US 20150283123A1
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`( 19) United States
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`(12) Patent Application Publication (10) Pub. No.: US 2015/0283123 A1
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`WATTS et al.
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`(43) Pub. Date:
`Oct. 8, 2015
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`(2006.01)
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`A6IK47/26
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`A6111! 11/00
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`A61K47/36
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`A6IK 9/00
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`(52) U.S. Cl.
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`CPC ........... .. A61K 31/4468 (2013.01); A6IK47/36
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`(2013.01); A61K 9/0043 (2013.01); A61K
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`47/26 (2013.01); A61M11/00 (2013.01); A6111!
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`15/08 (2013.01)
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`(57)
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`ABSTRACT
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`A11 i11tranasal spray device contains a composition for the
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`intranasal delivery of fentanyl or a pharmaceutically accept-
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`able salt thereof to a11 animal includes a11 aqueous solution of
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`fentanyl or a pharmaceutically acceptable salt thereof and a
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`pharmaceutically acceptable additive selected from (i) a pec-
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`tin and (ii) a poloxamer and ehitosan or a salt or derivative
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`thereof; provided that when the composition comprises a
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`pectin it is substantially free of divalent metal ions; and
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`which, in comparison to a simple aqueous solution offentanyl
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`administered intranasally at the same dose, provides a peak
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`plasma co11ce11tration of fentanyl (Cmx) that is from 10 to
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`80% of that achieved using a simple aqueous solution of
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`fentanyl adrninistered intra11asally at an identical fentanyl
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`dose. A method for treating or managing pain by intranasally
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`administering the composition is also disclosed.
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`INTRANASAL SPRAY DEVICE CONTAINING
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`PHARMACEUTICAL COMPOSITION
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`(71) Applicant: DEPOMED, INC., Newark, CA (US)
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`(72)
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`Inventors: Peter James VVATTS, Nottingham (GB);
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`Jonathan David CASTILE,
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`Nottingham (GB); VVilliam Columbus
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`Ian LAFFERTY, Leieestershire (GB);
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`Alan SMITI-I, Nottingham (GR)
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`Appl, No.: 14/747,289
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`Filed:
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`Jun. 23, 2015
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`Related U.S. Application Data
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`Continuation of application No. 13/541,325, filed on
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`Jul. 3, 2012, now Pat. No. 9,078,814. which is a divi-
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`sion of application No. 12/047,388, filed on Mar. 13,
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`2008, now Pat. No. 8,216,604, which is a division of
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`application No. 10/753,628, filed on Jan. 8, 2004, now
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`abandoned.
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`(30)
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`Foreign Application Priority Data
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`Jan. 10, 2003
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`(GB) ................................. .. 0300531.1
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`Publication Classification
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`(2006.01)
`(2006.01)
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`(51)
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`Int. Cl.
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`A 61K 31/4468
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`A 61M 15/08
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`Page 1 of 10
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` Insys Exhibit 2015
`CFAD v. Insys
`IPR2015-01797
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`[V€Zl€8Z0/SIOZS11zJ0ImusSIOZ‘s"130U0!lF3!l‘l“dl10!11?3![ddVJuamd
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`Mean concentration profiles following intranasal administration of fentanyl
`solutions to sheep (n=8, 18D)
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`—as-
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`Fentanyl solution with chitosan
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`-9-
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`Fentanyl solution
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`1200
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`600
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`Plasmafentanyl(pg/ml) 1.00
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`200 1’
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`R
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`]
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`_....
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`ii.
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`200
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`350
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`(.00
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`Fig. J
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`Time (min)
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`Page 2 of 10
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`[V€Zl€8Z0/SIOZS11zJ0zmusSIOZ‘s"130U0!lF3!l‘l“dl10!11?3![ddVJuamd
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`—9—Chitosan
`—I~ Pectin
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`~X— Actiq
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`‘-|r- ChitosanIP0loxamer
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`-—-‘L )‘*%:‘&‘_* i.
