`
`r
`‘ 4 -
`RavinayAS y
`
`bsJ j
`
`, ‘7Sy-in
`
`* 7Loip a — =
`
`Handbookof
`Pharmaceutical Excipients
`
`Collegium v. Purdue, PGR2018-00048
`
`Sixth edition
`*
`y
`Edited By
`Paul JSheskey andMarianE Quinn)_
`ths
`
`Purdue 2025
`
`Purdue 2025
`Collegium v. Purdue, PGR2018-00048
`
`

`

`Handbookof PharmaceuticalExcipients
`
`Purdue 2025
`Collegium v. Purdue, PGR2018-00048
`
`Purdue 2025
`Collegium v. Purdue, PGR2018-00048
`
`

`

`Handbookof
`Pharmaceutical Excipients
`
`SIXTH EDITION
`
`Edited by
`Raymond C RowesPharm, PhD, DSC, FRPharmS, FRSC, CPhys, MlnstP
`Chief Scientist
`Intelligensys Ltd, Stokesley, North Yorkshire, UK
`
`Paul J Sheskey Bsc, RPh
`Application Development Leader
`The Dow Chemical Company, Midland, MI, USA
`
`Marian E QuinnBsc, MSc
`DevelopmentEditor
`Royal Pharmaceutical Society of Great Britain, London, UK
`
`Londons Chicago
`
`Pharmaceutical Press
`
`Purdue 2025
`Collegium v. Purdue, PGR2018-00048
`
`Purdue 2025
`Collegium v. Purdue, PGR2018-00048
`
`

`

`Published by the Pharmaceutical Press
`Animprint of RPS Publishing
`
`1 Lambeth High Street, London SE] 7JN, UK
`100 South Atkinson Road, Suite 200, Grayslake, IL 60030-7820, USA
`
`and the American Pharmacists Association
`2215 Constitution Avenue, NW, Washington, DC 20037-2985, USA
`
`© Pharmaceutical Press and American Pharmacists Association 2009
`
`(PP) is a trade mark of RPS Publishing
`
`RPS Publishing is the publishing organisation of the Royal Pharmaceutical Society of Great Britain
`
`First published 1986
`Secondedition published 1994
`Third edition published 2000
`Fourth edition published 2003
`Fifth edition published 2006
`Sixth edition published 2009
`
`Typeset by Data Standards Ltd, Frome, Somerset
`Printed in Italy by L.E.G.O.S.p.A.
`
`ISBN 978 0 85369 792 3 (UK)
`ISBN 978 1 58212 135 2 (USA)
`
`All rights reserved. No part of this publication may be
`reproduced, stored in a retrieval system, or transmitted in any
`form or by any means, without the prior written permission
`of the copyright holder.
`The publisher makes no representation, express or implied,
`with regard to the accuracy of the information containedin
`this book and cannot accept any legal responsibility or
`liability for any errors or omissions that may be made.
`
`A catalogue record for this book is available from the British Library
`
`Purdue 2025
`Collegium v. Purdue, PGR2018-00048
`
`Purdue 2025
`Collegium v. Purdue, PGR2018-00048
`
`

