IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`(Atty. Docket No, 06-796)
`
`In the Application of:
`
`Fanara et al.
`
`Thomas
`Serial No.
`
`10/599,451
`
`Filing Date:
`
`September 28, 2006
`
`For:
`
`Pharmaceutical Composition of Piperazine
`Derivatives
`
`eeeeeee
`eeeeereete8
`
`Examiner: Timothy P.
`
`Art Unit: 1614
`
`Confirmation No.: 9142
`
`DECLARATION OF DOMENICO FANARA UNDER37 CFR 1.132
`
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`I, Domenico Fanara, in support of the above-identified patent application, do aver and
`
`state as follows:
`
`I am the first named inventor of this application.
`
`I received a Pharmacy degree from University of Li¢ge Belgium in 1986
`
`Thave been employed by UCB Pharma SA since 1993 after having spent 6
`
`years in another pharmaceutical company Galephar 5.A as head of
`
`formulation development.
`
`A copy of my CYis attached hereto as Exhibit A that includelist of
`
`publications
`
`Levocetirizine and particularly its dihydrochloride salt are knownto be useful
`
`_as antihistamines, Levocetirizine dihydrochloride is available in solid dosage
`
`form, The present invention is directed to a formulation that allows for the
`
`availability of levocetirizine andits salts in liquid dosage form.
`
`Apotex (IPR2019-00400) Ex. 1027, p. 001
`
`Apotex (IPR2019-00400) Ex. 1027, p. 001
`
`

`

`One common problem with liquid pharmaceutical formulations in generalis
`
`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 dosing implements. Thus, it has
`
`become commonpractice to include preservatives in such formulations to
`
`prevent the growth of such microorganisms. Methyl parahydroxybenzoate
`
`and propy] parahydroxybenzoate, commonly known as methyl paraben and
`
`propyl paraben, respectively (hereinafter “MP” and “PP,” together
`
`“parabens”), are frequently used for this purpose.
`
`The combined parabensin 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, 21“ 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
`
`ourinvention that levocetirizine has antimicrobial properties, This led to our
`
`discovery that liquid pharmaceutical compositions of levocetirizine could be
`
`formulated with lower paraben concentrations than previously thought
`
`necessary and without additional preservatives.
`
`10.
`
`Submitted herewith as Exhibit C are the resuits of testing of antimicrobial
`
`efficacy on several batchesof oral drop solution having 5 mg/ml of
`
`levocetirizine, 0.3375 mg/ml MP and 0.0375 mg/ml of PP, for an MP/PPratio
`
`Apotex (IPR2019-00400) Ex. 1027, p. 002
`
`Apotex (IPR2019-00400) Ex. 1027, p. 002
`
`

`

`of 9 and a total parabens content of 0.375 mg/ml. The compositions contained
`
`no other preservative, The batch sizes varied from 100 1. to 1000 L. The
`
`testing results confirmed that inoculated test samples of al] of the batches were
`
`essentially free of both bacteria and fungus 14 and 28 days after inoculation.
`
`This result is surprising because the amount of parabens used was less than
`
`one fifth of the minimum recommended by the Remington treatise.
`
`Submitted herewith as Exhibit D are the results of testing of antimicrobial
`
`efficacy on two batches of oral solution containing 0.5 mg/ml of
`
`levocetirizine, 0.675 mg/ml MP and 0.075 mg/ml of PP, for an MP/PPratio of
`
`9 and a total parabens content of 0.750 mg/ml. The compositions contained
`no otherpreservative. 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.
`
`12.
`
`Ihave reviewed the references cited by the U.S. 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, lines18-22, 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 amountsof 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
`
`wasat least the minimum of 2 mg/mlasset forth in the Remingtontreatise
`
`and as generally understood atthat time as being a typical concentration of
`
`preservative for a liquid pharmaceutical product,
`
`Apotex (IPR2019-00400) Ex. 1027, p. 003
`
`Apotex (IPR2019-00400) Ex. 1027, p. 003
`
`

