IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`(Atty. Docket No. 06—796)
`
`Examiner: Timothy P.
`
`Art Unit: 1614
`
`Confirmation N0.: 9142
`
`) )
`
`) )
`
`VVVVUV
`
`In the Application of:
`
`Fanara et al.
`
`Thomas
`
`Serial No.
`
`10/599,451
`
`Filing Date:
`
`September 28, 2006
`
`For:
`
`Pharmaceutical Composition of Piperazine
`Derivatives
`
`DECLARATION OF DOMENICO FANARA UNDER 37 CFR 1.132
`
`Commissioner for Patents
`PO. Box 1450
`
`Alexandria, VA 223134450
`
`I, Domenico Fanara, in support of the above~identified patent application, do aver and
`
`state as follows:
`
`1.
`
`2,
`
`3.
`
`4.
`
`5.
`
`I am the first named inventor of this application.
`
`I received a Pharmacy degree from University of Liege Belgium in 1986
`
`I have been employed by UCB Pharma SA since 1993 after having Spent 6
`
`years in another pharmaceutical company Galephar S.A as head of
`
`formulation development.
`
`A copy of my CV is attached hereto as Exhibit A that include list of
`
`publications
`
`Levocetirizine and particularly its dihydrochloride salt are known to be useful
`
`. as antihistamines. Levocetirizine dihydrochloride is available in solid dosage
`
`form. The present invention is directed to a formuiation that allows for the
`
`availability of levocetirizine and its salts in liquid dosage form.
`
`Apotex (11311201900400) EX. 1027, p. 001
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`

`

`One common problem with liquid pharmaceuticai formulations in general is
`
`that the presence of water can allow for the growth of microorganisms,
`
`particularly after the seal on the product packaging has been broken. and when
`
`the contents of the packaging are exposed to closing implements. Thus, it has
`
`become common practice to include preservatives in such formulations to
`
`prevent the growth of such microorganisms. Methyl parahydroxybenzoate
`
`and propyl parahydroxybenzoate, commonly known as methyl paraben and
`
`propyl paraben, respectively (hereinafter “MP” and “PP.” together
`
`“parabens”), are frequently used for this purpose.
`
`The combined parabens in typical pharmaceutical preparations is at least
`
`about 2 mg/ml, as shown by an accepted pharmaceutical treatise (see,
`
`Remington, The Science and Practice of Pharmacy, 21St ed., 2005, pp. 748-
`
`749, EX. B, hereinafter “the Remington treatise”).
`
`In the course of developing liquid pharmaceutical formulations of
`
`levocetirizine and its salts, we were surprised to discover that levocetirizine
`
`itself can act as an anti~microbial. This is shown in Tables 5 and 6 of the
`
`present application, in which samples of an oral solution and oral drops
`
`containing 0.5 and 5.0 mg/ml of levocetirizine hydrochloride, respectively,
`
`and which were inoculated with various microbes, were essentially free of
`
`bacteria 14, 21, and 28 days after inoculation. The oral drop formulation that
`
`contained the higher concentration of the drug also was substantially free of
`
`fungal infection 21 and 28 days after inoculation.
`
`This result was totally unexpected. Even though levocetirizine and its salts
`
`were well characterized, to our knowledge it had not been recognized prior to
`
`our invention that levocetirizine has antimicrobial properties. This led to our
`
`discovery that liquid pharmaceutical compositions of levocetirizine could be
`
`fonnulated with lower paraben concentrations than previously thought
`
`necessary and without additional preservatives,
`
`10.
`
`Submitted herewith as Exhibit C are the results of testing of antimicrobial
`
`efficacy on several batches of oral drop solution having 5 mg/ml of
`
`levocetirizine, 0.3375 mg/ml MP and 0.0375 mg/ml of PP, for an MP/PP ratio
`
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`

