26-NAY-1995 BLDscsosroN SPA
`DRUG DEVE OPNENT AND INOUST
`LS23 ?8Q
`RIAL PHARMifC'r'
`
`PB
`
`Zl
`
`f'JART 12
`
`111
`6-
`
`Drug Regulatory Affairs
`
`Formulation Including
`Pharmacokinetic Aspr
`~-~
`International Pharma~t?uticallssues
`Good Manufacturing Practice
`
`Quality Control
`
`VOLUME 21
`
`NUMBER 12
`
`1995
`
`Supplied by the British Library 06 Feb 2018, 14:06 (GMT)
`
`KASHIV1028
`IPR of Patent No. 9,492,392
`
`

`

`DRUG DEVELOPM ·NT AND INDUSTRIAL PHARMACY, 21(12), 1411-1428 (1995)
`
`APPLICATION OF POLY(OXYETHYLENE)
`HOMOPOLYMERS IN SUSTAINED RELEASE SOLID
`FORMULATIONS
`
`Atttollio Moront and l aac Ghebre-Sellassie
`
`Parke-Davis Phannaceutical Research,
`Warner-Lambert Company, Morris Plains, NJ 07950 U.SA.
`
`ABSTRACT
`
`Water oJuble poly( oxyethylene) homopolymers, with molecular mass
`ranging from four hundred thou and to four million, were used as carriers
`to generate, by direct compression techniques. sustained release matrix
`tablet of hoth water-soluhl and in. oluble bioactive agents. Dissolution
`howed that the release kinetic of the tablets depends upon the
`studie
`solubility and molecular mas of polymer, solubility of drug, and the ratio of
`the drug to polymer in the tablets. Following drug release, the tablet
`component di solved lt!aving behind no residue, or "ghost", as is commonly
`observed with wax-ha ed . ystem ..
`
`• Currently nflilimed with The Quantum Group, Inc., 2103 Red Forest Road, Greensboro,
`N.C., ~7410.
`
`Copyright <0 1995 by Marcel Dekker, Inc.
`
`1411
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`1412
`
`MORONI AND GHEBRE-SELLASSIE
`
`INTRODUCTION
`
`Owing to the worldwide:: decline in the number of pharmacologically active
`new chemical entities reaching the marketplace, interest in the
`development of n w drug delivery systems, particularly in the area of
`controlled release, ha been on the forefront of pharmaceutical research
`(1). Thi i h cause a well·designed dosage form may not only improve the
`efficacy and safety of the active ingredient, but also can help to extend the
`patent life and hence the profitability derived from the marketed products.
`
`Over the years dif~ rent type of controlled release dosage forms, including
`matrix ystems have been developed (2, 3). Fabrication of matrix type oral
`dosage forms generally involves direct compression of tablet excipients, or
`preparation of aqueou , olvent or wax-based granulations whkh are
`subsequently compres ed to provide tablets of different izes and shapes.
`These systems are capable of sustaining the release of drugs over an
`extended period of time and are not susceptible to dose dumping. Most of
`these, however, leave behind, following drug release, tablet residues or
`"ghosts" which can cast doubt in the patient's mind regarding the
`performance of the dosage form. Ideally, therefore, the tablets should
`contain a carrier or binder that dissolves in body fluids once it delivers the
`active agent as intended. In these systems, the carrier on the surface of the
`tablet initially hydrates during dissolution, to generate an outer viscous gel
`layer ( 4). This phase is then followed ·equentially by tablet bulk hydration,
`swelling and erosion. The overall di solution rate and, ultimately, drug
`availability are controlled by the rate of swelling, diffusion through the gel
`layer (5,6) anti/or erosion (7, X, 9).
`
`Recent work with poly(ethylen oxide) homopolymers (10 ll),(supplied hy
`Union Carbide under the trade name of "Polyox .. (12)), indicated that
`tablets containing the e polymers a carriers do not only have sustained
`release properties hut they also do not leave residues following drug
`relea e. These polymers are, therefore, suitable for the development of
`controlled release tahl ts. The homopolymer are prepared by anionic
`polymerization of ethylene oxide and have an average molecular mass
`ranging from one hundred thousand to eight million. As polyethers, the
`polymeric chain are apable of forming strong hydrogen bonds with water,
`a property that is rc ponsible for their high water uptake and eventual
`dissolution. Because these polymers hydrate. swell and eventually erode
`during the di solution course the mechanism of release is a complex
`process involving drug diffusion, polymer swelling and/or erosion. The
`
