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`An Official Journal of the American Association of Pharmaceutical Scientists
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`PHARMACEUTICAL RESEARCH
`An Offici!J.I Journal·ofthe American Association of Pharmaceutical Scientists
`Phatmaceutical Research publishes innovative basic research and tecill}ological advances in the pharmaceutical-biomedical sciences. Research areas covered in
`the journal inClude:· pharmaceutics and drug delivery,_ pharmacokinetics and pharmacodynamics, drug metabolism, pharmacology and toxicology, medicinal
`chemistry; natural products chemistry, analyticaL chemistry, chemical kinetics and drug stability, biotechnology, pharmaceutical technology, and clinical inves(cid:173)
`tigations, as well as articles on the social, economic, or management aspects of the pharmaceutical scien~es.
`EDITOR·IN·CIIIEF .
`.
`·
`·
`..
`'. ·
`Ken-ichi Inul, Kyoto University Hospital, Kyoto, Japan
`Myron K. Jacobson, University of Kentucky, Lexington, Kentucky
`Vincent H. L. Lee, Department of}>harmaceutical Sciences, University of
`Southern Californhi,_ Los· ~geles;' California· ·
`Rudy L. Juliano, University of North Carolina, Chapel Hill, North Carolina
`Hans E, Junginger, University of Leiden, Leiden, The Netherlands
`William J, Jusko, SUNYB School of Pharmacy, Amherst, New York
`Tetsuya Kamataki, Hokkaido University, Sapporo, Japan
`Neil Kaplowitz, University of Southern California, Los Angeles, California
`Jan w. Kellaway, Welsh School of Pharmacy, Cardiff, Wales
`Sung Wan Kim, University of Utah, Salt Lake City, Utah
`Thomas Kissel, University of Marburg, Marburg,Germany
`Joachim Kohn, Rutgers University, Picataway, New Jersey
`Peter A. Kollman, University of California, San Francisco, California
`Jlndrich Kopecek, University of Utah, Salt Lake City, Utah
`Thomas M. Ludden, University of Nebraska Medical Center, Omaha,
`Nebraska
`Susan M. Lnnte, University of Kansas, Lawrence, Kansas
`Gordon McKay, University of Saskatchewan, Saskatchewan, Canada
`Hans P. Merkle, Swiss Federal Institute of Technology, Zurich,
`Switzerland
`Kamal K. Midha, University of Saskatchewan, Saskatchewan, Canada
`Duane D. Miller, University of Tennessee, Memphis, Tennessee
`Randall J, Mrsny, Genentech, South San Francisco, California
`Bernd W. Muller, Christian-Aibrechts-Universitat, Klel, Germany
`Shozo Muranishi, Kyoto Pharmaceutical University, Kyoto, Japan
`Tsuneji Nagai, Hoshi University, Tokyo, Japan
`·
`Masahiro Nakano, Kumamoto University Hospital, Kumamoto, Japan
`Teruo Okano, Tokyo Women's Medical College, Tokyo, Japan
`Michael J, Pika!, University of Connecticut, Storrs, Connecticut
`Veronique Preat, Universite Catholique de Louvain, Bruxelles, Belgium
`Ronald E. Reid; University of British Columbia, Vancouver, Canada
`Jim E. Riviere, North Carofina State University, Raleigh, North Carolina
`Joseph R. Robinson, University of Wisconsin, Madison, Wisconsin
`Malcolm Rowland, University of Manchester, Manchester, England
`Wolfgang Sadee, University of California, San Francisco, California
`Toml K. Sawyer, Parke-Davis/Warner-Lambert, Ann Arbor, Michigan
`Wei-Chiang Shen, University of Southern California, Los Angeles,
`California
`Valentino J, Stella, University of Kansas, Lawrence, Kansas.
`Andy Stergachls, University of Washington, Seattle, Washington
`Yuichl Sugiyama, University of Tokyo, Tokyo, Japan
`Eric Tomlinson, GeneMedicine, The Woodlands, Texas
`Akira Tsuji, Kanazawa University, Kanazawa, Japan
`.
`John Urquhart, University of Limburg, Maastricht, The Netherlands
`Timothy S. Wiedmann, University of Minnesota, Minneapolis, Minnesota
`Robert J, Wills; R. W. Johnson Pharmaceutical Research InS'titute,
`Raritan, New Jersey
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`>.
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`c
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`Keljl Yamamoto, Chiba t!niversity, Chiba,.Japan:
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`·.