`of 9 and a total parabens content of 0.375 mg/ml. The compositions contained
`
`no other preservative. The batch sizes varied from 100 L to 1000 L. The
`
`testing results confirmed that inoculated test samples of all of the batches were
`
`essentially free of both bacteria and fungus 14 and 28 days after in0culation.
`
`This result is surprising because the amount of parabens used was less than
`
`one fifth of the minimum recommended by the Remington treatise.
`
`ll.
`
`Submitted herewith as Exhibit D are the results of testing of antimicrobial
`
`12.
`
`13.
`
`efficacy on two batches of oral solution containing 0.5 rag/ml of
`
`levocetirizine, 0.675 mg/ml MP and 0.075 mg/ml of PP, for an MP/PP ratio of
`
`9 and a total parabens content of 0.750 mg/ml. The compositions contained
`no other preservative. The batch sizes were each 1000 L. The testing results
`
`confirmed that inoculated test samples of both of the batches were essentially
`
`free of bacteria and two of three species of fungus 14 and 28 days after
`
`inoculation. This result is surprising because the amount of parabens used
`
`was less than one half of the minimum recommended by the Remington
`
`treatise.
`
`I have reviewed the references cited by the US. Patent and Trademark Office
`
`against this application.
`
`WO 02/47680 of DeLongueville et al. relates to earlier work on cetirizine and
`
`its optically active isomers, performed by the present assignee. The only
`
`mention of any Specific preservative is at page 6, lineslS—ZE, which states,
`
`“As an example of a composition according to the present invention, the
`
`following formulation of a syrup (oral drops) is preferred: cetirizine
`
`dihydrochloride, methyl— and propyparaben, saccharinum, and purified
`
`water.” There is no teaching or suggestion as to the relative amounts of any of
`
`these components of the composition. As one skilled in the art, upon reading
`
`this disclosure I would understand that the amount of total parabens intended
`
`was at least the minimum of 2 mg/ml as set forth in the Remington treatise
`
`and as generally understood at that time as being a typicai concentration of
`
`preservative for a liquid pharmaceutical product.
`
`Apotex (IPR2019-00400) EX. 1027, p. 003
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`

`14.
`
`Gilliland et al., J. Applied. Bacteriology, 1992, 72, 252—257 (”Gilliland 1”),
`
`reports a study on the effect of temperature on the kill rate of E. coli by
`
`methyl and propyl parabens. Solutions containing 0.12% MP (1.2 mg/ml) and
`
`0.012% PP (.12 mg/ml) were evaluated at temperatures of 34, 37, 40, and
`
`42°C, which are well beyond the temperatures at which most pharmaceutical
`
`compositions are stored. The combined parabens in the tested solutions was
`
`1.32 mg/ml, more than 10% higher than the 1.125 rug/ml maximum parabens
`
`concentration of our invention. The longest time period over which
`
`measurements were made was 28 hours (Fig. 5) so that the results cannot be
`
`properly extrapolated to pharmaceutical compositions which require long—
`
`term storage. No pharmaceutical component of any type was included in the
`
`formulations evaluated.
`
`In a test run in which the temperature of the sample
`
`was constantly altered rather than being held at a steady state, the authors
`
`found that
`
`the viable count of E. coli showed variability that was too high to
`
`enable adequately precise rate constants to be calculated, such that the method
`
`was of little value in that experiment (p. 257). The amount of parabens used
`
`in lGilliland l is outside the claims of our invention; the experiments of
`
`Gilliland were conducted at different temperatures, and for much shorter times
`
`than the experiments of our application. For at least these reasons, as one
`
`skilled in the art, it is my opinion that Gilliland Iwould be afforded little
`
`weight by those of ordinary skill in the art with respect to its relevance to the
`
`present invention and does not teach or suggest a pharmaceutical solution of
`
`ievocetirlzine or one of its salts, and with a combined parabens of no more
`
`than 1.125 mg/ml.
`
`15.
`
`Gilliland et al., J. Applied. Bacteriology, 1992, 72, 258—261 (”Gilliland 2”),
`
`reports a study on whether methyl and propyl paraben act synergistically.
`
`Various solutions were prepared with MP at either 0.12% or 0.14%, and with
`
`PP at 0.012% and 0.014%. These concentration levels were selected because
`
`at these levels the kill rate was slow enough that the rate constants could be
`
`calculated; higher concentrations killed bacteria too quickly for the required
`
`sampling to be carried out satisfactorily. (p. 259) To me, as one skilled in the
`
`Apotex (11311201900400) EX. 1027, p. 004
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`

