PHARMACY LIBRARY
`UNIVERSITY OF WISCONSIN
`.JUN 1 4 2001
`Madison = \.!VI 53705
`
`KASHIV1029
`IPR of Patent No. 9,492,392
`
`

`

`Pharmaceutical Development
`and Technology
`
`Editor
`
`MICHAEL J. AKERS
`Akers Consulting and Training Services
`Cook Pharmaceutical Solutions
`2514 Fox cliff Estates North
`Martinsville, IN 46151
`
`BRADLEY ANDERSON
`University of Kentucky
`Lexington, KY
`
`LARRY AUGSBURGER
`University of Maryland
`Baltimore, MD
`
`GILBERT BANKER
`University of Iowa
`Iowa City, IA
`
`KURT H. BAUER
`Albert Ludwigs Universitat
`Freiburg, Germany
`
`SIMON BENITA
`Hebrew University of Jerusalem
`Jerusalem, Israel
`
`ROBIN H. BOGNER
`University of Connecticut
`Storrs, CT
`
`JAMES BOYLAN
`Gurnee, IL
`
`GAYLE A. BRAZEAU
`State University of New York
`at Buffalo
`Amherst, NY
`
`HARRY G. BRITTAIN
`Center for Pharmaceutical Physics
`Milford, NJ
`
`Editorial Advisory Board
`
`CARLA CARAMELLA
`Universita degli Studi di Pavia
`Pavia, Italy
`
`METIN (:ELIK
`Pharmaceutical Technology
`International, Inc.
`Belle Meade, NJ
`
`YIE W. CHIEN
`Kaohsiung Medical University
`Kaohsiung, Taiwan
`
`DAAN J. A. CROMMELIN
`Utrecht University
`Utrecht, The Netherlands
`
`PATRICK P. DELUCA
`University of Kentucky
`Lexington, KY
`
`GFORGE DIGENIS
`University of Kentucky
`Lexington, KY
`
`DOMINIQUE DUCHENE
`Universite de Paris-Sud
`Chatenay Malabry, France
`
`GORDON L. FLYNN
`University of Michigan
`Ann Arbor, MI
`
`SYLVAN G. FRANK
`Ohio State University
`Columbus, OH
`
`~ ru
`c.._
`a.
`c
`:z
`(/)
`0
`_::J ~
`~
`~ ('..)
`c:::>
`01
`c:::>
`VJ
`-..,J
`0
`01
`
`c z <-o
`
`mi
`::0)>
`(f):::O
`-~ ~)>
`oo
`'Tl-<
`~c _ClJ
`(f)::U
`0)>
`0:::0
`z-<
`(/)
`z
`
`ROBERT M. FRANZ
`Glaxo Research Institute
`Research Triangle Park, NC
`
`WOLFGANG FRIESS
`University of Erlangen
`Erlangen, Germany
`
`LARRY A. GATLIN
`Andover, MA
`
`WAYNE R. GOMBOTZ
`Immunex Corporation
`Seattle, WA
`
`DAVID J. W. GRANT
`University of Minnesota
`Minneapolis, MN
`
`ROBERT GURNY
`Universite de Geneve
`Geneve, Switzerland
`
`RICHARD J. HARWOOD
`North Bensalem, PA
`
`KENNETH R. HEIMLICH
`Blue Bell, PA
`
`STANLEY L. HEM
`Purdue University
`West Lafayette, IN
`
`ANTHONY HICKEY
`University of North Carolina
`Chapel Hill, NC
`
`(continued)
`
`KASHIV1029
`IPR of Patent No. 9,492,392
`
`

`

`PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY
`Indexing and Abstracting Services. Articles published in Pharmaceutical Development and Technology are selectively
`indexed or abstracted in:
`ADONIS • Chemical Abstracts • Corporate Alert • Derwent Information, Ltd. • Discovery Agent • EMBASE/
`Excerpta Medica • Index Medicus/MEDLINE • INIST-Pascal/CNRS • International Pharmaceutical Abstracts (IPA)
`• Journal Tracker • Medical and Pharmaceutical Biotechnology Abstracts • Personal Alert • Referativnyi Zhurnal/
`Russian Academy of Sciences • Research Alert • SciSearch/SCI-Expanded
`Manuscript Preparation and Submission. See end of issue.
`Disclaimer. The material in this publication is for general information only and is not intended to provide specific advice
`or recommendations for any individual. This publication is sold with the understanding that the publisher is not engaged
`in rendering professional services. In such a case where medical or other professional advice is needed, you should
`consult the appropriate health care or other professional for advice with regard to your individual situation. The publisher
`disclaims all liability in connection with the use of information contained in this publication.
`Contributions to this journal are published free of charge. This journal is printed on acid-free paper.
`Copyright © 2001 by Marcel Dekker, Inc. All rights reserved. Neither this work nor any part may be reproduced or
`transmitted in any form or by any means, electronic or mechanical, microfilming and recording, or by any information
`storage and retrieval systems without permission in writing from the publisher.
`
`www.dekker.com
`
`KASHIV1029
`IPR of Patent No. 9,492,392
`
`

