Silicones in Pharmaceutical Applications
`Andre Colas, Dow Corning
`
`DOW CORNING
`
`Dr. Reddy's Laboratories
`v.
`Fresenius Kabi USA, LLC
`U.S. Patent No. 8,476,010
`Exhibit 1025
`
`Exh. 1025
`
`

`
`Exh. 1025
`Exh_ 1025
`
`

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`Duw Corning 1-fea/thm•-p lndusfliPs
`
`Silicones in Pharmaceutical Applications
`
`Andre Colas, Dow Corning
`
`1. Introduction
`
`The n a m e si licone e n co mpasses a la r ge n u mbe r of compounds uasetl or1
`polydialkylsiloxanes; amongst them, the most common are the trimethylsilyloxy(cid:173)
`terminated polydimethylsiloxanes of the structure:
`
`Me
`I
`Me - Si- 0 -
`I
`Me
`
`Me
`Me
`I
`I
`(Si- 0) - Si- Me
`I
`I
`"
`Me
`Me
`
`or
`
`These are linear polymers, liquid even at very high molecular weights.
`
`Numerous other strucn1res can easily be obtained, either by substitution of methyl
`groups by other groups like -CH = CH2, -H , -CH2-CH 2-CF3 or by replacing some of the
`Me2Si0 212 chain units with MeSi0312 or Si0412 units where the silicon is substituted
`with 3 or 4 oxygens to give non-linear branched structures (11. The preferred
`polymers for pharmaceutical applications are the ones essentially substituted by
`methyl groups.
`
`2. Silicone
`Prepara tion
`
`The silicones used in pharmaceutical applications are of 3 kinds: polymers,
`elastomers or pressure sensitive adhesives.
`
`2.1 Polymers synthesis
`
`Polydimethylsiloxanes polymers are prepared by the following 3 steps synthesis ( I J.
`
`2.1.1 Dimethyldichlorosilane synthesis
`
`The dimethyldichlorosilane is isolated by distillation after the reaction between
`methyl chloride with silicon:
`
`2 MeCI + Si _ ,.. Me2SiCI2
`+ other silanes
`dirnelhyldichlorosilane
`[ 1]
`
`2.1.2 Dimet.hyldichlorosilane hydrolysis
`
`The Si-CI bond is highly polarised and prone to nucleophilic attack. I n presence of
`water, the attack of the 2 Si-C! bonds in the d imethyld ichlorosilane [l] leads to the
`formation of a dimethyldisilanol [2], which is unstable and readily condenses,
`intermolecularly, to give linear oligome rs [3]. Small linears can a lso condense
`intramolecularly to give cyclic oligomers [ 4]:
`
`x Me2SiCI2
`
`[1]
`
`+H20
`,.. x "Me2Si(OH) 2"
`_
`- HCl
`disilanol
`[2]
`
`_
`
`,.. y HO (Me2SiO),H
`linears
`[3]
`n = 20 - 50
`
`+ z (Me2Si0 ),.
`cyclics
`[4]
`m = 3, 4, 5, ... (mainly 4)
`
`Note that the H CI re leased is recycled by reaction with methanol to p1·oduce the methyl chl01ide
`used in the first step.
`
`Silicones in Pharmaceutical ApplicaLions
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`2.1.3 Octame thyltetracyclosiloxane polymerisation
`
`Silicone polymers for pharmaceutical applications are preferably manufactured from
`cyclic oligomers, e.g. the octamethyltetracyclosi[oxane (Me2Si0) 4 r 41 rather than
`linear, as the octamethyltetracyclosiloxane can be isolated by distillation and
`therefore with a high level of purity. The ring opening polymerisation is catalysed by
`bases e.g. KOH which is neuu·alised at the end of the reaction with C02• The KlC0 3
`formed can be eliminated by fi ltration:
`
`x (Me2Si0) 4 + KOH --+
`[4]
`
`+ C02
`>- HO (Me2Si0)"H
`KO(Me~iO).,H -
`- K2CO;
`
`to give hydroxy terminated polydjmethylsiJoxanes.
`
`This polyme1isation can be conducted in presence of hexamethyldisiloxane [5], which
`will act as a cham endblocker to give trimethylsilyloxy terminated polymers [6]:
`
`Me3SiOSiMe3 + x (Me2Si0) 4
`[5]
`[4]
`
`cat.