`

`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. cali 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 parabensin the tested solutions was
`
`1.32 mg/ml, more than 10% higher than the 1,125 mg/m] 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
`
`wasoflittle value in that experiment (p. 257). The amount of parabens used
`
`in Gilliland {| 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 I would 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
`
`levocetirizine 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 MPateither 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 (IPR2019-00400) Ex. 1027, p. 004
`
`Apotex (IPR2019-00400) Ex. 1027, p. 004
`
`

`

`art, this suggests that the concentrations selected for study were nat
`
`necessarily optimal for use in a pharmaceutical composition that have to be
`
`essentially free of such bacteria,
`
`I also note that the time period aver which
`
`testing was done was about six hours, so thal the results cannot be properly
`
`extrapolated to pharmaceutical compositions which require long-term storage,
`
`16.
`
`Doron discloses compositionsthat significantly reduce E.coli, but at paraben
`
`concentration that are 37% and 248% greater than the concentrations used in
`
`our invention. As one skilledin the art, this reference suggests to me that at
`
`the MP/PPratios 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.
`
`17.|As one skilled in the art, the combination of Doron, DeLongueville, Gilliland
`
`Land Gilliland II does not teach or suggest that a pharmaceutical formulation
`
`could be preparedthat is maintained substantially free of bacteria and having
`
`the a total of MP and PP ofno greater than 1.125 mg/ml, and no other
`
`preservative, Gilliland I and IT 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 staternents and the like are
`
`punishable by fine or imprisonment, or both (18 U.S.C. 1001), and that such willful false
`
`statements may jeopardize the validity of the application or document or any registration
`
`resulting therefrom, and I declare that all statements made of my own knowledgeare
`
`true; and all statements made on information and belief are believed to be true.
`
`Domenico Fanara
`
`Apotex (IPR2019-00400) Ex. 1027, p. 005
`
`Apotex (IPR2019-00400) Ex. 1027, p. 005
`
`

`

`
`
`Apotex (IPR2019-00400) Ex. 1027, p. 006
`
`Apotex (IPR2019-00400) Ex. 1027, p. 006
`
`

`

`Domenico Fanara, Ind. Pharm.
`
`Inte
`
`Home Address:
`
`Rue Font de Soleil, 2A,
`B-4520 Wanze
`
`Telephone (wk); +32.2.386.20.04
`Telephone (hm): +32.85.23.57.69
`Mobile : +32.494.578.142
`E-mail: domenico.!anara@ucb.com
`
`Current Position:
`
`Date of birth; October 31", 1963
`Senior Director
`Innovation & Technology Development
`UCB Pharma S.A,
`B-1420 Braine-l’ Alleud.
`
`Expertise: Specific Skills
`
`Fully familiar with pharmaceutical sciences and drug development.
`«
`es Extensive experience in the development of novel technologies for compounds with
`poorsolubility
`.
`° Extensive experience in the developmentof slow release formulations
`© Evaluation of external technologies to support own projects
`®* Program and project managementskills including goal setting, planning, budget
`forecasting and tracking and progress reporting
`°® Experience in management of developmentstaffs with global footprint,
`e Management of budget (OPEX,External,Investment)
`
`Strengths:
`e Creativity, focus, and result oriented
`
`General skills;
`
`® Trilingual English, French (mother tongue) Italian
`e
`Fully familiar with the main computer softwares (Word, Excel, PowerPoint, Access,
`Outlook ..,)
`
`Apotex (IPR2019-00400) Ex. 1027, p. 007
`
`Apotex (IPR2019-00400) Ex. 1027, p. 007
`
`

`

`Domenico Fanara, Ind. Pharm.
`
`Employment:
`April 2010
`2009
`
`2006-2009
`1995
`4993
`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 §.A. ( 85 FTE’s)
`Drug Product R&D Senior Director, UCB Pharma S.A, (135 FTE’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 managementof all activities of the Drug
`Product and Delivery Route Research & Development department in accordance with the
`Pharmaceutical Sciences mission statements.
`
`The fulfilmentof this role will therefore require the active provision of strategic technical
`guidancefor the initiation and managementof development projects and for the supply of
`Drud Product (DP) for early clinical trials. In connection with this, J ensure the
`managementof the departmentvia the effective management of resources (specifically
`staff, facilities and the relevant budgets).
`
`*
`
`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 Departmentwill also be responsiblefortransferring
`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 forall 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
`
`Apotex (IPR2019-00400) Ex. 1027, p. 008
`
`

