Controlled
`
`REVISED
`July 1999
`
`Release Society, Inc.
`
`An international society advancing the science and technology
`of chemical and biological delivery systems.
`
`PROCEEDINGS BOOK
`
` THE 26TH INTERNATIONAL SYMPOSIUM ON
`CONTROLLED RELEASE OF
`BIOACTIVE MATERIALS
` THE SECOND CONFERENCE ON
`CONSUMER AND
`DIVERSIFIED PRODUCTS
`
`P
`pe
`he
`
`LS] a
`
`! i 7
`( Aaschutx)
`
`
`
`June20-25, 1999
`
`
`PROGRAM COCHAIRS
`VLaApMoR Torcumun, Northeastern University, USA
`FRANCESCO M. VERONESE, University of Padova,Italy
`
`June 20-23, 1999
`
`Proceed, Int'l Sym ia1995ee Bloact.
`eens,26. Revie
`Jul
`Controlled se Society,Inc.
`aa:
`
`Boston MarrioTT Copiey PLAce, Boston, MA USA
`
`0001
`
`Noven Pharmaceuticals, Inc.
`EX2010
`Mylan Tech., Inc. v. Noven Pharma, Inc.
`IPR2018-00174
`
`

`

`
` #5123
` This matenai moy be protecied by Copyrghl law (Tile 17 U.S, cous|
`
`EFFECT OF SILICONE / ACRYLIC PSA BLENDS ON SKIN PERMEATION
`
`J.Mantelle', D. Kanios, S. Rossi-Montero, D. Houze, V. Nguyen, K. Moncada
`'Noven Pharmaceuticals, Inc., Miami, Florida 33186
`
`Introduction
`Rate and extent of skin permeation from
`drug-in-adhesive
`(DIA)
`transdermal
`drug
`delivery systems (TDDS) has traditionally
`been attributed solely to the barrier properties
`of the stratum corneum, a fact that has shed a
`negative light on the perceived ability of these
`DIA products to reproducibly attain the target
`pharmacological doses. Modification of these
`stratum corneum barrier properties has been
`sought by incorporation into these products of
`chemical enhancers such as fatty acids, esters,
`etc...alone or in combination with polyhydric
`alcohols.
`Although
`effective
`in
`skin
`permeations
`enhancement,
`chemical
`modification has a significant down side
`potential
`stemming
`from the
`increasing
`irritation potential
`that accompanies higher
`concentrations of these. Additionally, in DIA
`systems,
`these chemical enhancers typically
`possess
`surfactant
`properties
`that
`detrimentally affect
`the pressure sensitive
`adhesive (psa) properties of these and thus the
`wear properties of the finished product.
`
`Drug solubility modification via the blending
`of psa's has been shown to beas effective as
`chemical enhancement with the added benefit
`of having increased versatility in attainment
`of the required wear properties. PSA blends,
`and more specifically, blends of acrylic psa's
`with silicone psa's have been shown to afford
`the formulator the ability to manipulate the
`height of the initial delivery peak (burst
`effect), the lag time, and the length of time
`the product can sustain the pseudo-zero-order
`delivery of the permeant molecule. These
`performance characteristics are achieved by
`maximizing thermodynamic driving force
`with the minimal drug content by
`
`manipulation of the silicone to acrylic psa
`ratio.
`
`Experimental Method
`Two different drugs were evaluated in order
`to demonstrate the effects of varying the
`silicone to acrylic psa ratio. The two drugs
`selected, selegiline and estradiol, were picked
`based on their differences. Selegiline baseis a
`volatile liquid at room temperature whereas
`estradiol
`is a solid. Selegiline doses are
`targeted in the area of 5-10 mg/day whereas
`estradiol is targeted at 0.05-0.10 mg/day both
`from a 10 cm?patch area.
`
`The selegiline formulations were made at
`12% w/w drug while varying the acrylic psa
`content between 15 and 60% and thesilicone
`psa between
`28
`and 63%. No further
`excipients were used.