`>- Me3Si0 (Me2Si0). SiMe3
`-
`[6]
`
`or in presence of divinyltetramethyldisiloxane [7] to give vinyldimethylsilyloxy
`terminated polymers [8]:
`
`cat.
`ViMe2SiOSiMe2Vi + x (Me2Si0) 1 -
`>- ViMe2SiO(Me2SiO)r SiMe2Vi
`[8]
`[7]
`[4]
`
`which will be used to prepare silicone elastomers.
`
`The above polymers display a distribution of molecular weight around an average mass,
`depending on the amount of chain endblocker. Moreover, all these reactions are
`equilibrium reactions during which a certain quantity of oligomers, e.g. cyclics, is
`formed. The most volatiles will essentially be removed under vacuum at elevated
`temperatures. This explains why a ll silicones contain a certain a mount of residual
`volatile oligomers.
`
`The synth esis of silicone polymers is characterised by the high level of purity, which can
`be achieved in their preparation. The starting monomer, the dimethyldichlorosila ne
`[1], is purified by distillation and is exU"emely reactive (strictly speahlng, there is no
`residual monomer); after hydrolysis, the octametl1yltetracyclosiloxane [ 4] is isolated by
`distillation before further polymerisation; the reactions used do not involve organic
`solvents or heavy metals; the catalysts used are strong bases or sU"ong acids which are
`easily eliminated thanks to the high hydrophobicity of silicones. These advantages allow
`maximising the purity of silicones.
`
`Using oligomers that are substituted by groups other than methyl, it is possible to
`prepare copolymers such as:
`
`cat.
`Me3SiOSiMe3 + x (Me2Si0)4 + Me3Si0 (MeHSiO)xSiMe3---+ Me3SiO(Me2SiO)y(MeHSiO),SiMe3
`[5]
`[4]
`[9]
`
`or polydimethyl-methylhydrogensiloxane [9], which can be used to prepare silicone
`elastomers (see further).
`
`Silicones in Pharmaceutical Applications
`
`2
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`

`
`2.2 Elastomer
`manufacture
`
`The polydimethylsiloxanes, very flexible with a very low glass transition temperature
`(Tg = 146 K) (2>, are easily crosslinked into 3-dimensional networks o r elastomers by
`the formation of covalent bonds between adjacent c haiins <1>.
`
`Duw Corning 1-fea/thm•-p lndusfliPs
`
`Different crosslinking reactions can be used: condensation with the liberation of a by(cid:173)
`product; initiation with a peroxide with the formation of peroxide by-pmducts.
`
`For pharmaceutical applications, crosslinking by addition is preferred using vinyl
`endblocked polymers [8] a nd polymers (or crosslinkers) carrying many SiH groups
`[9] as shown below:
`
`r...r 0Me 2Si- CH= CH 2
`vinyl endblocked polymer
`
`(liquid)
`[8)
`
`Pt cat.
`
`+
`
`H - Si ==
`cross linker with
`many SiH groujJs
`(liquid)
`[9)
`
`/"V'"'0Me2Si - CH2 - CH 2- Si ==
`tridimensional network 01·
`elastomer
`(solid)
`
`where
`valences.
`
`re presents the remain in g part of t h e polymer a n d
`
`the other Si
`
`T his addition reaction requires very low levels of a platinum complex as catalyst (5 -
`20 ppm as P t) a nd does not generate an y by-products, h ence its advantages in
`pharmaceutical applicatio ns <3>. Using a polymer carr ying many SiH groups, many
`vinyl endblocked chains can be crosshnked together. A large number of commercial
`products are available as ready-to-use 2-part elastomers. Usually, the part A contains
`the vinyl e ndblocked polymer and the platinum catalyst and the part R contains the
`vinyl endbloclked polymer and the polymer carrying the SiH groups. These 2 parts
`are stored separately before use a nd the crosslinking reactio n will on ly start upon
`mixing the parts A and B in a defined ratio, usually 50:50. The reaction can take
`place at room temperature or be heat accelerated to crosslink the elastomer in a few
`minutes after extrusion, injectio n or moulding. H eat curable 1-part materials have
`a lso appeared recently on the market; yet if this eases the h a ndling prior to use (no
`mixing) , th ese 1-part materials h ave a very limited shelf life.
