83
`
`Poly(ethylene oxide) (PEO) and
`different molecular weight PEO blends
`monolithic devices for drug release
`A. Apicella, B. Cappello*, M.A. Del Nobile, M.I. La Rotonda*,
`G. Mensitieri and L. Nicolais
`Department of Materials and Production Engineering, *Department of Pharmaceutical and Toxicological
`Chemistry, University of Naples Federico II, 80131 Naples, Italy
`
`An interpretation of the drug release from monolithic water-swellable and soluble polymer
`tablets is presented. A convenient parameter, a, which compares the drug-diffusive conductance
`in the gel layer with the swelling and dissolving characteristics of the unpenetrated polymer was
`used to describe the release behaviour of /3-hydroxyethyl-theophylline (etotylline) from
`compression-moulded tablets of hydrophilic pure semicrystalline poly(ethylene oxides) of mol wt
`600 000 and 4 000 000 and of two blends of the two molecular weights of poly( ethylene oxides).
`The water swelling and dissolution characteristics of two polymers and two blends were
`analysed, monitoring the thickness increase of the surface-dissolving layer and the rates of
`water swelling and penetration in the tablets. The drug diffusivities in the water-penetrated
`polymer gels were measured by carrying out permeation tests. finally, drug release tests were
`performed to investigate the release kinetics of the different systems in an aqueous environment
`at 37°C. The drug release from the high molecular weight poly(ethylene oxide) is principally
`related to the material swelling rather than polymer dissolution, leading to a progressive
`decrease of the drug's diffusive conductance in the growing swollen layer, and hence to a non-
`constant release induced by the prevailing diffusive control. Conversely, drug release from the
`low molecular weight poly(ethylene oxide) is strictly related to the polymer dissolution
`mechanism. The achievement of stationary conditions, in which the rate of swelling equals the
`rate of dissolution, ensures a constant release rate, even in the case of very low drug-diffusive
`conductance in the external gel layer. Intermediate behaviours were detected in the case of the
`two blends.
`Keywords: Poly(ethylene oxide), controlled release, drug delivery, diffusion
`Received 12 December 1991; accepted 10 June 1992
`
`Diffusion-controlled release technology, based on polymer
`barrier characteristics, is a good alternative to con-
`ventional delivery systems. Complex reservoir systems
`and monolithic matrix systems are two important
`applications. For the former, a zero-order kinetic release
`may be maintained until the drug activity in the reservoir
`can be kept constant. However, environmentally passive
`monolithic matrix systems, containing dispersed or
`dissolved active ingredients, are not able to give a
`constant delivery rate, at least for simple device geometries.
`In such cases, the diffusion control generally leads to a
`square root of time dependency of the drug delivery.
`Alternatively, the use of environmentally interactive
`monolithic devices made with hydrophilic polymers was
`first proposed by Hopfenberg et al. 1• 2, and extensively
`investigated3- 8• As the penetrant enters the drug-entrapping
`matrix, the polymer swells and the active ingredient
`diffuses from the swollen part. This relaxation-controlled
`
`Correspondence to Dr A. Apicella.
`
`© 1993 Butterworth-Heinemann .ltd
`0142-9212/93/020083-08
`
`sorption is governed by the solvent concentration at the
`interface separating the swollen from the unpenetrated
`polymer. The polymer at the interface relaxes and swells
`at a constant rate as long as the penetrant concentration
`at the moving boundary remains constant. Zero-order
`release from this type of device requires a constant
`surface area and a constant swelling rate of the polymer
`matrix [limiting Case II sorption) as well as a high
`diffusivity of the entrapped species. These conditions,
`generally, cannot be protracted for long release times 2
`,
`since they are strongly dependent on the time evolution
`of the interactions involving polymer, penetrant and
`solute. It is only in the early stages of polymer swelling
`that, due to the small thickness of the swollen layer, the
`diffusive conductances of both the solvent toward the
`unpenetrated core and the drug moving outside are much
`higher than the swelling rate, and the constant delivery is
`brought about by the constant rate polymer relaxation.