`

`Polyoxylglycerides
`
`PhEur:
`
`1
`BP:
`
`Nonproprietary Names
`Caprylocaproyl Macrogolglycerides
`Lauroyl Macrogolglycerides
`Linoleoy! Macrogolglycerides
`Oleoyl Macrogolglycerides
`Stearoyl Macrogolglycerides
`Caprylocaproyl Macrogolglycerides
`Lauroyl Macrogolglycerides
`Linoleoyl Macrogolglycerides
`Oleoyl Macrogolglycerides
`Stearoy! Macrogolglycerides
`USP-NF: Caprylocaproy] Polyoxylglycerides
`Launroyl Polyoxylglycerides
`Linoleoyl Polyoxylglycerides
`Oleoyl Polyoxylglycerides
`Stearoyl Polyoxylglycerides
`
`Caprylocaproyl polyoxylglycerides Mixtures of monoesters, die-
`sters, and triesters of glycerol and monoesters and diesters of
`polyethylene glycols with mean relative molecular mass berween
`200 and 400. They are obtained by partial alcoholysis of
`medium-chain triglycerides using polyethylene glycol or by
`esterification of glycerin and polyethylene glycol with caprylic
`{octanoic) acid and capric (decanoic) acid or a mixture of
`glycerin esters and condensates of ethylene oxide with caprylic
`acid and capric acid. They may contain free polyethylene glycols.
`Lauroyl polyoxylglycerides Mixtures of monoesters,diesters, and
`triesters of glycerol and monoesters and diesters of polyethylene
`glycols with mean relative molecular mass between 300 and
`1500, They are obtained by partial! alcoholysis of saturated oils
`mainly containing triglyceridesof lauric (dodecanoic) acid, using
`polyethylene glycol, or by esterification of glycerol and
`polyethylene glycol with saturated fatty acids, or by mixing
`glycerol esters and condensates of ethylene oxide with the fatty
`acids of these hydrogenated oils.
`Linoleoy! polyosxylglycerides Mixtures of monoesters, diesters,
`and triesters of glycerol and monoesters and diesters of
`polyethylene glycols. They are obtained by partial alcoholysis
`of an unsaturated oil mainly containing triglyceridesoflinoleic
`(cis,cis-9,12-octadecadienoic) acid, using polyethylene glycol
`TableI:Synonymsofpolyoxylglycerides (macrogolglycerides).
`with mean relative molecular mass between 300 and 400, or by
`
`
`Name Synonyms=meeeoe8
`esterification of glycerol and polyethylene glycol with unsatu-
`rated fatty acids, or by mixing glycerol esters and condensates of
`Caprylocaproyl
`Labrasol; macregolglyceridorum
`nO iglycerides
`caprylocaprates; PEG 400 caprylic/
`ethylene oxide with the fatty acids of this unsaturated oil.
`capric glycerides
`Oleoyl polyoxylglycerides Mixtures of monoesters, diesters, and
`Gelucire 44/14; hydrogenated coconutoil
`Lauroyl polyoxylglycerides
`triesters of glycerol and monoesters anddiesters of polyethylene
`PEG 1500 esters; hydrogenated palm/
`glycols. They are obtained by partial alcoholysis of an
`palm kernel oil PEG 300esters;
`unsaturated oil mainly containing triglycerides of oleic (cis-9-
`macrogolglyceridorum laurates
`Corn oilPEG 300 esters; Labrafil
`octadecenoic) acid, using polyethylene glycol with mean relative
`molecular mass between 300 and 400, or by esterification of
`M2125CS; macrogolglyceridorum
`glycerol and polyethylene glycol with unsaturated fatty acids, or
`linoleates
`by mixing glycerol esters and condensatesof ethylene oxide with
`Apricot kernel oil PEG 300 esters; Labrafil
`the fatty acids of this unsaturated oil.
`M1944CS; macrogolglyceridorum
`oleates; peglicol5-cleate
`Stearoyl polyoxylglycerides Mixtures of monoesters, diesters,
` Gelucire 50/173; hydrogenated palm oil
`and triesters of glycerol and monoesters and diesters of
`PEG 1500 esters; macrogolglyceridorum
`polyethylene glycols with mean relative molecular mass between
`stearates
`300 and 4000. They are obtained by partial alcoholysis of
`saturatedoils containing mainly triglycerides of stearic (octade-
`canoic) acid, using polyethylene glycol, or by esterification of
`33Chemical Name and CAS Registry Number
`glycerol and polyethylene glycol with saturatedfatty acids, or by
`See TableII.
`mixture of glycerol esters and condensatesof ethylene oxide with
`the fatty acids of these hydrogenatedoils.
`4=Empirical Formula and Molecular Weight
`Polyoxylglycerides are mixtures of monoesters, diesters, and
`5=Structural Formula
`triesters of glycerol, and monoesters and diesters of polyethylene
`See Section 4.
`glycols (PEG).
`
`Synonyms
`2
`Polyoxylglycerides are referred to as macrogolglycerides in Europe;
`see Table I.
`
`Linoleoyl polyoxylglycerides
`
`Oleoyl polyoxylglycerides
`
`Stearayl polyoxylglycerides
`
`
`
`Lauroyl polyoxylglycerides
`
`[57107-95-6]
`
`[27194-74-7]
`
`[223129-75-7]
`
`
`Nabble ChemicalfaresaneCAS repisrynumbersof pelyenvielycerides.
`
`
` Name _ ____CAS number
`Chemical name
`Decanoic acid, mixed monoesters with glycerol and octanoic acid; polyloxy-
`Caprylocaproyl polyoxylglycerides
`[73398-61-5]
`1,2-ethanediyl), o-hydro-w-hydroxy-, mixed decanoate and octanoate
`lauric acid, diester with glycerol; pobyicag1 ,2-ethanediyl), «-(1-oxododecy))-
`-[(]-oxododecyl}oxy]-
`Cornoil, ethoxylated; 9,12-octadecadienoic acid (9E,12£}-monoester with
`1,2,3-propanetriol
`9-Octadecenoic acid (9Z)-, monoester with 1,2,3-propanetriol; poly(oxy-] ,2-
`ethanediyl), «-[(9Z}-1-oxo-9-octadecenyl]<a-hydroxy-
`Distearic acid, diester with glycerol; poly(oxy-1,2-sthanediyl), o-{1-
`oxooctadecyl)-[(1-oxcoctadsation
`
`Linoleoyl polyoxylglycerides
`
`(61789-25-1]
`
`Oleoyl polyoxylglycerides
`
`[68424-61-3]
`
`[9004-96-0]
`
`Stearayl polyoxylglycerides
`
`[1323-83-7]
`
` [9005-08-7]
`
`557
`
`Purdue 2025
`Collegium v. Purdue, PGR2018-00048
`
`Purdue 2025
`Collegium v. Purdue, PGR2018-00048
`
`