`
`Some precautions are required with t his addition reaction as platinum catalysts can
`be poisoned by many nucleophilic substances possibly present as contaminants like
`amines or sulphur compounds (containers, g loves, ... ) and which can form with the
`p latinum catalyst more stable complexes, inactive as catalyst. This leads to a n
`inhibition of the addition crosslinking reaction.
`
`Silicone elastomer properties are strongly dependent of the structure of the po lymer
`and crosslinker used. Hard elastomers will be obtained when the crosslinking density is
`high. On the contrary, a low crosslinking density will lead to soft and more plastic
`e lastomers. An amorphous silica with a h igh specific surface area is normally included in
`the formulation of silicone elastomers to improve their mechanical properties.
`
`Other ingredients can also be used, like an alcoh o l capable to react with SiH g roups
`to liberate hydrogen according to:
`
`ROH
`
`+
`
`H- Si ==
`
`Pt cat. - RO - Si ==
`
`+
`
`T his reaction is catalysed by the same p latinum complex as the addition reaction: as tl1e
`hydrogen is evolved at the same time as the crosslinking take p lace, this leads to silicone
`e lastomeric foams <·•>. This is used to cast a silicone foam d ressing in deep ca\~ty wounds.
`
`Silicones in Pharmaceutical ApplicaLions
`3
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`Dmv Corning HealthcarP fndttSL1ies
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`2.3 Pressure sensitive
`adhesives
`preparation
`
`3. Physico(cid:173)
`Chemical
`Properties
`
`3.1 Intramolecular
`interactions
`
`3.2 Intermolecular
`interactions
`
`All the above polymers are linear but it is also possible to prepare branched silicone
`structures which behave as pressure sensitive adhesives (PSA). These are prepared
`from silylated polysilicate resins like (Me 3S i0 112) x(Si0,112) l'' a sil icate with
`trimethylsilyloxy groups and usually containing some silanol groups. These silanol
`groups can be condensed with hydroxy terminated polydimethylsiloxanes in
`presence of ammonia as catalyst according to (5):
`
`Si- OH
`Me3Si0
`I
`\
`-"-""'Me~i- OH + C=:>
`I
`\
`HO - Si
`Si- OH
`
`I
`
`\
`Si- OH
`
`where C:=:> represents the polysilicate part, (Si0,112)x, of the resin.
`
`The reaction product is made of a disu·ibut.ion of chains linked to resin particles and
`exhibits a pressure sensitive adhesive behaviour as a function o.f the relative ratio
`between the amount of polymer and resin. The polymer chains e nsure wetting of the
`substrate surface because of their low surface tension (see further) whilst the resin
`will d ictate the visco-elastic behaviour.
`
`However, after condensation, the product still comains some residual SiOH groups.
`These are susceptible to further condensation, particularly in presence of a basic
`active drug, e.g. when the latter contains amine functions. To avoid this reaction,
`which would completely crosslink the PSA and reduce its adhesive properties, the
`residual SiOH groups are silylated (5) to prepare "amine resistant" PSA:
`
`Me3Si0
`Si - 0 - SiMe2 -"-""'
`\
`I
`c=:>
`
`\
`Si- OH
`
`Me3Si0
`Si - 0 - SiMe2 -"'-"'
`\
`I
`c:::>
`\
`I
`Si- 0 - SiMe3
`-'""'--'"' Me2Si - 0 - Si
`
`Polydimethylsiloxanes are characterised by strong chemical bonds, not easily broken
`by homolytic scission because of their polarity ( J) _ O nly strong acids or strong bases
`are capable to depolymerise the siloxane chain. As a result, the polydimethylsiloxanes
`are not very susceptible to oxidation or thermal degradation and they can be
`sterilised by heat.
`
`Wh i le the siloxane backbone is made of very polar S i-0-Si bonds, the
`polydimethylsiloxanes are actually very hydrophobic as the methyl groups shield the
`polar backbone, a feature enhanced by the very low energy of rotation around a
`Me2Si • 0 bond (rotation barrier = 3.3 kJ/ mol) which a llow polydjmethylsiloxanes to
`reduce their surface energy and their surface tension by exposing a maximum
`number of methyl groups (2l . The polydimethylsiloxane low surface tension property
`is used to prepare antifoam agents.