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`POL Y(OXYETHYLENE) HOMOPOL YMERS
`
`l413
`
`dominance of one mechanism over the others depends upon tablet
`excipients and solubility of the active ingredient.
`
`The objective of this tudy is, therefore, to describe and characterize the
`release kinetics in aqueous media of tablets containing poly(oxyethylene) as
`the rate controlling carrier and model drugs that are either highly water-
`soluble or poorly water soluble.
`
`THEORETICAL CONSIDERATIONS
`
`Four main mechanisms of release are possible from monolithic tablets
`containing an uniformly distributed load of drug. The first and most often
`encountered mechanism is drug diffusion through the outside layers of the
`tablet, al o known a "Ficknian" release, or ''Case I" mechanism ( 4). The
`release rate of monolithic tablets containing a water insoluble carrier and a
`water oluble drug decreases as a function of time, because the diffusional
`path length for drug relea e increases with time, as the solvent front moves
`toward the center of the tablet. The release kinetic foUows the square
`root of time up to 60 % drug depletion ( 13, 14) a de cribed in equation
`(1 ):
`
`(1) MJMoo = (A(D C, (2Cd- C.)])112 t112
`where A is the tablet surface area D i the drug diffusivity, c. is the drug
`solubility in the dis olution medium and cd is the drug loading
`concentration in the matrix. This relation holds true until drug depletion or
`tablet erosion cause, respectively a negative or positive deviation from the
`square-root of time dependance ( 15).
`
`The . econd ca. e, where drug release i swelling controUed, is known as
`"zero order" release or 11Case II" mechanism ( 4). In thi case, the following
`equation can successfully describe the fraction of drug released:
`
`where r is the radius of sphere or cylinder or half thickness of a slab,
`is
`the ero~ion constant, Cu the uniform initial drug concentration, and n an
`exponent depending on the geometry of the release device, and which is 3,
`2 or 1 in the case of a sphere cylinder or infinite slab, respectively (11).
`
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`KASHIV1028
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`1414
`
`MORONI AND GHEBRE-SELLASSIE
`
`In the case of an infinite slab where the surface does not change with
`time, n = 1 and (2) • implifies as follows:
`
`(3)
`
`MJMoo = ko t I Co r
`
`In this case, the release rate is independent of time and follows the "zero
`order" kinetics. In practice, this ideal situation has never been obsetved.
`A third mechanism of release involves devices made from water soluble or
`swellable polymer , where drug diffusion and tablet swelling occur
`concurrently. This mechanism has heen described as "non- Ficknian"
`transport and the release is controlled both by swelling and diffusion (8).
`
`The release rate may he described by a combined t1n I zero order kinetics,
`as shown by equation (4):
`
`where k1 and k2 are two phenomenological constant describing respectively
`the square root of time dependent release and the time independent
`release. The use of two independent constants k1 and k2 allows the
`quantitative evaluation of the contribution of Ficknian or non-Ficknian
`release to the overall rate of release.
`
`A fourth mechanism of drug release from soluble matrices is erosion.
`During dissolution, the outer gel layer fully hydrates, swells and erodes.
`The sequential steps of wetting, hydration, swelling, and erosion continue
`throughout the dis olution course until the water-soluble components of the
`tablets dis olve completely.
`
`Mathematical expres ions describing the release rates of solely erodible
`systems are usually quite involved and may be written only if the
`solubilization kinetic of the polymer are known (7). This mechanism of
`release is described as "Super Case II" (16) and often fol1ows a super-linear
`kinetic of release as described hy equation (5):
`
`where m may he equal or greater than 1 and depends on the relative rates
`of tablet t!ro ·ion and tablet swelling.
`
`In some cases, the release kinetics may approach zero order if the rate of
`solvent front advancing toward the tablet core and the rate of surface
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`KASHIV1028
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`