`

`Domenico Fanara, Ind. Pharm.
`
`As deputy of the head of Pharmaceutical Sciences:
`
`© To coordinate Development’s activities related to Pre-formulation ,Formulation &
`Drug Delivery Developments for NBE’s and NCE’s
`e To manage the availability of DP for Clinicaltrials.
`® To obtain and to ensure the coherence between all different Projects, in order to
`prioritize responsibilities and tasks in the department.
`e To ensure full compliance with QA, cGMPorrelated requirements.
`* To strengthen the UCB IP position through innovation.
`®
` loversee and advice for the developmentof 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:
`
`e Development of intellectual property fillings with for freedom to operate and
`potential exclusions,
`® Developrnent of extensions for current UCB proprietary drug delivery technologies.
`
`Education:
`
`Industrial Pharmacist
`1989
`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
`
`Apotex (IPR2019-00400) Ex. 1027, p. 009
`
`

`

`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
`
`1995
`
`1995
`
`1995
`
`Symposium drug delivery
`
`Pharmaceutical technology: lipidic vehicles (Gattefasse)
`
`Pharmaceutical technology conference (Amsterdam)
`
`First europeanintensive course on new forms a,nd new routes of administrations or drugs
`
`(Coimbra)
`
`1994 GTRY (Paris)
`
`1994
`
`Pharmaceutical technology conference (Barcelona)
`
`1993
`
`1993
`
`Statistic course (ULB)
`
`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 Litge
`
`(Prof. Delarge)
`
`1985 Work experience in the clinical biology laboratory of the University of Liége Prof,
`Heusghem)
`
`Apotex (IPR2019-00400) Ex. 1027, p. 010
`
`Apotex (IPR2019-00400) Ex. 1027, p. 010
`
`

`

`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
`Journal 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(11):745-9, 1991 Nov.
`
`Preparation and in vitro/in vivo evaluation of nano-sized crystals for dissolution rate enhancementof
`UCB-35440-3, a highly-dosed poorly water soluble weakbase.
`Eur. J. Pharm. & Biopharm, 64, 360-368
`(2006)
`
`In vitro transport studies of nifedipine nanoparticules across Caco-2/HT29-5M21 cultures & co-
`cultures
`Bur. J. Pharm. & 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 98/41 194 and US Patent 6,699,502
`
`Pseudopolymorphic forms of 2-[2-[4-[Bis (4-fluorophenyl) methyl]-1-piperazinyljethoxyacetic acid
`dihydrochloride
`International patent application WO 99/28310 and US Patent 6,335,331
`
`Tablet comprising efletirizine and pseudoephedrine.
`International patent application: WO 2003/059328
`
`Tablet comprising efletirizine
`International patent application: WO 2003/057198
`
`Oral formulationsfor cetirizine and related compounds.
`International patent Application: WO 99/01 133 and US patent US 6,455,533
`
`Apotex (IPR2019-00400) Ex. 1027, p. O11
`
`Apotex (IPR2019-00400) Ex. 1027, p. 011
`
`

`

`Domenico Fanara, Ind. Pharm.
`
`Pharmaccutical compositions for oral administration comprising substituted benzhydrylpiperazines
`and a cyclodextrin.
`US Patent US 6,455,533 - Buropean Patent EP 0 994 710,
`
`Use of pharmaceutical compositions capable of being gelled in periodontolozy
`International patent application WO 56726 and US Patent US 6,818,224
`
`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
`Internationa] 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
`
`Pharmaceutical oral compositions
`International patent application WO 2010/057869
`
`Pharmaceutical oral compositions
`Internationa) patent application WO 2010/057870
`
`Other interests:
`
`Reading, cycling, swimming.
`
`Apotex (IPR2019-00400) Ex. 1027, p. 012
`
`Apotex (IPR2019-00400) Ex. 1027, p. 012
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`

`

`
`
`Apotex (IPR2019-00400) Ex. 1027, p. 013
`
`Apotex (IPR2019-00400) Ex. 1027, p. 013
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`

