`
`(12) United States Patent (cid:9)
`Cartt et al. (cid:9)
`
`(10) Patent No.: (cid:9)
`(45) Date of Patent: (cid:9)
`
`US 9,763,876 B2
`*Sep. 19, 2017
`
`(54) ADMINISTRATION OF BENZODIAZEPINE
`COMPOSITIONS
`
` 514/221
`USPC (cid:9)
`See application file for complete search history.
`
`(71) Applicant: Hale Biopharma Ventures, LLC,
`Encinitas, CA (US)
`
`(72)
`
`Inventors: Steve Cartt, Union City, CA (US);
`David Medeiros, South San Francisco,
`CA (US); Garry Thomas Gwozdz, Jim
`Thorpe, PA (US); Andrew Loxley,
`Philadelphia, PA (US); Mark
`Mitchnick, East Hampton, NY (US);
`David Hale, San Diego, CA (US);
`Edward T. Maggio, San Diego, CA
`(US)
`
`(73) Assignee: Hale Biopharma Ventures, LLC,
`Encinitas, CA (US)
`
`( * ) Notice: (cid:9)
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 17 days.
`
`This patent is subject to a terminal dis-
`claimer.
`
`(21) Appl. No.: 14/527,613
`
`(22) Filed: (cid:9)
`
`Oct. 29, 2014
`
`(65)
`
`Prior Publication Data
`
`US 2015/0065491 Al (cid:9)
`
`Mar. 5, 2015
`
`Related U.S. Application Data
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,102,116 A (cid:9)
`3,109,843 A (cid:9)
`3,136,815 A (cid:9)
`3,243,427 A (cid:9)
`3,296,249 A (cid:9)
`3,299,053 A (cid:9)
`3,340,253 A (cid:9)
`3,371,085 A (cid:9)
`3,374,225 A (cid:9)
`3,547,828 A (cid:9)
`3,567,710 A (cid:9)
`3,609,145 A (cid:9)
`3,722,371 A (cid:9)
`3,849,341 A (cid:9)
`3,987,052 A (cid:9)
`4,280,957 A (cid:9)
`4,397,951 A (cid:9)
`4,608,278 A (cid:9)
`4,748,158 A (cid:9)
`4,826,689 A (cid:9)
`4,868,289 A (cid:9)
`4,921,838 A (cid:9)
`4,973,465 A (cid:9)
`4,997,454 A (cid:9)
`5,091,188 A (cid:9)
`5,100,591 A (cid:9)
`5,118,528 A (cid:9)
`5,145,684 A (cid:9)
`5,182,258 A (cid:9)
`5,188,837 A (cid:9)
`5,192,528 A (cid:9)
`5,236,707 A (cid:9)
`5,268,461 A (cid:9)
`5,308,531 A (cid:9)
`
`Chase et al.
`8/1963
`Reeder et al.
`11/1963
`Reeder et al.
`6/1964
`Reeder et al.
`3/1966
`Bell
`1/1967
`Archer et al.
`1/1967
`Reeder et al.
`9/1967
`Reeder et al.
`2/1968
`Reeder et al.
`3/1968
`Mansfield et al.
`12/1970
`Fryer et al.
`3/1971
`Moffett
`9/1971
`Boyle
`3/1973
`Lambeiti
`11/1974
`Hester, Jr.
`10/1976
`Walser et al.
`7/1981
`Taki et al.
`8/1983
`Frank et al.
`8/1986
`Biermann et al.
`5/1988
`Violanto et al.
`5/1989
`Magnusson et al.
`9/1989
`Catsimpoolas et al.
`5/1990
`Baurain et al.
`11/1990
`Violante et al.
`3/1991
`Haynes
`2/1992
`Leclef et al.
`3/1992
`Fessi et al.
`6/1992
`Liversidge et al.
`9/1992
`Chiou
`1/1993
`Domb
`2/1993
`Radhakrishnan et al.
`3/1993
`Stewart
`8/1993
`Shoji et al.
`12/1993
`Urfer et al.
`5/1994
`(Continued)
`
`FOREIGN PATENT DOCUMENTS
`
`7/2001
`1303674 A (cid:9)
`11/1990
`0396777 Al (cid:9)
`(Continued)
`
`OTHER PUBLICATIONS
`
`(63) Continuation of application No. 13/495,942, filed on
`Jun. 13, 2012, now Pat. No. 8,895,546, which is a
`continuation-in-part of application No. 12/413,439,
`filed on Mar. 27, 2009.
`
`(60) Provisional application No. 61/040,558, filed on Mar.
`28, 2008, provisional application No. 61/497,017,
`filed on Jun. 14, 2011, provisional application No.
`61/570,110, filed on Dec. 13, 2011.
`
`CN
`EP
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2017.01)
`(2006.01)
`(2006.01)
`
`(51) Int. Cl.
`A61K 9/00 (cid:9)
`A61K 45/06 (cid:9)
`A61K 31/355 (cid:9)
`A61K 31/5513 (cid:9)
`A61K 9/08 (cid:9)
`A61K 47/10 (cid:9)
`A61K 47/22 (cid:9)
`A61K 47/26 (cid:9)
`(52) U.S. Cl.