`

`Pharmaceutical Development and Technology, 6(2), 247-254 (2001)
`
`RESEARCH ARTICLE
`
`Effects of Formulation Variables and
`Post-compression Curing on Drug Release
`from a New Sustained-Release Matrix
`Material: Polyvinylacetate-Povidone
`
`Zezhi J. Shao,* Mohammad I. Farooqi, Steven Diaz,
`Aravind K. Krishna, and Nauman A. Muhammad
`
`Formulation R&D, Pfizer Global Research and Development,
`170 Tabor Road, Morris Plains, NJ 07950
`
`Received May 5, 2000; Accepted September 24, 2000
`
`ABSTRACT
`
`A new commercially available sustained-release matrix material, Kollidon® SR,
`composed of polyvinylacetate and povidone, was evaluated with respect to its
`ability to modulate the in vitro release of a highly water-soluble model compound,
`diphenhydramine HCl. Kollidon SR was found to provide a sustained-release effect
`for the model compound, with certain formulation and processing variables playing
`an important role in controlling its release kinetics. Formulation variables affecting
`the release include the level of the polymeric material in the matrix, excipient
`level, as well as the nature of the excipients (water soluble vs. water insoluble).
`Increasing the ratio of a water-insoluble excipient, Emcompress®, to Kollidon SR
`enhanced drug release. The incorporation of a water-soluble excipient, lactose,
`accelerated its release rate in a more pronounced manner. Stability studies conducted
`at 40°CI75%RH revealed a slow-down in dissolution rate for the drug-Kollidon SR
`formulation, as a result of polyvinylacetate relaxation. Further studies demonstrated
`that a post-compression curing step effectively stabilized the release pattern of
`formulations containing ?:.47% Kollidon SR. The release mechanism of Kollidon-drug
`
`*Corresponding author. Fax (973) 385-2397; E-mail: z.jesse.shao@pfizer.com
`
`247
`
`Copyright© 2001 by Marcel Dekker, Inc.
`
`www.dekker.com
`
`KASHIV1029
`IPR of Patent No. 9,492,392
`
`

`

`248
`
`Shao et al.
`
`and drug-Kollidon-Emcompress formulations appears to be diffusion controlled,
`while that of the drug-Kollidon-lactose formulation appears to be controlled pre-
`dominantly by diffusion along with erosion.
`KEY WORDS: Diphenhydramine HCl; Kollidon SR; Matrix
`Pol yviny !acetate; Sustained-release.
`
`tablets;
`
`INTRODUCTION
`
`The use of polymeric materials in sustained/controlled
`drug delivery is best exemplified by hydroxypropyl-
`methylcellulose (HPMC), due in part to its ready avail-
`ability of various grades, differing in molecular weights
`and viscosity, its ability to accommodate host molecules
`of varying physicochemical properties, and its good reg-
`ulatory acceptance (1). Other commonly used matrix ma-
`terials include carbomers (2), methyllethylcellulose and
`derivatives (3), natural gums (4), etc. Polyvinylacetate
`(PVAc) has also been reported to be effective in con-
`trolling the release of various chemical entities, includ-
`ing theophylline (5), nifedipine (6), and chlorpromazine
`hydrochloride (7). However, the use of PVAc in previous
`publications all involved a particle coating method, due to
`the unavailability of a directly compressible material.
`Recently, a physical mixture of PVAc and povidone
`(Kollidon SR) has become commercially available (8).
`This directly compressible excipient has been demon-
`strated to effectively retard the release of propranolol HCl
`and caffeine (9). The material forms a matrix block upon
`compression as it is composed of eight parts of water-
`insoluble PVAc and two parts of water-soluble povidone.
`The povidone component gradually leaches out of the ma-
`trix during dissolution thereby creating pores for the active
`to diffuse out. The compressed PVAc component main-
`tains tablet core structure during the dissolution run.
`The amorphous nature of PVAc coupled with its un-
`usually low glass transition temperature of 28-31 oc (1 0)
`imparts certain unique characteristics to this binary matrix.
`It is therefore the purpose of this research to examine key
`formulation and process variables that could affect the re-
`lease kinetics, by using diphenhdyramine HCl as a model
`compound. Additionally, the mechanism(s) of release of
`such a highly water-soluble compound from Kollidon SR
`matrix tablets, formulated with and without additional ex-
`cipients, has also been elucidated.
`
`MATERIALS AND METHODS
`
`Materials
`
`Diphenhydramine hydrochloride USP was internally
`obtained from Parke-Davis Chemical Development.
`
`Kollidon SR was obtained from BASF Corporation
`(Mount Olive, NJ). Lactose monohydrate, Fast-Flo®
`grade, was obtained from Foremost Farms USA (Baraboo,
`WI). Calcium phosphate dibasic dihydrate (Emcompress)
`was purchased from Edward Mendell Co. (Patterson, NY).
`Magnesium stearate of nonbovine origin was obtained
`from Mallinckrodt Inc. (St. Louis, MO).
`
`Tablet Preparation
`
`Diphenhydramine HCl, Kollidon SR, and a selected
`excipient were blended in an 8-qt. Patterson-Kelly (East
`Stroudsburg, PA) V-blender for 5 minutes. Magnesium
`stearate was passed through a 30-mesh screen and added
`to the V-blender. Mixing was continued for an addi-
`tional 5 min. The blend was compressed on a Korsch
`(Somerset, NJ) PHl 06 rotary press using oval-shaped tool-
`ing with the dimension of 0.750" x 0.390" x 0.062" at a
`compression force of '"'-'33 KN. Tablets were compressed
`to a target weight of 800 mg with each tablet containing
`300 mg of diphenhydramine HCl with varying amounts
`of Kollidon SR, with or without lactose or Emcompress,
`and 4 mg (0.5 wt%) magnesium stearate as the lubricant.
`
`Tablet Curing
`
`For the curing duration study, the tablets were cured
`at 60°C in a Hotpack Supermatic oven (Philadelphia, PA)
`for varying lengths of time ranging from 10 minutes to
`18 h. All other batches were cured at 60°C for a fixed time
`of 15 hours. Dissolution testing and hardness measure-
`ments were performed after the cured tablets were cooled
`to room temperature for overnight or longer.
`
`Stability Testing Protocol
`
`Tablets were packaged in 20s into 90-cc high-density
`polyethylene bottles. One 1-gm Sorbit® desiccant car-
`tridge (United Desiccants, Belen, NM) was placed into
`each bottle. The bottles were then closed with 3 8-400 C/R
`caps, and induction-sealed using an Enercon LM3620-01
`induction sealer (Enercon Industries Corp., Menomonee
`Falls, WI). The bottles were then placed inside Espec
`humidity cabinets preequilibrated to 25°C/60%RH and
`40°C/75%RH (Tabai Espec Corp., Osaka, Japan). At
`
`KASHIV1029
`IPR of Patent No. 9,492,392
`
`