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`Plasma concentration profiles following administration of fentanyi by
`intranasal (100 mcg) and oral transmucosal (200 mcg) routes (mean, n=18)
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`Plasmafentanyi(pg/ml) 8O
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`50
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`180
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`21.0
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`300
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`360
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`Page 3 of 10
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`US 2015/0283123 A1
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`Oct. 8, 2015
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`INTRANASAL SPRAY DEVICE CONTAINING
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`PI-IARMACEL TICAL COMPOSITION
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`CROSS—REFERENCE IO R A LA1 A D
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`APPI ICATIONS
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`[0001] This application is a continuation of U.S. patent
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`application Ser. No. 13/541,325, filed Jul. 3, 2012, now
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`allowed, which is a division of US. patent application Ser.
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`No. 12/047,388, filed Mar. 13, 2008, now U.S. Pat. No. 8,21 6,
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`604, which in tum is a division ofU.S. patent application Ser.
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`No. 10/753,628, filed Jan. 8, 2004, now abandoned, the dis-
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`closures ol‘ each of which are hereby incorporated herein by
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`reference in their entirety.
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`BACKGROUND OF THE INVENTION
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`[0002] This invention relates to pharmaceutical coinposi-
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`tions for the intranasal administration of fentanyl.
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`[0003] The nasal route of drug delivery can afford rapid
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`onset of action and convenience to patients and/or care giver.
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`In particular, this route can provide rapid absorption of drugs
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`into the blood circulation. In some cases absorption of almost
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`the whole dose can be achieved and the pharrnacokinetics can
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`be similar to intravenous administration. Such rapid and
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`effective drug delivery can be useful in the treatment of crisis
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`situations such as pain, including breakthrough pain, head-
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`ache and migraine (Nasal Systemic Drug Delivery, Chien et
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`al. (eds), Dekker, New York, 1987).
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`[0004]
`Fentanyl (N —(1 —pl1enethyl—4—piperidyl)propionanil—
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`ide) is a potent opioid analgesic and may be used in the
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`treatment of severe acute ai1d chronic pain.
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`It has been reported that fentanyl is rapidly a11d well
`[0005]
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`absorbed from the nasal cavity (Striebel et al., Brit. J. Anaes-
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`thesia, 96, suppl 1, 108, 1993). In addition, the effectiveness
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`of intranasal fentanyl in providing analgesia in patients has
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`been demonstrated in a number of studies (for example Strie-
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`bel et al., Brit. J. Anaesthesia, 96. suppl 1, 108 a11d 109, 1993;
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`Striebel et al.,Anaesthesia, 48, 753-757, 1993; Majushree et
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`al., Can. J. Anesth., 49, 190-193, 2002; Toussaint et 211., Can.
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`J. Anesth., 47, 299-302, 2000).
`I11 all of these studies the
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`intranasal administration of fentanyl appears to have been
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`achieved by dropping or spraying a commercially available
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`i11j ectio11 fonnulation into the nose (SUBLIMAZE®, from
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`Janssen). The commercially available injection formulation
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`of fentanyl contains 0.05 111g of fe11tanyl, in the fonn of the
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`citrate salt, in 1 ml of sodium chloride solution and necessi-
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`tates the intranasal administration of a large volume of liquid
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`in order to provide a therapeutically effective dose of drug.
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`[0006]
`Fentanyl is also currently available iii a transdennal
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`patch a11d a transmucosal lozenge. The transdermal patch (for
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`example DUROGESIC® from Janssen) provides a steady
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`concentration of fentanyl in plasma over a prolonged period
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`and is not suitable for the rapid relief of severe pain, such as
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`breakthrough pain associated with terminal illness or acute
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`pain associated with trauma or following surgery. The trans-
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`mucosal lozenge (ACTIQ®, Cephalon Inc) is used in the
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`treatment ofbreakthro ugh pain a11d is available in a number of
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`dose strengths ranging from 0.2 to 1.6 mg. The absorption of
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`fentanyl from the trans111ucosal formulation is relatively slow.