`

`l6.
`
`17.
`
`art, this suggests that the concentrations selected for study were not
`
`necessarily optimal For use in a pharmaceutical composition that have to be
`
`essentially free of such bacteria.
`
`I also note that the time period over which
`
`testing was done was about six hours, so that the results cannot be properly
`
`extrapolated to pharmaceutical compositions which require long~term storage.
`
`Doron discloses compositions that significantly reduce Ecoli. but at paraben
`
`concentration that are 37% and 248% greater than the concentrations used in
`
`our invention. As one skilled in the art, this reference suggests to me that at
`
`the MP/PP ratios of Doron, a much greater total concentration of parabens is
`
`necessary to achieve a composition that remains substantially free of bacteria
`
`than was achieved with our invention.
`
`As one skilled in the art, the combination of Doron, DeLongueville, Gilliland
`
`Iand Gilliland 11 does not teach or suggest that a pharmaceutical formulation
`
`could be prepared that is maintained substantially free of bacteria and having
`
`the a total of MP and PP of no greater than M25 mg/ml, and no other
`
`preservative. Gilliland l and II were thermal and kinetic studies of parabens.
`
`The authors indicate that the concentrations chosen were those that facilitated
`
`their measurements; there is no suggestion that the concentrations chosen for
`
`evaluation in these studies would be suitable for use in actual pharmaceutical
`
`compositions.
`
`I hereby state that I have been warned that willful false Statements and the iikc are
`
`punishable by fine or imprisonment, or both ([8 U.S.C.
`
`lDOl), and that such willful false
`
`statements may jeopardize the validity of the application or document or any registration
`
`resulting titerefrom, and Ideclare that all statements made of my own knowledge are
`
`true; and all statements made on information and belief are believed to be true.
`
`Domenico Fanara
`
`Apotex (IPR2019-00400) EX. 1027, p. 005
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`

`Domenico Fanara, Ind. Pharm.
`
`Inte
`
`Home Address:
`
`Rue Pont de Soleil, 2A,
`B-4520 Wanze
`
`Telephone (wit): +32.2.386.20.04
`Telephone (hm): +32.85.23.57.69
`Mobile : +32.494.578.142
`E—mail: domcnico.I’anura@uch.com
`
`Current Position:
`
`Date of birth: October 3 1"“, 1963
`Senior Director
`Innovation 8.: Technology Development
`UCB Pharma S.A.
`B-l420 Braine-l’Alleud.
`
`Expertise: Specific Skills
`
`Fully familiar with pharmaceutical sciences and drug development.
`6
`0 Extensive experience in the development of novel technologies for compounds with
`poor solubility
`9 Extensive experience in the development of slow release formulations
`9 Evaluation of external technologies to support own projects
`a Program and project management skills including goal setting, planning, budget
`forecasting and tracking and progress reporting
`9 Experience in management of development staffs with global footprint.
`0 Management of budget (OPEX,EXterna1,Investment)
`
`Strengths:
`0 Creativity, focus, and result oriented
`
`General skills:
`
`. Tn'lingual English, French (mother tongue) Italian
`0
`Fully familiar with the main computer softwares (Word, Excel, PowerPoint, Access,
`Outlook ...)
`
`Apotex (IPR2019-00400) EX. 1027, p. 007
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`