`

`Release of Diphenhydramine from Kollidon® SR Matrix Tablets
`
`predetermined timepoints, a bottle was pulled from a sta-
`tion and tested for hardness by Distek HC97 (EL Ektronik
`Gmbh, Germany) and dissolution.
`
`Dissolution Methodology
`
`Dissolution testing was performed using an automated
`Distek 2000 apparatus (North Brunswick, NJ) with a
`model HP8453A diode-array spectrophotometer (Hewlett
`Packard, Palo Alto, CA) using a detection wavelength of
`258 nm. Paddle method (USP Apparatus II) was used with
`900 mL purified water as the medium, at a water bath tem-
`perature of 37°C, and a paddle speed of 50 rpm. The av-
`erages of five determinations were reported for each run.
`
`249
`
`where Q is the percentage of drug released at time t, k
`is the release rate constant, and n is the release expo-
`nent. For matrix tablets, an n value of "-'0.5 indicates
`diffusion-controlled mechanism while ann value of ,._..., 1.0
`indicates erosion-controlled release. Intermediate values
`suggest dual mechanisms of both diffusion and erosion
`(11). Tso%. the time to reach 50% of drug release, was
`then calculated from the above fitted equation for each
`formulation, by using mean dissolution data.
`
`RESULTS AND DISCUSSION
`
`Basic Formulation Composed of
`Diphenhydramine and Kollidon SR
`
`Drug Release Modeling
`
`To determine the release kinetics of diphenhydramine
`HCl from the Kollidon SR-based matrices, attempts were
`made to fit the data corresponding to .::::;80% of release ·
`using the following equation (11,12):
`
`(I)
`
`Diphenhydramine HCl was first formulated with 62
`wt% of Kollidon SR (and 0.5 wt% magnesium stearate),
`without any additional diluents. The initial release pro-
`file is shown in Figure 1A. Kollidon SR has effec-
`tively sustained the release of diphenhydramine HCl
`such that complete release was achieved at "-'420 min.
`This batch was subsequently placed on stability and
`
`"0
`Cll
`
`Ill "'
`Cll
`(jj
`tt::
`'#.
`
`A
`
`120
`
`100
`
`80
`
`60
`
`40
`
`•
`•
`•
`•
`20 •
`
`0
`
`. . •
`• •
`•
`
`•
`
`' I • '
`
`I
`
`I
`
`• Initial Uncured Tablets
`• 25C/60%RH 1-month
`• 25C/60%RH 2-months
`• 25C/60%RH 3-months
`
`0
`
`200
`
`400
`Time (min)
`
`600
`
`800
`
`120
`
`100
`
`B
`
`"0 80
`Q)
`~
`Q) 60
`(i;
`0:::
`~ 40
`
`20
`
`0
`
`••
`••
`•
`
`'
`
`• • i i
`• i i
`• i
`i
`
`' I '
`
`+Initial Uncured Tablets
`o 40C/75%RH 1 week
`A 40C/75%RH 2 weeks
`e40C/75%RH 1 month
`.A 40C/75%RH 2 months
`• 40C/75%RH 3 months
`
`0
`
`200
`
`400
`Time(min)
`
`600
`
`800
`
`0
`
`0
`
`200
`
`400
`Time(min)
`
`600
`
`800
`
`Figure 1. Release profiles of diphenhydramine HCl from Kollidon SR matrix tablets placed on stability at different conditions.
`A) uncured tablets at 25°C/60%RH; B) uncured tablets at 40°C/75%RH; C) cured tablets at 25°C/60%RH; D) cured tablets at
`40°CI75%RH.
`
`c
`
`120
`
`100
`
`Q)
`
`"0 80
`:(l
`Q) 60
`(i;
`0:::
`~
`
`40
`
`•
`•
`•
`•
`20 •
`
`• * •
`• ••
`• •
`••
`••
`
`1 I II I •
`
`•Initial Cured Tablets
`• 25C/60%RH 1-month
`• 25C/60%RH 2-months
`• 25C/60%RH 3-months
`
`I.
`
`0
`
`0
`
`120
`
`D
`
`100
`
`"0 80
`Cll
`
`60
`
`Ill "'
`Cll
`(jj
`tt::
`'#. 40
`
`•''
`•'
`••
`••
`••
`•
`• •
`20 • •
`
`200
`
`400
`Time(min)
`
`600
`
`800
`
`••••••
`
`I I I
`
`•Initial Cured Tablets
`• 40C/J5%RH 1-month
`• 40C/75%RH 2-months
`• 40C/75%RH 3-months
`
`KASHIV1029
`IPR of Patent No. 9,492,392
`
`