`However, as the swollen thickness increases, lower
`values of the diffusive conductance are attained and both
`
`Biomaterials 1993, Vol. 14 No. 2
`
`KASHIV1049
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`
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`

`84
`
`swelling and release rates are progressively reduced.
`Hopfenberg et al. 2 and Peppas and Franson3 proposed
`similar dimensionless parameters to identify zero-order
`release conditions in terms of initial solvent penetration
`rate, swelling thickness, and diffusivity of the active
`ingredient in the swollen polymer. To guarantee zero-
`order releases from swelling systems of increasing
`thicknesses, the drug should present the proper high
`diffusivity in the swollen polymer. The addition of water-
`soluble components in the polymer has been proposed4 to
`enhance the diffusivity of the drug in the more porous
`swollen layers created.
`Poly(ethylene oxide) (PEO)-based systems have been
`proposed as drug delivery devices. In particular, Graham
`et al. reported the constant release of prostaglandin E2
`from cross-linked crystalline-rubbery hydrogel matrices
`based on PEO which were undergoing solvent sorption
`and from crystallites melting in aqueous environments9- 11•
`In the case of uncross-linked PEO matrices, the solubility
`of the polymer can alter the characteristics of the
`penetrated layer, leading to different behaviours in
`systems presenting different dissolution features. To
`control the release of the active agent, there should be a
`balance between diffusion of the active agent and
`solubilization of the polymer matrix. The diffusivity of
`the drug through the matrix, the swelling of the polymer,
`and its solubilization rate can be biased by changing the
`molecular weight of the polymer or blending polymer
`fractions with different molecular weights.
`Mucoadhesive capability is another important property
`of a polymer to be used as matrix for monolithic drug
`delivery devices. In fact, in the development of oral-
`controlled release devices, considerable benefit may
`result from the use of bioadhesive polymers providing
`relatively short-term adhesion between the drug delivery
`system and the epithelial surface of the gastrointestinal
`tract. Due to the linear flexible structure of the PEO
`macromolecule, this polymer shows a particular ability
`to form entangled physical bonds by interpenetrating
`deeply and rapidly into mucous substratum networks.
`The mucoadhesive properties of PEO reported in the
`literature are strongly dependent on the polymer molecular
`weight and are more pronounced in the case of the high
`molecular weight materials12- 14• In particular PEO shows
`a behaviour14 ranging from no bioadhesion at mol wt
`20 000 to very good bioadhesion at mol wt 4 000 000.
`Consequently, both the release and the mucoadhesive
`properties of PEG-based systems are expected to be
`finely tuned by blending PEO fractions with different
`molecular weights.
`We were therefore interested in the analysis of the
`capability of PEO to be used as mucoadhesive control
`release devices. In the present investigation, we relate
`the sorption, melting and dissolution characteristics of
`two PEOs of different molecular weight to the diffusivities
`in the swollen polymer of an active ingredient (etofylline)
`and the release behaviour observed.
`
`RELEASE MECHANISMS FROM
`MONOLITHIC DEVICES
`
`The release rate of a dissolved or dispersed drug from a
`polymeric film or tablet introduced in a specific environ-
`
`Biomaterials 1993, Vol. 14 No. 2
`
`PEO devices for drug release: A. Apicella et at.
`
`ment, strongly depends on the nature of the diffusion and
`sorption processes involving the polymer/environment
`system and the polymer/drug system.
`
`Diffusion-controlled devices
`The dissolved species will diffuse from a matrix which
`does not actively interact with the external environment
`according to an ordinary diffusion law [Figure la). In
`such a case, the concentration profile in the slab
`decreases with time leading to the progressive reduction
`of the release rate (i.e. the slope of the fractional release
`versus time curve).