`POL Y(OXYETHYLENE) HOMOPOL YMERS
`
`1415
`
`ero ion are comparable and occur at the same time (17, 18). Under such
`conditions, the drug diffusive path length will approximately remain
`constant and, assuming no surface area changes, provide zero order release
`kinetics. Since tablets containing water-soluble polymers also swell and
`erode, it is possible to assume that the total tablet area will remain
`constant for most of the dissolution course.
`
`EXPERIMENTAL
`
`Materials
`Polyox polymer (Union Carbide, Danbury, Cf, M. M. (Average) =
`4,000 000, 2,000,000 and 400,000), diphenhydramine hydrochloride (Parke
`Davis Holland, Ml), Cl-936 (diphenylethyl(adenosine), Parke-Davis, Ann
`Arbor, MI), and magnesium stearate (Witco) were used as received.
`
`Polymer Characterization
`Poly( oxyethylene) polymers were characterized by viscosity measurement
`u jng a Brookfield viscometer according to the procedure described in the
`manufacturer technical bulletin (11). Values obtained for each grade were
`within pecifications.
`
`Tablet Compression
`The carrier and the active ingredient were first blended in different ratios.
`After the addition of a lubricant, the final blend was compressed into
`tablets using a single punch Stokes E tablet machine and standard concave
`(3/8") tooling.
`
`Dis olution
`Dis ·olution studies were conducted using USP Apparatus II (paddles), at a
`rotation speed of 75 r.p.m. The dissolution medium for diphenhydramine
`hydrochloride tablets was water while 0.1 N hydrochloric acid was used for
`CJ-936, an experimental drug with poor water solubility. Samples were
`withdrawn automatically at preset time intervals and analyzed
`spectrophotometrically.
`
`R ULTS AND DISCU
`
`Consistent with the properties of water-solub!e, high molecular mass
`polymers poly(oxyethylene) polymers di solve slowly to generate highly
`
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`KASHIV1028
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`t _
`~- ;
`
`1416
`
`MORONI AND GHEBRE-SELLASSIE
`
`viscous solutions ( 12). It is these characteristics that make them suitable for
`the development of controlled-release solid dosage forms. During
`dissolution, tablets containing these polymers produce a gel layer on the
`surface and swell upon contact with the dissolution media. The thickness
`of the gel layer controls drug release. The thickness of the gel changes
`depending on the rate of solvent front progress toward the inside of the
`tablet, the degree of swelling, and on the erosion rate of the tablet outer
`layers. The rate of the solvent front advancement is controlled by drug
`properties, a well as the relative amounts of the drug and polymer in the
`tablet formulation. The rate of erosion of the outer layers i also
`controlled by factors such as solubility of drug and polymer, the
`drug/polymer ratio and polymer average molecular mass. Therefore during
`dissolution, the gel layer thickness may increase, decrease, or remain
`constant as a function of time, thereby modifying the release rate
`accordingly.
`
`Water Soluble Dru~
`The release of diphenhydramine hydrochloride a highly water soluble drug
`( solubility > 1 g/ml ), from tablets containing poly( oxyethylene)
`homopolymers as carriers appears to be controlled, after a brief induction
`time, by a contribution of drug diffusion, through the outer hydrated layers
`of the poly( oxyethylene) matrix, and surface erosion. Following the
`induction time, the release kinetics approximate the square root of time
`with a positive deviation from linearity toward the end of the dis elution
`course (Figs. 1-3). This deviation becomes more pronounced as the
`average molecular mass of the polymer decrea es. A probable cause of the
`positive deviation may be the disintegration and subsequent dissolution of
`the release modulating gel layer. While poly( oxyethylene) homopolymer
`are water soluble, they erode very slowly during the early part of the
`dissolution course. This is probably because diphenhydramine hydrochloride
`locally produces a high ionic concentration in the hydrated layer of the
`tablet and delays polymer dissolution until most of the drug is depleted.
`Examination of the tablets made from the two higher average molecular
`mass polymers shows that, during dissolution, they swell but do not appear
`to erode substantially until most of the drug is released. The overall
`release rates of the tablets decreased with an increase in polymer fraction
`irrespective of the polymer molecular mas es.
`
`Furthermore, tablets containing a very high drug content (9: I) relative to
`the polymers of the three different average molecular masses rdease the
`drug at fast rates and show marked positive deviations from lineadty. The
`
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`KASHIV1028
`IPR of Patent No. 9,492,392
`
`