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`Times to achieve the peak plasma concentration (Tmx) of
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`from 20 to 480 minutes have been reported (pp. 405-409,
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`Physician’ s Desk Reference, 54th edition, Medical Econo1n-
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`ics Company, Montvale, N.J., 2000).
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`[0007] Thus, there remains a need for alternative means for
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`the delivery of fentanyl, for example via the intranasal route.
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`[0008] The listing or discussion of a prior-published docu-
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`ment in this specification should not necessarily be taken as
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`an acknowledgement that the document is part of the state of
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`the art or is common general knowledge.
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`BRIEF SUMMARY OF THE INVENTION
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`[0009] The present invention provides a composition suit-
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`able for the intranasal administration of fentanyl that over-
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`comes one or more of the problems described above, and a
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`method ofusing it to treat or manage pain in a subject.
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`[0010] More specifically, the present invention relates to a
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`method of treating or managing pain by intranasally admin-
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`istering to an animal in need thereof in an amount to effec-
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`tively treat or manage pain a phamiaceutical composition
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`comprising an aqueous solution of
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`fentanyl or a pharmaceutically acceptable salt
`[0011]
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`thereof in an amount to effectively treat or manage pain and
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`[0012]
`a pectin having a degree of esterification (DE value)
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`of less than 30%, provided that the composition is substan-
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`tially free of divalent metal ions;
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`[0013] wherein the animal administered the composition is
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`provided with a peak plasma concentration offentanyl (CMX)
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`that is from 10 to 80% oftl1at achievedusing a simple aqueous
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`solution of fentanyl administered intranasally at an identical
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`fentanyl dose.
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`BRIEF DESCRIPTION OF THE DRAWINGS
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`[0014] The foregoing summary, as well as the following
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`detailed description of preferred embodiments of the inven-
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`tion, will be better understood when read in conjunction with
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`the appended drawings. For the purpose of illustrating the
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`invention, there is shown in the drawings embodiments which
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`are presently preferred. It should be understood, however, that
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`the invention is not limited to the precise arrangements and
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`instrumentalities shown.
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`In the drawings:
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`FIG. 1 shows meanplasma concentration profiles of
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`fentanyl following the administration of a fentanyl solution
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`comprising chitosan and a fentanyl solution that did not con-
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`tain chitosan to sheep obtained in Example 7.
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`[0017]
`FIG. 2 shows plasma concentration of fentanyl pro-
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`files for three intranasal and one transmucosal fonnulation
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`obtained in Example 8.
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`DETAILED DESCRIPTION OF THE INVENTION
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`[0018]
`Surprisingly, it has been found hat it is possible to
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`administer fentanyl intranasally in a practical dose volume
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`and provide rapid absorption in combination with a lower
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`peak plasma concentration than that provided using a simple
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`aqueous solution and an extended plasma concentration—time
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`profile. These advantages can be achieved while maintaimng
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`a bioavailability that is comparable to that obtained by the
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`intranasal administration of a simple aqueous solution coin-
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`prising fentanyl.
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`[0019] By “comparable bioavailability,” it is meant that the
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`area under the plasma concentration vs. time curve (AUC) is
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`at least 50%, n1ore preferably at least 60% and most prefer-
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`ably at least 70% of that for a simple aqueous solution of
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`fentanyl administered intranasally at the same dose.
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`[0020] By “simple aqueous solution,” it is meant fentanyl
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`and an ingredient to make the solution isotonic, such as man-
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`Page 4 of 10
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`

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`US 2015/0283123 A1
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`Oct. 8, 2015
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`nitol, dextrose or sodium chloride, dissolved in water. A
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`simple aqueous solution may optionally contain a preserva-
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`tive, such as benzalkonium chloride. An example of such a
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`simple aqueous solution comprises 1.57 mg/ml fentanyl cit-
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`rate. 48 mg/ml marmitol and 0.15 mg/ml benzalkonium chlo-
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`ride in water.