`

`7
`
`Applications in Pharmaceutical Formulation or
`Technology
`Polyoxylglycerides are used as self-emulsifying and solubilizing
`agents in oral and topical pharmaceutical formulations. They are
`also used in cosmetic and food products.
`See also Tables II, IV, V, VI, and VI.
`TableIllsUsesofcaprylocoproy|polyoxylglycerides,
`
`Use
`Concentration
`Reference io
`Dermalroute
`10-55%
`1-11
`Nasal route
`2-22%
`12, 13
`Oralroute
`Capsule
`
`Sublingual route
`
`10-99%
`10-35%
`
`14-32
`33
`
`Table IV: Uses of lauroyl polyoxylglycerides.
`
`Use
`Concentration
`Reference
`Oral route
`‘Adsorption {lable!}) <80%
`Capsule
`60-99%
`
`34, 35
`14, 29, 31, 32, 34,
`36-40, 41-44
`Melt granulation
`15-50%
`34, 44, 45
`
`__ Spray drying
`<60%
`=
`30, 34, 35
`
`Table V: Uses of linoleoylpolyoxylglycerides.
`;
`
`Use
`Concentration :
`-
`Reference
`Dermal route
`95-20%
`23
`Oral route
`
`Capsule
`10-90%
`16, 18, 46, 47
`
`Table VI: Uses of oleoyl polyoxyiglycerides.
`
`Use
`Concentration
`Reference
`Dermal route 5-20%
`2
`Nasal route
`8%
`13
`Oral route
`
`Capsule
`10-90%
`16, ] 8, 26, 31, 44, 48, 49
`
`_TableVil:Usesof stearoy!polyoxylglycerides.
`
`Ue
`Barrios —
`Oral route
`Adsorption (tablet}| <80%
`Capsu
`60-99%
`Melt gronuiotion
`15-50%
`Spray congealing
`95%
`Sproy drying
`<60%
`
`34,35, 50
`34, 39, 51-54
`at 55-57
`34, 54
`
`Description
`8
`Polyoxylglyceridesare inert liquid or semi-solid waxy materials and
`are amphiphilic in character. Caprylocaproyl polyoxylglycerides are
`pale-yellow oily liquids. Lauroyl polyoxylglycerides and stearoyl
`polyoxylglycerides occur as pale-yellow waxy solids. Oleoyl
`polyoxylglycerides and linoleoyl polyoxylglycerides occur as amber
`
`558—Polyoxylglycerides
`
`6 “FunctionalCategory
`Dissolution enhancer; emulsifying agent; nonionic surfactant;
`penetration agent; solubilizing agent; sustained-release agent.
`
`oily liquids, which maygive rise to a deposit after prolonged periods
`at 20°C.
`
`Pharmacopeial Specifications
`9
`See Tables VII and IX.
`
`10 Typical Properties
`Solubility
`Caprylocaproyl and lauroyl polyoxylglycerides: dispersible in
`hot water; freely soluble in methylene chloride.
`Linoleoyl and oleoy!l polyoxylglycerides: practically insoluble
`but dispersible in water; freely soluble in methylene chloride.
`Stearoyl polyoxylglycerides: dispersible in warm water and
`warm liquid paraffin; soluble in warm ethanol; freely soluble
`in methylene chloride.
`Viscosity
`Linoleoyl polyoxylglycerides: 70-90 mPas at 20°C, +35 mPas
`at 40°C for PEG 300.
`
`Oleoyl polyoxylglycerides: 75-95 mPas at 20°C, =35 mPas at
`40°C for PEG 300.
`See also Section 9.
`See also Table X.
`
`Stability and Storage Conditions
`11
`Polyoxylglycerides are very stable and inert. However, preventive
`measures againsttherisk of oxidation or hydrolysis may be taken to
`ensure stability during handling. See Section 15.
`Polyoxylglycerides should be preservedin their original contain-
`ers, and exposure to air,
`light, heat, and moisture should be
`prevented.
`
`12 Incompatibilities
`
`13. Method of Manufacture
`
`Polyoxylglycerides are obtained bypartial alcoholysis of vegetable
`oils using macrogols, by esterification of glycerol and macrogols
`with unsaturated fatty acids, or by mixing glycerol esters and
`condensates of ethylene oxide with the fatty acids of the vegetable
`oil,
`
`14 Safety
`Polyoxylglycerides are used in oral and topical pharmaceutical
`formulations, and also in cosmetics and food products. They are
`generally regardedasrelatively nonirritant and nontoxic materials.
`Caprylocaproyl polyoxylglycerides:
`LDso (rat, oral): >22 ml/(kg day).'5”
`Lauroyl polyoxylglycerides:
`LD(rat, oral): >2004 mg/(kg day).
`
`15 Handling Precautions
`Observe normal precautions appropriate to the circumstances and
`quantities of the material handled (refer to manufacturers’ safety
`information).
`Polyoxylglycerides are heterogeneous. Owing to their composi-
`tion and physical characteristics, semisolid polyoxylglycerides can
`segregate by molecular weight over time during storage in contain-
`ers,
`resulting in a nonhomogenous distribution.
`In addition,
`semisolid polyoxylglycerides must be heated to at least 20°C above
`melting point in order to ensure thatall crystallization clusters are
`fully melted. Therefore,it is essential that the entire contents ofeach
`container are melted to facilitate sample withdrawal or transfer,
`ensuring sample homogeneity.
`For liquid polyoxylglycerides, owing to their composition and
`physical characteristics, partial crystallization of saturated glycer-
`
`Purdue 2025
`Collegium v. Purdue, PGR2018-00048
`
`Purdue 2025
`Collegium v. Purdue, PGR2018-00048
`
`