`

`Domenico Fanara, Ind. Pharm.
`
`Employment:
`
`April 2010
`2009
`
`2006 £009
`1995
`1993
`1988
`1986
`
`Senior Director Head of Innovation and Technology Development
`Delivery Route R&D Senior Director and Deputy of the head of pharmaceutical Sciences
`UCB Pharma S.A. ( 85 FTE's)
`Drug Product R&D Senior Director, UCB Pharma SA. (135 FI‘E’S)
`Manager of Pharmaceutical Development, UCB Pharma
`Galenic Development, UCB Pharma
`Head of Pharmaceutical Development. SMB «- Galephar
`Pharmaceutical Development, SMB — Galephar
`
`Current key and past accountabilities:
`
`To support a harmonized consistent approach to new technologies development
`To support the development of new tools, new technologies to optimize processes .
`To participate in the integration of innovation in the design of the future manufacturing
`processes (Chemical DS, Chemical DP, Biological DS, Biological DP, analytical Tools).
`To develop internal expertise and competences at UCB for these novel technologies
`
`The key requirement of my function is the management of all activities of the Drug
`Product and Delivery Route Research & Development department in accordance with the
`Pharmaceutical Sciences mission statements.
`
`The fulfilment of this role will therefore require the active provision of strategic technical
`guidance for the initiation and management of development projects and for the supply of
`Drud Product (DP) for early clinical trials. In connection with this, Iensure the
`management of the department via the effective management of resources (specifically
`staff, facilities and the relevant budgets).
`
`0
`
`To lead pharmaceutical development globally encompassing all projects from the
`Research to Development transition point through proof of concept transition into DP
`D&I Department. The DP R&D Department will also be responsible for transferring
`processes, technology, data and preparing regulatory submissions with its business
`partner DP DI (Global Technical Operations). (The role has a global remit and must
`ensure the optimal use of resources across UCB for all projects. This is a line function
`and I’m a member of the Pharmaceutical Sciences and NonClinical Management
`Team).
`
`Apotex (IPR2019-00400) EX. 1027, p. 008
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`

`

`Domenico Fanara, Ind. Pharm.
`
`As deputy of the head of Pharmaceutical Sciences :
`
`e To coordinate Development’s activities related to Pre—formuiation ,Formulation &
`Drug Delivery Developments for NBE’s and NCE’s
`- To manage the availability of DP for Clinical trials.
`0 To obtain and to ensure the coherence between all different Projects, in order to
`prioritize responsibilities and tasks in the department.
`a To ensure full compliance with QA, cGMP or related requirements.
`a To strengthen the UCB IP position through innovation.
`8
`l oversee and advice for the development of pre-clinical and clinical formulations
`and characterization of materials as well as development of manufacturing processes
`for all products in the portfolio.
`
`I am also responsible for managing the:
`
`a Development of intellectual property fillings with for freedom to operate and
`potential exclusions.
`
`- Development of extensions for current UCB preprietary drug delivery technologies.
`
`Education:
`
`1989
`
`Industrial Pharmacist
`
`1986 Pharmacist, University of Liége, Belgium
`198] Humanities (applied sciences section), Provincial Institute of secondary
`Education, Seraing, Belgium.
`
`Apotex (IPR2019-00400) EX. 1027, p. 009
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`

`

`Domenico Fanara, Ind. Pharm.
`
`Other Relevant courses and workshops attended:
`
`2008 Global Leadership program
`
`2008 Leadership and innovation
`
`2007
`
`Internal training on NBE’s
`
`2004 ~ 2005 Leadership and Management ~— Internal Training
`
`2001
`
`Change management — Internal Training
`
`2000 Management by objectives -— Internal Training
`
`1999 UCB Global leadership program — Internal Training
`
`1998
`
`Experimental planification —- Internal Training
`
`1998 Goal directed project management — Internal Training
`
`1998
`
`Compression: simple and double layer tablets (Courtoy)
`
`1997 New drug delivery systems (P. Couvreur)
`
`1996
`
`Symposium drug delivery
`
`1995
`
`Pharmaceutical technology: lipidic Vehicles (Gattefosse)
`
`1995
`
`Pharmaceutical technology conference (Amsterdam)
`
`1995
`
`First european intensive course on new forms a,nd new routes of administrations or drugs
`
`(Coimbra)
`
`1994 GTRV (Paris)
`
`1994
`
`Pharmaceutical technology conference (Barcelona)
`
`1993
`
`Statistic course (ULB)
`
`1993
`
`European congress of biopharmaceutics and pharmacokinetics
`
`1993 — 1995 Experimental Work of a PHD Thesis — “Oral drug delivery of peptides” (ULB)
`
`1992
`
`Peptide and protein drug delivery (V. Lee)
`
`1986 Work experience in the pharmaceutical chemistry laboratory of the University of Liége
`
`(Prof. Delarge)
`
`1985 Work experience in the clinical biology laboratory of the University of Lifege Prof.
`
`Heusghem)
`
`Apotex (11311201900400) EX. 1027, p. 010
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`