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`[0021] The present invention provides a composition for
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`the intranasal delivery of fentanyl or a pharmaceutically
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`acceptable salt thereof to an animal, which comprises an
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`aqueous solution of
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`fentanyl or a pharmaceutically acceptable salt
`[0022]
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`thereof and
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`a pharmaceutically acceptable additive selected
`[0023]
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`from
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`[0024]
`[0025]
`thereof;
`[0026]
`provided that when the composition comprises a
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`pectin it is substantially free of agents that cause the pectin to
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`gel, such as divalent metal ions, especially calcium ions.
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`[0027] The additive may be a pectin, a poloxamer, a cl1ito-
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`san (or a salt or derivative thereof) or it may be a mix of two
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`or more of these additives.
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`[0028]
`In comparison to a simple aqueous solution of fen-
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`tanyl administered intranasally at the same dose, the compo-
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`sitions of the present
`invention provide a lowered peak
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`plasma concentration of fentanyl (Cmm) and optionally an
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`extended plasma-concentration time profile. The peak plasma
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`concentration (Cmx) achieved using a composition of the
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`present invention is from 10 to 80%, preferably from 20 to
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`75% and more preferably from 30 to 70% of that achieved
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`usi11g a simple aqueous solution administered intranasally at
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`an identical fentanyl dose. This means, for example, if a
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`simple aqueous solution of fentanyl produces a (Cmx) of
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`1000 ug/ml, the (Cmx) produced by a composition of this
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`invention following administration of an identical dose of
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`fentanyl, is in the range 100-800 ug/ml. preferably 200-750
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`ug/ml and more preferably 300-700 ug/ml.
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`[0029] The time to achieve the peak plasma concentration
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`(Tmx) by nasal administration of a composition ofthe present
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`invention is preferably from 5 to 60 minutes, more preferably
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`from 5 to 45 minutes and most preferably from 5 to 30
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`minutes.
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`[0030]
`Fentanyl is preferably used in the form of a pharma-
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`ceutically acceptable salt. Most preferably fentanyl citrate is
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`used.
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`[0031] The concentration of fentanyl or a salt thereofin the
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`compositions of the invention is preferably in the range of
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`from 0.05 to 30 mg/ml, more preferably from 0.1 to 20 mgml
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`and most preferably from 0.2 to 16 mg/ml (expressed as
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`fentanyl base).
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`[0032] The term “pharmaceutically acceptable” is readily
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`understood in the art and can be considered to include mate-
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`rials that may be used in commercially available pharmaceu-
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`tical or food products and/or have GRAS (generally regarded
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`as safe) status and/or are listed ii1a pharmacopoeia suchas the
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`United States Pharmacopoeia or the European Pharmaco-
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`poeia.
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`ln one aspect, the present invention provides a com-
`[0033]
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`position for the intranasal delivery of fentanyl or a pham1a-
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`ceutically acceptable salt thereof, comprising an aqueous
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`solution of fentanyl or a pharinaceutically acceptable salt
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`thereof and a pectin and which provides a peak plasma con-
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`max
`centration (C
`) of fentanyl of from 10 to 80% of that
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`a pectin and
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`a poloxarner and cl1itosar1 or a salt or derivative
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`achieved using a simple aqueous solution administered intra-
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`nasally at an identical fentanyl dose.
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`[0034]
`Pectins are polysaccharide substances present in the
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`cell walls of all plant tissues. Commercially they are gener-
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`ally obtained from the dilute acid extract of the inner portion
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`of the rind of citrus fruits or from apple pomace. Pectins are
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`heterogeneous materials, comprising partially methoxylated
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`polygalacturonic acids.
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`[0035] The proportion of galacturonic acid moieties in the
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`methyl ester form represents the degree ofesterification (DE).
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`The term “D3” is well understood by those skilled in the art
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`and may be represented as the percentage of the total number
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`of carboxyl groups that are esterified. i.e., if four out of five
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`acid groups is esterified this represents a degree of esterifica-
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`tion of 80%, or as the methoxyl content of the pectin. The
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`respective theoretical maximum for each is 100% and 16%
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`respectively. “DE” as used herein refers to the total percent-
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`age of carboxyl groups that are esterified. The degree of
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`esterification (DE) of pectins found naturally can vary con-
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`siderably (from 60 to 90%).