`
`Swelling-controlled devices
`Completely different release behaviour is observed for
`hydrophilic polymers when water sorption is followed
`by significant polymer swelling. Limiting Case II sorption
`occurs when constant rate water absorption is associated
`with a front advancing at a constant rate into the confines
`of the glassy polymer. A sharp boundary separates the
`essentially unpenetrated core from an uniformly swollen
`shell [Figure 1b). The polymer relaxation and swelling is
`driven by the osmotic stresses generated at the moving
`boundary by the presence of the penetrant15- 17 and
`remains constant as long as a constant local concentration
`persists. Drug release is controlled quantitatively by the
`invasion of the swelling solvent and by the solute counter
`diffusion in the swollen polymer. Zero-order release
`kinetics may be achieved from a polymer which swells at
`a constant rate and with a constant penetration surface
`area, but only if the counter diffusion of the solute
`molecules is rapid compared with the swelling rate.
`
`Intermediate cases
`There are intermediate cases in which both the swelling
`and the diffusive control can be important during drug
`release. The swelling front advancing rate (v) and the
`diffusive conductance (the ratio between the solute
`diffusivity and the shell thickness at a given time D/c5(t))
`have been used2 to define a convenient dimensionless
`parameter:
`a = D/[cS(t) X v]
`which accounts for the relative contribution of the solute
`counter diffusion and of the penetrant uptake rate to the
`overall rate of release.
`In the early stages of swelling, the diffusive con-
`ductance is high, due to the small value of the swollen
`shell thickness (c5(t)). Release is controlled by the
`polymer swelling rate [Figure 1) and values of a > 1 are
`measured. Conversely, the diffusion of the solute
`molecules through the outer shell will increasingly
`control the release kinetic observed as the swollen layer
`progressively thickens. In this case, values of a smaller
`than unity are observed. Diffusive control is reflected by
`the fractional release versus time curve as a progressive
`reduction of the release rate [Figure 1b). For low values
`of a, the polymer rapidly swells, after which the drug is
`depleted by an exclusively diffusive mechanism2 • As a
`consequence, a zero-order release rate is expected when
`a(t) > 1 and the penetration rate of the swelling agent is
`constant.
`
`KASHIV1049
`IPR of Patent No. 9,492,392
`
`

`

`PEO devices for drug release: A. Apicella et al.
`
`85
`
`Release from monolithic devices
`
`Fickian diffusion
`
`Limiting Case II sorption
`
`Release rate
`
`ll = D/{o{t) ·v J
`Swelling rate
`{constant)
`v = cm/s
`Diffusion conductance
`{variable)
`D/6{t) = cm/s
`
`L/2
`
`Penetrated
`polymer
`
`oL------------'
`Time
`
`a
`b
`Figure 1 Release mechanisms from monolithic devices. a, Fickian diffusion; b, limiting Case II sorption.
`
`Time
`
`A theoretical framework of penetrant uptake and
`solute release was developed by Peppas et aP· 18 and by
`Davidson and Peppas19• 20 to characterize monolithic
`swellable systems for controlled drug release. It has been
`shown that two dimensionless parameters should be
`used to predict the release behaviour of these systems.
`The swelling interface number, Sw (1/a in the present
`context), and the diffusional Deborah number, De, have
`been introduced. The former represents the ratio of the
`penetrant uptake rate to the rate of solute diffusion. The
`latter represents the ratio of the characteristic swelling
`time of polymer chains, related to the presence of the
`swelling penetrant, to the characteristic diffusion time of
`the penetrant into the polymer. Zero-order release rates
`should be expected if both the solute diffusion through
`the swollen polymer layer is rapid compared to the
`penetrant uptake rate (Sw « 1) and the penetrant uptake
`is controlled by polymer relaxation (De :;- 1). As con-
`sequence the solute release kinetics cannot be uniquely
`related to a (or 1/Sw) and also the value of De has to be
`taken into account.