`

`as apecicealnghetteleeee:SEe
`TableVill:Phormacopeial specificationsfor polyoxylglycenides.
`ii
`ee
`RES Yl
`ny Ree ee
`
` Test Caprylocoproy!pepolyoxylglycerides_lauraylpolpotyoxylghycerides Linoleoylpolyoxylglycerides Choo sihzaiidliwedi prone palynlghycrten
`|
`USP32-NF27
`PhEur 6.0
`PhEur 6.0 USP32-NF27
`USP32-NF27
`USPI2-NF27 PhEur 6.0}
`PhEur 6.0
`USP32-NF27
`PhEur 6.0
`Identification
`+
`+
`+
`+
`+
`+
`+
`+
`+
`+
`|
`Characters
`+
`-
`+
`-
`+
`-
`+
`=
`+
`-
`Ore point ["C)
`EG 300
`-
`-
`33-38
`-
`-
`-
`=
`=
`—
`_
`PEG 400
`-
`-
`36-41
`-
`-
`=
`-
`=
`-
`_
`PEG 600
`-
`=
`384300
`-
`=
`re
`=
`=
`x
`PEG 1500
`-
`-
`42.5475 —
`_
`=
`-
`_
`=
`-
`Viscosity at 20°C & 5°C
`PEG 200
`30-50
`=
`=
`=
`=
`=
`=
`=
`=
`=
`PEG 300
`460-80
`=
`ws
`=
`=
`a
`ae
`=
`=
`=
`PEG 400
`80-110
`=
`—_
`=
`-
`=
`-
`om
`=
`ee
`Acid value
`<2.0
`<2.0
`€2.0
`€2.0
`=2.0
`=2.0
`€2.0
`€2.0
`62.0
`<2.0
`.
`lroxyl value
`PEG 200
`80-120
`80-120
`_-
`36-85
`-
`-
`-
`-
`25-56
`25-56
`PEG 300
`36-85
`140-180
`140-180
`65-85
`45-65
`45-65
`45-65
`45-65
`25-56
`25-56
`PEG 400
`170-205
`170-205
`60-80
`36-85
`45-65
`45-465
`45-65
`45-45
`25-56
`25-56
`PEG 600
`=
`-
`50-70
`36-85
`-
`-
`=
`=
`25-56
`25-56
`PEG 1500
`-
`-
`36-56
`36-85
`_
`-
`=-
`=
`25-56
`25-56
`lodine value
`$2.0
`£2.0
`€2.0
`$2.0
`90-110
`90-110
`75-95
`75-95
`42.0
`62.0
`Peroxide value
`£6.0
`66.0
`€6.0
`€£6.0
`<12.0
`<£12.0
`=£12.0
`<12.0
`€6.0
`£60
`Soponification value
`PEG 200
`265-285
`265-285
`-
`-
`150-170
`150-170
`150-170
`150-170
`67-112
`67-112
`PEG 300
`17-190
`170-190
`190-204
`79-204
`150-170
`150-170
`150-170
`150-170
`67-112
`67-112
`PEG 400
`85-105
`85-105
`170-190
`79-204
`-
`-
`-
`-
`67-112
`67-112
`PEG 600
`-
`-
`150-170
`79-204
`-
`=
`=
`=
`67-112
`67-112
`PEG 1500
`-
`-
`79-93
`79-204
`-
`=
`-
`-
`A7-112
`67-112
`Alkaline impurities
`+
`+
`+
`-
`+
`-
`+
`-
`+
`-
`Frea glycerol
`<5.0%
`<5.0%
`23.0%
`aC.
`<3.0%
`£3.0%
`£3.0%
`<5.0%
`<3.0%
`<£5.0%
`Dioxane
`<10ppm
`<10ng/g
`<10ppm <l0he/g
`<10ppm <l0ra/g
`<10ppm < oua/g
`<10ppm =< 10ug/g
`
`Ethylene oxide <Ippm=<$ 1 g/g<1 <|ng/q <1 ppm <1 <1 pg/s <1 ppm $4048
`
`
`
`
`
`
`
`Heavy metals
`=10ppm
`«0.001%
`<10ppm <0.001
`<10
`20.00
`<10
`=0.001
`<lOppm =< 0.001%
`Water
`<1.0
`<1.0%
`<1.0%
`= 1.0%
`el.
`<1.0%
`li.
`210%
`=1.0%
`= 1.0%
`Total ash
`<0.1%
`<0.1%
`<£0.)%
`<0.W% <0.1%
`<0.1%
`<0.1%
`<0.1%
`<0.2%
`20.2%
`
`|
`|
`
`|
`
`“Table1X:Pharmacopeiol specifications forpolyoxylglycerides (fattyacids composition), Se
`Caprylocaproyl polyoxylglycerides Lauroyl polyoxylglycerides Lincleoyl polyoxylglycerides Oleayl polyoxylglycerides Stearayl polyaxylglycerides
`PhEur 6.0
`USP32-NF27
`PhEur 6.0 USP32-NF27
`PhEur 6.0 USP32-NF27
`<2%
`<2%
`&
`=
`=
`Cs = Caproie acid
`50-80%
`50-80%
`<15%
`=
`<3%
`Cg = Caprylic acid
`20-50%
`20-50%
`<12%
`-
`<3%
`Cio = Capric acid
`<3%
`<3%
`30-50%
`<S%
`<5%
`Cy = Lauric acid
`<1%
`<1%
`5-25%
`<S%
`<5%
`Cia =
`Myristic acid
`-
`-
`4-25%
`>90%
`40-50%
`Cig = Polmitic acid
`-
`-
`5-35%
`>90%
`48-58%
`Cig = Stearic acid
`=
`-
`-
`cil
`_
`Cis.) = Oleic acid
`=
`=
`=
`oe
`=
`Cia= Lincleic acid
`
`Ciea=linolenicocid=— - - - -
`
`
`
`
`Cro = Arachidic acid=— ss = at =
`
`
`
`C29,1 = Eicosenoic acid —
`-
`-
`=
`=
`
` Fatty acid
`
`$3Puscd|GyAxodjoy
`
`i
`
`Purdue 2025
`Collegium v. Purdue, PGR2018-00048
`
`Purdue 2025
`Collegium v. Purdue, PGR2018-00048
`
`