` A61K 9/0043 (2013.01); A61K 9/008
`CPC (cid:9)
`(2013.01); A61K 9/08 (2013.01); A61K 31/355
`(2013.01); A61K 31/5513 (2013.01); A61K
`45/06 (2013.01); A61K 47/10 (2013.01); A61K
`47/22 (2013.01); A61K 47/26 (2013.01)
`(58) Field of Classification Search
`CPC (cid:9)
` A61K 9/0043; A61K 45/06; A61K 9/008;
`A61K 31/355; A61K 31/5513; A61K
`9/08; A61K 47/10; A61K 47/22; A61K
`47/26
`
`CA 2,723,470 Office Action dated Feb. 19, 2015.
`(Continued)
`
`Primary Examiner — Adam C Milligan
`(74) Attorney, Agent, or Firm — Wilson Sonsini Goodrich
`& Rosati
`
`(57) (cid:9)
`
`ABSTRACT
`
`The invention relates to pharmaceutical compositions com-
`prising one or more benzodiazepine drugs for nasal admin-
`istration, methods for producing and for using such compo-
`sitions.
`
`36 Claims, 5 Drawing Sheets
`
`AQUESTIVE EXHIBIT 1001 page 0001
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`
`
`(56) (cid:9)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5,317,010 A
`5,369,095 A
`5,457,100 A
`5,550,220 A
`5,560,932 A
`5,639,733 A
`5,661,130 A
`5,662,883 A
`5,665,331 A
`5,716,642 A
`5,738,845 A
`5,780,062 A
`5,789,375 A
`5,795,896 A
`5,814,607 A
`5,817,634 A
`5,831,089 A
`5,861,510 A
`5,863,949 A
`5,955,425 A
`5,981,719 A
`6,004,574 A
`6,090,925 A
`6,143,211 A
`6,165,484 A
`6,193,985 Bl
`6,235,224 Bl
`6,254,854 Bl
`6,268,053 Bl
`6,316,029 Bl
`6,316,410 B1
`6,375,986 Bl
`6,395,300 Bl
`6,428,814 Bl
`6,458,387 Bl
`6,461,591 Bl
`6,482,834 B2
`6,495,498 B2
`6,524,557 Bl
`6,607,784 B2
`6,610,271 B2
`6,616,914 B2
`6,627,211 Bl
`6,794,357 Bl
`6,869,617 B2
`6,884,436 B2
`6,908,626 B2
`6,932,962 Bl
`6,991,785 B2
`7,008,920 B2
`7,037,528 B2
`7,132,112 B2
`7,434,579 B2
`8,530,463 B2
`8,895,546 B2
`2001/0042932 Al
`2002/0110524 Al
`2002/0127278 Al
`2002/0141971 Al
`2002/0168402 Al
`2003/0017203 Al
`2003/0031719 Al
`2003/0040497 Al
`2003/0087820 Al
`2003/0100755 Al
`2003/0118547 Al
`2003/0118594 Al
`2003/0158206 Al
`2003/0170206 Al
`2003/0181411 Al
`2004/0101482 Al
`2004/0115135 Al
`2004/0126358 Al
`2004/0141923 Al
`2004/0147473 Al
`
`5/1994 Pang et al.
`11/1994 Kee et al.
`10/1995 Daniel
`8/1996 Meyer et al.
`10/1996 Bagchi et al.
`6/1997 Koike et al.
`8/1997 Meezan et al.
`9/1997 Bagchi et al.
`9/1997 Bagchi et al.
`2/1998 Bagchi et al.
`4/1998 Imakawa
`7/1998 Frank et al.
`8/1998 Mukae et al.
`8/1998 L6froth et al.
`9/1998 Patton
`10/1998 Meezan et al.
`11/1998 Huber
`1/1999 Piscopio et al.
`1/1999 Robinson et al.
`9/1999 Morley et al.
`11/1999 Woiszwillo et al.
`12/1999 Backstrom et al.
`7/2000 Woiszwillo et al.
`11/2000 Mathiowitz et al.
`12/2000 Raad et al.
`2/2001 Sonne
`5/2001 Mathiowitz et al.
`7/2001 Edwards et al.
`7/2001 Woiszwillo et al.
`11/2001 Jain et al.
`11/2001 Barbier et al.
`4/2002 Ryde et al.
`5/2002 Straub et al.
`8/2002 Bosch et al.
`10/2002 Scott et al.
`10/2002 Keller et al.
`11/2002 Spada et al.
`12/2002 Niemiec et al.
`2/2003 Backstrom et al.
`8/2003 Kipp et al.
`8/2003 Wermeling
`9/2003 Ward et al.
`9/2003 Choi et al.
`9/2004 Backstrom et al.
`3/2005 Kipp
`4/2005 Kipp
`6/2005 Cooper et al.
`8/2005 Backstrom et al.
`1/2006 Frey
`3/2006 Kimura et al.
`5/2006 Kipp
`11/2006 Choi et al.
`10/2008 Young et al.
`9/2013 Cartt
`11/2014 Cartt
`11/2001 Mathiowitz et al.
`8/2002 Cowan et al.
`9/2002 Kipp
`10/2002 Frey
`11/2002 Kipp
`1/2003 Crofts et al.
`2/2003 Kipp
`2/2003 Teng et al.
`5/2003 Young et al.
`5/2003 Sham et al.
`6/2003 Vandenberg
`6/2003 Nag et al.
`8/2003 Billotte et al.
`9/2003 Rasmussen et al.
`9/2003 Bosch et al.
`5/2004 Sanders
`6/2004 Quay
`7/2004 Warne et al.
`7/2004 Dugger et al.
`7/2004 Warrell, Jr.