`
`Polymer swelling and dissolution-controlled
`devices
`Thermoplastic polymers which are sufficiently hydro-
`philic are also water soluble. A sharp advancing front
`divides the unpenetrated core from a swollen and
`dissolving shell. Under stationary conditions, a constant
`thickness surface layer (<5) is formed by the swollen
`polymer and by a high concentration polymer solution21•
`In fact, once the hydrodynamic external conditions
`are defined, a stationary state is reached where the rate of
`penetration of the moving boundary ( v) equals the rate of
`removal of the polymer at the external surface. The time
`lapse until the quasi stationary state is reached is swelling
`time21 •
`Figure 2 reports the typical polymer concentration in
`
`Penetrating
`front
`I.. +-
`Cll
`E +-
`>-
`0 +-
`a.
`""0
`....
`Cll
`"'
`.....
`I..
`Cll
`c
`Cll +-
`a. c
`::> +-
`
`When:
`
`Swelling rate =dissolving
`rate
`
`~
`
`o(t) =constant
`
`~o!tl~
`Figure 2 Polymer concentration profile for swelling and
`dissolving materials.
`
`the surface layer of a dissolving polymer. If the
`dissolution occurs normally, the steady-state surface
`layer consists of four different sublayers21
`liquid
`:
`sublayer (adjacent to the pure solvent), gel sublayer, solid
`swollen sublayer and infiltration sublayer (adjacent to
`the polymer base into which the solvent has not yet
`migrated). If the test temperature is higher than the glass
`transition temperature of the polymer, the surface layer
`consists of only liquid and gel sublayers.
`At steady state, the dissolution rate is constant and can
`be defined equally by either the velocity of the retracting
`front of the polymer or the velocity of the front
`separating the pure penetrant and the liquid dissolving
`sublayer. Thus both fronts are synchronized.
`The dissolution rate strongly depends on hydrodynamic
`conditions, temperature, polymer molecular weight and
`crystallinity level. Close analogies have been found
`between crystallization and dissolution behaviours for
`semicrystalline polymers21• In fact, dissolution and
`crystallization rates are maximal when plotted as
`
`Biornaterials 1993, Vol. 14 No. 2
`
`KASHIV1049
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`
`

`

`86
`
`function of temperature and are both expected to
`decrease with increasing polymer molecular weight.
`In the case of a dissolving polymer, a dimensionless
`parameter a(t) can still be defined as the ratio of the
`diffusive conductance D/c5(t) and dissolution (or penetra-
`tion) rate v. Consistent with the previous discussion
`concerning swellable polymers, a zero-order release rate
`is to be expected only if a > 1 and the dissolution rate is
`constant with time. Two different dissolution stages can
`be identified: the initial time lapse (swelling time) and the
`steady-state conditions. During the initial transient,
`neither the thickness of the dissolving surface layer or
`the dissolution rate are yet constant. A time-dependent
`diffusive conductance (D/c5(t)) and a time dependent
`dissolution rate (v(t)) should be considered for the
`evaluation of the parameter a(t). Conversely, under
`steady-state conditions, a constant diffusive conductance
`(constant gel layer thickness) and a constant dissolution
`rate are attained. As a consequence, in the first stage a
`changes during the dissolution; release process and
`release rate can be a function of time. During the second
`stage, however, a time-independent concentration profile
`develops into the external surface layer. A constant
`release rate is obtained, determined by the penetrating
`front rate or equally by the rate of advancement of the
`liquid sublayer-pure solvent boundary, synchronized to
`the penetrating front. A similar example of zero-order
`release kinetics resulting from the synchronization of
`front velocities of the identical velocities of diffusing and
`eroding fronts in erodible polymer matrix delivery
`systems22•
`
`MATERIALS AND METHODS
`Materials
`PED of average mol wt of 600 000 (Aldrich Chimica S.r.l.,
`Catalogue No. 18,202-8) and 4 000 000 (Aldrich Chimica
`S.r.l., Catalogue No. 18,946-4) were used. Analytical
`grade
`(purity 99.6%) {j-hydroxyethyl-theophylline
`(etofylline) was supplied by Sigma Chemical. The
`materials were used as received.