`

`Polyoxyiglycerides
`560
`TableX:TypicalpropertiesofSTS
`mivccidaiiesps
`caemnteni
`
`Property
`
`
`
`4 0
`
`14
`.95
`1.0
`1.465-].475
`
`1.450-1.470
`
`HLB value
`PEG 300
`PEG 400
`PEG 1500
`Relative density (at 20°C)
`Refractive index{at 20°C)
`
`Purdue 2025
`Collegium v. Purdue, PGR2018-00048
`
`al
`
`nn
`
`~ o
`
`o
`
`oS
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`19
`
`21
`
`23
`
`24
`
`25
`
`26
`
`27
`
`Kikwai L et al. Effect of vehicles on the transdermal delivery of
`melatonin across porcine skin in vitro. | Control Release 2002; 83(2):
`307-311.
`Kim J et al. Effect of vehicles and pressure sensitive adhesives on the
`permeation oftacrine across hairless mouse skin. Int J Pharm 2000;
`196(1): 105-113.
`Kreilgaard M.Influence of microemulsions on cutaneousdrug delivery.
`Bulletin technique Gattefossé 2002; 95: 79-100.
`Kreilgaard M etal. Influence of a microemulsion vehicle on cutaneous
`bioequivalenceof a lipophilic model drug assessed by microdialysis and
`pharmacodynamics. Pharm Res 2001; 18(5): 593-599.
`Minghetti P et al, Evaluation of ex vivo human skin permeation of
`genistein and daidzein, Drug Deliv 2006; 13(6): 411-415,
`Rhee YS et al. Transdermal delivery of ketoprofen using microemul-
`sions. Int | Pharm 2001; 228(1-2): 161-170.
`Zhao X et al. Enhancement of transdermal delivery of theophylline
`using microemulsion vehicle. Int } Pharm 2006; 327(1-2): 58-64.
`Dingemanse J et al. Pronounced effect of caprylocaproyl macrogolgly-
`cerides on nasal absorption of JS-159, a peptide serotonin 1B/1D-
`receptor agonist. Clin Pharmacol Ther 2000; 68(2): 114-121.
`Zhang Q et al. Preparation of nimodipine-loaded microemulsion for
`intranasal delivery and evaluation on the targeting efficiency to the
`brain. Int | Pharm 2004; 275(1-2): 85-96.
`Aungst BJ et al. Improved oral bioavailability of an HIV protease
`inhibitor using gelucire 44/14 and labrasol vehicles. Bulletin technique
`Gattefossé 1994; 87: 49-54.
`Chang RK, Shojaei AH.Effect of a lipoicic excipient on the absorption
`profile of compound UK 81252 in dogs after oral administration. J
`Pharm Pharm Sci 2004; 7(1): 8-12.
`Cirri M et al, Liquid spray formulations of xibornol by using self-
`microemulsifying drug delivery systems. Int J Pharm 2007; 340(1-2):
`84-91.
`Demirel M etal. Formulation and in vitro-in vivo evaluationofpiribedil
`solid lipid micro- and nanoparticles, J Microencapsul 2001; 18(3); 359-
`371,
`Devani M et al. The emulsification and solubilisation properties of
`polyglycolysed oils in selfemulsifying formulations. J Pharm Pharma-
`col 2004; $6(3): 307-316.
`Table XI: EINECSnumbersfor polyoxylglycerides.
`Djordjevic L et al. Characterization of caprylocaproy! macrogolglycer-
`Name
`EINECS number
`ides based microemulsion drug delivery vehicles for an amphiphilic
`drug. Int J Pharm 2004; 271(1-2); 11-19,
`rs styonialeer
`248-3154
`
`
`CapiCaprylocaproylpo!alyo: lycerides 277-452-2
`
`20
`Esposito E et al. Amphiphilic association systems for amphotericin B
`Oleoyl povonlarcendes
`270-312-1
`delivery. Int J Pharm 2003; 260(2); 249-260.
`215-359-0
`
`Stearoy!polyonyghyceridesles
`Hu Z et al. A novel emulsifier, Labrasol, enhances gastrointestinal
