United States Patent
`US 8,895,546 B2
`(10) Patent No.:
`(12)
`Cartt et al.
`(45) Date of Patent:
`Nov. 25, 2014
`
`
`US008895546B2
`
`(75)
`
`(54) ADMINISTRATION OF BENZODIAZEPINE
`COMPOSITIONS
`Inventors: Steve Cartt, San Carlos, CA (US);
`David Medeiros, South San Francisco,
`CA (US); Garry Thomas Gwozdz, Jim
`Thorpe, PA (US); Andrew Loxley
`;
`edalmhi
`ATS):
`Philadelphia, PA (US); Mark
`Mitchnick, Bast Hampton, NY (US);
`David Hale, San Diego, CA (US);
`EdwardT. Maggio, San Diego, CA
`(US)
`.
`:
`(73) Assignee: Hale Biopharma Ventures, LLC,
`Encinitas, CA (US)
`
`(*) Notice:
`
`(21) Appl. No.: 13/495,942
`
`(22)
`
`Filed:
`
`3/1973 Boyle
`3,722,371 A
`11/1974 Lambeiti
`3,849,341 A
`10/1976 Hester, Jr.
`3,987,052 A
`eions Walser eral
`aoroat A
`8/1986 Frank etal.
`4,608,278 A
`5/1988 Biermann etal.
`4,748,158 A
`5/1989 Violantoetal.
`4,826,689 A
`9/1989 Magnussonet al.
`4,868,289 A
`5/1990 Catsimpoolaset al.
`4,921,838 A
`11/1990 Baurain etal.
`4,973,465 A
`3/1991 Violanto et al.
`4,997,454 A
`2/1992 Haynes
`5,091,188 A
`3/1992 Leclefet al.
`5,100,591 A
`6/1992 Fessiet al.
`5,118,528 A
`9/1992 Liversidge etal.
`5,145,684 A
`1/1993 Chiou 8
`5,182,258 A
`2/1993 Domb
`5,188,837 A
`3/1993 Radhakrishnan etal.
`5,192,528 A
`8/1993 Stewart
`5,236,707 A
`Subject to any disclaimer, the term ofthis
`12/1993 Shojiet al.
`5,268,461 A
`patent is extended or adjusted under 35
`5/1994 Urfer et al.
`5,308,531 A
`U.S.C. 154(b) by 0 days
`
`
`whe yVcays. 5,317,010 A 5/1994 Pangetal.
`
`5,369,095 A
`11/1994 Kee etal.
`5,457,100 A
`10/1995 Daniel
`5,550,220 A
`8/1996 Meyeret al.
`5,560,932 A
`10/1996 Bagchietal.
`Jun. 13, 2012
`5,639,733 A
`6/1997 Koikeet al.
`5,661,130 A
`8/1997 Meezan et al.
`‘
`*
`one
`5,662,883 A
`Prior Publication Data
`(65)
`9/1997 Bagchi et al.
`
`US 2013/0065886 Al—Mar. 14, 2013 5,665,331 A 9/1997 Bagchiet al.
`
`5,716,642 A
`2/1998 Bagchiet al.
`sas
`5,738,845 A
`4/1998 Imakawa
`Related U.S. Application Data
`5,780,062 A
`7/1998 Frank etal.
`(63) Continuation-in-part of application No. 12/413,439,
`5,789,375 A
`8/1998 Mukaeet al.
`filed on Mar. 27, 2009.
`(Continued)
`(60) Provisional application No. 61/497,017, filed on Jun.
`FOREIGN PATENT DOCUMENTS
`14, 2011, provisional application No. 61/570,110,
`filed on Dec. 13, 2011.
`
`(51)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`:
`
`Int. Cl.
`A6IK 31/55
`AGIK 9/00
`A6IK 31/355
`AGOIK 31/5513
`AGOIK 45/06
`(52) US.Cl
`De
`CPE on(013.01),AOIK3185130013.01)467K
`9/008 (2013 01 - AGIK 45/06 2013 01
`(
`01);
`(
`01)
`USPC beceseneeeecooseteeneneninsteneeeeeeneenee 514/221
`(58) Field of Classification Search
`}
`USPC viececceccsesctecseseeseceseeseseescneeeeeecneeeseeeees 514/221
`See application file for complete search history.
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`3,102,116 A
`3,109,843 A
`3,136,815 A
`3,243,427 A
`3,296,249 A
`30es ‘
`3.371.085 A
`3,374,225 A
`3,547,828 A
`3,567,710 A
`3,609,145 A
`
`8/1963 Chaseet al.
`11/1963 Reederetal.
`6/1964 Reederet al.
`3/1966 Reederetal.
`1/1967 Bell
`jioey ae “ at
`9/1968 Ree‘ler at al
`3/1968 Reederetal.
`12/1970 Mansfield et al.
`3/1971 Fryeret al.
`9/1971 Moffett
`
`EP
`EP
`
`0396777 Al
`606046
`
`11/1990
`7/1994
`(Continued)
`
`OTHER PUBLICATIONS
`
`U.S. Appl. No. 60/148,464, filed Aug. 12, 1999, Noe.
`Wermeling et al., “Pharmacokinetics and pharmacodynamics of a
`new intranasal midazolam formulation in healthy volunteers,” Anes-
`thesia & Analgesia 103 (2):344-349 (2006).
`EP08747813 Supplementary Search Report dated Jun. 2, 2010.
`PCT/US09/38696 Search Report dated Sep. 28, 2009.
`PCT/US08/62961 Search Report dated Jul. 25, 2008.
`PCT/US2012/042311 Search Report dated Aug. 31, 2012.
`AUapplication 2009228093 First exam report dated Jul. 19, 2013.
`PP.
`P
`
`(Continued)
`
`Primary Examiner — Adam C Milligan
`(74) Attorney, Agent, or Firm — Wilson Sonsini Goodrich &
`Rosati
`
`(57)
`
`ABSTRACT
`
`The invention relates to pharmaceutical compositions com-
`prising one or more benzodiazepine drugsfor nasal adminis-
`tration, methods for producing and for using such composi-
`tions.
`
`22 Claims, 5 Drawing Sheets
`AQUESTIVE EXHIBIT 1003
`
`AQUESTIVE EXHIBIT 1003 page 0001
`
`page 0001
`
`