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`Pectins can be categorized into those having a low
`[0036]
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`degree ofesterification (low methoxylation) or a high degree
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`of esterification (high methoxylation). A “low DE” or “LM”
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`pectin has a degree of esterification below 50% whereas a
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`“high DE” or “HM” pectin has a degree of esterification of
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`50% or above.
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`[0037] The gelling properties of aqueous pectin solutions
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`can be controlled by the concentration of pectin, the type of
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`pectin, especially the degree of esterification of the galactur-
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`onic acid units, and the presence of added salts.
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`[0038]
`Preferably low D3 pectins are used in the composi-
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`tions ofthe present invention. More preferably pectins having
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`a degree of esterification o less than 35%. for example from
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`5 to 35%. preferably from 7 to 30%, such as from about 10 to
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`about 25%, for example rom 15 to 25% are used in the
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`present invention.
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`[0039] Low DE pectins are usually prepared by the de-
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`esterification of extracted pectins, normally on a bench scale,
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`by way of an enzymatic process, or, on an industrial scale, by
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`treatment with acid or ammonia in an alcoholic heteroge-
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`neous medium. Treatment with ammonia creates so—called
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`1'
`low DE amidated pectins. As used herein, the term “low D,
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`3
`pectin” includes both amidated and non-amidated low Di
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`pectins.
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`[0040] Low DE pectins may be purchased commercially.
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`An example of a low DE pectin which may be used in the
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`present invention is SLENDID® 100, supplied by CP Kelco
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`(Lille Skensved, Denmark) which has a degree of esterifica-
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`tion of about 15 to 25%.
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`[0041] The primary mechanism by which low DE pectins
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`gel in aqueous solution is through exposure to metal ions,
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`such as those found iii the nasal mucosa] fluid as described in
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`W098/47535.
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`[0042] The solutions of the invention should not gel or1
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`storage. Thus, solutions containing a pectin are substantially
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`free of agents that cause the pectin to gel, such as divalent
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`metal ions, especially calcium ions. By “substantially free” of
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`divalent metal ions it is meant greater than 97%, preferably
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`greater than 99%, more preferably greater than 99.9% and
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`especially greater than 99.99% free of divalent metal ions.
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`[0043] VVhen a composition of the invention contains a
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`pectin, the concentration ofpectin is preferably in the range of
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`from 1 to 40 mg/inl, more preferably from 2 to 30 mg/ml and
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`most preferably from 5 to 25 mg/ml.
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`Page 5 of 10
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`

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`US 2015/0283123 A1
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`Oct. 8, 2015
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`[0044] A preferred pectin containing composition of the
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`invention comprises 0.2 to 16 mg/ml offentanyl (expressed as
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`fentanyl base) and 5 to 25 mg/ml ofa pectin having a D3 value
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`of from 7 to 30% and has a pH of from 3.4 to 5.0 and an
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`osmolality of from 0.25 to 0.35 osmol/kg.
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`In one aspect, the present invention provides a C0111-
`[0045]
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`position comprising fentanyl or a pharmaceutically accept-
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`able salt thereof and a poloxamer and chitosan or a salt or
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`derivative thereof.
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`[0046]
`Poloxarners are block copolymers of ethylene oxide
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`and propylene oxide. They l1ave the general
`formula
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`I1O(C2H_,,O)a(C31I6O)b(C2114O)aI1 wherein a is typically
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`from 2 to 130 and b is typically from 15 to 67. Poloxamers
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`have a number ofpharmaceutical applications such as viscos-
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`ity modifiers, solubilising agents or emulsifiers. They may be
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`used in the compositions of the present invention as thicken-
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`ing agents and in order to control and modify the absorption
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`of fentanyl into the systemic circulation such that a peak
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`plasma concentration (Cmfl) offentanyl of from 10 to 80% of
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`that achieved using a simple aqueous solution administered
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`intranasally at an identical fentanyl dose is achieved.