`
`Because of its low rigidity, the siloxane backbone allows the methyl groups to be
`easily exposed to the outside and as a result, the polydimethylsiloxanes are
`characterised by low intermolecula r interactions. T his is demonstrated in several
`ways:
`· even at high molecular weight, the polydimethylsiloxanes are liquid;
`
`Silicones in Pharmaceutical Applications
`
`4
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`- the polydimethylsiloxanes p roper ties are not very tem perature dependent;
`- the polydimethylsiloxanes, compared to other polymers, are ver y permeable to the
`d iffusion of various substances, gases or active drugs (table 1).
`
`Table 1: Compmison of the polydimethylsiloxane perrneability with other polyme~-s (6, 7• 8! .
`
`Type
`
`Po lydimeth ylsiloxane
`Polyethylene
`Po lytetrafluoroethyle ne
`
`Permeability to C02
`Permeability to 0 2
`(cm3.cm)/(s.cm2.kPa) x J0 ·7 (cm 3.cm)/(s.cm2.kPa) x 10·7
`79
`0.002
`0.001
`
`405
`0.007
`0.003
`
`Relative permeability
`to Progesterone
`
`100
`0.1
`0.1
`
`4. Silicone
`Analysis
`
`Among the many an alytical methods used to characterise silicones, only a few and the
`more re levant to pharmaceutical applications will be p•·esented here:
`
`4.1 The Pharmacopoeia
`
`Silicones appear in many compendia (table 2).
`
`Table 2 : The silicones in the Eu1"0pean Pha·rmacopoeia (EP), United States Phannacopeia
`(US_?t}) and United States NationalFormul.ary (NF).
`
`Compound
`
`Dimethicone
`Simethicone*
`
`Simethicone emulsion
`Cyclomethicone
`
`Typical applications
`
`References
`
`Anti-foa m, anti-flatule n t EP, NF
`Anti-foam, anti-flatulent EP, USP
`
`Anti-foam, anti-flatulent USP
`Volatile carrier
`NF
`
`Lubrican t
`Silicone o il as lubricant
`Silicone elastomer for closures and tubing's Closures, tubing's
`
`EP
`EP
`
`(*)a blend ofDimethicone and silicon dioxide.
`
`For silicone e lastomers, the European Pharmacopoeia an alytical methods include,
`amongst o thers, a product identification by IR spectroscopy and an evaluation of their
`purity. Yet, beside th e h eavy metal quantification, the proposed methods like the
`"substances soluble in hexane" or the "volatiles" provide for an overall quantification,
`but not for a specific measure of the low molecular weight residual impurities, like the
`different types of polydimethylcyclosiloxanes [ 4] remainiing after polyme1isation.
`
`Because of their low intermolecular interactions and their high thermal stability,
`silicone polymers are easily analysed by chromatography, possibly after silylation if
`h ydroxy groups are present. This a llows quantifying the low molecular weight
`oligomers, wlhich a re always present in silicon e polymers. As mentioned above,
`polymerisation reactions lead to the formation of two molecular weight distributions,
`polymers around a degree of polymerisation r and cycl ics a rou nd a degree of
`polymerisation m , th e lowest molecula r weight species be ing el iminated by
`"stripping" under vacuum at elevated tempe rature:
`
`[5]
`
`[4]
`
`KOH
`
`Me3SiO (Me2SiO)r SiMe3 + (Me2Si0) 111
`[6]
`
`Various techniques can be used to evaluate th e polyme rs and to identify and quantify
`th e lowest molecular weight species present: GC, GPC or SFC (figure 1).
`
`Silicones in Pharmaceutical ApplicaLions
`
`5
`
`Exh. 1025
`
`4.2 Polymer
`composition
`analysis
`
`

`
`Dmv Corning HealthrrtTP lmlusllies
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`GC
`
`I
`0
`
`I
`10
`
`I
`20
`
`I
`JO
`
`I
`<O
`
`13
`
`I
`0
`
`I
`2
`
`I
`4
`
`I
`6
`
`I
`8
`
`I
`10
`
`' 116
`
`I
`18
`
`GPC
`
`SFC
`
`2
`
`13
`
`3
`
`I
`20
`
`I
`0
`
`Figure 1: Comparison between dijferent chromatographic techniques with a tnmethylsilyloxy
`terminated polydimethylsilox(tne f 9J: fJea.k 1 to 12 = C)•clics {4} (m = 4 to 15) cmd fJeak 13 =
`polymer {6}.