`absorption of gentamicin. Life Sci 2001; 69(24): 2899-2910,
`Ito Y et al. Oral solid gentamicin preparation using emulsifier and
`adsorbent. J] Control Release 2005; 105(1-2): 23-31.
`Kim H]et al. Preparation and ivt vitro evaluation ofself-microemulsify-
`ing drug delivery systems containing idebenone. Drug Dev Ind Pharm
`2000; 26(5); 523-529,
`Kommuru TR etal. Self-emulsifying drug delivery systems (SEDDS) of
`coenzyme Q10: formulation development and bioavailability assess-
`ment. Int ] Pharm 2001; 212(2): 233-246.
`Rama Prasad Y'V et al. Evaluation of oral fornmulations of gentamicin
`containing labrasol in beagle dogs. Int J Pharn: 2003; 268(1-2): 13-21,
`Shen H, Zhong M. Preparation and evaluation ofself-microemulsifying
`drug delivery systems (SMEDDS) containing atorvastatin. | Pharm
`Pharmacol 2006; 58(9); 1183-1191.
`Shibata N et al. Application of pressure-controlled colon delivery
`capsule to ora! administration of glycyrrhizin in dogs. J Pharm
`Pharmacol 2001; 53(4): 441-447.
`
`ides may be observed after long-term storage. In case of crystal-
`lization, heat to 60—70°C beforeuse.
`Polyoxylglycerides are hygroscopic. Only heat in a water bath if
`the materials are contained in a sealed glass container or are for
`immediate use. Otherwise, heat in a microwave or convention oven.
`Avoid exposure to excessive and repeated high temperatures (i.e.
`above 100°C) and cooling cycles,
`To ensure stability during handling, and avoid the risk of
`oxidation or hydrolysis, the following measures should be taken:
`Risk of oxidation:
`@ minimize aeration of the mixture (avoid use of high-speed
`homogenizers);
`® minimize and control the degree of exposure to heat andlight;
`use a nitrogen blanket.
`Risk of hydrolysis:
`@ minimize and controlrelative humidity;
`e do not heat near a source of humidity (c.g. water bath).
`
`16 Regulatory Status
`Lauroyl polyoxylglycerides and stearoyl polyoxylglycerides are
`approved asfood additives in the USA. Included in the FDA Inactive
`Ingredients Database (oral
`route: capsules,
`tablets, solutions;
`topical route: emulsions, creams, lotions; vaginal route: emulsions,
`creams). Oleyl polyoxylglycerides are included in a topical cream
`formulationlicensed in the UK.
`
`17 Related Substances
`
`18 Comments
`See Table XI for EINECS numbersfor polyoxylglycerides.
`
`19 Specific References
`1 pips Aetal. Theeffectofskin permeation enhancers on the formation
`of porphyrins in mouse skin during topical application of the methyl
`ester of $-aminolevulinic acid. J] PhotochemPhotobiol B 2006; $3(2):
`94-97,
`2 Ceschel G et al. Solubility and transdermal permeation properties of a
`dehydroepiandrosterone cyclodextrin complex from hydrophilic and
`lipophilic vehicles. Drug Deliv 2005; 12(5): 275-280,
`3 Cheong HA, Choi HK. Effect of ethanolaminesalts and enhancers on
`the percutaneous absorption of piroxicam from a pressure sensitive
`adhesive matrix. Eur J Pharm Sci 2003; 18(2): 149-153.
`Jurkovic P et al, Skin protection against ultraviolet inducedtree radicals
`with ascorbyl palmitate in microemulsions, Eur J Pharm Biopharm
`2003; 56(1): 59-66.
`
`4
`
`Purdue 2025
`Collegium v. Purdue, PGR2018-00048
`
`