`
`US 9,763,876 B2
`Page 2
`
`2004/0258663 Al (cid:9)
`2005/0130260 Al (cid:9)
`2005/0234101 Al (cid:9)
`2006/0045869 Al (cid:9)
`2006/0046962 Al (cid:9)
`2006/0046969 Al (cid:9)
`2006/0106227 Al (cid:9)
`2006/0147386 Al (cid:9)
`2006/0198896 Al (cid:9)
`2007/0059254 Al (cid:9)
`2007/0098805 Al (cid:9)
`2007/0298010 Al (cid:9)
`2008/0200418 Al (cid:9)
`2008/0248123 Al (cid:9)
`2008/0268032 Al (cid:9)
`2008/0279784 Al (cid:9)
`2008/0299079 Al (cid:9)
`2009/0047347 Al (cid:9)
`2009/0130216 Al (cid:9)
`2009/0163447 Al (cid:9)
`2009/0258865 Al (cid:9)
`2009/0297619 Al (cid:9)
`2009/0304801 Al (cid:9)
`2010/0068209 Al (cid:9)
`2010/0203119 Al (cid:9)
`2010/0209485 Al (cid:9)
`2011/0172211 Al (cid:9)
`2011/0257096 Al (cid:9)
`2012/0196941 Al (cid:9)
`2013/0065886 Al (cid:9)
`2014/0128479 Al (cid:9)
`2014/0170220 Al (cid:9)
`
`Quay et al.
`12/2004
`Linden et al.
`6/2005
`Stenkamp et al.
`10/2005
`Meezan et al.
`3/2006
`3/2006 Meezan et al.
`3/2006 Maggio
`5/2006 Reddy et al.
`7/2006 Wermeling
`9/2006 Liversidge et al.
`3/2007 Singh
`5/2007 Liversidge
`12/2007 Maggio
`8/2008 Maggio
`10/2008 Swanson et al.
`10/2008 Maggio
`11/2008 Cartt
`12/2008 Meezan et al.
`2/2009 Maggio
`5/2009 Cartt
`6/2009 Maggio
`10/2009 Cartt et al.
`12/2009 Swanson et al.
`12/2009 Liversidge et al.
`3/2010 Maggio
`8/2010 Leane et al.
`8/2010 Maggio
`7/2011 Baek et al.
`10/2011 Maggio
`8/2012 Maggio
`3/2013 Cartt
`5/2014 Maggio
`6/2014 Cartt
`
`FOREIGN PATENT DOCUMENTS
`
`606046
`EP (cid:9)
`00780386
`EP (cid:9)
`0818442
`EP (cid:9)
`931788
`EP (cid:9)
`0945485
`EP (cid:9)
`1004578
`EP (cid:9)
`1208863 A2
`EP (cid:9)
`1417972 Al
`EP (cid:9)
`1-151528
`JP (cid:9)
`2003-505403
`JP (cid:9)
`2005-508939
`JP (cid:9)
`2007-510722
`JP (cid:9)
`2011516425 A
`JP (cid:9)
`WO-90-05719
`WO (cid:9)
`WO-91-19481
`WO (cid:9)
`WO-94-05262 Al
`WO (cid:9)
`WO-95-00151 Al
`WO (cid:9)
`WO-95-31217 Al
`WO (cid:9)
`WO-96-27583
`WO (cid:9)
`WO-96-33172
`WO (cid:9)
`WO-97-14407 Al
`WO (cid:9)
`WO-98-03516
`WO (cid:9)
`WO-98-07697
`WO (cid:9)
`WO-98-30566
`WO (cid:9)
`WO-98-33768
`WO (cid:9)
`WO-98-34915
`WO (cid:9)
`WO-98-34918
`WO (cid:9)
`WO-99-07675
`WO (cid:9)
`WO-99-29667
`WO (cid:9)
`WO-99-52889
`WO (cid:9)
`WO-99-52910
`WO (cid:9)
`WO-00-01390 Al
`WO (cid:9)
`WO-00-74681
`WO (cid:9)
`WO-03004015 Al
`WO (cid:9)
`WO-03-055464
`WO (cid:9)
`WO (cid:9) WO-2005-018565 A2
`WO (cid:9) WO-2005-044234 A2
`WO (cid:9)
`WO-2005-089768
`WO (cid:9) WO-2005-117830 Al
`WO (cid:9) WO-2006-025882 A2
`WO (cid:9)
`WO-2006-055603
`WO (cid:9) WO-2006-075123 Al
`WO (cid:9)
`WO-2006-088894
`WO (cid:9) WO-2007-043057 A2
`
`7/1994
`6/1997
`1/1998
`7/1999
`9/1999
`5/2000
`5/2002
`5/2004
`6/1989
`2/2003
`4/2005
`4/2007
`5/2011
`5/1990
`12/1991
`3/1994
`1/1995
`11/1995
`9/1996
`10/1996
`4/1997
`1/1998
`2/1998
`7/1998
`8/1998
`8/1998
`8/1998
`2/1999
`6/1999
`10/1999
`10/1999
`1/2000
`12/2000
`1/2003
`7/2003
`3/2005
`5/2005
`9/2005
`12/2005
`3/2006
`5/2006
`7/2006
`8/2006
`4/2007
`
`AQUESTIVE EXHIBIT 1001 page 0002
`
`
`
`US 9,763,876 B2
`Page 3
`
`(56)
`
`References Cited
`
`FOREIGN PATENT DOCUMENTS
`
`WO WO-2007-144081 Al
`WO WO-2008-027395 A2
`WO WO-2009-120933 A2
`WO
`WO-2009121039 A2
`
`12/2007
`3/2008
`10/2009
`10/2009
`
`OTHER PUBLICATIONS
`
`CN 201280039077.9 Office Action dated Dec. 26, 2014.