`RefJ·rocluced with authorisation, all 1ights reserved, from the Analytical Chemist1y of Silicones,
`A . Lee Smith edit., copyright co 1991 john Wile)• and Sons, Inc
`
`Silicones in Pharmaceutical A pplications
`6
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`
`

`
`4.3 Polymer structural
`analysis
`
`Because of its high re lative abundance, the 29Si (r==l / 2; 4,7 %) allows the study of the
`structure of silico ne polymers by NMR analysis. The imerpretation is eased by large
`chemical shifts. This allows ide ntifyi ng and studying the distribution of various
`groups within a copolymer (figure 2).
`
`Duw Corning 1-fea/thm•-p lndusfliPs
`
`Me 3Si0 112
`(terminalion)
`
`Me3Si0212
`(polymer)
`
`Si0412
`(resin)
`
`ppm
`
`Si0 3120H
`(silanol)
`
`20
`
`0
`
`-20
`
`-40
`
`-60
`
`.so
`
`-100
`
`· 120
`
`Figure 2: 29Si NMR spectrum of a pressure sensitive adhesive (PSA) ( I OJ.
`
`4. 4 Thermal analysis
`
`H - Si ..,.
`
`The addition reaction used to crosslink silicone e lastome rs:
`Pt cat .
`_ ,..
`
`..,. Si - CH = CH 2
`
`+
`
`is characterised by an exotherm (- t..H == 120- 170 kJ/ mol). This allows the use of the
`differential scanning calorimetry to characterise the crosslinking and optimise the
`elastomer formulation based on the te mperatures corresponding to the onset of cure
`or the maximum cure rate (figure 3).
`
`111~..: 1U.M
`tJ/g: -8 .041
`
`I)
`
`811.00
`
`ID.OO
`
`181.00
`
`Figure 3: Differential scanning calorimetry of the reaction between polymers with SiVi groups
`[8] and with SiH [9] groups in presence of aPt catalyst fiiJ
`
`Silicones in Pharmaceutical Applications
`7
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`5. Toxicology and
`Biocompatibility
`
`6. Epidemiology
`
`The most widely used silicones a re the polydimethylsiloxanes, Me3SiO(SiMe20),.SiMe3
`[6], with viscosities between 10 to 100,000 mPa.s. These have n ot shown toxicity
`during administration via typical exposure routes. Due to the ir hig h molecular weight,
`they ;:u·e not <Ibsorbed in the G.L tr<Ict and <Ire excreted without modific<Ition, nor <Jre
`they absorbed through the skin <12l . In vitro studies have not indicated mutagenic
`effects <12) . Repeated oral or cutan eous dosages have not indicated effects on different
`species <12>. Inhalatio n of aerosols of oily or fatty-type materials, including silicon es,
`into alveolar regions of the lung may result in physical disturbances of the lining of
`the lung with associated effects <13) .
`
`Lower molecular weight siloxanes are frequently used due th e ir volatility a nd
`generally dry skin feel. These can include linear as well as cyclic siloxanes.
`
`The lowest molec ular weight linear material is hexamethyldisiloxane,
`(Me) ~Si0Si(Me) 3 (HMDS) [5], which has a viscosity of 0.48 mPa.s. HMDS has
`generally shown little effects toxicologically, though recent data has indicated slig htly
`earlier incidence of testicular tumors in male rats exposed to high levels of material
`via inhalation; the relevance of this effect to humans is not yet known <14>. Other
`linear molecules of three, four, or five siloxane units [6] do not exhibit toxic effects
`though the data is limited for long-term exposure <15>. The materials have very limited
`absorption via typical exposure routes. Like the highe r molecular weight polymers,
`the low molecular weight linears a re not mutagenic, irri tating, o r acutely toxic.
`
`Cyclic siloxanes, (SiMe20),. [4] a re widely used in skin car e products, in particular
`the four (n = 4) and five (n = 5) members cyclics. None of these materials have
`exhibited toxicity except for the four members cyclic (n = 4), which has shown a
`•·eduction in litter size with a reduction of impla ntation sites in the ute•·us of exposed
`female rats; this effect is not expected to occur in humans <16· 17l . These effects were
`not measu red in the five (n = 5) members or othe1· cyclic siloxanes <18l .