`

`US 8,895,546 B2
`
`Page 2
`
`11/2008 Cartt
`12/2008 Meezan et al.
`2/2009 Maggio
`5/2009 Cartt
`6/2009 Maggio
`10/2009 Cartt etal.
`12/2009 Swansonetal.
`12/2009 Liversidgeetal.
`3/2010 Maggio
`8/2010 Leane etal.
`8/2010 Maggio
`7/2011 Back et al.
`10/2011 Maggio
`8/2012 Maggio
`3/2013 Cartt
`
`
`
`FOREIGN PATENT DOCUMENTS
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`PPPPrPrPrrrPS
`
`2008/0279784 Al
`2008/0299079 Al
`2009/0047347 Al
`2009/0130216 Al
`2009/0163447 Al
`2009/0258865 Al
`2009/0297619 Al
`2009/0304801 Al
`2010/0068209 Al
`2010/0203119 Al
`2010/0209485 Al
`2011/0172211 Al
`2011/0257096 Al
`2012/0196941 Al
`2013/0065886 Al
`
`L6froth etal.
`8/1998
`5,795,896
`Patton
`9/1998
`5,814,607
`Meezan etal.
`10/1998
`5,817,634
`Huber
`11/1998
`5,831,089
`1/1999
`5,861,510
`Piscipioet al.
`Robinsonetal.
`1/1999
`5,863,949
`9/1999
`5,955,425
`Morleyet al.
`Woiszwillo et al.
`11/1999
`5,981,719
`Backstrom et al.
`12/1999
`6,004,574
`Woiszwillo et al.
`7/2000
`6,090,925
`Mathiowitzet al.
`11/2000
`6,143,211
`Raadet al.
`12/2000
`6,165,484
`Sonne
`2/2001
`6,193,985
`Mathiowitzet al.
`5/2001
`6,235,224
`Edwardset al.
`7/2001
`6/1997
`00780386
`EP
`6,254,854
`Woiszwillo et al.
`7/2001
`1/1998
`0818442
`EP
`6,268,053
`Jain et al.
`11/2001
`7/1999
`931 788
`EP
`6,316,029
`Barbieretal.
`11/2001
`9/1999
`0945485
`EP
`6,316,410
`4/2002
`5/2000
`1004578
`EP
`6,375,986
`Rydeet al.
`Straubet al.
`5/2002
`5/2004
`1417972 Al
`EP
`6,395,300
`Boschet al.
`8/2002
`6/1989
`1-151528
`JP
`6,428,814
`Scott et al.
`10/2002
`2/2003
`2003-505403
`JP
`6,458,387
`Kelleret al.
`10/2002
`4/2005
`2005-508939
`JP
`6,461,591
`11/2002
`4/2007
`2007-5 10722
`JP
`6,482,834
`Spadaetal.
`Niemiecetal.
`12/2002
`5/1990
`WO-9005719
`WO
`6,495,498
`Backstrom et al.
`2/2003
`12/1991
`WO-91-19481
`WO
`6,524,557
`8/2003
`3/1994
`WO-94-05262 Al
`WO
`6,607,784
`Kippet al.
`8/2003
`1/1995
`WO-95-00151 Al
`WO
`6,610,271
`Wermeling
`Ward etal.
`9/2003
`11/1995
`WO-95-31217 Al
`WO
`6,616,914
`Choiet al.
`9/2003
`9/1996
`WO-9627583
`WO
`6,627,211
`Backstrom et al.
`9/2004
`10/1996
`WO-9633172
`WO
`6,794,357
`3/2005
`4/1997
`WO-97-14407 Al
`WO
`6,869,617
`Kipp
`4/2005
`1/1998
`WO-9803516
`WO
`6,884,436
`Kipp
`6/2005
`2/1998
`WO-9807697
`WO
`6,908,626
`Cooperet al.
`Backstrom et al.
`8/2005
`7/1998
`WO-9830566
`WO
`6,932,962
`1/2006
`8/1998
`WO-9833768
`WO
`6,991,785
`Frey
`Kimuraetal.
`3/2006
`8/1998
`WO-9834915
`WO
`7,008,920
`5/2006
`8/1998
`WO-9834918
`WO
`7,037,528
`Kipp