`U.S. Appl. No. 60/148,464, filed Aug. 12, 1999, Noe
`Ahsan et al., "Effects of the permeability enhancers,
`tetradecylmaltoside and dimethy1-13-cyclodextrin, on insulin move-
`ment across human bronchial epithelial cells", European Journal of
`Pharmaceutical. Sciences, 2003; 20: 27-34.
`Ahsan et al., "Sucrose cocoate, a component of cosmetic prepara-
`tions enhances nasal and ocular peptide absorption", Int J Pharm,
`2003; 251: 195-203.
`Albert et al., "Pharmacokinetics of diphenhydramine in man", J.
`Pharmacokinet, Biopharm., 3(3):159-170 (1975).
`Arnold et al., "Correlation of tetradecylmaltoside induced increases
`in nasal peptide drug delivery with morphological changes in nasal
`eithelial cells", J. Pharm. Sci. 93(9):2205-2213 (2004).
`AU application 2009228093 First exam report dated Jul. 19, 2013.
`Beam et al., "Blood, Brain, Cerebrospinal Fluid Concentrations of
`Several Antibiotics in Rabbits with Intact and Inflamed Meninges",
`Antimicrobal Agents and Chemotherapy, Dec. 1977, pp. 710-716.
`Bhairi S.M., "A guide to the properties and uses of detergents in
`biological systems", Calbiochem, pp. 1-42 (2001).
`Birkett et al., "Bioavailability and First Pass Clearance", Australian
`Prescriber, 1991, pp. 14-16, vol. 14.
`Birkett et al., "How Drugs are Cleared by the Liver", Australian
`Prescriber, 1990, pp. 88-89, vol. 13, No. 4.
`CA 2,723,470 Office action dated Jun. 7, 2012.
`Castro et al., "Ecologically safe Alkyl glucoside-based gemini
`surfactants", ARKIVOC, xii:253-267 (2005).
`Chavanpatil and Vavia, "Nasal drug delivery of sumatriptan suc-
`cinate", Pharmazie., May 2005:60(5):347-349.
`Chen et al., "Peptide Drug Permeation Enhancement by Select
`Classes of Lipids", presented ath the 45th American Society of Cell
`Biology, S.F., CA, Dec. 10-14, 2005; 1 page total.
`Chen-Quay et al., "Identification of tight junction modulating
`lipids", J. Pharm. Sci., 98(2):606-619 (2009).
`Chiou et al., "Improvement of Systemic Absorption of Insulin
`Through Eyes with Absorption Enhancers", Journal of Pharmaceu-
`tical Sciences, Oct. 1989, pp. 815-818, vol. 78, No. 10.
`Chiou et al., "Systemic Delivery of Insulin Through Eyes to Lower
`the Glucose Concentration", Journal of Ocular Pharmacology, 1989,
`pp. 81-91, vol. 5, No. 1.
`Chinese Patent Office from Application No. CN200980157305.0
`dated Jan. 28, 2013.
`Davis and Ilium, "Absorption enhancers for nasal drug delivery",
`Clin. Pharmacokine., 2003:42(13):107-28.
`De Vry and Schreiber, "Effects of selected serotonin 5-HT(1) and
`5-HT(2) receptor agonists on feeding behavior: possible mecha-
`nisms of action", Neurosci. Biobehay. Rev., 24(3):341-53 (2000).
`Definition downloaded Sep. 13, 2012 at the medical-dictionary.
`thefreedictionaiy.com/p/encephalin.
`Definition of pilus, Merriam-Webster Medical Dictionary, http://
`www.merriam-webster.com/medical/pilus, accessed online on May
`28, 2013.
`Definition of villus, Merriam-Webster Medical Dictionary, http://
`www.merriam-webster.com/medical/villus, accessed online on May
`28, 2013.
`Drewe et al., "Enteral absorption of octreotide: absorption enhance-
`ment by polyoxyethylene-24-cholesterol ether", Br. J. Pharmacol.,
`108(2):298-303 (1993).
`Duquesnoy et al., "Comparative clinical pharmacokinetics of single
`doses of sumatriptan following subcutaneous, oral, rectal and
`intranasal administration", Eur. J. Pharm. Sci., 6(2):99-104 (1998).
`
`Edwards CM., "GLP-1: target for a new class of antidiabetic
`agents?", J.R. Soc. Med., 97(6):270-274 (2004).
`Eley and Triumalashetty, "In vitro assessment of Alkylglycosides
`as permeability enhancers", AAPS PharmsciTech., 2(3): article 19,
`pp. 1-7 (2001).
`EP application 09723906.5 Extended European search report dated
`Jun. 3, 2013.
`EP08747813 Supplementary Search Report dated Jun. 2, 2010.
`European Search Report (ESR) from EP 09 83 5809 dated Nov. 13,
`2012.
`Fix, "Oral controlled release technology for peptides: status and
`future (cid:9)
`prospects", (cid:9)
`Pharmaceutical (cid:9)
`Research (cid:9)
`Dec.
`1996; 13(12): 1760-1764 .
`Fricker et al., "Permeation enhancement of octreotide by specific
`bile salts in rats and human subjects: in vitro, in vivo correlations",
`Br. J. Pharmacol., 117(1):217-23 (1996).