`

`250
`
`Shao et al.
`
`Hardness Values of Diphenhydramine HCl-Kollidon SR Tablets on Storage
`
`Table 1
`
`Hardness (Kp)
`
`Uncured Tablets
`
`Cured Tablets
`
`Initial
`
`1 week
`2 weeks
`1 month
`2 months
`3 months
`
`15.7 ± 2.0
`19.8 ± 2.3a
`19.2 ± 1.1a
`20.2 ± 1.9a
`20.0 ± 3.1a
`20.8 ± 1.5a
`
`N.D.
`N.D.
`17.5 ± 1.8
`16.2 ± 1.7
`16.8 ± 2.0
`
`21.4 ± 2.6
`N.D.
`N.D.
`20.7 ± 1.7
`22.6 ± 1.6
`21.4 ± 2.6
`
`N.D.
`N.D.
`21.7 ± 2.4
`19.8 ± 2.1
`20.4 ± 1.0
`
`Notes: Results are the means ±SD of 10 determinations. N.D. - not determined.
`a statistically different (P < 0.01) from initial.
`
`the pulled samples tested for dissolution. No significant
`trend was found for samples stored at 25°C/60%RH for
`upto 3 months (Fig. lA). Testing of samples stored at
`40°C/75%RH, on the other hand, revealed a decrease
`in dissolution rate, as shown in Figure lB. The slowing
`down effect appeared to have stabilized after 2 weeks of
`storage.
`The decrease in dissolution rate is accompanied by a
`corresponding increase in tablet hardness. As shown in
`Table 1, the hardness values of uncured tablets stored
`at 25°C/60%RH stayed constant at "-'16-18 Kp. How-
`ever, on exposure to 40°C/75%RH, the hardness values
`of uncured tablets increased to "-'20 Kp, being statisti-
`cally different (P < 0.01) from initial. An increase in
`tablet hardness value following curing at 60°C has been
`previously observed for oven-cured ethylcellulose matrix
`tablets (3).
`·
`Such a change in dissolution profile is usually indica-
`tive of polymer structural relaxation ( 13-15), necessitat-
`ing a curing evaluation study. Tablets were then cured at
`60°C for different periods of time and tested for disso-
`lution and the results are illustrated in Figure 2. Curing
`at 60°C stabilized the dissolution rate and a curing time
`of at least 1-h has been identified as a suitable condition.
`No deleterious effect was found with extended curing for
`up to 18 h. This time frame coincide well with reported
`oven-curing conditions for ethylcellulose matrix tablets
`and coated beads, i.e., 60-90°C from a few hours to 1 day
`(3,16).
`Cured tablets were subsequently placed on stability and
`samples were pulled at monthly intervals. Figures 1 C and
`D illustrate the dissolution profiles of cured tablets stored
`at 25°C/60%RH and 40°C/75%RH, respectively. As ex-
`
`120
`
`100
`
`"0 80
`(I)
`Ill
`ns
`(I)
`Gi
`It:
`~ 40
`
`60
`
`••
`20 •
`
`0
`
`t
`
`• IIIII
`•
`• t
`• '
`• •
`•
`*
`
`~
`
`I
`ll
`
`I I
`
`I
`
`• Uncured Tablets
`• 60C, 10 min
`.t. 60C, 1 hr
`c 60C, 7 hrs
`A 60C, 18 hrs
`
`I
`
`••
`
`0
`
`200
`
`400
`Time(min)
`
`600
`
`800
`
`Figure 2. Release profiles of diphenhydramine HCl from
`Kollidon SR matrix tablets cured at 60°C for different lengths of
`time.
`
`pected, the post-compression curing step has stabilized the
`dissolution profile satisfactorily and no further change in
`tablet hardness was observed (Table 1).
`
`Formulations Containing an Additional
`Diluent
`
`To further clarify whether the observed curing-
`dependency is indigenous to the drug-polymer mixture
`only, 15 wt% Kollidon SR in the formula was replaced
`by either lactose or Emcompress. The drug-Kollidon for-
`mulation was again manufactured, along with the formu-
`lations containing either lactose or Emcompress, to con-
`firm reproducibility of the observed curing phenomenon.
`A portion from each of the three batches was subsequently
`cured at 60°C for 15 h.
`
`KASHIV1029
`IPR of Patent No. 9,492,392
`
`