`Choiet al.
`11/2006
`2/1999
`WO-9907675
`WO
`7,132,112
`10/2008
`6/1999
`WO-9929667
`WO
`7,434,579
`Younget al.
`Cartt
`9/2013
`10/1999
`WO-9952889
`WO
`8,530,463
`Mathiowitzet al.
`11/2001
`200 1/0042932
`10/1999
`WO-9952910
`WO
`Cowan etal.
`8/2002
`2002/01 10524
`1/2000
`WO-00-01390 Al
`WO
`9/2002
`2002/0127278
`12/2000
`WO-0074681
`WO
`Kipp
`10/2002
`2002/0141971
`7/2003
`WO-03-055464
`WO
`Frey
`11/2002
`2002/0168402
`3/2005
`WO-2005-018565 A2
`WO
`Kipp
`Crotts etal.
`1/2003
`2003/0017203
`5/2005
`WO-2005-044234 A2
`WO
`2/2003
`2003/003 1719
`9/2005
`WO-2005-089768
`WO
`Kipp
`2/2003
`2003/0040497
`
`WO WO-2005-117830 Al=12/2005
`Tenget al.
`2003/0087820
`5/2003
`WO
`WO-2006-025882 A2
`3/2006
`Younget al.
`2003/0100755
`5/2003
`Sham etal.
`WO
`WO-2006-055603
`5/2006
`2003/0118547
`6/2003
`WO
`WO-2006-075123 Al
`7/2006
`Vandenberg
`2003/0118594
`6/2003
`WO
`WO-2006-088894
`8/2006
`Naget al.
`2003/0158206
`8/2003
`Billotte et al.
`WO
`WO-2007-043057 A2
`4/2007
`2003/0170206
`9/2003
`Rasmussenetal.
`WO WO-2007-144081 Al—12/2007
`
`2003/0181411
`9/2003
`Boschet al.
`WO
`WO-2008-027395 A2
`3/2008
`2004/0115135
`6/2004
`WO
`WO-2009-120933 A2
`10/2009
`Quay
`2004/0126358
`7/2004
`Warneetal.
`OTHER PUBLICATIONS
`2004/014 1923
`7/2004
`Duggeret al.
`2004/0147473
`7/2004
`Warriell, Jr.
`2004/0258663
`12/2004
`Quayetal.
`2005/0130260
`6/2005
`Lindenetal.
`2005/0234101
`10/2005
`Stenkampet al.
`2006/0045869
`3/2006
`Meezan etal.
`2006/0046962
`3/2006
`Meezan etal.
`2006/0046969
`3/2006
`Maggio
`2006/0106227
`5/2006
`Reddyetal.
`2006/0147386
`7/2006
`Wermeling
`2006/0198896
`9/2006
`Liversidge etal.
`2007/0059254
`3/2007
`Singh
`2007/0098805
`5/2007
`Liversidge
`2007/0298010
`12/2007
`Maggio
`2008/02004 18
`8/2008
`Maggio
`2008/0248123
`10/2008
`Swansonetal.
`2008/0268032
`10/2008
`Maggio
`
`EP application 09723906.5 Extended European search report dated.
`Jun. 3, 2013.
`JP application 2010-507633 Decision of refusal dated Jul. 9, 2013.
`Ahsan
`et
`al.
`“Effects
`of
`the
`permeability
`enhancers,
`tetradecylmaltoside and dimethy1-B-cyclodextrin, on insulin move-
`ment acress human bronchial epithelial cells”, European Journal of
`Pharmaceutical. Sciences, 2003; 20: 27-34.
`Ahsan et al., “Sucrose cocoate, a component ofcosmetic preparations
`enhancesnasal 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).
`Arnoldet 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).
`AQUESTIVE EXHIBIT 1003
`
`AQUESTIVE EXHIBIT 1003 page 0002
`
`page 0002
`
`