`

`POLY(OXYETHYLENE) HOMOPOLYMERS
`
`1417
`
`120
`
`100
`
`80
`
`v
`
`D D
`0
`
`0
`
`0
`
`"'0
`Q)
`en
`~
`Q)
`Q)
`~
`
`60
`
`OJ
`::J
`~ "0
`~ 40
`
`20
`
`0
`
`0
`
`4
`
`B
`
`20
`16
`12
`v'Time (min. 1/2)
`
`~ Drug/Polymer 9/1
`<> Drug/Polymer 4/1
`tJ. Drug/Polymer 7/3
`o Drug/Polymer 1/1
`o Drug/Polymer 317
`24
`28
`
`FIGURE 1.
`Release Profiles of Diphenhydramine HCI / Poly(oxyethylene)
`4 Million Average Molecular Mass Tablets in Water.
`USP II (paddles), 75 rpm, 37" C.
`Symbols: Experimental Points. Line: Model.
`
`limited amount of polymer in the formulation cannot generate a firm gel,
`and promote erosion for an extended period of time.
`
`The overall release rate of diphenhydramine hydrochloride was also found
`to depend upon the molecular mass of the polymer in the tablet
`formulation. As expected as the average molecular mass of the polymer
`is increased, the release rates decreased proportionately.
`
`Since tablets containig the highly water soluble diphenhydramine
`hydrochloride, hydrate, swell and erode, the release rates are controlled
`simultaneously by diffusion and erosion. A!i a result, the release kinetics of
`diphenhydramine hydrochloride from poly(oxyethylene) based tablets
`follows a mixed zero/one-half order as described by eyuation ( 4) where the
`zero order relea e mechanism contributes sub tantially to the total release,
`
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`KASHIV1028
`IPR of Patent No. 9,492,392
`
`

`

`1418
`
`MORONI AND GHEBRE-SELLASSIE
`
`120
`
`100
`
`80
`
`0
`
`0 0
`
`"0
`cu
`f/)
`tO
`Q)
`Q)
`
`60
`
`...
`Cl
`::I L..
`"0
`~ 40
`
`20
`
`0
`
`0
`
`4
`
`8
`
`12
`V Time
`
`20
`16
`<min. 1/2)
`
`v Drug/Polymer 9/1
`o Drug/Polymer 4/1
`t. Drug/Polymer 7/3
`o Drug/Polymer 111
`o Drug/Polymer 3/7
`24
`28
`
`FIGURE 2.
`Release Profiles of Diphenhydramine HCI / Poly(oxyethylene)
`2 Million Average Molecular Mass Tablets in Water.
`USP II (paddles), 75 rpm, 37° C.
`Symbols: Experimental Points. Line: Model.
`
`especially at high drug/polymer ratios and using poly( oxyethyJene) of low
`molecular mass, which dissolves faster than the other two grades.
`
`The release con tants k1 (min:112, diffusion control) and k2 (min:• ,ero ion
`control) are given in Table 1-3. The values were calculated by fitting the
`experimental data, between of 10 and 70 % of drug release, for tablets
`based on poly( oxyethylene) 2 ans 4 million average molecular mass, and
`between 5 and 70 % for poly(oxyethylene) 400,000, to a non-linear
`regression based on equation ( 4).
`
`The results obtained show that diffusion controlled release rate constant k1
`decreases with decrease in drug/polymer ratio to a limiting value which it is
`independent of the polymer molecular mas (Fig. 4).
`
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`KASHIV1028
`IPR of Patent No. 9,492,392
`
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`