`

`Domenico Fanara, Ind. Pharm.
`
`Bibliography (literature & patents)
`
`Literature
`
`Preparation and characterization of nanocrystals for solubility and dissolution rate enhancement of
`nifedipine.
`Source
`
`International Journal of Pharmaceutics. 299(1-2):167—77, 2005 Aug 11.
`
`Correlation of extrusion forces, raw materials and sphere characteristics.
`Source
`
`Journai of Pharmacy & Pharmacology. 44(8):676—8, 1992 Aug.
`
`Instrumentation of a gravity feed extruder and the influence of the composition of binary and
`ternary mixtures on the extrusion forces.
`Source
`
`Journal of Pharmacy & Pharmacology. 43(1 I):745-9, 1991 Nov.
`
`Preparation and in vitro/in vivo evaluation of nano-sized crystals for dissolution rate enhancement of
`[ICE-354406, a highly-dosed poorly water scluble weak base.
`Eur. J. Pharm. &Biopharm, 64, 360-368
`(2006)
`
`In vitro transport studies of nifedipine nanoparticules across Caco-ZIHT29-5M21 cultures & co-
`cultures
`
`Eur. J. Pharm. Sr. Biopharm, submitted,
`
`(2007)
`
`Patents
`
`Tablet comprising cetirizine and pseudoephedrine
`International patent application WO 03/002098 and US Patent 7,014,867
`
`Pharmaceutical compositions for controlled release of active substances
`International patent application WO 98/41194 and US Patent 6,699,502
`
`Pseudopolyrnorphic forms of 2-[2-[4-[Bis (4~fluoropheny1} methyl}1-piperazinylkthoxflacetic acid
`dihydrochloride
`International patent application WO 99/28310 and US Patent 6,335,331
`
`Tablet comprising efletirizine and pseudoephedrine.
`Internationai patent application: WO 2003/059328
`
`Tabiet comprising efletirizine
`International patent application: WO 2003/057198
`
`Oral formulations for cetirizine and related compounds.
`International patent Application: WO 99/01133 and US patent US 6,455,533
`
`Apotex (IPR2019-00400) EX. 1027, p. 011
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`Apotex (IPR2019-00400) Ex. 1027, p. 011
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`

`

`Domenico Fanara, Ind. Pharm.
`
`Pharmaceutical compositions for oral administration comprising substituted benzhydrylpiperazines
`and a cyclodextrin.
`US Patent US 6,455,533 « European Patent EP 0 994 710.
`
`Use of pharmaceutical compositions capable of being gelled in periodontology
`International patent application WO 56726 and US Patent US 6.318.224
`
`Pharmaceutical compositions capable of being gelled
`International patent application WO 99/56725 and US Patent US 6,464,987
`
`Pharmaceutical composition of piperazine derivatives.
`International patent application WO 2006/005507
`
`Pharmaceutical compositions comprising Levetiracetam
`International patent application WO 2010/006929
`
`Liquid composition of Brivaracetam
`International patent application WO 2009/109547
`
`Pharmaceutical compositions comprising 2-oxo-1-pyrrolidine derivatives
`International patent application WO 2010/086315
`
`Pharmaceutical compositions comprising Brivaracetam
`International patent application WO 2010/089372
`
`Pharmaceuticai oral compositions
`International patent application WO 2010/057869
`
`Pharmaceutical oral compositions
`International patent application WO 2010/057870
`
`Other interests:
`
`Reading, cycling, swimming.
`
`Apotex (IPR2019-00400) EX. 1027, p. 012
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`
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`
`
`EflST EDITION
`
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`flee $€l$fi€® aml Mam
`
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`a? leagmaey
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`A Wolters Kluwer Company
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`Buenos Aires - Hong Kong - Sydney - Tokyo
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`
`
`. .A treatise on the theory
`Remington: The Science and Practice of Pharmacy .
`and practice of the pharmaceutical sciences, with essential
`information about pharmaceutical and medicinal agents; also, a
`guide to the professional responsrbilities of the pharmacist as the
`drug information speciaiist of the health team .
`.
`. A textbook and
`reference work for pharmacists, physicians, and other practitioners of
`the pharmaceuticai and medical sciences.
`
`EDITOREAL BOARD
`
`Paul Beringer
`
`Ara DerMarderosian
`
`Linda Felton
`
`Steven Gelone
`
`Pardeep K. Gupta
`
`John E. Hoover
`
`Nichoias G. Popovick
`
`William i. Reilly, Jr
`
`Alfonso R. Gennaro
`
`Randy Hendrickson, Chair
`
`AUTHORS
`
`The 133 chapters of this edition of Remington were written by
`
`the editors, by members of the Editorial Board, and by the au—
`
`thors listed on pages xi to xv.
`
`Director
`
`Philip P Gerbino 1995-2005
`
`* Twenty—first Edition~2005
`
`Published in the 185th year of the
`PHELADELPHIA COLLEGE OF PHARMACY AND SCIENCE
`
`31
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`Apotex (IPR2019-00400) Ex. 1027, p. 015
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`