`

`US 8,895,546 B2
`Page 3
`
`(56)
`
`References Cited
`OTHER PUBLICATIONS
`
`Beam etal., “Blood, Brain, Cerebrospinal Fluid Concentrations of
`Several Antobiotics 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 pagetotal.
`Chen-Quayetal., “Identification oftightjunction 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.
`Chiouet 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 Illum, “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 mechanisms
`of action”, Neurosci. Biobehav. Rev., 24(3):341-53 (2000).
`Definition downloaded Sep. 13, 2012 at the medical-dictionary.
`thefreedictionary.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.
`Dreweet al., “Enteral absorption of octreotide: absorption enhance-
`ment by polyoxyethylene-24-cholesterol ether’, Br. J. Pharmacol.,
`108(2):298-303 (1993).
`Duquesnoyetal., “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).
`European Search Report (ESR) from EP 09 83 5809 dated Nov. 13,
`2012.
`Frickeret al., “Permeation enhancementofoctreotide by specific bile
`salts in rats and human subjects: in vitro, in vivo correlations”, Br. J.
`Pharmacol., 117(1):217-23 (1996).
`Gordonetal., “Nasal Absorption of Insulin: Enhancement by Hydro-
`phobic Bile Salts”, Proceedings ofthe National Academyof 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 organicacids, on viability of Escherichia coli 0157:H7”, Food
`Microbiology, vol. 13, Issue 3, 213-225 (1996).
`Hovgaardet al., “Insulin Stabilization and GI Absorption”, Journal of
`Controlled Release, Mar. 1992, pp. 99-108, vol. 19, Issue 1-3.
`Hovgaardetal., “Stabilization ofinsulin by alkylmaltosides. A. Spec-
`troscopic evaluation”,
`International
`Journal of Pharmaceutics,
`132(1-2):107-113 (1996).
`
`access
`
`Hovgaardetal., “Stabilization of Insulin by Alkylmaltosides. B. Oral
`Absorption in Vivo in Rats”, International Journal of Pharmaceutics,
`1996, pp. 115-121, vol. 132.
`International Search Report (ISR) from PCT/US2011/056735 dated.
`Jun. 22, 2012.
`JP2010-507633 Office Action dated Oct. 23, 2012.
`Katzung, B., “Basic and Clinical Pharmacology, 7th Edition’,
`Appleton & Lange: Stamford, Connecticut, 1998, pp. 34-49.
`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.
`Lehningeret al., “Principles of Biochemistry with an Extended Dis-
`cussion of Oxygen-Binding Proteins”, 1982, pp. 150-151, Worth
`Publishers, Inc.
`Maa andPrestrelski, “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-Dodecyl-B-
`d-Maltopyranoside, Anagrade, Dated: Jan. 25, 1994 and Revised:Jul.
`15,
`2004, —hhtp://media.affymetrix.com/estore/browse/level__
`three)category_and_products.jsp?category=35843
`&categoryldClicked=35843 &expand=true&parent=35900,
`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).
`Matsumuraet al., “Surface activities, biodegrabalbility and antimi-
`crobial
`properties of n-alkyl
`glucosides, mannosides
`and
`galactosides”, Journal of the America Oil Chemists’ Society,
`67(12):996-1001 (1990).
`Moseset al., “Insulin Administered Intranasally as an Insulin-Bite
`Salt Aerosol—Effectiveness and Reproducibility in Normal and Dia-
`betic Subjects”, Diabetes, Nov. 1983, pp. 1040-1047, vol. 32.
`Murakamiet al., “Assessment of Enhancing AbititY of Medium-
`Chain Alkyl Saccharides as New Absorption Enhancers in Rat Rec-
`tum”, 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
`amphiphilic drugs and oppositely charged surfactants”, Pharm, Res.,
`18(11):1586-1592 (2001).
`PCT/US08/62961 International Preliminary Report on Patentability
`dated Nov. 10, 2009.
`PCT/US09/38696 International Preliminary Report on Patentability
`dated Sep. 28, 2010.
`Phillips, A., “The challenge of gene therapy and DNAdelivery”, J.
`Pharm Pharmacology 53: 1169-1174, 2001.
`Pillion et al., “Synthetic long-chain alkyl maltosidee 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.
`Interfering RNA:
`Pirollo et al., “Targeted Delivery of Small
`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 etal., “Intranasal Aerosolized Insulin”, The New England
`Journal of Medicine, Apr. 25, 1985, pp. 1078-1084, vol. 312, Issue
`17.
`Sanders et al., “Pharmacokinetics of ergotamine in healthy volun-
`teers following oral and rectal dosing”, Eur. J. Clin. Pharmacol.,
`30(3):33 1-334 (1986).
`AQUESTIVE EXHIBIT 1003
`
`AQUESTIVE EXHIBIT 1003 page 0003
`
`page 0003
`
`