`

`eeel
`
`Polyoxylglycerides
`
`561
`
`48
`
`49
`
`50
`
`$1
`
`52
`
`53
`
`54
`
`53
`
`56
`
`57
`
`52
`
`60
`
`20 General References
`Gattefossé. Technical literature: Gelucire 44/14, 2007.
`Gattefossé. Technicalliterature: Gelucire 50/13, 2005.
`Gartefossé. Technical literature: Oral route excipients, 2007.
`
`
`
`28
`
`29
`
`30
`
`31
`
`32.
`
`33
`
`34
`
`35
`
`36
`
`37
`
`38
`
`39
`
`41
`
`42
`
`43
`
`45
`
`46
`
`47
`
`Subramanian N e¢ al. Formulation design of self-microemulsifying drug
`dispersing formulation and a microsuspension. Int J Pharm: 2002;
`245(1-2); 143-151.
`delivery systems for improved oral bioavailability of celecoxib. Biol
`Pharm Bull 2004; 27(12): 1993-1999,
`Fernandez-Carballido A et al. Biodegradable ibuprofen-loaded PLGA
`Venkatesan N et al. Gelucire 44/14 and Labrasol in enhancing oral
`microspheres for
`intraarticular administration. Effect of Labrafil
`absorption of poorly absorbable drugs. Bulletin technique Gattefossé
`addition on release in vitro, Int J Pharm 2004; 279: 33-41.
`2006; 99: 79-88,
`Kang BK et al. Controlled release of paclitaxel from microemulsion
`Venkatesan N etal. Liquid filled nanoparticles as a drug delivery tool
`containing PLGA and evaluation of anti-tumoractivity in vitro and in
`for protein therapeutics. Biomaterials 2005; 26(34): 7154-7163.
`vivo, Int J Pharm 2004; 286(1-2): 147-156.
`Wei L ef al. Preparation and evaluation of SEDDS and SMEDDS
`Gupta MKet al. Enhanced drug dissolution and bulk properties of solid
`containing carvedilol. Drug Dev Ind Pharm 2005; 31(8): 775-784.
`dispersions granulated with a surface adsorbent. Pharm Deu Technol
`Yiiksel N et al. Enhanced bioavailability of piroxicam using Geltcire
`2001; 6(4): 563-572.
`44/14 and Labrasol: in vitro and in vivo evaluation. Eur J Pharm
`Craig DQM. Lipid matrices for sustained release —- an academic
`Biopharm 2003; 56(3); 453-459.
`overview, Bulletin technique Gattefossé 2004; 97: 9-19,
`sublingually
`Shephard SE ef al, Pharmacokinetic behaviour of
`Galal S et al. Study of in-vitro release characteristics of carbamazepine
`administered 8-methoxypsoralen for PUVA therapy. Photodermatal
`extended release semisolid matrix filled capsules based on Gelucires.
`Photoimmunol Photomed 2001; 17(-1): 11-21.
`Drug Dev Ind Pharm 2004; 30(8); 817-829.
`Jannin V et al. Approaches for the developmentof solid and semi-solid
`Khan N, Craig DQ. The influence of drug incorporation on the
`lipid-based formulations. Ady Drug Deliv Rev 2008; 60(6): 734-746.
`structure and release properties of solid dispersionsin lipid matrices. J
`Chauhan B et al. Preparation and evaluation of glibenclamide-
`Control Release 2003; 93(3): 355-368.
`polyglycolized glycerides solid dispersions with silicon dioxide by spray
`Shimpi SL et al. Stabilization and improved in vivo performance of
`drying technique. Eur | Pharnt Sci 2005; 26(2): 219-230.
`amorphous ctoricoxib using Gelucire S0/13. Pharm Res 2005; 22(10):
`Aungst BJ et al. Amphiphilic vehicles improve the oral bioavailability of