`
`Methods
`
`Thblet preparation
`The polymer and the etofylline powders were first
`desiccated under vacuum, next mixed in the desired
`proportions, then dissolved in chloroform. The solution
`was stirred well to assure a homogeneous mixing of the
`components. Polymer films containing the drug were
`obtained by casting. After desiccation, several film
`layers were then compression moulded at 75°C to form
`sheets from which were cut circular tablets (25 mm
`diameter) with thicknesses of 2.0 or 3.3 mm. Four
`different kinds of tablets were produced, all containing
`10% etofylline. The four different polymer matrices used
`were: pure PED (mol wt = 600 000), pure PED (mol
`wt = 4 000 000), 50% b.w. blend of the two PEDs and
`87% b.w. mol wt of 4 000 000 and 13% b.w. mol wt of
`600 000 blend of the two PEDs (50% mol blend).
`
`Biomaterials 1993, Vol. 14 No. 2
`
`PEO devices for drug release: A. Apicella et at.
`
`Calorimetric analysis
`In order to characterize PEDs and PEDs/etofylline
`mixtures, a Du Pont differential scanning calorimeter
`(DSC instrument 910) operating under nitrogen flux and
`at a heating rate of 10°C/min was used.
`
`Gel layer thickness measurement
`Water swelling and penetration depths, and gel layer
`evolution were optically measured during the water
`conditioning at fixed times. The samples were cleaved on
`glass plates and placed in thermostated distilled water
`held at 37°C. The water was continuously stirred and
`measurements were taken using a cathetometer.
`
`Etofylline permeation tests through the swollen
`polymers
`An apparatus equipped with a cell for liquid permeation
`measurements in membranes was used for the permeability
`measurements (absorption simulator made by Sartorius
`AG). The polymers, free of drug, were confined in the cell
`between two semipermeable cellulose acetate membranes
`and equilibrated with distilled water at 37°C before the
`start of the permeability measurements. The equilibrium
`water swelling thicknesses of the four different polymeric
`materials confined in the cell were measured and used
`in the calculation of the permeability values. The con-
`centration increase of the etofylline in the downstream
`chamber of the permeability cell was monitored. The
`amount of drug passing through the polymer was then
`evaluated as function of time.
`Reference permeation tests were performed to determine
`the influence of the supporting cellulose acetate mem-
`branes on the drug permeation kinetics. The resistance to
`the drug transport due to the supporting membranes was
`found to be negligible compared to the values detected
`during the permeation tests performed on swollen
`polymers. The drug concentration into the swollen
`polymer on the upstream side was evaluated from the
`permeation tests by means of the calculated water-
`swollen polymer etofylline partition coefficient. The
`resulting concentration was approximately ten times
`lower than the tablet drug loading. Accordingly, a
`different drug diffusion rate could occur in the tablet
`dissolving layer. Nevertheless, a drug concentration
`lower than the drug loading is to be expected in the
`dissolving layer of the tablet, due to the swelling. For this
`reason, the diffusion constant evaluated by means of the
`permeation tests was used in the evaluation of the
`dimensionless numbers introduced in the previous
`sections. Eventual composition dependence of etofylline
`diffusivity through the surface tablet layer not measured.
`
`Drug release kinetics analysis
`A dissolution apparatus (Erweka D.T.) operating at
`50 rev min -l and at a constant temperature was used for
`the evaluation of the etofylline release kinetics from the
`polymer tablets. Each tablet was placed in a container
`filled with a known amount of distilled water and the
`increasing concentration of etofylline in the aqueous
`conditioning environment was measured as function of
`time.