`

`Release of Diphenhydramine from Kollidon® SR Matrix Tablets
`
`Dissolution profiles of uncured and cured tablets were
`determined and illustrated in Figure 3. The drug-Kollidon
`SR formulation (Fig. 3A) again exhibited curing depen-
`dency with respect to dissolution, as shown by the differ-
`ence between the uncured and cured profiles, thus con-
`firming previous observation. The formulation containing
`lactose (Fig. 3B) exhibited some significant differences
`between uncured and cured tablets, although limited to
`the time points of 60-180 min. Additionally, the formu-
`lation containing Emcompress (Fig. 3C) similarly exhib-
`ited a discernable difference between uncured and cured
`
`120
`
`100
`
`A
`
`80
`
`"0
`Cl)
`VI
`C1)
`Cl)
`Qj
`0::
`~ 40
`
`60
`
`20
`
`0
`
`•
`I •
`
`t
`
`•
`•
`
`. .
`• • • • • • •
`•
`
`• Uncured
`• Cured
`
`0
`
`100
`
`200
`
`400
`500
`300
`Time (min)
`
`600
`
`700
`
`800
`
`120 r----------------------------------,
`8
`
`n • * • • • • • • • •
`
`100
`
`80
`
`VI
`
`-g
`IV "* 60
`
`0:::
`~ 40
`
`n •
`a a
`I
`•
`•
`
`20
`
`• Uncured
`• Cured
`0 +---~---r--~----r---~--~--~--~
`100
`300
`400
`500
`600
`700
`0
`200
`800
`Time(Min)
`
`120 .----------------------------------.
`
`.. ·.:.:·•··
`
`•
`• ••
`•
`• ••
`••
`•
`
`•
`•
`
`100
`
`80
`
`60
`
`VI
`
`0::
`
`-g
`IV "*
`I •
`~ 40 •'
`
`• Uncured
`'
`20
`• Cured
`0 +---,---~--~----r---~---r--~--~
`0
`100
`200
`300
`400
`500
`600
`700
`800
`Time (min)
`
`Figure 3. Release profiles of uncured and cured tablets com-
`posed of A) drug-Kollidon SR; B) drug-Kollidon SR-lactose;
`or C) drug-Kollidon SR-Emcompress. Significantly different
`at P < 0.01(-l)..) and P < 0.001 (~) by one-tailed t-test for
`plot B.
`
`251
`
`tablets. This observation proved that a decrease in release
`rate is expected for formulations with or without additional
`excipients.
`The hardness values of uncured tablets for the for-
`mulations containing no additional diluent, 15% lac-
`tose, and 15% Emcompress were found to be 15.4 ± 1.1,
`16.6 ± 0.9, and 14.6 ± 1.0 Kp, respectively. The hardness
`values of cured tablets of the above formulations were
`22.2 ± 0.8, 20.6 ± 1.1, and 17.6 ± 1.3 Kp. Statistical anal-
`ysis (t-test) revealed significant differences (P < 0.001)
`between cured and uncured hardness values for all three
`formulations. Therefore, curing at 60°C resulted in promi-
`nent increases in tablet hardness.
`
`Formulations Containing Lower Levels
`of Kollidon SR and Higher Levels
`of Emcompress
`
`Formulations containing increased levels of excipi-
`ents, and lower levels of the Kollidon SR, were then
`made by further increasing Emcompress levels to 25,
`35, and 45 wt%, thus reducing the levels of Kollidon
`SR to 37, 27, and 17 wt%. Portions of the tablets were
`cured at 60°C for 15 hand their dissolution profiles were
`determined.
`Figure 4 schematically illustrates the dissolution pro-
`files of each formulation, before and after curing. There
`are little or no differences between the cured and uncured
`tablets for these batches. It is therefore important to ratio-
`nalize that curing dependency in Kollidon SR matrices is
`the direct result of the high level of this polymeric matrix
`former.
`The tablet hardness values of formulations containing
`various levels of Kollidon SR, before and after curing,
`are shown in Figure 5. Increases in the Kollidon SR level
`widened the gap in hardness profiles of cured and uncured
`tablets, thus indicating physical strengthening of the tablet
`matrix following curing.
`
`Mechanisms of Drug Release from
`Kollidon SR Matrices
`
`Initial dissolution profiles (up to 80% drug release) of
`formulations containing different levels of Kollidon SR
`and Emcompress were fitted into Equation (1) and the
`results are plotted in Figure 6. All profiles were well
`fitted as shown by the excellent correlation coefficient
`(Table 2). The kinetic parameters were thereby derived and
`tabulated in Table 2. Since the release exponent (n) is close
`to 0.5, release of the highly water-soluble drug appears to
`be by diffusion-controlled mechanism. This conclusion
`
`KASHIV1029
`IPR of Patent No. 9,492,392
`
`