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`Several different types of poloxamer are available
`[0047]
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`co111r11ercia1ly, fror11 suppliers such as BASF, and vary with
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`respect to molecular weight and t11e proportions of ethylene
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`oxide “a” units and propylene oxide “b” units. Poloxamers
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`suitable for use in the present invention typically have a
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`molecular weight of from 2,500 to 18,000. for example from
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`7,000 to 15,000 Da. Examples of commercially available
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`poloxamers suitable for use in the present invention include
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`poloxamer 188, which structurally contains 80 “a” units and
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`27 “b“ units, and has a molecular weight in the range 7680 to
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`9510 and poloxamer 407 which structurally contains 101 “a"
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`units and 56 “b” units, and l1as a molecular Weight in the range
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`9840 to 14600 (Handbook of Pharmaceutical Excipients, edi-
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`tor A. H. Kippe, 3rd edition, Pharmaceutical Press, London,
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`United Kingdom, 2000). Preferably the poloxamer is polox-
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`amer 188.
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`[0048] When the compositions of the present invention
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`comprise a poloxamer, the poloxamer is preferably present at
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`a concentration in the range of from 50 to 200 ing/ml, more
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`preferably from 65 to 160 mg/ml and most preferably from 80
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`to 120 ing/ml.
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`[0049] Compositions of the invention that comprise a
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`poloxamer also comprise chitosan or a salt or derivative
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`thereof.
`
`[0050] Chitosans are cationic polymers that have mucoad—
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`hesive properties. The mucoadhesion is thought to result from
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`an interaction between the positively charged chitosan mol-
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`ecule and the negatively charged sialic acid groups on mucin
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`(Soane eta1.1nt. J. Pharm., 178, 55-65, 1999).
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`[0051] By the term “chitosan,” it is meant all derivatives of
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`chitin, or poly—N—acetyl—T)—glucosamine, including all poly-
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`glucosamines and oligoiners ofglucosamine materials of dif-
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`ferent molecular weights, in which the greater proportion of
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`the N-acetyl groups 11ave been removed through hydrolysis
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`(deacetylation). Preferably, the chitosan is produced from
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`chitin by deacetylation to a degree of greater than 40%, pref-
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`erably between 50 and 98%, more preferably between 70%
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`and 90%.
`
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`[0052] The chitosan, cl1itosa11 derivative, or salt used ir1 the
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`present invention preferably has a molecular weight of 4,000
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`Da or n1ore, preferably fror11 10,000 to 1,000,000 Da, more
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`preferably from 15,000 to 750,000 Da and most preferably
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`from 50,000 to 300,000 Da.
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`[0053]
`Salts of chitosan are suitable for use in the present
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`invention. Suitable salts include, but are not limited to, the
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`nitrate, phosphate, glutamate, lactate, citrate, hydrochloride
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`and acetate salts. Preferred salts are chitosan glutamate and
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`chito san hydrochloride.
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`[0054] Chitosan derivatives are also suitable for use in the
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`present invention. Suitable c11itosa11 derivatives include, but
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`are not limited to, ester, ether or other derivatives fomied by
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`bonding acyl a11d/or alliyl groups with the hydroxyl groups,
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`but not the amino groups of chitosan. Examples are O-allxyl
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`ethers of chitosan and O-acyl esters of chitosan. Modified
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`chitosans, such as those conjugated to polyethylene glycol
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`may be used in the present invention.
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`[0055] Low and medium viscosity chitosans suitable for
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`use in the present invention may be obtained from various
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`sources,
`including NovaMatrix, Drammen, Norway;
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`Seigagaku America 1nc., Maryland, United States of
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`America; Meron (India) Pvt, Ltd; India; Vanson Ltd, Vir-
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`ginia, United States of America; and AMS Biotechnology
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`Ltd., United Kingdom. Suitable derivatives include those that
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`are disclosed in Roberts, Chitin Chemistry, MacMillar1 Press
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`Ltd., London (1992).
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`[0056]
`Particularly preferred chitosan compounds that may
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`be mentioned include the “PROTOSANTM” types available
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`from NovaMatrix, Dranmien, Norway.