`
`BOOK REVIEW EDITOR
`Klnam Park, Purdue University, School of Pharmacy, West Lafayette,
`Indiana 47097
`
`EDITORIAL ASSISTANTS
`Ruth Ellis-Ballard
`Elizabeth B. Gongora
`Hldeo Ueda
`
`EDITOR-EUROPE
`Bemnl'd Testa, University of Lau~anne, Lausanne, Switzerland
`
`EDITOR-JAPAN
`Mltsuru Hashida, Kyoio University, Kyoto~Japan
`
`.
`ASSOCIATE 'EOITORS
`William E. Evnns,,St. Jtid~~rChi)d~¢n's Research Hospital, Memphis,
`Tennessee
`· ·
`·
`Klnam Park, Purdue University, West Lafayette, Indiana
`Bonnie L •. Svarstad, UniversitY of Wisconsin, Madison, Wisconsin
`
`ASSISTANT EDITOR-EUROPE
`Joachim ]\'l. H; ·Mayer, University of Lausanne, Lausanne, Switzerland
`
`EDITOR-SPECIAL FEATURES
`Daan Crommelin, Utrecht Institute for Pharmaceutical Sciences, Utrecht,
`The Netherlands
`
`EDITORIAL ADVISORY BOARD
`Gordon L. Amidon, University of Michigan, Ann Arbor, Michigan
`Per Artursson, University of Uppsala, Uppsala, _Sweden
`Jessie Lai·Sim Au, Ohio State University, Columbus, Ohio
`Shoji Awazu, Tokyo University of Pharmacy & Life Science, Tokyo, Japan
`Michael B. Bolger, University of Southern California, Los Angeles,
`California
`J, Lyle Hootman, University of Arizona, Tucson, Arizona
`Ronald T. Borchardt, University of Kansas, Lawrence, Kansas
`Harold G. Boxenbaum, Otsuka America Pharmaceutical, Rockville,
`Maryland
`D. Craig Brater, Indiana University, Indianapolis, Indiana
`Douwe D. Breimer, University of Leiden, Leiden, The Netherlands
`Alice Clark, University of Mississippi, University, MisSissippi
`Patrick Couvreur, Universite de Paris-Sud, Chatenay-Malabry, France
`Richard N. Dalby, UMAB School of Pharmacy, Baltimore, Maryland
`Stanley s. Davis, The University of Nottingham, Nottingham, England
`Jennifer B. Dressman; Johann Wolfgang Goethe-Universitat, Frankfurt,
`Germany
`Alexander T. li'lorence, University of London, London, lj:ngland.
`John ·(}. Gamtiertogllo, University of California, San Francisco;· ·
`.•
`Cillifornia
`KathleiJn M. Gl.acominl, University of California_ at San Francis9_o,
`San Francisco, . California
`. .
`.
`·
`Robert Gul'ny, Universite o;le Geneve, Gene've, Switzeriand-
`.
`Jonathan Hadgraft, University or Wales, Cardiff; Wales
`Abraham G. Hartzema, University of North Carolina, Chapel Hill,
`North Carolina
`Joel Hay, University of Southern California, Los Angeles, California
`Susan Hershenson, Amgen Inc., Thousand Oaks, California
`Brian B. Hoffman, Stanford University, Palo Alto, California
`Anton J, Hopfinger, University of Illinois, Chicago, Illinois
`Tatsuji Jga, University of Tokyo Hospital, Tokyo, Japan
`
`Phannaceutical Research is published monthly by Plenum PubUshlng Co1poratlon, 233 Spring Street, New York, N.Y. 10013. Phannaceut/cal Research is abstracted or indexed in Bioscience
`Abstracts, Chemical Abstracts, Bxee1pta Medlca, Gazette de I'APGI, Index Medlcus/MEDLARS, and International Pharmaceutical Abstracts. © 1997 Plenum Publishing Co1poration.
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`

`
`mglmL with radioactivity between 30-40 #A-CilmL. Paired rabbit corneas
`were mounted on a modified Ussing dual-chambered perfusion apparatus.
`One cornea of each matched pair was mounted with the epithelium intact
`(epi-int), while its mate was carefully de-epithelialized (epi-de) with a Gill
`corneal knife. Both the donor and the receptor chambers were filled with
`approximately 7 mL of glutathione bicarbonate Ringers solution (GBR).
`The solutions were warmed to 37°C and bubbled with 5% C02 and 95% air
`to maintain temperature and physiological pH, respectively. Radio labeled
`BCX-34 ophthalmic solutions were added to the GBR in the donor chamber
`to allow for an initial concentration of either 0.125 mglmL (solution A) or
`0.25 mg/mL (solution B). Samples were taken from each chamber at 15
`minute time intervals for the duration of the 3 hour experiment. The
`radioactivity in these samples were measured by scintillation spectroscopy.
