.... ,. .
`
`1 : ~,·
`
`. . ··
`
`:
`
`•
`
`Technical Report No. 12
`
`Siliconization of
`Parenteral Drug
`Packaging Components
`
`v.
`Fresenius Kabi USA, LLC
`U.S. Patent No. 8,476,010
`Exhibit 1004
`
`Exh. 1004
`
`

`
`Siliconization of Parenteral Drug Packaging Components
`
`Lubrication of Packaging Components Task Force Members
`
`Anthony 0. DeMarco
`Wyeth Laboratories
`611 E. Niclds Street
`West Chester, PA 19382
`(215) 696-3100
`
`John T. Cronin
`Helvoet
`9012 Pennsauken Ave.
`Pennsauken, NJ 08110
`(609) 663-2202
`Also: Burlington, NJ
`(609) 386-9101
`
`Edward J. Smith, Chairman
`The West Company
`Technical Center
`Route 113
`Phoenixville, PA 19460
`(215) 935-5302
`
`Martin W. Henley, Co-Chairman
`Merck, Sharp & Dohme
`Summeytown Pike
`West Point, PA 19486
`(215) 661-5207
`
`Elaine F. Adams, Co-Chairman
`The West Company
`Technical Cente:r .
`Route 113
`Phoenixville, PA 19460
`(215) 935-5302
`
`Dietmar M. Wagenknecht
`Dupont Critical Care
`1600 Waukegan Road
`Waukegan, IL 60085
`(3 12) 473-3000
`
`Garry Bates
`Tompkins Rubber Co.
`Blue Bell, PA 19422
`(215) 825-3400
`
`Dr. Martin Musolf
`Dow-Corning Corporation
`. ..
`P.O. Box 187
`12334 Geddes Road
`Hemlock, MI 48626
`(517) 642-5201 Ext. 2414
`
`ii
`
`ii
`J!
`
`Exh. 1004
`
`

`
`Siliconization of Parenteral Drug Packaging Components
`
`·I
`~;
`'
`
`~r
`I Lubrication of Packaging Components Task Force
`I
`[~'")O(o
`
`'
`
`'
`
`'
`
`Contents
`
`I. Scope .. ~ ................ . . , .... . . ....................... _ ....... .. ; .. . ...... .
`II."
`Introduction . ..... .. ... ... .. . . .. . . ..... . .... . .... . . .............. . .......... .
`iii. Reasons for Lubrication ... .. .... .. . . . ............... . ........ . ..... : . ..... . .. . .
`A. Machinability ....... . ...... ... .... ... .. . ...... .... .. . ....... . . :; ........ , ..
`B. Reduction of Insertion Force-Seating . .. . . .... . ...... : ..................... ; ..
`C. Sealability .. . ... .. .. . .. . .. 1
`.•••• • • • ••• • .••• • ••••• •• •••• •••• ••••• ; • • · ••••• : • •
`D. Minimize Breakloose and Extrusio_n Force . . ..... . ........ . ............. ..... . .. .
`E. Syringe Barrel L ubrication . .... . ... ... ......... ...... . .......... . . .... ... . .. .
`F. Hypodermic Needle Lubrication ............ . ... .. ..... . . . .. .. ... . .... , ... . .. .
`G. Drainage of Vial Contents . . . .. . . ......... , ... . ... . ............. . .... . ...... .
`IV. Compendia! References .. . . .. .. • ....... . ............................ ... ........ .
`A. Medical Grade Silicone .. .... .. .. , . . ......... . .......... . .................. .
`B. USP XXI, NF XVI ......... .. . .. ... . ............... ... . .. . ... . ...... . . . .... .
`C. Cosmetic, Toiletry, and Fragrance Association (CFTA) ... .. .. ............. . . . .... .
`D. Code of Federal Regulations (CFR) ... . ...... ...... . ...... . ... . ....... . .. .. .. .