`
`Theestradiol formulations all contained 1.6%
`estradiol, 7.5% kollidon-30, 8% dipropylene
`glycol and 6% oleyl alcohol. The acrylic psa
`content was varied between 10 and 20% in
`conjunction with a silicone psa vanation
`between 66.9 and 56.9% by weight in the
`finished product.
`
`The diffusion rate of the drug is determined
`through a disc of cadaver skin. Epidermal
`discs from the same donorandsite were used
`in the study to factor out
`inter-subject
`variability in permeability.
`The receiving
`solution is an isotonic saline solution with a
`sodium azide preservative (0.9% NaCl and
`0.01% NaN3) with a pH of 6.7. The cell
`is
`kept at a constant temperature of 32 °C and
`stirred continuously at ~300 rpm.
`The
`number ofreplicate cells per formulation in
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`Proceed, Int'l. Symp. Control. Rel. Bloact. Mater., 26 (Revised July 1999) Controlled Release Society, Inc.
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`the experiment was four. A known volumeof
`saline was removed from the cell at specified
`time points. The complete contents of the
`receiver was removed and replaced with fresh
`saline to guard against solution saturation.
`The concentration of each sample ofsaline is
`determined through High Precision Liquid
`Chromatography with a detection wavelength
`of 220 nm.
`
`Results and Discussion
`SELEGILINE
`Figure #1 shows the effect of increased ratio
`of silicone to acrylic psa while holding the
`drug concentration constant at 12% drug. As
`can beseenin this plot, as the ratio ofsilicone
`to acrylic psa went from 28:60 to 58:30 to
`73:15,
`the
`corresponding
`average
`skin
`permeation rate went from 13.5 to 18.4 to
`29.7 ug/cm?with no significant changein the
`shape of the permeation curve (i.e.
`initial
`peak followed by a gradual fall off to the 26
`hour timepoint). Based on this performance,
`attaining equivalent rate and extent between
`the three formulations from a bioequivalence
`viewpoint could be achieved by varying the
`patchsize,
`
`:3== “
`
`
`
`AvemgeMasispfeenn
`
`“
`
`a
`
`‘met |aor
`
`D
`
`Figure 1 - Effect of Silicone to Acrylic Ratio ce Selegiline Flux
`
`ESTRADIOL
`Figure #2 illustrates the in-vitro performance
`of
`the
`estradiol
`formulations where
`the
`silicone to acrylic psa ratio was varied at a
`
`#5123
`
`constant concentration of estradiol (1.6% by
`weight). As shown, varying the silicone to
`acrylic psa ratio from 56.9:20 to 61.9:15 to
`66.9:10 resulted in an average flux rate
`increase from 1.01 to 1.09 to 1.25 ug/em’/hr
`with the additional effect of having altered the
`initial burst effect and subsequent sustenance
`of the pseudo-zero-order delivery profile. As
`can be seen in Figure #2, higher silicone to
`acrylic psa ratios resulted in a shift of the
`permeation profile from a pseudo-zero-order
`to a first order delivery system incapable of
`sustaining the targeted 84 hour delivery,
`
`
`& er
`
`teas
`|
`decane
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`amaele
`AvomgePin(poycme)
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`
`Figure 2 - Effect of Silicone to Acrylic Ratlo on Estradiol Flax
`
`Conclusion
`Alteration of thermodynamic driving force in
`& drug-in-adhesive transdermal drug, delivery
`system by manipulation of pressure sensitive
`adhesive
`ratios
`in
`a
`blend of
`these,
`specifically silicone and acrylic psa's, can
`havea substantial effect on the rate and extent
`of skin permeation for selected molecular
`entities. By adjusting the ratio of these,
`the
`formulator
`is
`afforded
`a
`cost-effective
`alternative
`to
`permeation
`enhancement
`without the deleterious effects on the physical
`and wear properties of the product which
`result from addition of large amounts of drug
`or surfactant-like channel enhancers,
`
`Acknowledgements
`To Dow coming Corporation and National
`Starch Companyfor their technical support of
`our research and developmentprojects.
`
`416
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`Proceed, int'l. Symp. Control, Rel. Bloact. Mater., 26 (Revised July 1999) Controlied Release Society, Inc.
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