`POLY(OXYETHYLENE) HOMOPOLYMERS
`
`1419
`
`120
`
`100
`
`0
`
`0
`
`80
`
`"0
`Q)
`(/)
`10
`G)
`-a;
`'-
`0>
`.:::J
`'-
`"0
`~ 40
`
`60
`
`20
`
`0
`
`0
`
`4
`
`8
`
`12
`16
`1/Time <min. 1/2)
`
`"l Drug/Polymor 9/1
`o Drug/Polymer 4/1
`tJ. Drug/Polymer 7/3
`o Drug/Polymer 111
`o Drug/Polymer 3/7
`24
`28
`20
`
`FIGURE 3.
`Release Profiles of Diphenhydramine HCI/ Poly(oxyethylene)
`400,000 Average Molecular Mass Tablets in Water.
`USP II lpaddlesl. 75 rpm, 37" C.
`Symbols: Experimental Points. Line: Model.
`
`TABLE 1.
`Dissolution Rate Con. tants for Diphenhydramine Hydrochloride/
`Poly(oxyethylene) Four Million Tablets.
`k.
`
`Drug/Polymer
`
`k2
`
`Correlation
`Coefficient
`
`9/1
`4/1
`7/3
`1/1
`3/7
`
`.03040
`.02915
`.02 47
`.02544
`.02462
`
`.001002
`.000709
`.000510
`.000379
`.000275
`
`.9997
`.9999
`.9999
`.99
`.9984
`
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`KASHIV1028
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`

`1420
`
`MORONI AND GHEBRE-SELLASSIE
`
`TABLE 2.
`Di solution Rate Constants for Diphenhydramine Hydrochloride/
`Poly(oK}'ethylene) Two Million Tablets.
`k.
`
`Drug/Polymer
`
`k2
`
`Correlation
`Coefficient
`
`9/1
`4/ 1
`
`7/3
`
`1/1
`3/7
`
`.03332
`.02970
`.02927
`.026783
`.02511
`
`.002063
`.001264
`.000831
`.000508
`.000415
`
`.9998
`.9998
`.9999
`.9998
`.9997
`
`TABLE 3.
`Dissolution Rate Constants for Diphenhydramine Hydrochloride/
`Poly( OK}'ethylene) 400,000 Tablets.
`k.
`
`k2
`
`Correlation
`Coefficient
`
`Drug/Polymer
`
`9/1
`4/1
`
`7/3
`J/1
`Jn
`
`.05765
`.04258
`
`.02912
`.02744
`
`.02461
`
`.00574
`.00374
`
`.00196
`.00129
`
`.00068
`
`.9994
`.9997
`
`.9994
`.9998
`.9998
`
`Polymers with high average molecular masses have a high number of chain
`entanglement or crystallites per unit volume which reduce the permeation
`rate of the dissolution medium through the tablets and the subsequent
`diffu ·ion of the drug molecules through the gel layer. Con equently, the
`average path length that drug molecules traverse before they are relea ed
`becomes both longer and more tortuou as polymer average molecular
`mass increases.
`
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`