`V. Toxicity of Polydimethylsiloxane Fluids ... . .. . . . .. . . . ..... .. . .. ...... . . ..... . . .. . .
`A. Introduction . .. .............. . .. .. . ... . . ... .......... · ................. .. ..... .
`B. Skin . . ..... . ..... . ..... . . . . .............. . ... .. ... . .. .......... .. . . ...... .
`C. Oral . . ..... . ................... . .......... . . .. ..... . . . , , ................ .
`D. intraperitoneal . ... . .... . . . ................ . . . ...... . .. ........ ..... ...... . .
`E. Eye ....... . .. .. . . ........ .. ........ . ..... . .... ... . .. ... . ...... .... .. .. . . .
`F. Subcutaneous Administration .. . . . ..... . ......... . ................... . ...... .
`G. Intravenous Administration .... . . . . ......................................... .
`H. Inhalation . . .. .............. . . . . ........ . . .. .... : ................... . .. .. .
`I. Reproduction ......... . ...... . ... . ... . . ..... . ..... .. .. .. ....... ... ....... .
`J. H uman . . ......... . .. . ...... . . . ... .. . .. , .. .... ... .... .... . .. . . .. ... ..... .
`VI. Types of Silicone Lubricants ....... .. . . ..... . . ... . . ......... . .................. .
`A. Polydimethylsiloxane Fluid ("Silicone Oil") ........ . . .......... . . ... . ... ... ..... .
`B. Silicone Emulsions ............. . ....... : ... ... .... ........ . . ............... .
`C. Air Curable Silicones .... ... ....... ..... ... .. : .. .. . ..... . : . . . .... .. .. ... ... .
`VII. Methods of Application of Silicones ... . ........... . ........ ... ........... . ...... .
`A. Introduction ....... . ......... ............ . ........... . . ......... . ....... . . .
`B. Preparations .. .. . . ..... . ..... ... ..... . . . . .. ........... · ................. . . .
`C. Applications to Elastomeric Materials .. .... ... . .. .. . .. ........... ... ....... . . . .
`D. Application to Glass ............. . .. . ..... .. . . .. ... . . . .. • .......... ~ ........ .
`E. Application to Plastics ...... . ..... .. . ...... . . . . . .......... . . . ....... . .. . .... .
`VIII. Measuring Application Consistency . .. .. .. .. . . ............ . . . ... . .. . ........... . .
`A. Functional Testing .. . ... . ...... .. .... ... .. ....... . ............ . ... . , ..... . . .
`B. Analytical Determinations .......... . ............ ...... ... .. . ........ .. ..... .
`IX. Particulate Matter ............. .. ..... . . .. ......... . .............. .... . ... . .. .
`A. Haze on Reconstitution ..... .... . . .. .. .. . . . .... ... . . ... . ................. . . .
`B. PDMS Fluid Effect on Particle Counting Instrumentation .... .. ... ..... ........ . . . .
`C. Cleanability of Siliconized vs. Nonsiliconized Closures ..... .................. .... .
`X. Nonsiliconc Lubrication . , . . ............ .. .... . .... .. ... .. . .. .. . . .. . . ... ....... .
`A . Internal Lubrication .... .... .... .. . ... ............ . ... . ................. ... .
`B. Surface Chlorination ... ... . . . . : . ... . .... .. .... . ..... . . ....... . ......... .. . .
`C. Films and Coatings ....... . .. . ... ........ . .. . ....... : ....... .. . .... .... . ... .
`D. Chemical Modification . ............ . . . .. ... . . ..... ........ . . ... ....... .. .... .
`XI. Survey Results .............. . ...... ... ..... . .. . . . . ... . .. · .. .. .... ... ....... . . .
`XII. Glossary ........ . . . ...... . . . ..... . .. .. . . . .. . .. ...................... . .. .. ; . . . .