`

`37% Kollidon SR
`
`a•
`at • a
`a
`
`t
`
`'
`·'
`•• +
`
`at t * • • • • • •
`•••
`
`+Uncured
`• Cured
`
`1 00
`
`200
`
`300
`
`400
`Time (min)
`
`500
`
`600
`
`700
`
`800
`
`25
`
`Q: 20
`~
`Ill
`Ill 15
`Q)
`
`1: "E cu 10
`J: a;
`j5 5
`cu
`I-
`
`0
`
`0
`
`Shao et al.
`
`--+--Cured Tablets
`~ Uncured Tablets
`
`20
`
`40
`Kollidon SR %w/w
`
`60
`
`80
`
`252
`
`120
`
`100
`
`80
`
`60
`
`40
`
`20
`
`-o
`5l ro
`<!)
`Q)
`0:::
`'Cf.
`
`120
`
`100
`
`80
`
`60
`
`40
`
`20
`
`"0 5l ro
`
`<!)
`Q)
`0:::
`'Cf.
`
`100
`
`80
`
`60
`
`40
`
`"0 5l ro
`
`<!)
`Q)
`0:::
`'Cf.
`
`27% Kollidon SR
`
`••••••••
`••••••
`•
`• • •
`• • •
`' ' '
`'
`
`+Uncured
`• Cured
`
`1 00
`
`200
`
`300
`
`500
`
`600
`
`700
`
`800
`
`400
`Time (min)
`
`120~----------------~
`17% Kollidon SR
`
`••••••••••••
`
`Figure 5. Effect of curing on tablet hardness, plotted as a func-
`tion of Kollidon SR level in the matrices. Emcompress is the
`diluent. Significantly different: * at P < 0.01, ** at P < 0.001
`(one-tailed t -test).
`
`formulation
`lactose-containing
`The profiles of
`(Fig. 3B) were also fitted into Equation (1), with excellent
`fit (r 2 > 0.999 for both cured and uncured tablets). The
`release exponents (n) are 0.639 and 0.577, respectively,
`for uncured and cured tablets. These values (>0.5) sug-
`gest that erosion mechanism contributes to the observed
`overall release. Visual observation of tablet cores during
`dissolution runs also supports this conclusion .
`The release mechanisms and kinetics from this new
`polymer blend faired well with historical results involv-
`ing other polymeric matrices such as HPMC and carbo mer
`(1,2). Fickian and non-Fickian mechanisms, resulting in
`diffusion, relaxation, and erosion processes, appear to ap-
`ply to all these polymeric matrices and various mathemat-
`ical models (12, 17, 18) can be adopted.
`
`100 -....-----------------::.....---~--------,
`
`D 62% Kollidon SR
`
`10
`
`100
`Time(min)
`
`1000
`
`Figure 6. Release profiles of diphenhydramine HCl from
`Kollidon SR matrix tablets containing different levels of
`Kollidon SR, as fitted by Equation 1. All tablets were cured at
`60oc.
`
`, ..
`• . '
`
`•
`• •
`•
`• •
`'
`
`20
`
`+Uncured
`• Cured
`0 <+---.-----,..-----,.--.---...,....----,------,------4
`1 00
`200
`300
`400
`500
`600
`700
`800
`Time (min)
`
`Figure 4. Release profiles of diphenhydramine .HCl from
`Kollidon SR matrix tablets containing different levels of
`Kollidon SR. Emcompress is the diluent.
`
`supports the diffusion mechanism proposed by BASF (8).
`It was further noted that the tablets containing Kollidon SR
`and Emcompress swelled only moderately during dissolu-
`tion run. Ritger and Peppas (17) had deemed Equation (1)
`suitable for matrices with moderate swelling. Increases
`in Kollidon SR level in the matrix resulted in decreases
`in the kinetic release constant (k), similar to the obser-
`vation made by Shah et al. (18) on theophylline release
`from HPMC. These researchers further established that
`drug release at a given time point is inversely related to
`the square-root of polymer concentration in the matrix.
`
`KASHIV1029
`IPR of Patent No. 9,492,392
`
`

