Controlled
`
`REVISED
`July 1 999
`
`Release Soclety, Inc.
`
`An inlcmallonal society advancing the science and lcchnology
`of chcmlcal and biological dcllvcry syslcrm.
`
`PROCEEDINGS BOOK
`
` THE 26TH INTERNATTONAL SYMPOSIUM ON
`CONTROLLED RELEASE OF
`BIOACTIVE MATERIALS
`
` THE SECOND CONFERENCE ON
`CONSUMER AND
`DIVERSIFIED PRODUCTS
`
` JuneZO-ZS, I999
`
`
`
`1 (
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`PROGRAM COCHAIRS
`VLADIMIR TOW. NnrthcaSIL-m University. USA
`FRANCESCO M. Venom. University (If Padnva. Italy
`
`June 20-23, 1999
`
`Proceed. 1111’] SH!
`£31. Conlrol. Re]. Bloacl.
`uly 1999)
`Mater. Jillian-in
`ISSN anB-DIFS
`mm. b . the
`Contrallud clause Society. Inc.
`
`303mm MARRlO'I'l‘ COPLEY PLACE, BOSTON, MA USA
`
`Noven Pharmaceuticals, Inc.
`EX2010
`
`0001
`
`Mylan Tech., Inc. v. Noven Pharma, Inc.
`IPR2018—00174
`
`

`

`
` #5123
` rm. mallnalmny n. pmtseled by eapmm I-w ITlla 17 u s. Cod-L]
`
`EFFECT OF SILICONE / ACRYLIC PSA BLENDS ON SKIN PERMEATION
`
`LMgmgfle'. D Kanios, S Rossi-Montero, D. Houze, V. Nguyen, K. Moncada
`lNoven Pharmaceuticals, Inc, Miami, Florida 33186
`
`Introduction
`Rate and extent of skin permeation from
`dmg-in-adhesive
`(DIA)
`transdennal
`drug
`delivery systems (TDDS) has traditionally
`been attributed solely to the barrier properties
`of the stratum mmeum, 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 comeum banier properties has been
`sought by incorporation into these products of
`chemical enhancers such as fatty acids, esters,
`etc. . .alone or in combination with polyhydr'ic
`alcohols.
`Although
`effective
`in
`skin
`permeations
`enhancement,
`chemical
`modification has a significant down side
`potential
`stemming
`from the
`increasing
`imitation 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
`
`Dmg solubility modification via the blending
`of psa's has been shown to be as 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 formulatcr 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.
`'I'hese
`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 base is 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 0.05010 myday both
`from a 10 cm2 patch area.
`
`The selegiline formulations were made at
`12% w/w drug while varying the acrylic psa
`content between 15 and 60% and the silicone
`psa between
`28
`and 63%. No further
`excipients were used.
`
`The estradiol 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 variation
`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 donor and site were used
`
`inter-subject
`in the study to factor out
`The receiving
`variability in permeability.
`solution is an isotonic saline solution with a
`sodium azide preservative (0.9% NaCl and
`0.01% NaNg) 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 of replicate cells per formulation in
`
`Proceed. Int'l. Symp. Control. Rel. Bloom. Match. 26 (fievlsed July 1999) Control“ "'1'“. 300M» Inc.
`
`0002
`
`

`

`the experiment was four. A known volume of
`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 of saline 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 be seen in this plot, as the ratio of silicone
`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/cmz with no significant change in 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
`patch size.
`
`\ all
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`
`ESYRADIOL
`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 56.9220 to 61.9215 to
`66.9210 resulted in an average flux rate
`increase from 1.01 to 1.09 to 1.25 ug/cmzlhr
`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.
`
`
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`
`Conclusion
`
`Alteration of thermodynamic driving force in
`a dmg-in-adhcsive transdermal drug delivery
`system by manipulation of pressure sensitive
`adhesive
`ratios
`in
`a
`blend of
`these,
`specifically silicone and acrylic psa's, can
`have a 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 Company for their technical support of
`our research and development projects.
`
`418
`
`m "'1"- SYMP- Control. R". 810m- Main. 26 (Revised July 1999) Controlled Release Society. Inc.
`
`L___
`
`0003
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