`POL Y(OXYETHYLENE) HOMOPOL YMERS
`
`1421
`
`0.08
`
`0.06
`
`.......
`
`I
`c:
`
`C\1 ' ,.....
`.E -,.....
`
`.X
`
`0.04
`
`0.02
`
`!
`I
`
`400,000
`A
`2 miiUon
`o
`4 mil6on
`o
`0.00 +---- -.----- r------.----"""-T-
`- ----.
`0
`2
`4
`6
`8
`10
`Drug I Polymer Ratio
`
`FIGURE 4.
`Release Constant k1 as a Function of Drug to Polymer Ratio
`and Polymer Average Molecular Mass from Tablets
`Containing Diphenhydramine HCI and Poly(oxyethylene).
`95 % Confidence Interval.
`
`At low drug to polymer ratios, the polymer fraction is so high that it will
`not allow the formations of preferential channels in the matrix trough
`which the drug can he rete ed. Furthermore, the polymeric chains are
`completely entangled, regardless of their length, and drug can only be
`relea ed hy diffusion through them, thu explaining the similarities in k1
`values.
`
`O n the other hand, at higher drug/polymer ratios preferential drug release
`channels can he formed and also the level chains entanglement becomes
`dependent on average chain lenght so that diffusional release rates become
`dependent on polymer molecular mass.
`
`Ero ion controlled release rate constant k1 (Fig. 5) increases with increase
`in drug/polymer ratio; it also decrea es a polymer average molecular mass
`
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`

`1422
`
`MORONl AND GHEBRE-SELLASSIE
`
`r=--
`
`0.008
`
`0.006
`
`0_004
`
`-~ I
`
`.&
`E
`.......
`C\1
`~
`
`I
`
`0.002 I
`1
`l~
`
`0 .000
`
`0
`
`4
`
`8
`Drug I Polymer Ratio
`
`I
`
`I
`I
`
`:m.
`
`A
`a
`0
`
`400,000
`2 million. k2
`4 mltllon
`12
`
`FIGURE 5.
`Release Constant k2 as a Function of Drug to Polymer Ratio
`and Polymer Average Molecular Mass from Tablets
`Containing Diphenhydramine HCI and Poly(oxyethylene).
`95 % Confidence Interval.
`
`increa es, since polymers of high molecular mass dissolve at a slower rate
`and are more sensitive to " alting out" effects.
`
`Comparison of k1 and k2, after dimensional normalization done by squaring
`k.,(Fig. 6), shows their relative contribution to the overall release rate from
`each polymeric system. At all drug/polymer ratios, diffusion release
`constant k1 is slightly higher, than kl for poly(oxyethylene) 4 million based
`tablets, while the opposite happens for poly(oxyethylene) 2 million; on the
`other hand, tablets made from poly( uxyethyJene) 400,000 show a k2 that is
`substantially higher than k1, an indication that erosion is the dominant
`mechanism in the overall relea ·e rate.
`
`Poorly Water Soluble Drui.
`Cf-936 chemically known as diphcnylethyl(adenosine) is an experimental
`drug that has a low water oluhility ( about 2.5 mg/ml). Tablets containing
`
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`KASHIV1028
`IPR of Patent No. 9,492,392
`
`

`

`POL Y(OXYETHYLENE) HOMOPOL YMERS
`
`1423
`
`0.008
`
`0.006
`
`0 .004
`
`I
`
`..-
`I
`.~
`
`E -C\1
`
`~
`~
`(\J
`* *
`.,....
`~ 0.002
`
`I
`I
`ll i
`
`+
`
`0
`
`0.000
`
`! • 400,000, k1 .. 2
`• 2 million, k1''2
`• 4 million, k1"'2
`t
`
`400.000. k2
`6
`D 2m !on. k2
`4 mUQon. k2
`0
`12
`
`fi
`
`4
`
`8
`Drug I Polymer Ratio
`
`FIGURE 6.
`Release Constants k1 2 and k2 as a Function of Drug to
`Polymer Ratio and Polymer Average Molecular Mass from
`Tablets Containing Diphenhydramine H Cl and
`Poly(oxyethylene).
`
`the drug showed a dissolution behavior that is quite different from that
`descrihed above. Because of the low solubility of the drug in the medium
`dissolution of the drug in the solvent front is limited. Furthermore, the
`drug does not ionize and consequently does not affect polymer dissolution
`appreciably. As a result, surface erosion is the dominant release
`mechanism, although initially the release rate of CI-936 appears to be
`controlled to a large extent by diffusion of the drug through the gel layer
`which form. on the surface of the tablet following hydration. The release
`rate of CI-936 decreases with a decrea e in the drug/polymer ratio down to
`a minimum ( 5/5 for poly(oxyethylene) 4 and 2 million or 7/3 for the
`400,000 grade) then increase again (Fig. 7-9). The release rate appears to
`be controlled by erosion at both high and low drug to polymer ratio and by
`diffu ion at intermediate ratio .
`
`Supplied by the British Library 06 Feb 2018, 14:06 (GMT)
`
`KASHIV1028
`IPR of Patent No. 9,492,392
`
`