`

`US 8,895,546 B2
`Page 4
`
`(56)
`
`References Cited
`OTHER PUBLICATIONS
`
`Shim and Kim, “Administration Route Dependent Bioavailability of
`Interferon-c and Effect of Bile Salts on the Nasal Absorption”, Drug
`Development and Industrial Pharmacy, 19(10):1183-1199 (1993).
`Stevens and Guillet, “Use of Glucagonto 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
`Microbiology. vol. 53, No. 3, 505-508, 1987.
`Turkeret al., “Nasal route and drug delivery systems”, Pharm. World
`Sei., 26(3):137-42 (2004).
`Turton et al., “A role for glucagon-like peptide-1 in the central regu-
`lation 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.
`Vidaletal., “Making sense of antisense”, European Journal of Can-
`cer, 41:2812-2818, 2005.
`
`Watanabeetal., “Antibacterial Carbohydrate Monoesters Suppress-
`ing Cell Growth of Streptoccus mutansin the Presence of Sucrose”,
`Current Microbiology, Sep. 2000, pp. 210-213, vol. 41, No. 3.
`Weberand Benning, “Metabolism of orally administered alkyl beta-
`glycosides in the mouse”, J. Nutr., 114:247-254 (1984).
`Webpage for Anatrace products of Affymetrix, http:/Avww.af-
`fymetrix.com/estore/browse/level_three_category_and_products.
`Jsp?category=3 5843&categoryldClicked=35843&expand=true
`&parent=35900, accessed online on Dec. 13, 2012.
`Yamamoto etal., “The Ocular Route for Systemic Insulin Delivery in
`the Albino Rabbit”, The Journal of Pharmacology and Experimental
`Therapeutics, Apr. 1989, pp. 249-255, vol. 249; No. 1.
`Yu Xinrui et al., “Triptan Medicament and Migraine”, World Phar-
`macy (Synthetic Drug and Biochemical Drug Formulation
`Fascicule), 22(2):91-92 (2001).
`Fix, “Oral controlled release technology for peptides: status and.
`future prospects”, Pharmaceutical Research Dec. 1996; 13(12):1760-
`1764.
`Hussain etal, “Absorption enhancers in pulmonaryprotein delivery.”
`J Control Release. Jan. 8, 2004;94(1): 15-24.
`Kissel
`et
`al.,
`“Tolerability and absorption enhancement of
`intranasally administered octreotide by 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 ofa novel antimicrobialcatheter lock for
`biofilm eradicationin vitro.” J Clin Microbiol. Jul. 2004;42(7):3073-
`3076.
`“Interaction between chitosan and alkyl P-D-
`al.,
`Liu et
`glucopyranoside andits effect on their antimicrobial activity”, Car-
`bohydrate Polymers. 2004; 56: 243-250.
`USS. Appl. No. 12/413,439 Office action mailed Jun. 19, 2014.
`
`AQUESTIVE EXHIBIT 1003
`
`AQUESTIVE EXHIBIT 1003 page 0004
`
`page 0004
`
`