`The etofylline concentrations in the aqueous solutions
`during the permeability and the release tests were
`determined by means of UV spectroscopy using a
`
`KASHIV1049
`IPR of Patent No. 9,492,392
`
`

`

`PEO devices for drug release: A. Apicella et a/.
`
`Beckman DU-40 spectrometer operating at 262 nm. All
`tests were carried out at 37°C.
`
`RESULTS AND DISCUSSION
`
`Drug release system characterization
`To characterize properly the drug release from the
`present swelling and dissolving systems, the solvent
`penetration, polymer swelling and dissolution behaviour,
`drug solubility in the host polymer and diffusion in the
`swollen and gelled layer were examined.
`
`Differential scanning calorimetry [DSC)
`The DSC thermograms of etofylline, PEO and of tablets
`made of the four different PEO matrices containing 10%
`etofylline were taken. The thermogram relative to the
`etofylline shows a well-defined melting peak around
`170°C while that of the semicrystalline pure PEOs and
`blends present a melting peak in the range 63-65°C. Only
`the melting peak of the polymer matrix is evident in the
`thermogram of tablets made of PEOs blended with
`etofylline. The absence of the melting peak of the
`etofylline indicates complete dissolution of the drug in
`the amorphous regions of the polymer. The crystalline
`fraction of the tablet matrices was about 0.65. This value
`was evaluated23 assuming an enthalpy of crystallization
`of PEO equal to -210 Jig.
`
`Polymer swelling and dissolution properties
`The photo reproduced in Figure 3 shows the initial
`swelling conditions observed for the two homopolymer
`tablets of different molecular weights. Figures 4 and 5
`report the penetration depth evolution kinetics in the
`case of the tablets made of pure PEOs with average mol
`wt of 600 000 and 4 000 000 containing 10% etofylline.
`The PEO of mol wt of 600 000 (Figure 4) shows an almost
`linear shape of the penetration depth curve as a function
`of time which indicates that, after a very short initial
`transient, the penetration front moves into the polymer at
`a constant rate. The higher molecular weight PEO tablet
`(Figure 5) is characterized by an initial rapid water
`penetration rate. A sharp front moves at a constant rate
`through the unpenetrated tablet core after a swelling time
`significantly larger than the time lapse detected for lower
`
`Figure 3 Water swelling of PEO tabs of mol wt of 600 000 (left)
`and 4 000 000 (right).
`
`87
`
`/
`
`/
`
`2.0
`
`1.5
`
`1.0
`
`0.5
`
`E
`E
`Ul
`Ul
`
`~
`
`Ql c:
`-~ ..c:
`1-
`
`0
`
`100
`
`200
`Time (min)
`Figure 4 Penetration depth kinetics of water at 37°C in mol wt
`of 600 000 PEO: the horizontal dotted line represents the time
`corresponding to the total penetration in the case of a 3.3 mm
`thick tablet. v = 1.3 X 10-4 mm/s.
`
`300
`
`1.2
`
`1.0
`
`E 0.8
`E
`Ul
`Ul
`
`0.6
`
`~
`
`Ql c:
`-~ ..c:
`1-
`
`0.4
`
`0.2
`
`0
`
`100
`
`200
`300
`Time (min)
`Figure 5 Penetration depth kinetics of water at 37°C in mol wt
`of 4 000 000 PEO: the horizontal dotted line represents the time
`corresponding to the total penetration in the case of a 2 mm
`thick tablet. v = 5.0 x 10-s mm/s.
`
`400
`
`500
`
`molecular weight PEO. The behaviour of PEO blends is
`similar to that of pure PEO with a mol wt of 4 000 000.
`The corresponding values of the steady-state penetration
`rates for the four kinds of polymer matrices, vs, are
`reported in Th.ble 1. As expected v decreases with
`increasing molecular weight. The PEO crystallization
`rate is reported24 to decrease with increasing molecular
`weight for mol wt values exceeding about 2-8 X 105 •
`Hence, as previously discussed, similar behaviour was
`observed in the case of dissolution rate.