`

`
`
`
`
`
`
`20ST EDITION
`
`
`
`Tne Science ano Practi
`
`
`of Pharmacy
`
`A Wolters Kluwer Company
`Philadelphia « Baltimore « New York « London
`Buenos Aires « Hong Kong + Sydney + Tokyo
`
`
`
`Apotex (IPR2019-00400) Ex. 1027, p. 014
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`

`

`
`
`Remington:The Science and Practice of Pharmacy. .. A treatise on the theory
`and practice of the pharmaceutical sciences, with essential
`information about pharmaceutical and medicinal agents;also, a
`guide to the professional responsibilities of the pharmacist as the
`drug information specialist of the health team .. . A textbook and
`reference work for pharmacists, physicians, and other practitioners of
`the pharmaceutical and medical sciences.
`
`EDITORIAL BOARD
`
`Paul Beringer
`Ara DerMarderasian
`Linda Felton
`Steven Gelone
`Alfonso R. Gennaro
`
`Pardeep K. Gupta
`John E. Hoover
`Nicholas G. Popovick
`William J. Reilly, Jr
`Randy Hendrickson, Chair
`
`AUTHORS
`
`The 133 chapters of this edition of Remington were written by
`the editors, by membersof 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
`PHILADELPHIA COLLEGE OF PHARMACY AND SCIENCE
`
`
`
`a1
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`
`
`Apotex (IPR2019-00400) Ex. 1027, p. 015
`
`

`

`
`
`”
`
`‘Editer: David B. Tray
`Managing Editor: Matthew J. Hauber
`Marketing Manager: Marisa A. O'Brien
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`.
`The publisheris nat responsible (as a matter ofproductliability, negligence or otherwise) for anyinjury resulting from any
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`be construed as specific instructions for individual patients. Manufacturer's product information and package inserts should be
`yeviewed for current information, including contraindications, dosages and precattions.
`Printed in the United States of America
`Entered according to Act of Congress, in the year 1885 by Joseph P Remington,in the Office ofthe Librarian ofCongress,at
`
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`Copyright 1989, 1894, 1905, 1907, 1917, byJoseph 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 ofthe Sciences in Philadelphia
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`The use ofstructuralformulasfrom USANand the USPDictionary ofDrugNames is bypermission ofThe USP Convention. The
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`Notice—This text is not intended to represent, nor shall it be interpreted to be, the equivalent ofor a substitute for the official
`United States Pharmacopeia (USP) and/or the National Formulary (NF). In the eventofany difference or discrepancy between the
`current official USP orNFstandardsofstrength, quality, purity, packoging and labelingfor drugs and representations ofthem
`herein, the context and effect ofthe official compendia shall prevail.
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`Apotex (IPR2019-00400) Ex. 1027, p. 016
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`12345678910
`
`
`
`
`
`PEATTATSsgeccuenpnageePDISSSSELINAom
`
`eeepeennnSTEREESHEAMRMAPETO
`
`Apotex (IPR2019-00400) Ex. 1027, p. 016
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`