`
`The innocuity of silicones explains their numerous applications where a prolonged
`contact with the huma n body is involved: on textile fabrics, in cosmetics, in contact
`with food and in medical applicatio ns. Silicone elastomers are used in many class II
`or III medical devices regulated by the European Medical Devices Directive such as
`tubing for extra-corporeal circulation used during cardiac surgery, hydrocephalic
`shunts or pacemakers leads. The ir excellent biocompatibility is partly due to the low
`ch e mical reactivity displayed by silicones, th e ir low surface energy and their
`hydrophobicity <2>.
`
`While the legal controversy regarding silicone gel-filled implants continues in the
`United States (US), these me dical devices are widely available worldwide and are
`available with some resu·iction in the US where they have been used since the early
`1960's. Th e controversy in the 1990's initially involved breast cancer, then evolved to
`autoimmu ne connective tissue disease, and continued to evolve to the frequency of
`local or surgical complications such as rupture, infection or capsular contracture.
`Epidemiology studies have consistently found no association between breast implants
`and cancer, including breast cancer <19-24>. In fact, some studies suggest that women
`with implants may have decreased r isk of breast can ce r <23• 24>. The research o n
`auto immune or conn ective tissue disease has also been remarkably consistent and
`concludes there is n o causal association between breast implants and connective
`tissue disease <2"'w>.
`
`7. Silicones
`and the
`Environment
`
`High mo·lecular weight polydimethylsiloxanes are used in many pharmaceutical
`applications but in relatively small quantities compared to the amounts used in other
`industrial applications. Silicone polymers in anti-flatulents and silicone e lastomers in
`
`Silicones in Pharmaceu tical Applications
`8
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`t·ubings to transport various Ouids a re p robably the largest pharmaceutical applications
`for polydimetbylsiloxanes. The environmental fate and effect of silicones will depend to
`a large extend on the physical form of the material.
`
`Silicone elastomers (solid) in the form of tubings have a negligible impact on the
`environment. For safety reasons, they are incin e rated as other clin ical wastes.
`Incineration converts polydimethylsiloxane elastomers to inorganic constituents, carbon
`dioxide, water and amorphous silica <31>. As the polydimethylsiloxanes contain no
`halogens, no toxic halogenated species, such as chloro- or bromodibenzodioxins are
`formed.
`
`Silicone polymers (liquid) used in an ti-flatulents will ultimately become part of the
`liquid waste discharged to municipal treatment plants. Even high concentrations of
`polydimethylsiloxanes in effluent cause no observed effects on waste water u·eatment
`processes; extensive studies show that more than 95% silicones are removed from effluents
`by adsorption o nto the sludge and that the silicone concentration in these effluent sn·eams
`is reduced to a very low level, at or below the level of detection (5 pg/ 1) <32· 33>. Adsorption is
`favoured by the low water solubility of polydimethylsiloxanes.
`
`The subsequent fate of the silicones will depend on the fate of the sludge. u· incinerated,
`the silicones degrade as indicated previously. The other principal outlet for sludge is use
`as a soil conditioner or amendment. In mesocosm studies, the application of sludge(cid:173)
`bound polydim ethylsiloxane to soil caused no observed adverse effects on crop growth
`or soil organism s <:~<•>. With radio-labelled compounds, little or no uptake of radioactivity
`into the plants was observed, which is consistent with a nimal studies, which show that
`high molecular weight polydimethylsiloxanes are too large to pass through biological
`membr<Jnes into either crops or· ;mima ls. Extensive studies ranging fr·om small snrle
`laboratory tests <35· 36J to mesocosm <3~- 37l show that sewage-sl udge bound
`polydimethylsiloxanes degrade in soils as a result of contact with clay minerals. These
`clays will act as catalysts to depolymerise the siloxane backbone <35>, a reaction favoured by
`the polarity of the molecular chain (-SiO ) .,-and its susceptibility to heterolytic scission (ll.
`The primary degradation product, regardless of the polydimethylsiloxane molecular
`weight is dimethyldisilanol, Me2Si(OH)2 <36>. Depending on the soil type, this undergoes
`further degradation either in the soil via biodegradation <38l or evaporates into the
`atmosphere <39> where, by analogy to trimethylsilanol, it is expected to be degraded by
`oxidation via reaction witl1 hydroxyl radicals <40>. In both cases, there is conversion to
`inorganic constin1ents, carbon dioxide, water and amorphous silica.