`

`
`
`Editor: David 13. Troy
`Managing Editor: Matthew J. Hauber
`Marketing Manager: Marisa A. O’Brien
`
`Lippincott Williams & Wilkins
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`material contained herein. This publication contains information relating to general principles ofmedical care which should not
`be construed as specific instructions for individual patients. Manufacturer’s product information and package inserts should be
`reviewed for current information, including contraindications, dosages and preeaufions.
`
`Printed in the United States of America
`Entered according to Act of Congress, in the year 1885 by Joseph P Remington, in the Office of the Librarian of Congress, at
`Washington DC
`
`Copywight 1839, 1894, 1905, 1907, 1917, by'Joseph P Remington
`
`Copyright 1926, 1936, by the Joseph P Remington Estate
`Copyright 1948, 1951, by the Philadelphia College ofPharmacy and Science
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`Copyright 2000, 2006, by the University of the Sciences in Philadelphia
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`All Rights Reserved
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`ISBN 0-3817-4673—6
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`The use ofstructural formulas from USAN and the USP Dictionary ofDrug Names is bypermission ofThe USP Convention. The
`Convention is not responsible for any inaccuracy contained herein.
`Notice—This text is not intended to represent, nor shall it be interpreted to be, the equivalent afar a substitute for the official
`United States Pharmacopeia (USP) and/or the National Formulary (NF). In the event ofany difi’erence or discrepancy between the
`current official USP or NF standards ofstrength, quality, purity, packaging and labeling for drugs and representations ofthem
`herein, the context and reflect of the official compendia shall prevail.
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`Apotex (IPR2019-00400) EX. 1027, p. 016
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`12345678910
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`
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`733mm?!ammuymmmxrmwmrnmfmnymfimfi‘""-'
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`
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`Apotex (IPR2019-00400) Ex. 1027, p. 016
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`