`

`Release of Diphenhydramine from Kollidon® SR Matrix Tablets
`
`253
`
`Table 2
`
`Kinetic Parameters Based on Equation (1) for Tablet Formu-
`lations Containing Different Levels of Kollidon SR
`
`% Kollidon SR
`
`k (min- n)
`
`n
`
`r 2
`
`Tso%(min)
`
`17
`27
`37
`47
`62
`
`8.32
`7.61
`6.43
`4.57
`4.01
`
`0.456
`0.442
`0.450
`0.483
`0.502
`
`0.9996
`0.9999
`0.9983
`0.9971
`0.9967
`
`51
`71
`95
`142
`152
`
`Notes: k- release kinetic constant; n- release exponent; r2 -
`correlation coefficient squared; Tso%- the time for 50% drug to be
`released.
`
`Polymer Blends in Sustained-Release Tablets
`
`Although polymers of different physicochemical prop-
`erties (hydrophilicity/hydrophobicity, molecular weight,
`cross-linking, etc.) are commercially available, the use
`of a single polymer in regulating drug release may not
`be adequate enough. Aside from incorporating com-
`mon tab letting excipients ( dicalcium phosphate, lactose
`etc.) to tailor the release profile, a second polymer
`can be used successfully. Such polymer blending tech-
`niques have received more attention in recent years as
`evidenced by an increased number of publications and
`patents.
`The flexibility of blending polymers with different hy-
`drophilic characteristics to alter the dissolution kinetics
`of a host drug constitutes the main advantage in this ap-
`proach (19). Khan and Zhu (20) evaluated ibuprofen re-
`lease from Carbo pol 934 P and mixtures of 934 P and 971 P.
`The blended mixtures of Carbopol 934P and 971P re-
`sulted in more linear drug release at much lower poly-
`mer levels, compared to that of 934P alone. Apicella et al.
`(21) studied etofylline release from compression-molded
`matrix tablets of poly(ethylene oxide) (PEO) with low
`and high molecular weights. Drug release from the low
`molecular weight PEO is due to polymer dissolution while
`that from the high molecular weight polymer is related to
`material swelling. Physical blends of the two grades of
`PEO achieved intermediate drug release behavior. Kim
`and Kim (22) blended another low molecular weight
`PEO with hydrophobic polymers (polydimethylsiloxane
`or polyurethane) from which heparin release was evalu-
`ated. The authors demonstrated that heparin release could
`be controlled by varying the level of PEO, presumably
`through the creation of pores following the dissolution of
`PEO from the matrix. DiLuccio et al. (23) examined theo-
`phylline release from polymer blends of polyvinyl alcohol
`
`(PYA) and polyvinyl alcohol-methyl acrylate copolymer
`(PYA-MA). The ratio of PYA-MA to PYA was found to
`play an important role in controlling theophylline release
`and an optimal ratio of PYA-MA:PYA:drug (1 :9: 10) was
`identified.
`In addition to balancing the hydrophilicity of the poly-
`mer matrix, polymer blends have been shown to improve
`the hardness of tablets and drug release retardation ef-
`fects (24). These additional advantages may be the result
`of polymer-polymer interactions, as evidenced by NMR,
`DSC, and viscoelastic measures (25), through the work on
`PYA and gum arabica blend matrix.
`Our findings on diphenhydramine release from
`Kollidon SR matrix tablets further support the value of
`polymer blends in sustained drug delivery. Processing
`variables, such as post-compression curing, have been
`demonstrated to play an important role. Other amorphous
`and low-crystalline polymeric blends need to be similarly
`evaluated.
`
`CONCLUSIONS
`
`The use of polyvinylacetate and povidone to form
`a direct-compressible matrix resulted in the desired
`sustained-release effect on a highly water-soluble model
`compound, diphenhydramine HCl. Key formulations and
`process variables, however, make significant impact on the
`release patterns. Formulation variables include the level of
`the polymeric matrix material, the type of diluent, and the
`level of the diluent in the tablet. The presence of a wa-
`ter insoluble diluent, Emcompress, reduces the polymer
`level thus resulting in a faster release. The presence of
`a water-soluble excipient, such as lactose, also resulted
`in faster release, contributed by the addition of a second
`mechanism, i.e., erosion.
`A post-compression curing step was found to be critical
`in stabilizing the release rates of tablets containing high
`levels (2:47 wt%) of Kollidon SR. The curing duration
`study concluded that a few hours at 60°C is a sufficient
`curing condition for such tablets.
`The observation of curing-dependency for glassy amor-
`phous polymers such as polyvinylacetate is not surpris-
`ing. Spontaneous densification of polyvinylacetate dur-
`ing annealing is well known and can be modeled by
`means of volume and enthalpy recovery methods (13).
`Structural reorganization (14) of defects, caused by the
`manufacturing process (compression etc.), may well ac-
`count for the observed differences in tablet physical
`strength and dissolution between uncured and cured
`tablets.
`
`KASHIV1029
`IPR of Patent No. 9,492,392
`
`