`1727-1734.
`a poorly soluble HIV protease inhibitor at high doses. Int J Pharm
`1997; 156(1): 79-88.
`OchoaL et al. Preparation of sustained release hydrophilic matrices by
`Barakat NS, Etodolac-liquid-filled dispersion into hard gelatin capsules:
`melt granulationin a high-shear mixer, J Pharm Pharn: Sci 2005; 8(2):
`132-140.
`an approach to improve dissolution and stability of etodolac formula-
`tion. Drug Dev Ind Pharm 2006; 32(7): 865-876.
`Schaefer T. Pelletisation with meltable binders, Bulletin technique
`Barker SA et al. An investigation into the structure and bioavailability
`Gattefossé 2004, 97; 113-124.
`of a-tocopheroldispersions in Gelucire 44/14. ] Control Release 2003;
`Seo A et al, The preparation of agglomerates containing solid
`91(3): 477-488.
`dispersions of diazepam by melt agglomeration in a high shear mixer.
`Bowtle W. Lipid formulations for oral drug delivery. Pharm Technol
`Int | Pharm 2003; 259(1-2): 161-171.
`Eur 2000; 12(9); 20-30,
`58
`Passerini N e¢ al. Evaluation of mele granulation and ultrasonic spray
`40
`TwanagaKet al. Disposition oflipid-based formulationin the intestinal
`congealing as techniques to enhance the dissolution of praziquantel. [nt
`tract affects the absorption of poorly water-soluble drugs. Biol Pharm
`J] Pharm 2006; 318(1-2): 92-102.
`Bull 2006; 29(3): 508-512.
`Gattefossé. Labrasol: GAT-89107. Test to evaluate the acute oral
`Kane A ef al. A statistical mixture design approach for formulating
`toxicity following a single oral administration (LDsq) in rats, 1989.
`poorly soluble compounds in liquid filled hard shell capsules. Bulletin
`Gattefossé. Labrafil M2130C$: GAT-8815. Test
`to evaluate oral
`technique Gattefossé 2006; 99; 43-49.
`Khoo SM et al. The formulation of Halofantrine as either non-
`toxiciry following a single oral administration in the rat (limit test),
`1988.
`solubilising PEG 6000 or solubilising lipid based solid dispersions:
`physicalstabiliry and absolute bioavailability assessment. Jat J Pharm
`2000; 205{1-2): 65-78.
`SchampK et al, Developmentofanin vitro/in vivo correlation forlipid
`formulations of EMD 50733,
`a poorly soluble,
`lipophilic drug
`substance. Eur J Pharm Biopharm 2006; 62(3): 227-234.
`Chambin O,Jannin V, Interest of multifunctional lipid excipients: case
`of Gelucire 44/14. Drug Dev Ind Pharm 2005; 31(6): 527-534.
`YangD etal. Effect of the melt granulation techniqueon thedissolution
`characteristics of griseofulvin, Int J Pharm: 2007; 329(1-2): 72-80.
`Dordunoo SK. Sustained release liquid filled hard gelatin capsules in
`drug discovery and development: a small pharmaceutical company’s
`perspectives. Bulletin technique Gattefossé 2004; 97; 29-39.
`Bravo Gonzalez RC et al. Improved oral bioavailability of cyclosporin a
`in male Wistar rats. Comparison of a Solvtol HS 15 containing self-
`
`21 Author
`
`M Julien.
`
`22 Date of Revision
`3 March 2009.
`
`Purdue 2025
`Collegium v. Purdue, PGR2018-00048
`
`Purdue 2025
`Collegium v. Purdue, PGR2018-00048
`
`