`Gordon et al., "Nasal Absorption of Insulin• Enhancement by
`Hydrophobic Bile Salts", Proceedings of the National Academy of
`Sciences of the United States of America, Nov. 1985, pp. 7419-
`7423, vol. 82.
`Hathcox and Beuchat, "Inhibitory effects of sucrose fatty acid
`esters, Alone and in combination with ethylenediaminetetraacetic
`acid and other organic acids, on viability of Escherichia coli
`0157:H7", Food Microbiology, vol. 13, Issue 3, 213-225 (1996).
`Hovgaard et al., "Insulin Stabilization and GI Absorption", Journal
`of Controlled Release, Mar. 1992, pp. 99-108, vol. 19, Issue 1-3.
`Hovgaard et al., "Stabilization of insulin by Alkylmaltosides. A.
`Spectroscopic evaluation", International Journal of Pharmaceutics,
`132(1-2):107-113 (1996).
`Hovgaard et al., "Stabilization of Insulin by Alkylmaltosides. B.
`Oral Absorption in Vivo in Rats", International Journal of
`Pharmaceutics, 1996, pp. 115-121, vol. 132.
`Hussain et Al, "Absorption enhancers in pulmonary protein deliv-
`ery." J Control Release. Jan. 8, 2004;94(1):15-24.
`International Search Report (ISR) from PCT/US2011/056735 dated
`Jun. 22, 2012.
`JP2010-507633 Office Action dated Oct. 23, 2012.
`JP2010-507633 Decision of refusal dated Jul. 9, 2013.
`Katzung, B., "Basic and Clinical Pharmacology, 7th Edition",
`Appleton & Lange: Stamford, Connecticut, 1998, pp. 34-49.
`Kissel et al., "Tolerability and absorption enhancement of
`intranasally (cid:9)
`administered (cid:9)
`octreotide (cid:9)
`by (cid:9)
`sodium
`taurodihydrofusidate in healthy subjects." Pharm Res. Jan.
`1992;9(1):52-57.
`Kite et al., "Use of in vivo-generated biofilms from hemodialysis
`catheters to test the efficacy of a novel antimicrobial catheter lock
`for biofilm eradication in vitro." J Clin Microbiol. Jul.
`2004;42(7):3073-3076.
`Lacy, C, et al., "Drug Information Handbook, 7th Edition 1999-
`2000" Lexi-Comp, Inc., 1999, pp. 163-164.
`Lahat et al., "Intranasal midazolam for childhood seizures", The
`Lancet, 1998; 352: 620.
`Lehninger et al., "Principles of Biochemistry with an Extended
`Discussion of Oxygen-Binding Proteins", 1982, pp. 150-151, Worth
`Publishers, Inc.
`Liu et al., "Interaction between chitosan and Alkyl P-D-
`glucopyranoside and its effect on their antimicrobial activity",
`Carbohydrate Polymers. 2004; 56: 243-250.
`Maa and Prestrelski, "Biopharmaceutical powders: particle forma-
`tion and formulation considerations", Curr. Pharm. Biotechnol.,
`1(3):283-302 (2000).
`Material Safety Data Sheet for Anatrace, Inc. product n-Dodecy1-
`13-d-Maltopyranoside, Anagrade, Dated: Jan. 25, 1994 and Revised:
`Jul. 15, 2004, hhtp://media.affymetrix.com/estore/browse/level
`three)categoly and products.jsp?categoiy=35843
`&categoiyIdClicked=35843&expand=true&parent=35900, access
`online on Dec. 13, 2012.
`Mathew N.T., "Serotonin 1D (5-HT1D) agonists and other agents in
`acute migraine", Neurol. Clin., 15(1):61-83 (1997).
`Matsumura et al., "Surface activities, biodegradability and antimi-
`crobial properties of n-alkyl glucosides, mannosides and
`galactosides", Journal of the America Oil Chemists' Society,
`67(12):996-1001 (1990).
`
`AQUESTIVE EXHIBIT 1001 page 0003
`
`
`
`US 9,763,876 B2
`Page 4
`
`(56) (cid:9)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`Moses et al., "Insulin Administered Intranasally as an Insulin-Bite
`Salt Aerosol—Effectiveness and Reproducibility in Normal and
`Diabetic Subjects", Diabetes, Nov. 1983, pp. 1040-1047, vol. 32.
`Murakami et al., "Assessment of Enhancing AbititY of Medium-
`Chain Alkyl Saccharides as New Absorption Enhancers in Rat
`Rectum", International Journal of Pharmaceutics, Feb. 1992, pp.
`159-169, vol. 79, Issue 1-3].
`Ogiso et al., "Percutaneous Absorption of Elcatonin Chemical and
`Hypocalcemic Effect in Rat", Chemical & Pharmaceutical Bulletin,
`Feb. 1991, pp. 449-453, vol. 39, Issue 2, The Pharmaceutical
`Society of Japan, Tokyo, Japan.
`Olesen et al., "The Headaches", Lippincott Williams & Wilkins, p.
`474 (2005).
`Paulsson and Edsman, "Controlled drug release from Gels using
`surfactant aggregates. II Vesicles formed from mixtures of amphi-
`philic drugs and oppositely charged surfactants", Pharm, Res.,
`18(11):1586-1592 (2001).
`PCT/US08/62961 Search Report dated Jul. 25, 2008.
`PCT/US08/62961 International Preliminary Report on Patentability
`dated Nov. 10, 2009.
`PCT/US09/38696 Search Report dated Sep. 28, 2009.
`PCT/US09/38696 International Preliminary Report on Patentability
`dated Sep. 28, 2010.