`When the dissolution rate equals the penetration rate,
`a constant thickness surface layer should be observed.
`The dissolving layer evolution during water conditioning
`should reflect the different dissolution characteristics of
`the materials. The surface layer thicknesses as a function
`of time are compared in Figure 6. It is evident that a
`
`Biomaterials 1993, Vol. 14 No. 2
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`KASHIV1049
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`

`88
`
`PEO devices for drug release: A. Apicella et a/.
`
`Table 1 Swelling and diffusion parameters of PEOs
`v(cm/s)
`Polymer
`
`Gel layer (em)
`
`D (cm2/s)
`
`PEO 600000
`PEO blend (50% b.w.)
`PEO blend (87% b.w.)
`PEO 4000000
`
`13.0 X 10-6
`7.0 X 10-6
`7.6 X 10-6
`5.0 X 10-6
`
`0.1
`0.1-0.5
`0.1-0.5
`0.1-0.5
`
`7.0 X 10-8
`100.0 X 10-8
`150.0 x 10-8
`140.0 X 10-8
`
`(± 2 X 10-8)
`(± 20 X 10-8)
`(± 20 X 10-8)
`(± 20 X 10-8)
`
`5
`
`4
`
`3
`
`2
`
`E
`E
`Ill
`
`Ill cu c
`.l<:
`.!::!
`.c
`1-
`
`0.04
`
`0.03
`
`cu c
`~ 0.02
`0 ... cu
`
`01
`E
`
`0.01
`
`0
`
`Time (min)
`Figure 7 Etofylline permeation test in distilled water swollen
`mol wt of 4 000 000 PEO. D = U/(6 X t*) = 1.4 X 10-6 cm2/s.
`t* = L 2/6 D.
`
`PEO tablets show an almost constant release rate over
`the entire period of the test (Figure B). Under stationary
`swelling and dissolution conditions, a constant thickness
`dissolving surface layer, possessing a time-independent
`drug distribution profile, moves toward the inner part of
`the tablet. The constant delivery rate is determined by the
`constant penetration (or dissolution) rate.
`More complex behaviour has been observed for the
`
`0
`
`0 :; -... :;
`
`0
`
`100
`
`200
`
`300
`
`400
`
`Time/1 (min/mm)
`Figure 8 Release kinetics of etofylline at 37°C in distilled
`water from mol wt of 600 000 and 4 000 000 PEO tablets
`containing 10% by weight etofylline. 0, mol wt 600 000; 0, mol
`wt 4000 000.
`
`0
`
`100
`
`200
`Time (min)
`Figure 6 Gel layer development kinetic at 37°C in water-
`penetrated PEO and PEO blends tablets. 0, PEO mol wt
`4 000 000; •. PEO blend: 87% b.w. 4 000 000; e, PEO blend:
`50% b.w. 600 000; 0, PEO mol wt 600 000.
`
`300
`
`stationary thickness (about 1 mm) is readily reached only
`in the low molecular weight polymer. In the case of the
`high molecular weight PEO and of the two blends, it
`abruptly reaches an initial value (1 mm) in the very early
`stages of water sorption, then increases continuously (up
`to 5 mm in our test). It can be concluded that, in the case
`of the chosen tablet thicknesses, a steady-state dissolution
`rate (constant o) is detected only for PEO with an average
`mol wt of 600 000. The other three types of matrices do
`not reach the quasi stationary dissolution stage. A zero-
`order release rate is thus likely to be expected only in the
`case of tablets made of PEO with average mol wt of
`600 000. Conversely, the other three matrices should
`show more complex release behaviour.
`
`Drug diffusivities in the polymer gel
`Permeation tests of etofylline in water-swollen PEO
`were performed to evaluate the time lag. Figure 7 shows
`the drug amount released in the downstream chamber for
`tests made at 37°C for the high mol wt (4 000 000) PEO.