`

`U.S. Patent
`
`Nov. 25, 2014
`
`Sheet 1 of 5
`
`US 8,895,546 B2
`
`Figure 1
`
`ain
`
`4 b.
`
`“fa
`
`aa
`
`one eae?
`
`ah4
`Cagis
`
`“ea
`
`3vyAapeenccnccgpesedeigaesccengeee
`Cone
`
` sOorstan FU mig
`wees Nasal
`wx
`4x
`
`S~ Nasal Solution 10 mig
`~ ¥ smegg
`
`
`
`Tare ih}
`
`AQUESTIVE EXHIBIT 1003
`
`AQUESTIVE EXHIBIT 1003 page 0005
`
`page 0005
`
`

`

`U.S. Patent
`
`Nov. 25, 2014
`
`Sheet 2 of 5
`
`US 8,895,546 B2
`
`Figure 2
`
`Semi-togarithmic Scale
`
`PORN? ~igem Nasal Susman1) mg
`
` Saas
`*
`{Nasal Solauon ER) mg
`TY Sane
`wmbios TY S nag
`
`0
`
`MSM
`
`qe
`
`72
`
`OH
`
`PMG
`
`HS
`
`NUR HDG BNE
`
`Tome ch
`
`AQUESTIVE EXHIBIT 1003
`
`AQUESTIVE EXHIBIT 1003 page 0006
`
`page 0006
`
`

`

`U.S. Patent
`
`Nov. 25, 2014
`
`Sheet 3 of 5
`
`US 8,895,546 B2
`
`Figure 3
`
`Linear Scale
`
`
`
`Cone(rafal)
`
`weber Basal Nuapensicns TO nig
` fee Nusal Solutic
`
`weer DY S tig
`
`0 SiN)
`
`AQUESTIVE EXHIBIT 1003
`
`AQUESTIVE EXHIBIT 1003 page 0007
`
`page 0007
`
`

`

`U.S. Patent
`
`Nov. 25, 2014
`
`Sheet 4 of 5
`
`US 8,895,546 B2
`
`Figure 4: Flow Diagram for the Manufacture of Diazepam Solution
`
`Combine:
`e Vitamin E, USP
`e Benzyl Alcohol, NF
`e Dehydrated Alcohol, USP
`
`
`Heat to 45 + 2°C
`
`
`
`AddIntravail and mix until
`dissolved and homogeneous
`
`Maintaining temperature at 45°C,
`add Diazepam, USP and mix until
`dissolved and homogenous
`
`Cool to 25 +2°C
`
`Q:S. to final target weight with
`Dehydrated Alcohol, USP.
`
`AQUESTIVE EXHIBIT 1003
`
`AQUESTIVE EXHIBIT 1003 page 0008
`
`page 0008
`
`

`

`U.S. Patent
`
`Nov. 25, 2014
`
`Sheet 5 of 5
`
`US 8,895,546 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
`
`
`Ileat to 45 + 2°C and mix until
`Vitamin E Polyethylene Glycol
`Succinate, NF is dissolved.
`
`Add Povidone, USP and mix
`until dissolved.
`
`QS. to tinal target weight with
`Purified Water, USP. Mix well to
`assure homogeneity
`
`and mix vigorously to disperse.
`
`Iligh pressure/
`small size
`(Diazepam)
`
`Low pressure/
`larger size
`(DiazepamB)
`
`Add Methylparaben, NF,
`Propylparaben, NF and Intravail
`and mix until dissolved.
`
`Fill 3 mL finished product into
`5 mL Amberglass vial with
`PTFElined phenolic closure.
`
`Sample Diazepam A and Diazepam
`B tor in-process testing
`
`
`Cool to 25 4
`
`Add Micronized Diazepam A/B
`
`AQUESTIVE EXHIBIT 1003
`
`AQUESTIVE EXHIBIT 1003 page 0009
`
`page 0009
`
`