`PCT/US2012/042311 Search Report dated Aug. 31, 2012.
`Phillips, A., "The challenge of gene therapy and DNA delivery", J.
`Pharm Pharmacology 53: 1169-1174, 2001.
`Pillion et al., "Synthetic long-chain Alkyl maltosides and Alkyl
`sucrose esters as enhancers of nasal insulin absorption", J. Pharm.
`Sci., 91:1456-1462 (2002).
`Pillion et al., "Systemic Absorption of Insulin Delivered Topically
`to the Rat Eye", Investigative Ophthalmology & Visual Science,
`Nov. 1991, pp. 3021-3027, vol. 32, Issue 12.
`Pirollo et al., "Targeted Delivery of Small Interfering RNA:
`Approaching Effective Cancer Therapies", Cancer Res. 68(5):
`1247-1250, 2008.
`Richards R.M., "Inactivation of resistant Pseudomonas aeruginosa
`by antibacterial combinations", J. Pharm. Pharmacol., 23:136S-
`140S (1971).
`Salzman et al., "Intranasal Aerosolized Insulin", The New England
`Journal of Medicine, Apr. 25, 1985, pp. 1078-1084, vol. 312, Issue
`17.
`Sanders et al., "Pharmacokinetics of ergotam ne in healthy volun-
`teers following oral and rectal dosing", Eur. J. Clin. Pharmacol.,
`30(3):331-334 (1986).
`Shim and Kim, "Administration Route Dependent Bioavailability of
`Interferon-a and Effect of Bile Salts on the Nasal Absorption", Drug
`Development and Industrial Pharmacy, 19(10):1183-1199 (1993).
`Stevens and Guillet, "Use of Glucagon to Treat Neonatal Low-
`Output Congestive Heart Failure after Maternal Labetalol Therapy",
`The Journal of Pediatrics, Jul. 1995, pp. 151-153, vol. 127, Issue 1.
`Swarbrick et al., Encyclopedia of Pharmaceutical Technology,
`Informa Health Care, 2nd edition, vol. 1, p. 918 (2002).
`
`Tsuchido et Al„ "Lysis of Bacillus subtilis Cells by Glycerol and
`Sucrose Esters of Fatty Acids", Applied and Environmental Micro-
`biology. vol. 53, No. 3, 505-508, 1987.
`Tiirker et al., "Nasal route and drug delivery systems", Pharm.
`World Sci., 26(3):137-42 (2004).
`Turton et al., "A role for glucagon-like peptide-1 in the central
`regulation of feeding", Nature, 1996; 379:69-72.
`U.S. Appl. No. 12/116,842 Office action mailed May 25, 2011.
`U.S. Appl. No. 12/116,842 Office action mailed Apr. 2, 2013.
`U.S. Appl. No. 12/116,842 Office action mailed Nov. 15, 2011.
`U.S. Appl. No. 12/116,842 Office action mailed Dec. 17, 2013.
`U.S. Appl. No. 12/266,529 Office action mailed Jul. 10, 2012.
`U.S. Appl. No. 12/266,529 Office action mailed Nov. 16, 2011.
`U.S. Appl. No. 12/413,439 Office action mailed Mar. 18, 2011.
`U.S. Appl. No. 12/413,439 Office action mailed Nov. 21, 2011.
`U.S. Appl. No. 12/413,439 Office action mailed Jun. 19, 2014.
`U.S. Appl. No. 13/495,942 Office Action mailed Oct. 1, 2013.
`Vidal et al., "Making sense of antisense", European Journal of
`Cancer, 41:2812-2818, 2005.
`Watanabe et al., "Antibacterial Carbohydrate Monoesters Suppress-
`ing Cell Growth of Streptoccus mutans in the Presence of Sucrose",
`Current Microbiology, Sep. 2000, pp. 210-213, vol. 41, No. 3.
`Weber and Benning, "Metabolism of orally administered Alkyl
`beta-glycosides in the mouse", J. Nutr., 114:247-254 (1984).
`Webpage for Anatrace products of Affymetrix, http://www.af-
`fymetrix.com/estore/browse/level three category and prod-
`ucts j sp?category=35843&categoryIdClicked=35843&expand=true
`&parent=35900, accessed online on Dec. 13, 2012.
`Wermeling et al., "Pharmacokinetics and pharmacodynamics of a
`new intranasal midazolam formulation in healthy volunteers,"
`Anesthesia & Analgesia 103(2):344-349 (2006).
`Yamamoto et al., "The Ocular Route for Systemic Insulin Delivery
`in the Albino Rabbit", The Journal of Pharmacology and Experi-
`mental Therapeutics, Apr. 1989, pp. 249-255, vol. 249; No. 1.
`Yu Xinrui et al., "Triptan Medicament and Migraine", World
`Pharmacy (Synthetic Drug and Biochemical Drug Formulation
`Fascicule), 22(2):91 -92 (2001).
`Canadian Patent Application No. 2756690 Examiner's Report dated
`Oct. 20, 2015.
`Chinese Patent Application No. 201280039077.9 Office Action
`dated Nov. 21, 2016.
`Chinese Patent Application No. 2012800390779 Second Office
`Action dated Aug. 11, 2015.
`Chinese Patent Application No. 201280039077.9 Third Office
`Action dated Mar. 17, 2016.
`European Patent Application No. 12801372.9 Extended EP Search
`Report dated Mar. 26, 2015.
`European Patent Application No. 12801372.9 Communication
`dated Jul. 5, 2016.