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`[0057]
`Preferably, the cl1itosa11, or salt or derivative thereof
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`is Water-soluble.
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`[0058] An aqueous solution ofchitosan maybe prepared by
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`dissolving chitosan base or a derivative of chitosan base in a
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`pharmaceutically acceptable mineral or organic acid such as
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`hydrochloric, lactic, citric or glutamic acid or by dissolving a
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`chito san salt or a salt of a chitosan derivative in water.
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`[0059] VVhen the compositions of the present invention
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`comprise chitosan, a chitosan salt or a chitosan derivative, the
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`concentration ofchitosan is preferably from 0.1 to 20 mg/ml,
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`more preferably from 0.5 to 15 mg/ml and most preferably
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`from 1 to 10 mg/ml (expressed as chitosan base).
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`[0060] A preferred poloxamer and chitosan containing
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`composition of the invention comprises 0.2 to 16 mg/ml of
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`fentanyl (expressed as fentanyl base), 80 to 120 mg/1nl of a
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`poloxamer having a molecular weight of from 7,000 to
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`15,000 Da and 1 to 10 mgml (expressed as chitosan base) of
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`a chitosan having a molecular weight of from 50,000 to 300,
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`000 Da or a salt or derivative thereof and l1as a pH of from 3.0
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`to 5.0 and an osmolality of from 0.4 to 0.7 osmol/kg.
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`[0061] The pH of the compositions of the invention may be
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`regulated. For example, buffered aqueous solutions may be
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`used. Alternatively, the pH of the compositions of the present
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`invention may be adjusted using any pharmaceutically
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`acceptable acidifying or alkalizing agent that is compatible
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`with the other components of the compositions. Examples of
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`suitable pharmaceutically acceptable acidifying agents
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`include, but are not limited to. hydrochloric acid. acetic acid,
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`citric acid, methane sulphonic acid, lactic acid, tartaric acid,
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`fumaric acid and inalic acid. Examples of pharmaceutically
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`acceptable alkalizing agents include, but are not limited to,
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`sodium hydroxide, potassium hydroxide, meglumine,
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`tromethamine,
`sodium bicarbonate, monoethanolamine,
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`diethanolamine and triethanolamine. When the composition
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`oftl1e invention contains pectin, in order to prevent unwanted
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`gelling, the acidifying agent or alkalizing agent preferably
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`should not contain a11 alkali metal or alkaline earth metal ion,
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`for example it should not be sodium hydroxide, potassium
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`hydroxide or sodium bicarbonate.
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`Page 6 of 10
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`

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`US 2015/0283123 A1
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`Oct. 8, 2015
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`[0062] The pH of the compositions of the invention is gen-
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`erally preferably fron1 3 to 6. For the pectin containing coni-
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`positions ofthe invention, the pH is more preferably from 3.2
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`to 5 .5 and most preferably from 3 .4 to 5 .0. For the poloxamer-
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`and chitosan-containing compositions of the invention, the
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`pH is more preferably from 3.0 to 5.5 and most preferably
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`from 3.0 to 5.0.
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`[0063]
`To ensure that the compositions of the invention are
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`well tolerated by the patient when administered to the nose
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`(for example when sprayed into the nasal cavity), it is advan-
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`tageous that they have an osmolality close to that of plasma.
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`The osmolality is generally preferably from 0.1 to 1.0 osn1ol/
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`kg. For the pectin-containing compositions of the invention,
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`the osmolality is more preferably from 0.2 to 0.8 osmol/kg,
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`still more preferably from 0.2 to 0.4 osmol/kg and most
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`preferably fror11 0.25 to 0.35 osmol/kg. For the poloxamer-
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`and chitosan-containing compositions of the invention, the
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`osmolality is more preferably from 0.2 to 0.9 osmol/kg, still
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`more preferably from 0.3 to 0.8 osmol/kg and mo st preferably
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`from 0.4 to 0.7 osmol/kg.
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`[0064] The osr11olality of the compositions oftlie invention
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`may be adjusted t