`

` 748
`
`_
`
`;
`
`
`PART 5S: PHARMACEUTICAL MANUFACTURING
`
`
`
`Whena preservative is required,its selection is based upon
`tion of cytoplasmic constituents (protein precipitatio
`several considerations, in particular the site of use whether in-
`preservatives inhibit cellular metabolism by inte;
`
`ternal, external, or ophthalmic."3 Several researchers have de-
`anzyme systems or cell wall synthesis, oxidation of;
`scribed various interactions that must be considered when
`stituents, or hydrolysis.
`
`preservatives are selected.*> The major criteria that should
`Preservatives commonly used in pharmacey
`
`be considered in selecting a preservative are as follows: It
`are listed in Table 39-2 with typical concent
`
`should beeffective against a wide spectrum of microorganisms,
`Preservatives may be grouped into a number
`
`stable for its shelf life, nontoxic, nonsensitizing, compatible
`pending upontheir molecular structure. These ba:
`
`with the ingredients in the dosage form, inexpensive, and rela-
`discussed below.
`
`tively free of taste and odor.
`The chosen preservative should be sufficiently stable and
`soluble td aghieve adequate concentration to provide protection,
`
`This choice is more critical in two and three phase emulsion
`systems in which the preservative may be more soluble in the
`Ethanolis useful as a preservative whenit is used
`
`oil phase than in the aqueous phase.!*!6 The pH of the prepa-
`however, it does need a relatively high concentr:
`
`tation must be considered to ensure that the preservative does
`what greater than 15%,to be effective. Too high ac
`notdissociate renderingit ineffective or degradeby acid or base
`may result in incompatibilities in suspension and
`
`catalyzed hydrolysis. The undissociated moiety or molecular
`tems. 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
`
`the ionized form is unable to penetrate microorganisms. The
`in the range of 15% to 30%.It is not volatile like e
`preservative must be compatible with the formulation ingredi-
`used frequently not only in solutions but also
`
`ents‘and the product container or closure. Finally, the preser-
`and emulsions, Chlorobutanol and phenylethyl
`vative must noé impact the safety or comfort of the patient
`other alcohols used in lower concentrations (al
`
`when administered. For instance, preservatives used in oph-
`preservatives.
`thalmic preparations must be non-irritating. Chlorobutanol,
`
`benzalkonium chloride, and phenylmercuric nitrate are com-
`monly used in these applications.
`
`Although few microorganisms are viable below a pH of 3 ar
`
`above pH3, most aqueous pharmaceutical preparations are
`Bengoic acid has a low solubility in water, about 0
`
`manufactured within the favorable pH range, Acidic preserya-
`butthe apparent aqueous solubility of benzoic acl
`tives such as benzoic acid, boric acid, andsorbic acid are less
`
`hanced bythe addition ofcitric acid or sodium acetat
`
`dissociated and more effective in acidic formulations. Similarly,
`lution, The concentration range used for inhib
`
`alkaline preservatives are less effective in acidic or neutral con-
`varies from 0.1% to 0.5%. Activity depends on th
`ditions and more effective in alkaline formulations. The scien-
`medium because only the undissociated acid has
`
`tific literature is rife with examples of incompatibilities be-
`properties. Optimum activity occurs at pH values
`
`tween preservatives and other pharmaceutical adjuncts.‘*-9
`values above pH5, benzoic acid is almost inactive.”
`
`Commonly used macromolecules including cellulose deriva-
`reported that antimicrobial activity of benzoic acid
`
`tives, polyethylene glycol and tragacanth gum have been
`by the addition of the basic protein protamine.
`
`reported to cause preservative failure due to binding and
`also has 3 low solubility in water, 0.3% at 30°C
`adsorption.2°21
`
`centrations for preservative action are in.the rant
`
`The modeofaction by which preservatives interfere with mi-
`2%. Its preservative action is due to the non
`crobial growth, multiplication, and metabolism occurs through
`consequently, it is only effective in acid media.
`
`one ofseveral mechanisms, Preservativesoften alter cell mem-
`antibacterial activity is obtained at pH 4.5, and
`
`brane permeability causing leakage ofcell constituents (partial
`activity is observed above pH 6, Sorbic acid is
`lysis), complete lysis, and cytoplasmic leakage and / or coagula-
`oxidation, particularly in the presence oflight and
`
`
`
`
`Table 39-2, CommonPreservatives Used in Liquid Pharmaceutical Dosage Forms and Their Typical
`Concentration Levels
`
`
`
`TYPICAL USAGELEVEL (% W.
`ANTIMICROBIALPRESERVATIVES
` ANTIFUNGAL PRESERVATIVES
`
`Benzalkonium Chloride
`0,002-0.02%
`Buty! Paraben
`0.1-0.4%
`
`
`0.01-0.02%
`Benzethonium Chloride
`Methyl Paraben
`0.1-0.25%
`Benzyl Alcohol
`3.0%
`0.1-0.25%
`Ethyl Paraben
`Bronopol
`0.01-0.1%
`0.1-0.25%
`Propy! Paraben
`
`Benzoic Acid
`Cetrimide
`0.005%
`0.1-0.5%
`Cetylpyridinium chloride
`0.0005-0.0007%
`Potassium sorbate
`0.1-0.2%
`Chlorhexidine
`0.002-0.5%
`Sodium Benzoate
`0,1-0.2%
`Chlorobutanol
`0.5%
`5-10%
`Sodium Propionate
`Chloracresol
`0.2%
`Sorbic Acid
`0.05-0.2%
`Chioroxylenol
`0.1-0.8%
`Cresol
`0.15-0.3%
`Ethyt Alcohol
`15-20%
`Glycerin
`20-30%
`Hexetidine
`0.1%
`Imidurea
`0.03-0.5%
`Phenal
`0.4~0.5%
`Phenoxyethano!
`0.5-1.0%
`Phenylethyl Alcohol
`0.25-0.5%
`Phenylmercuric Nitrate
`0.002-0.01%
`Propytene Glycol
`15-30%
`
`
`
`
`
`
`
`
`
` 1027, p. 01
`
`Alcohols
`
`Acids
`
`Apotex (IPR2019-00400) Ex.
`
`Apotex (IPR2019-00400) Ex. 1027, p. 017
`
`