`

`1424
`
`MORONI AND GHEBRE-SELLASSIE
`
`120
`
`100
`
`80
`
`60
`
`40
`
`20
`
`"C
`Q)
`(I]
`«1
`Q)
`<1>
`L.
`C)
`:::J
`L.
`"C
`~
`
`0
`
`0
`
`240
`
`480
`
`720
`Time <min.)
`
`960
`
`>+-i< Drug/Polymer 9/1
`~ Drug/Polymer 7/3
`~ Drug/Polymer 1/1
`G--£J Drug/Polymer 3/7
`1200
`1440
`
`FIGURE 7.
`Release Profiles of Cl 936 I Poly(oxyethylene) 4 Million
`Average Molecular Mass Tablets in pH 1.2 HCI.
`USP II (paddles). 75 rpm, 37° c.
`
`At high drug/polymer ratio the release rate is fast not only because the
`quantity of polymer that is used tp bind the tablet components in the
`matrix is low, but also the gel layer that is formed on the surface is not
`strong enough to slow drug diffusion toward the outside of the tablet.
`Visual observation of the tablets during dissolution shows that they erode
`without significant swelling; this leads to a decrease in surface area which
`in turn is responsible for the reduction in the disso]ution rate.
`
`Tablets with an intermediate drug/polymer ratio contain enough polymer to
`form a gel layer capable of slowing drug diffusion and release as well as a
`sufficient quantity of poorly water soluble drug to reduce solvent
`penetration and delay polymer dissolution. A combination of these two
`factors, therefore, slows drug release, especially during the early part of
`dissolution. Release profi1es of intermediate formulations approximate the
`
`Supplied by the British Library 06 Feb 2018, 14:06 (GMT)
`
`KASHIV1028
`IPR of Patent No. 9,492,392
`
`

`

`POL Y(OXYETHYLENE) HOMOPOL YMERS
`
`1425
`
`120
`
`100
`
`80
`
`"'0
`Q,)
`(/J
`(1J
`Q)
`Q)
`~
`
`60
`
`C>
`::s
`.... "'0
`~ 40
`
`20
`
`0
`
`0
`
`240
`
`480
`
`720
`Time <minJ
`
`960
`
`>f-t< Drug/Polymor 9/1
`9-----9 Drug/Polymer 7/3
`~ . Drug/Polymer 111
`G-O Drug/Polymer 3/7
`G-O Drug/Polymer 114
`1200
`1440
`
`FIGURE 8.
`Release Profiles of Cl 936 I Poly(oxyethylene) 2 Million
`Average Molecular Mass Tablets in pH 1.2 HCI.
`USP II (paddles). 75 rpm, 3JO C.
`
`square root of time during the early part of dissolution and then show a
`discontinuity, suggesting that release control shifts from diffusion to erosion
`when the polymer becomes sufficiently hydrated.
`
`At low drug to polymer ratio, the release rates tend to be faster because
`the solvent penetrates the tablet core unimpeded, depending only on the
`hydration rate of the polymer. Hydration is followed immediately by
`surface erosion.
`
`In an attempt to better understand the physical changes occurring during
`dissolution, tablets with varying drug/polymer ratio were removed from the
`dissoJutjon medium during the dissolution course, dried, and visually
`evaluated. It was found out that tablets with intermediate drug/polymer
`ratio were, at a given time, larger than those with high or low drug to
`polymer ratio.
`
`Supplied by the British Library 06 Feb 2018, 14:06 (GMT)
`
`KASHIV1028
`IPR of Patent No. 9,492,392
`
`