` 748
`
`.
`
`Alcohols
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`Acids
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`PART 51FHARMACEUTICAL MANUFACTURING
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`When a preservative is required, its selection is based upon
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`several considerations, in particular the site of use whether in»
`ternal, external, or ophthalmic.” Several researchers have de-
`enzyme systems or cell wall synthesis, oxidation of'
`
`scribed various interactions that ,must be considered when
`stituents, or hydrolysis.
`‘
`
`preservatives are ',-3elected.1""15 The major criteria that should
`Preservatives commonly used in pharmacau
`
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`be considered in selecting a preservative are as follows: It
`are listed in Table 39~2 with typical concent
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`should be efl'ective against a wide spectrum of microorganisms,
`
`Preservatives may be grouped into a number
`stable for its shelf life, nontoxic, nonsensitizing, compatible
`pending upon their molecular structure. These be
`
`'
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`discussed below.
`with the ingredients in the dosage form, inexpensive, and rela—
`tively fi'ee of taste and odor.
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`rl‘he chosbn preservative should be sufficiently stable and
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`soluble to achieve adequate concentration to provide protection.
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`This'choice' is more critical in two and three phase emulsion
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`systems in which the preservative may be more soluble in the
`Ethanol is useful as a preservative when it is used
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`oil phase than in the aqueous phase.12'15 The pH of the prepa—
`however, it does need a relatively high concentc
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`ration must be considered to ensure that the preservative does
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`what greater than 15%, to be effective. Too high a ‘
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`notldissociate rendering it ineffective or degrade by acid or base
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`may result in incompatibilities in suspension and
`catalyzed hydrolysis. The undissociated moiety or molecular
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`terns. Propylene glycol also is used as a solvent in
`form of a preservative possesses preservative capacity because
`and topical preparations, and it can function as a
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`the ionized form is unable to penetrate microorganisms. The
`in the range of 15% to 30%. It is not volatile like a
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`preservative must be compatible with the formulation ingredi-
`used frequently not only in solutions but also
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`ents'and the product container or closure. Finally, the preser-
`and emulsions. Chlorobutanol and phenylethyl
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`vative must not impact the safety or comfort of the patient
`other alcohols used in lower concentrations (a
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`preservatives.
`when administered. For instance, preservatives used in oph—
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`thalmic preparations must be non-irritating. Chlorobutanol,
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`benzalkonium chloride, and phenylmercuric nitrate are com-
`monly used in these applications.
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`Although few microorganisms are viable below a pH of 3 or
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`above pH 9, most aqueous pharmaceutical preparations are
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`manufactured within the favorable pH range. Acidic preserva-
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`tives such as benzoic acid, boric acid, and‘sorbic acid are less
`diasociated and more efi‘ective in acidic formulations. Similarly,
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`alkaline preservatives are less efl‘ective in acidic 01- neutral con-
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`varies from 0.1% to 0.5%. Activity depends on till
`ditions and more effective in alkaline formulations. The scien-
`medium because only the undissociated acid has
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`tific literature is rife with examples of incompatibilities be-
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`properties. Optimum activity occurs at pH values
`tween preservatives and other pharmaceutical adjuncts."*19
`values above pH 5, benzoic acid is almost inactive
`
`Commonly used macromolecules including cellulose deriva-
`reported that antimicrobial activity of benzoic acid
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`tives, polyethylene glycol and tragacanth gum have been
`by the addition of the basic protein protamine 23
`reported to cause preservative failure due to binding and
`also has a low solubility in water, 0.3% at 30°C
`adsorption.m-21
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`The mode of action by which preservatives interfere with mi-
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`crobial growth, multiplication, and metabolism occurs through
`one ofseverol mechanisms. Preservatives ofien alter cell mem-
`brane permeability causing leakage of cell constituents (partiai
`lysis), complete lysis, and cytoplasmic leakage and / or coagula-
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`consequently, it is only effective in acid media.
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`antibacterial activity is obtained at pH 4.5, and
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`activity is observed above pH 6. Sorbic acid is
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`oxidation, particularly in the presence of light and
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`Table 39-2. Common Preservatives Used in Liquid Pharmaceutical Dosage Forms and Their Typical
`Concenration Levels
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`ANIIMIcaoBiAL'Pessesvmvss
` ANTIFUNGAi PRESERVATIVES
`
`‘ TYPICAL USAGE
`w W
`Benzalkonlum Chloride
`0.002—0.02%
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`
`Buty! Paraben
`0.1—0.4%
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`0.01-0.02%
`Benzethonium Chloride
`o 1—0.25%
`Methyl Faraben
`Benzyl Alcohol
`3.0%
`0 1—0 25%
`Ethy! Paraben
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`Bronopol
`0.01-0.1%
`Propyi Paraben
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`
`Benzoic Acid
`Cetrimlde
`0.005%
`
`
`Potassium sorbate
`Cetyipyridiniurn chloride
`0.0005—0.0007%
`
`Chlorhexidine
`0.002-0.5%
`Sodium Benzoate
`
`
`Chloroertanol
`0.5%
`Sodium Propionate
`Chlorocresol
`0.2%
`Sorbic Acid
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`Chloroxylenol
`0.1»«0.B%
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`Cresol
`0.15—0.3 %
`
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`Ethyl Alcohol
`15—20%
`Glycerin
`20—30%
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`Hexeticline
`0.1%
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`lmldurea
`0.03—0.5%
`
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`Phenol
`0.1~0.5%
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`Phenoxyethsnol
`0.5—1.0%
`Fhenylethyl Alcohol
`0.25w0.5%
`
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`Fhenylmercurlc Nitrate
`0.002—0.01 %
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`Propylene Giycol
`15—30%
`Apotex (IPR2019-00400) EX. 1027, p. 01
`
`Apotex (IPR2019-00400) Ex. 1027, p. 017
`
`