`The permeability coefficient (Ktran.) was calculated by the method of Maffly
`et al. The rate ofBCX-34 penetration (nglhr) through the cornea was also
`calculated. Results. The mean Ktran. values for solution A with epi-int and
`epi-de corneas are 9.73 x 10"7 and 1.66 x 10"5 em/sec, respectively.
`Similarly, the results for solution B are 1.12 x 10"6 and 1. 80 x 10"5 em/sec,
`respectively. The rate ofBCX-34 penetration for solution A with epi-int and
`epi-de corneas are 443.7 ±238 nglhr and 7,545 ±565 nglhr, respectively.
`The rate ofBCX-34 penetration for solution B with epi-int and epi-de
`corneas are 991.4 ±474 nglhr and 15,960 ±4,590 nglhr, respectively.
`Conclnsions. The permeability coefficient values or Ktnms are the same
`when the two doses ofBCX-34 solution were compared. However, de(cid:173)
`epithelialization results in a one-logarithm increase in Ktran. and a 16-17 fold
`increase in the amount ofBCX-34 crossing the cornea. Although the
`epithelium acts as a significant barrier to comeal penetration, the amount of
`peldesine delivered to the intact cornea may be sufficient for the treatment of
`T-cell related inflammatory disorders of the eye and its surrounding tissues.
`
`1127
`CYCLOSPORINE OPHTHALMIC 0/W EMULSION:
`FORMULATION AND EMULSION CHARACTERIZATION.
`Shulln Ding*, and Orest Olejnik. Phannaceutical Sciences, Research
`and Development, Allergan Inc., Irvine, CA 92612
`
`Objective. To develop a non-oily, water based cyclosporine eye drop for
`topical ophthalmic human use, and characterize its major physicochemical
`properties. Method. Standard methods were used for pH and osmolality
`measurements. Globule size was determined using single-particle optical
`sensing and static light scattering technologies. Rheologic properties were
`measured using a rheometer. A bench-top high-shear mixer was used for
`laboratory-scale emulsion preparation. Results, A stable, pH-adjusted, oil(cid:173)
`in-water emulsion was developed using castor oil as the internal phase to
`solubilize cyclosporine, polysorbate 80 as the primary emulsifier, and a
`polyelectrolyte as a stabilizer. The concentration of cyclosporine in the oil
`globule is formulated at the level of7.4% w/w, which is below the solubility
`ofthe drug in castor oil (9-10% w/w). Studies (solubility, interfacial tension,
`I; potential, stability) were conducted to support the use of each major
`excipient. The majority of globules are submicron in size with a bimodal
`size distribution profile. The globules bear negative charges with a I;
`potential of approximately -50 mv. The emulsion was demonstrated to be
`stable at room temperature for at least 18 months. Conclusion. An oil-in(cid:173)
`water emulsion of cyclosporine has been developed for topical ophthalmic
`human use.
`
`1128
`CONTROLLED AND SUSTAINED INTRA VAGINAL RING
`DELIVERY OF ESTRADIOL ESTERS FOR ESTROGEN
`REPLACEMENT THEORY. A. David Woolfson••, Grant R. E.
`Elliottb and Claire A. Gilliganb. •schoolofPhannacy, The Queen's
`University of Belfast, Belfast BT7 INN, Northern Ireland, UK; bGaien
`Ltd., Seagoe lndustriai Estate, Craigavon, Northern Ireland, UK.
`
`Objective, To determine the release in vitro of 17p-estradiol (E) and
`selected E esters from a core design intravaginal elastomeric ring (lVR), to
`relate in vitro with in vivo results and thus to determine ifiVR delivery ofE
`as an ester precursor, as compared to IVR delivery of E itself, can achieve E
`plasma levels appropriate for E replacement therapy. Methods.
`Polydimethylsiloxane elastomer was blended with n-propytorthosilicate
`(cross-linker) and 10% w/w ofE or an ester precursor, the mix being
`activated with 0.5% w/w stannous octoate. A drug loaded core was prepared
`by injection moulding of this mix, with curing at 80 for 2 minutes, A rate(cid:173)
`controlling membrane was prepared from a similar mix, omitting the active
`agent, by injection moulding of the mix around the active core, with
`
`identical curing. IVR devices were of cross-sectional diameter 9 mm, outer
`diameter 54 nun, with core cross-sectional diameter of2 mm and core length
`varied as required. in vitro drug release into either saline or, to ensure sink
`conditions, 1% w!V benzalkonium chloride (BKC) involved candidate IVR
`devices (n=4) being suspended in individual capped flasks at 37 with
`constant shaking, the release medium being replaced every 24 hours.