`

`254
`
`REFERENCES
`
`1. Sung, K.C.; Nixon, P.R.; Skoug, J.W.; Ju, T.R.; Gao, P.;
`Topp, E.M.; Patel, M.V. Effect of Formulation Variables
`on Drug Release from HPMC-Based Matrix Tablets, Int. J.
`Pharm. 1996, 142, 53-60.
`2. Huang, L.-L.; Schwartz, J.B. Studies on Drug Release from
`a Carbomer Tablet Matrix. Drug Dev. Ind. Pharm. 1995,21,
`1487-1501.
`3. Shao, Z.J.; Robins, D.S.; Shih, C.; Knight, P.J.; Huq, A.S.
`Formulation and Process Variables Affecting SCH 209149
`Release from Ethy !cellulose-Based Matrix Tablets, Pharm-
`Sci. 1998, 1, S-324.
`4. Alur, H.H.; Pather, S.I.; Mitra, A.K.; Johnston, T.P. Evalua-
`tion of the Gum from Hake a gibbosa as a Sustained-Release
`and Mucoadhesive Component in Buccal Tablets, Pharm.
`Dev. Tech. 1999,4,347- 358.
`5. Schmidt, W.G.; Mehnert, W.; Fromming, K.-H. Controlled
`Release from Spherical Matrices Prepared in a Labora-
`tory Scale Rotor-Granulator- Release Mechanism Interpre-
`tation Using Individual Pellet Data, Eur. J. Pharm. Bio-
`pharm. 1996, 42, 348-350.
`6. Ali, A.; Sharma, S.N. Sustained Release Through Coated
`Microparticles of Nifedipine, Indian Drugs 1996, 33,
`30- 35.
`7. Niwa, T.; Takeuchi, H.; Hino, T.; Itoh, A.; Kawashima, Y.;
`Kiuchi, K. Preparation of Agglomerated Crystals for Direct
`Tabletting and Microencapsulation by the Spherical Crys-
`tallization Technique with a Continuous System, Pharm.
`Res. 1994, 11,478- 484.
`8. Technical Information. Kollidon SR, BASF Aktienge-
`sellschaft, Germany, 1999; 1- 10,
`9. Ruchatz, F.; Kolter, K.; Wittemer, S.; Frauenhofer, W.
`Kollidon SR - a New Excipient for Sustained Release Ma-
`trices, Proc. Int. Symp. Control. Rel. Bioact. Mater. 1999,
`26, 6312.
`10. Daniels, W. Vinyl Ester Polymers. In Transitions andRe-
`laxations to Zwitterionic Polymerization, Vol. 17, Encyclo-
`pedia of Polymer Science and Engineering, 2nd Ed., Mark,
`H.F. Ed.; John Wiley & Sons: New York, 1989; 402- 425.
`11. Ford, J.F.; Mitchell, K.; Rowe, P.W.; Armstrong, D.J.;
`Elliott, P.N.C.; Rostron, C.; Hogan, J.E. Mathematical
`Modelling of Drug Release from HPMC Matrices: Effect
`ofTemperature. Int. J. Pharm. 1991,71,95-104.
`12. Korsmeyer, R.W.; Gurny, R.; Doelker, E.; Buri, R.;
`Peppas, N.A. Mechanisms of Solute Release from Porous
`Hydrophilic Polymers. Int. J. Pharm. 1983, 15, 25-35.
`
`Shao et al.
`
`13. Perez, J. Defect Diffusion Model for Volume and En-
`thalpy Recovery in Amorphous Polymers. Polymer 1988,
`29, 483- 489.
`14. Ali, M.S.; Sheldon, R.P. Structural Changes in Glassy Poly-
`mers. J. Appl. Polym. Sci. 1970, 14, 2619- 2628.
`15. Struik, L.C.E. Physical Aging in Amorphous Polymers and
`Other Materials; Elsevier: Amsterdam, 1978.
`16. Hutchings, D.; Kuzmak, B.; Sakr, A. Processing Consider-
`ations for an EC Latex Coating System: Influence of Curing
`Time and Temperature. Pharm. Res. 1994,11, 1474- 1478.
`17. Ritger, P.L.; Peppas, N.A. A Simple Equation for Descrip-
`tion of Solute Release. II. Fickian and Anomalous Release
`from Swellable Devices. J. Controlled Release 1987, 5,
`37-42.
`18. Shah, N.; Zhang, G.; Apelian, V.; Zeng, F.; Infeld, M.H. ;
`Malick, A.W. Prediction of Drug Release from Hydrox-
`ypropyl Methylcellulose (HPMC) Matrices: Effect of Poly- .
`mer Concentration. Pharm. Res. 1993, 10, 1693-1695.
`19. Polishchuk, A.Ya.; Zaikov, G.E. Fundamental Aspects of
`Drug Release from Polymers. II. Approaches to Governing
`Kinetics of Release. Oxid. Commun. 1999, 22, 342-364.
`20. Khan, G.M.; Zhu, J.-B. Studies on Drug Release Kinetics
`from lbuprofen-Carbomer Hydrop