`
`Low molecular weight silicones d isplay a different environmental profile. As a
`consequence of their very high volatility, they readily evaporate into the air, where they
`degrade as a result of reaction with hydroxyl radicals in the presence of sunlight. They
`are not however biodegradable, and as a consequence of this, and the fact that in a
`sealed system, they have the potential to bio accumulate, the Oslo Paris Commission
`(OSPAR), which is concerned with the discharge of man-made substances into the
`marine environment, have identified hexamethyld isil oxane (HMDS) as a potential
`"Priority Hazardous Substance". The European Silicone Industry Association (CES) is
`therefore conducting a risk assessment on HMDS us ing the EU model (EUSES) .
`However as both modelling data and e nvironmental monitoring do not indicate any
`significant inputs into the marine environment, the European Silicone Industry is
`confident of a favourable outcome ft·om the risk assessment.
`
`8. Silicones in
`Pharmaceutical
`Formulations
`
`More than 358 registered products containing silicones could be retrieved using CD
`Rom or internet databases such as the PDR;I'J (USA), Rote List~!' a nd Gelbe Lisle
`(Germany), MediaVida~ and BIAM (France), BNf® (UK), Kompendium (Switzerland)
`and AG!f\1® (Belgium). Searching was complex because silicones could be found in
`drug compositions under compendia's names (Dimethicone or Simethicone) as we!J
`
`Silicones in Pharmaceutical ApplicaLions
`9
`
`Exh. 1025
`
`

`
`Dmv Corning HealthrrtTP lmlusllies
`
`as under many other names like silicone, siloxane, methylsiloxane, polydimethylsiloxane
`or even trademarks such as Silastit}l!!. In many instances silicone (a polymer) was also
`confused with silicon (a metal) or silica (an inorganic compound). Some databases were
`more fi·iendly than others allowing for ''word search" as in the PDR or tor "list of n on
`active substances" as in the BIAM. The presence of silicone was thus found in many
`registered drugs and noted in some very familiar ones like Augmentin®, Maalo:xfl'J, Prozar!J,
`Tagarne~, Vicks VapoSteam® to name but a few.
`
`Silicones are used as actives, as Dimethicone or more often as Simethicone (a blend
`of Dimethicone and silicon dioxide), but surprisingly overall more often as excipients
`(table3).
`
`Table 3: Silicone occurrence as actives or excipients and physical form in registered dn;.gs
`expressed as percentage of the 358 products identified in above databases (41!.
`
`Silicone in composition
`
`As a ctive
`
`As excipient
`
`%
`
`24
`
`70
`
`Unknown
`
`6
`
`Form
`
`- -
`
`Simethicone
`Oimethicone
`Simethicone
`Simethicone emulsion
`Dimethicone
`Elastomer
`Silicone Oill
`Silicone Polrmer
`Others
`
`- -
`- -
`
`%
`
`13
`II
`14
`I I
`10
`6
`5
`5
`19
`
`While the ptn·pose of the silicones <IS <~c.tives is well documen ted <'Is <~n tifoam in a n ti(cid:173)
`gas or anti-acid formulations, the purpose of silicones as excipients is more difficult
`to determine. Information on excipients is still lim ited as of today and, in some cases,
`it was not even possible to identify the physican form of the silicone used. Some
`information could yet be collected indicating thai!: silicones are used as excipients in
`pharmaceutical formu lations for silicon isation (lubrication of syringe barrels,
`pistons, n eedles or lubrication of stoppers), as skin adhesives (drug permeable), as
`e lastomers (drug release control membrane), as release I iner coatin gs for
`transdermal patch (re lease coating), and, in skin topicals, as polymers, volatiles or
`not, or as copolymers to carry actives or to improve spreading and aesthetic qualities.
`The latter is not surprising as silicones are widely used in Personal Care products,
`with around 60 % of today's skin care products containing silicones <42> where they
`are recognised as safe, and known to p rovide for a pleasant "silky touch" non-greasy
`and non-staining feel.
`
`It is also worth noting that a substantial number of registered products contain
`silicones that are not described in any Compendia, e.g. methylpolysiloxane, silicone
`for powder treatment, silicone or fluoro silicone for polyester film coating, silicone
`copolyol, HMDS, Silasti~, silicone wax, ... : in these registered product formulations,
`the benefits brought by silicones were obviously offsetting the regulatory hurdle to
`file a drug formulation with a new excipient.