`

`US 8,895,546 B2
`
`1
`ADMINISTRATION OF BENZODIAZEPINE
`COMPOSITIONS
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a Continuation-in-Part of U.S. patent
`application Ser. No. 12/413,439, filed Mar. 27, 2009, pub-
`lished as US 2009/0258865 on Oct. 15, 2009, whichis incor-
`porated herein by reference in its entirety; this application
`also claimspriority to U.S. provisional application 61/040,
`558, filed Mar. 28, 2008, 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 incorpo-
`rated herein by referencein its entirety.
`
`10
`
`15
`
`FIELD OF THE INVENTION
`
`This applicationrelates to the nasal administration of ben-
`zodiazepine drugs and combinationsthereof.
`
`20
`
`BACKGROUND OF THE INVENTION
`
`Bywayof non-limiting example, the benzodiazepine fam-
`ily consists of drugs such as diazepam, lorazepam, and mida-
`zolam. The drugs in this family have been observed as pos-
`sessing
`sedative,
`tranquilizing
`and muscle
`relaxing
`properties. They are frequently classified as anxiolytic and
`skeletal muscle relaxants. They are thought to be useful in
`preventing, treating, or ameliorating the symptomsof anxi-
`ety, insomnia, agitation, seizures (such as those caused by
`epilepsy), muscle spasmsandrigidity, the symptomsof 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
`GABA,, receptorof a neuron, possibly causing the receptor to
`change shape and making it more accessible to gamma-ami-
`nobutyric acid (GABA).
`GABAis an inhibitory neurotransmitter that, when bound
`to the GABA, receptor, facilitates Cl” ions flooding into the
`neuron to which the receptor is bound. The increase in Cl-
`ions hyperpolarizes the membraneof the neuron. This com-
`pletely or substantially reduces the ability of the neuron to
`carry an action potential. Targeting this receptor is particu-
`larly useful in treating many disorders, such as tetanus and
`epilepsy, which mayresult 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 signifi-
`cantly limited due, in many cases, to solubility challenges.
`The oral route of administration may be considered sub-
`optimal due to several disadvantages. For example,
`the
`amountof time required for an orally administered benzodi-
`azepine drug to reach therapeutically relevant concentrations
`in blood plasma mayberather long, such as an hour or more.
`Moreover, as benzodiazepine drugs pass through theliver 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 patient or a
`care-giver to administer the benzodiazepine drug orally and
`care-givers may be reluctantto place their handsin patients’
`mouths.
`
`Intravenous administration perhaps providesa faster route
`of administration. However intravenous administration is
`
`generally limited to trained health care professionals in
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`tightly controlled clinicalsettings. Additionally, sterility must
`be maintained. Furthermore, administering any drug intrave-
`nously can be painful andis likely impractical for patients
`suffering from a phobia of needles. In addition, intravenous
`administration of benzodiazepinesis associated with respira-
`tory depression. Thus, use of intravenous benzodiazepinesis
`limited to professional health care environments.
`Rectal suppository compositions of benzodiazepine drugs
`can have a rapid onset of action. However, the inconvenience
`of rectally administered drug is an obvious impediment to
`their being administered by anyone outside a very small
`group of the patient’s intimate acquaintances and the
`patient’s professional medical care-givers.
`
`SUMMARY OF THE INVENTION
`
`In some embodiments, there are provided (non-aqueous)
`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
`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
`membranesofa patient. In some embodiments, the benzodi-
`azepine drug is dissolved in the one or more natural or syn-
`thetic 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 from
`the group consisting of: alprazolam, brotizolam, chlordiaz-
`epoxide,
`clobazam,
`clonazepam,
`clorazepam,
`demox-
`azepam, diazepam,
`flumazenil,
`flurazepam, halazepam,
`midazolam,
`nordazepam,
`medazepam,
` nitrazepam,
`oxazepam,
`lorazepam, prazepam, quazepam,
`triazolam,
`temazepam,
`loprazolam, any pharmaceutically-acceptable
`salts thereof, and any combinationsthereof. In some embodi-
`ments, the benzodiazepine drugis diazepam,or a pharmaceu-
`tically-acceptable salt thereof. In some embodiments, the
`solution contains about 1 to about 20% (w/v) of benzodiaz-
`epine, e.g. about 1 to about 20% (w/v) of diazepam. In some
`embodiments, the one or more natural or synthetic toco-
`pherols or tocotrienols are selected from the group consisting
`of a-tocopherol, B-tocopherol, y-tocopherol, 6-tocopherol,
`a-tocotrienol, £-tocotrienol, y-tocotrienol, 6-tocotrienol,
`tocophersolan, any isomers thereof, any esters thereof, any
`analogsor derivatives thereof, and any combinationsthereof.
`In some embodiments, the one or more alcohols are selected
`from the group consisting of ethanol, propyl alcohol, butyl
`alcohol, pentanol, benzyl alcohol, any isomers thereof, or any
`combinations thereof. In some embodiments, the solution
`contains two or more alcohols, such as ethanol (1-25% (w/v))
`and benzyl alcohol (1-25% (w/v)), or ethanol (10-22.5%
`(w/v)) and benzyl alcohol
`(7.5-12.5% (w/v)).
`In some
`embodiments, the benzodiazepine is present in the pharma-
`ceutical composition in a concentration from about 20
`mg/mL to about 200 mg/mL. In some embodiments, the one
`or more natural or synthetic tocopherols or tocotrienols, or
`any combinationsthereof, is in an amount from about 45% to
`about 85% (w/w). In some embodiments, the one or more
`natural or synthetic tocopherols or tocotrienols, or any com-
`binations thereof, is in an amount from about 50% to about
`75% (w/w). In some embodiments, the one or more alcohols
`or glycols, or any combinationsthereof, is in an amount from
`about 15% to about 55% (w/w), e.g. about 25% to about 40%
`AQUESTIVE EXHIBIT 1003
`page 0010
`
`AQUESTIVE EXHIBIT 1003 page 0010
`
`