`The time lag is defined by the intercept on the time axis of
`the stationary part of the permeability curve. Assuming
`that the first and second Pick's law for diffusive
`transport hold true, the time lag is equal to L2/6 D where
`L is the equilibrium swelling thickness of the polymer
`sample and D is the etofylline diffusivity. From the time
`lag D can be readily evaluated. The values obtained are
`reported in Table 1.
`
`Drug release rate
`As already pointed out a zero-order drug release is to be
`expected in the case of the tablets made of PEO with
`average mol wt of 600 000. The lower molecular weight
`
`Biomaterials 1993, Vol. 14 No. 2
`
`KASHIV1049
`IPR of Patent No. 9,492,392
`
`

`

`PEO devices for drug release: A. Apicella et a/.
`
`other three matrices adopted in the present investigation.
`In the case of tablets prepared with the higher molecular
`weight polymer (4 000 000), the value of a is likely to
`change with time due to both the continuous increase of
`the thickness (c5) ofthe dissolving surface layer and to the
`decrease of the dissolving rate in the initial transient. In
`fact, a(t) evaluated from experimental data ranges
`initially from values > 1 to values < 1 in the final stages.
`The development of drug diffusive resistance in the
`dissolving swollen layer becomes significant only when
`a thickness> 2.5-3.0 mm is formed. As a consequence,
`the drug release is governed by the dissolution rate during
`the initial stages of release, then controlled by the solute
`diffusion through the swollen dissolving layer in the final
`stage. The release kinetics from a tablet made of PEO
`with an average mol wt of 4 000 000 is also reported in
`Figure B. A roughly constant release rate stage is
`followed by a decreasing rate delivery.
`Release tests performed on tablets made of blends of
`the two PEDs are reported in Figure 9. In both cases, the
`values of a ranges during the test from values > 1 to
`values < 1. A behaviour similar to the case of pure PEO
`with average mol wt of 4 000 000 should hence be
`expected. However, an almost constant release, very
`close to the behaviour of tablets made of pure PEO with
`average mol wt of 600 000 was detected in the case of the
`blend containing the lower amount of high molecular
`weight PEO (50% b.w.). A release behaviour close to that
`of the tablets made of PEO with an average mol wt of
`4 000 000 was observed only in the case of the blend
`containing 87% by weight of the high molecular weight
`fraction. For tablets made of PEO blends, the parameter a
`does not provide an interpretation of the data which
`cannot be uniquely correlated with the parameter
`values.
`
`CONCLUSIONS
`Our results show that it is possible to obtain different
`release behaviours by changing the molecular weight of
`
`1.0
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`0
`0
`
`:::E -...
`
`:::E
`
`300
`
`400
`
`0
`
`100
`
`200
`Time/1 (min/mm)
`Figure 9 Release kinetics of etofylline at 37"C in distilled
`water from 50% b.w., mol wt of 4 000 000 and 87% b.w. mol wt
`of 4 000 000 PEO blends tablets containing 10% by weight
`etofylline. 0, mol wt 4 000 000 (87% b.w.); 0, mol wt 4 000 000
`(50% b.w.).
`
`89
`
`the soluble polymeric matrix-forming monolithic drug
`delivery devices. The low mol wt (600 000) PEO matrix
`showed a nearly constant drug delivery rate due to the
`synchronization of penetrating and dissolving fronts.
`Non-constant release behaviour has been detected in the
`case of the high mol wt (4 000 000) PEO matrix. The
`tablets made of a PEO blend containing 87% by weight of
`the high molecular weight fraction showed behaviour
`similar to the tablets made of pure PEO with mol wt of
`4 000 000. The best compromise between release and
`potential mucoadhesive properties was obtained from
`tablets made of 50% by weight blends of the two PEO
`fractions. The nearly constant release rate is coupled
`with good potential bioadhesive properties imparted by
`the high molecular weight fraction.
`
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`2
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