`Japanese Patent Application No. 2014-515967 Office Action dated
`Mar. 30, 2016.
`Japanese Patent Application No. 2014-515967 Office Action dated
`Nov. 28, 2016.
`Newman. Aerosol deposition consideration in inhalation therapy.
`Chest 152S-160S (1985).
`U.S. Appl. No. 12/413,439 Office Action dated Jul. 14, 2016.
`U.S. Appl. No. 12/413,439 Office Action dated Oct. 5, 2015.
`U.S. Appl. No. 14/948,081 Office Action dated Oct. 31, 2016.
`U.S. Appl. No. 12/116,842 Office Action mailed Jul. 8, 2015.
`U.S. Appl. No. 14/021,988 Office Action mailed May 22, 2015.
`
`AQUESTIVE EXHIBIT 1001 page 0004
`
`
`
`U.S. Patent (cid:9)
`
`Sep. 19, 2017
`
`Sheet 1 of 5 (cid:9)
`
`US 9,763,876 B2
`
`Linear Scale
`
`p 'Moat Swerision 10 mg
`SoIotion 10 tag
`— IV 5 mg
`
`1 l 1 192 2! 240
`
`AQUESTIVE EXHIBIT 1001 page 0005
`
`(cid:9)
`
`
`U.S. Patent (cid:9)
`
`Sep. 19, 2017
`
`Sheet 2 of 5 (cid:9)
`
`US 9,763,876 B2
`
`Figure 2
`
`Semi4c.varithmic Scale
`
`Nasal fic.spemioo tO
`$(>1):giint 10 In t?.
` IV 5 Trig
`
`U
`
`AQUESTIVE EXHIBIT 1001 page 0006
`
`(cid:9)
`(cid:9)
`
`
`U.S. Patent (cid:9)
`
`Sep. 19, 2017
`
`Sheet 3 of 5 (cid:9)
`
`US 9,763,876 B2
`
`Figure 3
`
`Li nee r .Sca ie
`
`—G-- Nat).11 Suwension Wing
`Solistiou nig,
`IV 5 mg
`
`0
`
`12
`
`16
`
`20
`
`24
`
`AQUESTIVE EXHIBIT 1001 page 0007
`
`(cid:9)
`
`
`U.S. Patent (cid:9)
`
`Sep. 19, 2017
`
`Sheet 4 of 5 (cid:9)
`
`US 9,763,876 B2
`
`Figure 4: Flow Diagram for the Manufacture of Diazepam Solution
`
`Combine:
`• Vitamin E, USP
`• Benzyl Alcohol, NF
`• Dehydrated Alcohol, USP
`
`1+
`Heat to 45 ± 2°C
`
`1+
`Add Intravail and mix until
`dissolved and homogeneous
`
`1+
`Maintaining temperature at 45°C,
`add Diazepam, USP and mix until
`dissolved and homogenous
`
`17
`Cool to 25 ± 2°C
`
`1+
`
`Q.S. to final target weight with
`Dehydrated Alcohol, USP.
`
`AQUESTIVE EXHIBIT 1001 page 0008
`
`(cid:9)
`
`
`U.S. Patent (cid:9)
`
`Sep. 19, 2017
`
`Sheet 5 of 5 (cid:9)
`
`US 9,763,876 B2
`
`Figure 5: Flow Diagram for Preparation of Diazepam Suspension
`
`Flow Diagram for the Manufacture of NRL-1A
`
`Sieve Diazepam, USP
`
`•
`
`Micronize Diazepam, USP
`
`Combine Propylene Glycol, USP
`Purified Water, USP, and
`Vitamin E Polyethylene Glycol
`Succinate, NF
`
`Add Povidone, USP and mix
`until dissolved.
`
`Heat to 45 ± 2°C and mix until
`Vitamin E Polyethylene Glycol
`Succinate, NF is dissolved.
`
`Q.S. to final target weight with
`Purified Water, USP. Mix well to
`assure homogeneity
`
`•
`
`•
`
`High pressure/
`small size
`(Diazepam)
`
`Low pressure/
`larger size
`(Diazepam B)
`
`Add Methylparaben, NF,
`Propylparaben, NF and Intravail
`and mix until dissolved.
`
`Fill 3 mL finished product into
`5 inL Amber glass vial with
`PTFE lined phenolic closure.
`
`Sample Diazepam A and Diazepam
`B for in-process testing
`
`Cool to 25 t 2°C.
`
`Add Micronized Diazepam ALB
`and mix vigorously to disperse.
`
`(cid:9)►
`
`AQUESTIVE EXHIBIT 1001 page 0009
`
`(cid:9)
`
`
`1
`ADMINISTRATION OF BENZODIAZEPINE
`COMPOSITIONS
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a Continuation of U.S. patent appli-
`cation Ser. No. 13/495,942, filed Jun. 13, 2012, which is a
`Continuation-in-Part of U.S. patent application Ser. No.
`12/413,439, filed Mar. 27, 2009, published as US 2009/
`0258865 on Oct. 15, 2009, which is incorporated herein by
`reference in its entirety, and which claims priority to U.S.
`provisional application 61/040,558, filed Mar. 28, 2008,
`which is incorporated herein by reference; U.S. patent
`application Ser. No. 13/495,942, filed Jun. 13, 2012, also
`claims priority to U.S. provisional application 61/497,017,
`filed Jun. 14, 2011 and U.S. provisional application 61/570,
`110, filed Dec. 13, 2011, each of which is incorporated
`herein by reference in its entirety.