`

`
`
`CHAPTER39: SOLUTIONS, EMULSIONS, SUSPENSIONS, AND EXTRACTS
`749
`
`
`compounds has an optimal activity over the pH range of 4 to
` Activity against bacteria can be variable because of
`10 and is quite stable at room temperature. Because of the
`‘stability. Thus, sorbic acid is frequently used in com-
`
`cationic nature of this type of preservative, it is incompatible
`with other antimicrobial preservatives or glycols in
`with many anionic compounds such as surfactants and can
`synergistic effects occur.
`
`bind to nonionic surfactants. Jt is used generally in prepara-
`tions for external use or those selutions that come in contact
`with mucous membranes. In ophthalmic preparations, benza-
`
`ikonium chloride is widely used at a concentration of
` ‘are eaters ofp-hydroxybenzoic acid and include the
`0.01-0.02% wiw. Often it is used in combination with other
`
`thyl, propyl, and butyl derivatives. The water selubil-
` AY
`preservatives or excipients, particularly 0.1% w/v disodium
`parabens decreases ag the molecular weight increases
`edetate, to enhance its antimicrobial activity against strains
`
`of Pseudomonas. A concentration of 0.002-0,02% is used in
`359 for the methyl ester to 0.02% for the butyl ester.
`
`mpornds are used widely in pharmaceutical products,
`nasal and otic formulations, sometimes in combination with
`
`0.002-0.005% thimernsal. Benzaikonium chloride 0.01% w/v
`ara pH range of 4 to 8, and have a broad spectrum of
`
`epobial activity, although they are most effective against
`is also employed as 2 preservative in small-volume parenteral
`
`“4inolds. Antimicrobial activity increases as the chain
`products.
`
`23the alkyl moiety is increased, but aqueous solubility
`Clearly, when the pharmacist dispenses or compoundslig-
`
`‘therefore, a raixture of parabens is frequently used
`uid preparations, responsibility is assumed, along with the
`de‘effective preservation. Preservative efficacy is also
`manufacturer, for the maintenance of product stability. Gen-
`
`the addition of propylene glycol (2-5%) or by using
`eral chapter (1191) of the USP describes stability considera-
`tions for dispensing, which should be studied in detail.? Stock
`combination with. other antimicrobial agents such
`
`Activity is reduced in the presence ofnonionic sur-
`should be rotated and replaced if expiration dates on the label
`
`so indicate. Products should be stored in the manner indicated
`gents due to binding. In alkaline solutions, ioniza-
`3
`“ter ighesplaceand this reduces their activity; in addition, hy-
`on the manufacturer’s label or in the compendium. Further,
`
`
`ipasition of the ester group occurs with a loss of
`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 ig a separation of an oil phase) the product is
`
`considered unstable. Sedimentation and calcing are primary in-
`
`dications of instability in suspensions. The presence of large
`
`particles may mean that excessive crystal growth has occurred
`88 Cy2Hes andCy,Hgs. This preservative is used at
`
`(Ostwald Ripening). Additional details on these topics are pro-
`aw concentration, 0.002% to 0.02%, depending on
`vided in the pertinent sections of this chapter.
`
`
`
`
`ploy one or several techniques such as applying heat, reducing
` omogeneous mi