`

`1426
`
`MORONI AND GHEBRE-SELLASSIE
`
`120
`
`100
`
`80
`
`60
`
`40
`
`20
`
`"0
`Q)
`Cl) co Q)
`Q) ... en
`.... "0
`
`::J
`
`~
`
`~ Drug/Polymer 9/1
`'0'---9 Orug/Polymar 7/3
`~ Drug/Polymer 1/1
`G-£1
`
`0~--~--~--r-~~-,--~---r--~--~--~--T---,
`240
`480
`0
`960
`1200
`1440
`720
`Time <min.>
`
`FIGURE 9.
`Release Profiles of Cl 936 I Poly(oxyethylene) 400,000
`Average Molecular Mass Tablets in pH 1.2 HCI.
`USP II (paddles), 75 rpm, 37° C.
`
`Tablets with high drug/polymer ratio exhibited overall higher release rates.
`The dissolution rates were high enough initially but decrease as dissolution
`proceed·. Tablet , with low drug to polymer ratio show a linearly time
`dependent release profiles which indicate that drug reJease become
`erosion controlled immediately. Furthermore, in this case, the tablets well
`considerably, whit eroding, thus keeping the total surface area from
`changing significantly.
`
`CONCLUSION
`
`Poly( oxyethylene) polymers are hydrophilic materials suitable for the
`development of monolithic drug delivery formuJations. These polymers can
`be easily loaded up with drugs of different soJubility characteristics and
`tailored to give the dc::sired release profiles.
`
`Supplied by the British Library 06 Feb 2018, 14:06 (GMT)
`
`KASHIV1028
`IPR of Patent No. 9,492,392
`
`

`

`POL Y(OXYETHYLENE) HOMOPOL YMERS
`
`1427
`
`The rerlease rate of the tablets do not only depend upon the common
`formulation variahles such as drug/polymer ratio, polymer average
`molecular mass, and the solubility of the drug but also on the ionization
`state of the drug molecules.
`
`REFERENCES
`
`1) R.S. Langer and N.A. Peppas, Presem and future applicatio11s of
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`
`2) R.S. Langer, Polymeric delivery systems for omrol/ed dmg release, Chern.
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`
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`4) P.l Lee and N.A. Peppas,Prediction of polymer dissolwion i11 swel/able
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`
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`
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`. Solomon, Comparison uf the in-
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`Supplied by the British Library 06 Feb 2018, 14:06 (GMT)
`
`KASHIV1028
`IPR of Patent No. 9,492,392
`
`

`

`1428
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`
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`
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`characteristics of Some bronclrodilatators from compressed hydrophylic
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`41, 55-62 (1988).
`
`14) J.L. Ford, M.H. Rubinstein, atul J.E. Hogan, Formulation of sustained
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`
`15) K.P. Dev~ K V Ratrga Rao, S. Baveja, M. Fatlt~ M. Roth, Zero-order
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`
`16) K. V Ranga Rao, K. Padmalatha Devi and P. Buri, Influence of
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`
`17) S.K. Baveja, K V Ra11ga Rao, and K. Padmalatlta Dev~ Zero order
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`
`18) R.S. Harland, A. Gazzaniga, M.E. Sangalli, P. Colombo, and N.A.
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`488-94 ( 1988).
`
`Supplied by the British Library 06 Feb 2018, 14:06 (GMT)
`
`KASHIV1028
`IPR of Patent No. 9,492,392
`
`