`

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`CHAPTER 39: SOLUTIONS, EMUISIONS, SUSPENSIONS. AND EXTRACl'S
`749
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` Activity against bacteria can be variable because of
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`d stability. Thus, sorbic acid is frequently used in com-
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`with other antimicrobial preservatives or glycols in
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`ynergistic effects occur.
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`are esters ofp-hydroxybenzoic acid and include the
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` ' r
`thyl, prupyl, and butyl derivatives. The water solubil»
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`parabens decreases as the molecular weight increases
`25% for the methyl ester to 0.02% for the butyl ester.
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`mijountlfi are used widely in pharmaceutical products,
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`' ga pH range of 4 to B, and have a broad spectrum of
`, on:
`:91 acfivity, although they are most efi'ective against
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`”d. olds. Antimicrobial activity increases as the chain
`of the alkyl moiety is increased, but aqueous solubility
`
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`therefore, a mixture of parabens is frequently used
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`Eective preservation. Preservative efficacy is also
`a
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`
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`the addition of propylene glycol (243%) or by using
`combination with other antimicrobial agents such
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`Activity is reduced in the presence ofnonionic sur-
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`gents due to binding. In alkaline solutions, ioniza—
`.
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`9”” {fissuplaceand this reduces their activity; in addition, by-
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`position of the ester group occurs with a loss of
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`gs (31‘2st and'Cqug. This preservative is used at
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`”w concentration, 0.002% to 0.02%, depending on
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`compounds has an optimal activity over the pH range of 4 to
`10 and is quite stable at room temperature. Because of the
`cationic nature of this type of preservative, it is incompatible
`with many anionic compounds such as surfactants and can
`bind to nonionic surfactants. It is used generally in prepara»
`tions for external use or those solutions that come in contact
`with mucous membranes. In ophthalmic preparations, benze-
`lkonium chloride is widely used at a concentration of
`0.01—0.02% wlw. Ofien it is used in combination with other
`preservatives or excipients, particularly 0.1% w/v disodium
`edetate, to enhance its antimicrobial activity against strains
`of Pseudomonos. A concentration of 0.002—0.02% is used in
`nasal and otic formulations, sometimes in combination with
`0.002—0.005% thirnerossl. Benaallsonium chloride 0.01% w/v
`is also employed as a preservative in smallmvolume parenteral
`products.
`Clearly, when the pharmacist dispenses or compounds liq—
`uid preparations, responsibility is assumed, along with the
`manufacturer, for the maintenance of product stability. Gen—
`eral chapter (1191) of the USP describes stability considera«
`tions for dispensing, which should be studied in detail.9 Stock
`should be rotated and replaced if expiration dates on the label
`so indicate. Products should be stored in the manner indicated
`on the manufacturer’s label or in the compendium. Further,
`products should be checked for evidence of instability. With re—
`spect to solutions, elixirs, and syrups, major signs of instability
`are color change, precipitation, and evidence of microbial or
`chemical gas formation. Emulsions may cream, but if they
`break (ie, there is a separation of an oil phase) the product is
`considered unstable. Sedimentation and caldng are primary in-
`dications of instability in suspensions. The presence of large
`particles may mean that excessive crystal growth has occurred
`(Ostwald Ripening). Additional details on these topics are pro
`vided in the pertinent sections of this chapter.
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`ploy one or several techniques such as applying heat, reducing
`the particle size of the solute, utilizing of a soiubilizing agent,
`or subje