`
`US 9,763,876 B2
`
`2
`patient or a care-giver to administer the benzodiazepine drug
`orally and care-givers may be reluctant to place their hands
`in patients' mouths.
`Intravenous administration perhaps provides a faster route
`5 of administration. However intravenous administration is
`generally limited to trained health care professionals in
`tightly controlled clinical settings. Additionally, sterility
`must be maintained. Furthermore, administering any drug
`intravenously can be painful and is likely impractical for
`0 patients suffering from a phobia of needles. In addition,
`intravenous administration of benzodiazepines is associated
`with respiratory depression. Thus, use of intravenous ben-
`zodiazepines is limited to professional health care environ-
`ments.
`Rectal suppository compositions of benzodiazepine drugs
`can have a rapid onset of action. However, the inconve-
`nience of rectally administered drug is an obvious impedi-
`ment to their being administered by anyone outside a very
`small group of the patient's intimate acquaintances and the
`20 patient's professional medical care-givers.
`
`15 (cid:9)
`
`FIELD OF THE INVENTION
`
`SUMMARY OF THE INVENTION
`
`This application relates to the nasal administration of
`benzodiazepine drugs and combinations thereof.
`
`BACKGROUND OF THE INVENTION
`
`By way of non-limiting example, the benzodiazepine
`family consists of drugs such as diazepam, lorazepam, and
`midazolam. The drugs in this family have been observed as
`possessing sedative, tranquilizing and muscle relaxing prop-
`erties. They are frequently classified as anxiolytic and skel-
`etal muscle relaxants. They are thought to be useful in
`preventing, treating, or ameliorating the symptoms of anxi-
`ety, insomnia, agitation, seizures (such as those caused by
`epilepsy), muscle spasms and rigidity, the symptoms of drug
`withdrawal associated with the continuous abuse of central
`nervous system depressants, and exposure to nerve agents.
`Benzodiazepines are thought to act by binding to the
`GABAA receptor of a neuron, possibly causing the receptor
`to change shape and making it more accessible to gamma-
`aminobutyric acid (GABA).
`GABA is an inhibitory neurotransmitter that, when bound
`to the GABAA receptor, facilitates Cl- ions flooding into the
`neuron to which the receptor is bound. The increase in Cl-
`ions hyperpolarizes the membrane of the neuron. This
`completely or substantially reduces the ability of the neuron
`to carry an action potential. Targeting this receptor is par-
`ticularly useful in treating many disorders, such as tetanus
`and epilepsy, which may result from too many action
`potentials proceeding through the nervous system.
`Current formulations of benzodiazepine drugs can be
`administered orally, rectally, or parenterally. The ability to
`utilize these and other types of formulations has been
`significantly limited due, in many cases, to solubility chal-
`lenges.
`The oral route of administration may be considered sub-
`optimal due to several disadvantages. For example, the
`amount of time required for an orally administered benzo-
`diazepine drug to reach therapeutically relevant concentra-
`tions in blood plasma may be rather long, such as an hour or
`more. Moreover, as benzodiazepine drugs pass through the
`liver a significant amount of the drug may be metabolized.
`Thus, large doses may be required to achieve therapeutic
`plasma levels. Furthermore, due to the nature of seizures and
`muscle spasms, it can be extremely difficult for either a
`
`In some embodiments, there are provided (non-aqueous)
`25 pharmaceutical solutions for nasal administration consisting
`of: (a) a benzodiazepine drug; (b) one or more natural or
`synthetic tocopherols or tocotrienols, or any combinations
`thereof, in an amount from about 30% to about 95% (w/w);
`(c) one or more alcohols or glycols, or any combinations
`30 thereof, in an amount from about 10% to about 70% (w/w);
`and (d) an alkyl glycoside, in a pharmaceutically-acceptable
`solution for administration to one or more nasal mucosal
`membranes of a patient. In some embodiments, the benzo-
`diazepine drug is dissolved in the one or more natural or
`35 synthetic tocopherols or tocotrienols, or any combinations
`thereof, in an amount from about 30% to about 95% (w/w);
`and the one or more alcohols or glycols, or any combinations
`thereof, in an amount from about 10% to about 70% (w/w).
`In some embodiments, the benzodiazepine drug is selected
`40 from the group consisting of: alprazolam, brotizolam,
`chlordiazepoxide, clobazam, clonazepam, clorazepam,
`demoxazepam, diazepam, flumazenil, flurazepam, halaze-
`pam, midazolam, nordazepam, medazepam, nitrazepam,
`oxazepam, lorazepam, prazepam, quazepam, triazolam,
`45 temazepam, loprazolam, any pharmaceutically-acceptable
`salts thereof, and any combinations thereof. In some
`embodiments, the benzodiazepine drug is diazepam, or a
`pharmaceutically-acceptable salt thereof. In some embodi-
`ments, the solution contains about 1 to about 20% (w/v) of
`so benzodiazepine, e.g. about 1 to about 20% (w/v) of diaz-
`epam. In some embodiments, the one or more natural or
`synthetic tocopherols or tocotrienols are selected from the
`group consisting of: a-tocopherol, 13-tocopherol, y-tocoph-
`erol, 8-tocopherol, a-tocotrienol, p-tocotrienol, y-tocotrie-
`55 nol, 8-tocotrienol, tocophersolan, any isomers thereof, any
`esters thereof, any analogs or derivatives thereof, and any
`combinations thereof. In some embodiments, the one or
`more alcohols are selected from the group consisting of:
`ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl
`60 alcohol, a