`Analysis was byHPLC using an ODS column (15 em), mobile phase
`MeCN/water 50:50, UV detection at 235 or 281 nm as appropriate. in vivo
`studies with ethical approval involved female post-menopausal subjects who
`gave informed consent, a randomised cross-over design, 2 week washout
`followed by 28 day treatment periods and plasma E determined at regular
`intervals throughout the washout and treatment periods. Results. Mean in
`vitro daily release (f.Lg) ofE from full core (141 mm) IVR devices into
`saline over 90 days was 8, compared to E-17 -propionate ester (26), E-17-
`acetate (24) and E-3-acetate (350). E-17-valerate gave no detectable release
`into saline, rising to 550 in BKC, with E-3-acetate increasing to 850 in this
`medium and E itself rising to 48. E-3-acetate IVR's releasing 120 (core
`length 24 mm) and 240 (core length 47 mm) f.Lg per day (as anhydrous E,
`determined under sink conditions in vitro) gave in vivo plasma E levels
`(pmol!L) of357±42 and 683±17 post-insertion, respectively, with mean
`pre-treatment levels of 47 and 44 pmoVL, respectively. An E-17-acetate ring
`releasing 100f.Lgper day (core length 141 mm, determined as anhydrous E
`under sink conditions) gave a mean in vivo plasma E level (pmoi!L) of
`108±8 (mean pre-treatment level of 48). An IVR releasing (nominally) 50
`f.Lg per day ofE itself in vitro gave a mean In vivo plasma level (pmoVL) of
`107±42. No significant increase over baseline plasma E was achieved with
`any IVR releasing E-17-valerate. Conclusions. The maximum release of E
`achievable from an injection-moulded core design lVR was not within the
`clinically desirable range forE replacement therapy. By contrast, this study
`demonstrates that E-3-acetate, in particular, provides controlled zero order
`release from a core design lVR sustained for at least one month, plasma E
`levels being maintained within the clinically desirable range throughout.
`The solubility characteristics of E-3-acetate allow sufficient flexibility (by
`altering core length) to design IVR devices capable of meeting a range of
`dosage requirements. in vitro release into saline was the best indicator of
`subsequent in vivo performance of candidate IVR devices.
`
`1129
`EVALUATION OF CARRAGEENANS AS A SUPPOSITORY BASE.
`Y. Lin, W.J. Reilly, and R.L. Schnaare*. Phannacentics, Philadelphia
`College of Phannacy and Science, Philadelphia, P A.
`
`Objective. To evaluate the potential of carrageenans for use as a
`suppository base; specifically to develop suitable compositions, evaluate
`their physical characteristics and evaluate their drug release properties.
`Methods. Aqueous dispersions containing 10% propylene glycol, 0.1%
`methylparaben, and carrageenans (!C, t, and A-: 0.1 to 2.3%, 0.5 to 3.55 and
`0 to 1% respectively) were prepared and evaluated quantitatively using a
`penetrometer modified for measuring a consistency index (compression of a
`1 cm3 sample under a constant toad). Those gels having properties suitable
`for use as suppository bases were evaluated for drug release using the
`methylparaben as a model drug. Release was determined using a dissolution
`procedure based on the "Enhancer Cell" and the USP basket method.
`Results. Two series of compositions were prepared, one containing all three
`carrageenans, the second containing kappa and iota carrageenan only.
`Multiple regression analysis for the three component formulations indicated
`that only kappa and iota carrageenan contributed to the consistency index (p
`>0.95) but that all three carrageenans influenced the release rate of the ·
`methylparaben (p > 0.85). Release rates ranged from 0.06 to 0.11 mg/..Jmin
`as detennined using the "Enhancer Cell". Forthetwo carrageenan system,
`both carrageenans significantly affected both the consistency index and drug
`release (p > 0.80) with release rates 0.1810 0.28 mg#squareroot#min as
`determined using the USP basket method. Drug release rate was poorly
`correlated with the consistency index for both series. Conclusions.
`Carrageenans are capable of forming matrices with characteristics suitable
`for use as suppository bases providing a linear ..Jtime drug release. Drug
`release and consistency are both functions of the carrageenan content;
`however, drug release is not simply a function of viscosity as measured by
`the consistency index. This study was supported by the FMC Corporation,
`Pharmaceutical Division.
`
`s- 41