`

`US 8,895,546 B2
`
`3
`(w/w). In some embodiments, the solution consists of diaz-
`epam (5-15% (w/v)), alkyl glycoside (0.01-1% (w/v)), vita-
`min E (45-65% (w/v)), ethanol (10-25% (w/v)) and benzyl
`alcohol (5-15% (w/v)). In some embodiments, the solution
`comprises at least about 0.01% (w/w) of an alkyl glycoside,
`e.g. about 0.01% to 1% (w/w) of an alkyl glycoside, such as
`dodecyl maltoside. In some embodiments, the solution con-
`sists ofdiazepam (5-15% (w/v)), dodecyl maltoside (0.01-1%
`(w/v)), vitamin E (45-65% (w/v)), ethanol (10-25% (w/v))
`and benzyl alcohol (5-15% (w/v)); moreparticularly the solu-
`tion may consist of diazepam (9-11% (w/v)), dodecyl malto-
`side (0.1-0.5% (w/v)), vitamin E (50-60% (w/v)), ethanol
`(15-22.5% (w/v)) and benzyl]alcohol (7.5-12.5% (w/v)); and
`even moreparticularly, the solution may consist of diazepam
`(10% (w/v)), dodecy] maltoside (0.15-0.3% (w/v)), vitamin E
`(50-60% (w/v)), ethanol (17-20% (w/v)) and benzyl alcohol
`(10-12% (w/v)).
`Some embodiments described herein provide a method of
`treating a patient with a disorder which maybetreatable with
`a benzodiazepine drug, comprising: administering to one or
`more nasal mucosal membranesofa patient a pharmaceutical
`solution for nasal administration consisting of a benzodiaz-
`epine drug, one or more natural or synthetic tocopherols or
`tocotrienols, or any combinationsthereof, in an amount from
`about 30% to about 95% (w/w); one or more alcohols or
`glycols, or any combinations thereof, in an amount from
`about 10% to about 70% (w/w); and an alkyl glycoside. In
`some embodiments, the benzodiazepine drug is dissolved in
`the one or more natural or synthetic tocopherols or tocot-
`rienols, 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 from the group consisting of:
`alprazolam, brotizolam, chlordiazepoxide, clobazam, clon-
`azepam, clorazepam, demoxazepam, diazepam, flumazenil,
`flurazepam,
`halazepam,
`midazolam,
`nordazepam,
`medazepam, nitrazepam, oxazepam, lorazepam, prazepam,
`quazepam,triazolam, temazepam, loprazolam, any pharma-
`ceutically-acceptable salts thereof, and any combinations
`thereof. In some embodiments, the benzodiazepine drug is
`diazepam, or a pharmaceutically-acceptable salt thereof. In
`some embodiments, the solution contains about 1 to about
`20% (w/v) ofbenzodiazepine,e.g. about 1 to about 20% (w/v)
`of diazepam. In some embodiments, the one or more natural
`or synthetic tocopherols or tocotrienols are selected from the
`group consisting of a-tocopherol, B-tocopherol, y-toco-
`pherol, 5-tocopherol, a-tocotrienol, B-tocotrienol, y-tocot-
`rienol, 5-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 alcohol, any
`isomers thereof, or any combinations thereof.
`In some
`embodiments, the solution contains two or more alcohols,
`such as ethanol (1-25% (w/v)) and benzyl] alcohol (1-25%
`(w/v)), or ethanol (10-22.5% (w/v)) and benzy] alcohol(7.5-
`12.5% (w/v)). In some embodiments, the benzodiazepine is
`present in the pharmaceutical composition in a concentration
`from about 20 mg/mLto about 200 mg/mL. In some embodi-
`ments, the one or more natural or synthetic tocopherol