`
`9. Silicones as
`Antifoams in
`Pharmaceutical
`Formulations
`
`Dimethicones and Simethicones are declared as actives and used as antifoams in
`numerous an ti-flatu lent o r anti-acid formulations, even if theit- efficacy has been
`questioned in some indications <43>. Overall, this is the largest single application for
`silicones in registered products (64 registered products or 16 % of the ones retrieved in
`the above databases) : among them Maalo:xfl'J, MylanuP and Gel de Polysilane-MidfJ.
`
`Silicones in these products help to suppress the for mation of foam in the stomach
`without modifying the gastric pH <44>. This is not surprising as silicones, with their low
`surface tension (and in particular when compounded with silicon dioxide) are known to
`
`Silicones in Pharmaceutical Applications
`10
`
`Exh. 1025
`
`

`
`10. Silicones as
`Excipients in
`Topical
`Formulations
`
`Duw Corning 1-fea/thm•-p lndusfliPs
`
`desu·oy foams in many applications, e.g. in petrol, paper pulp o r food processing. l n
`pharmaceutical formulations, while considered as actives, the mode of action is physical
`as the polydimethylsiloxanes are not metabolised but excreted as such Cll!) _ Silicones are
`often compounded with other anti-acid actives such as Al or Mg hydroxides, Mg orCa
`carbonates. Simethicones and Dimethicones also appear in many other anti-acid or anti(cid:173)
`flatulant formulations yet where the silicones are only declared as excipients and not as
`actives. Also declared as excipients, silicones appear in many liquid formulations like
`syrups as well as in effervescent tablets formulations, most likely eith er to control
`foan1ing during processing and filling operations or during use.
`
`As actives, silicones are also used in diagnostic formu lations to e liminate foam in the
`stomach during endoscopy or, in conj unction with barium sulphate, during X-Ray
`examination <45l .
`
`After their use as antifoams (see above), the next largest application fo•· silicones is in
`topical formulations. In the above databases, 36 products (10 % of the retrieved
`registered products) could be identified where silicones are used as excipients in
`topicals. Silicones were also declared as actives against acne in o ne product and for the
`prevention of skin ulceration around stoma in another, in the latter case possibly
`because NF grade Dimethicone is recognized as an active protecting the skin in OTC
`products (FDA tentative monograph 21 CFR Part 347).
`
`The largest indication is for skin diseases, mainly as creams followed by gels and lotions
`for the treatment of acne, fungal diseases or psoriasis. The non-<:omedogenic nature of
`silicone probably accounts for their use in anti-acne formulations w;l _ O ther topical
`applications include contact with fr-~gil e mucosa in the treatment of haemon·hoids, anal
`dermatoses or itch relief as well as for the delivery of antibiotics in gynaecological
`capsules or creams.
`
`When considering the type of silicones used, Dimethicones and Simethiicones account
`for most of the occurrences yet some other specific silicones used as excipients could be
`retrieved in registered products using the above databases:
`
`in Difnolene~ (Schering Pl ough) or as
`-Cyclomethicones [4], registered
`decamethylpentacyclosiloxane (Me2Si0) 5 in the formu lation Dexeryl Creme® (Pierre
`Fabre Sante); the exact purpose is not known, as for many excipie nts, but
`cyclomethicones are widely used in personal care because of their volatility, "aesthetic"
`and safety profile;
`- H examethyldisiloxane [5] : recent work <·•6l shows that the hexamethyldisiloxane,
`Me3SiOSiMe3 (Bp. = 100 °C), can be used as a volatile excipient in spray pump systems
`for topical a pplications, e.g. in combination with fu ngicides and was registered in
`Pevary~ (Janssen-Cilag) . The low surface tension of this disiloxane improves the
`coverage of the skin and possibly ino ·eases the bio-availability of the active drug. The
`advantage of this disiloxane, despite its flammability, is its very low heat of vaporisation,
`which, despite its rather high boiling point, allows the film to dry quickly;
`- Stearyloxytrimethylsilane, CH3(CH2) 170SiMe3, a wax with occlusive pro[perties but still
`\\~th a pleasan t silky feel as normally associated \\~th silicones, registered in RetinovfP
`(Roc -.Johnson and .Jo hnson);
`- Dimethicone copolyol used in conjunction with Cyclomethicones in Retin-A Micro®
`(Ortho Dermatological-.Johnson and j ohnson), yet the exact structure of this silicone
`glycol copolymer cannot be determined from the databases used.
`
`While the above silicones have certainly been used because of their biocompatibility and
`probably because of their aesthetic benefits, which is we