nanochannel is internal oxide layer. between approximately ten and twenty nanometers deep. 25 21. The method of claim 20, wherein forming a plurality 9. The method of claim 1, wherein the first sacrificial of inlet macrochannels comprises etching material from a material is subsequently removed by selective etching. back side of the first substrate, and wherein the etching is 10. The method of claim 1, wherein the first sacrificial terminated at the internal oxide layer. 22. The method of claim 21, further comprising removing material is tungsten. 30 11. The method of claim 1, wherein the second sacrificial of the internal oxide layer after etching material to form the material is filled into the plurality of inlet microchannels so inlet microchannel and inlet macrochannels to open a path- that the second sacrificial material extends above the top of way between the inlet microchannels and inlet macrochan- the plurality of inlet microchannels and is planarized by nels. chemical-mechanical planarization (CMP).