`XIII. References .. ... .. . . .... . . ... . ..... .... . .. . . .. ... . ....... .. .. . ... ........ . . , ..
`
`S4
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`S5
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`S7
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`S8
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`SIO
`Sll
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`S 12
`S l 2
`S l 2
`S l2
`
`Vol. 42, Supplement 1988
`
`53
`
`Exh. 1004
`
`

`
`I. Scope
`
`Most parenteral packagin~ components require the use
`of some form of lubrication in order to improve their
`processability and functionality. The Task Force on Lu(cid:173)
`brication of Packaging Components was formed because
`of an increasing number of questions about the use, mea(cid:173)
`surement, and toxicily oflubricants.
`The purpose for this publication is to present informa(cid:173)
`tion. The publication reviews the common lubricants, the
`reasons for their use, methods of application and analyti(cid:173)
`cal measurement.
`It is not the intent of this Task Force to recommend
`specific materials, methods of application, or analytical
`procedures, but rather to provide a source of information
`concerning t he use of lubrication on pharmaceutical pack(cid:173)
`aging components.
`
`II. Introduction
`
`One of the most commonly used lubricants for pharma(cid:173)
`ceutical packaging is polyd!methylsiloxane fluid often re(cid:173)
`ferred to as silicone fluid. Siliconization of packaging
`components such as glass, elastomeric closures, plastic,
`and metal, places an invisible water repellant film on the
`surface of the components. This film can aid in the free(cid:173)
`draining characteristics, processing and machinability of
`vials and elastomeric closures ( 1, 2). Silicone fluid is
`commonly applied to plastic syringe barrels and glass
`cartridges used as plunger barrels to facilitate easy move(cid:173)
`ment of the plunger within the barrel (3). The application
`of a silicone film to hypodermic needles reduces the fric(cid:173)
`tional drag and thus the pain associated with this drag as
`the coated needle passes through body tissue (4) .
`The term silicone was first used in the early 1900's in
`. England as a generic designation for a family of polymers
`based on the element silicon. Siloxane is an acronym
`derived from silicon, oxygen, and methane·(5). Commer(cid:173)
`cially, the siloxanes which are most often used are the
`polydimethylsiloxanes. These materials are a class of
`chemical compounds composed of alternating silicon and
`oxygen atoms in a linear arrangement with two methyl
`(CH3-) groups attached· to each silicon atom. The poly(cid:173)
`mers can be end-blocked by a variety of chemical struc(cid:173)
`tures. When the trimethylsi]oxy [(CH3)3SiO -
`] group is
`used, a series of linear silicone fluids is produced which
`possess the following general structure:
`
`The above formula represents molecules whose struc(cid:173)
`tures differ only in x, the number of dimethylsiloxane
`units; thus, as x increases the molecular weight and viscos(cid:173)
`ity of the fluid increases. The relationship between the
`degree of polymerization (x), t he molecular weight, and
`the viscosity of typical polydlimethylsiloxane fluids appear
`in an articlle by S. Braley ( 6). A 3 50 centis ~oke polydi(cid:173)
`methylsiloxane fluid would have an approximate x value
`of 130 and an average molecular weight of 9780.
`
`111. Reasons for Lubrication
`
`A. Machinability
`
`Machinability is greatly improved through the use of
`lubricated packaging components. Siliconization of rub(cid:173)
`ber products reduces the friction present between the rub(cid:173)
`ber closure and the metaHic machinery. Lubrication helps
`eliminate clumping of parts as they are smoothly fed from
`hoppers to machine paths. These lubricated components
`then .easily transverse down machine guides, reducing any
`possible problems, which are ultimately very costly in
`terms of lost production time.
`
`B. Reduction of Insertion Force-Seating
`
`After closures have been successfully transported to the
`vials, they must be inserted. Siliconization lowers the fric(cid:173)
`tion between the vial and the closure. This decrease in
`friction reduces the force necessary to insert vial stoppers
`properly.
`
`C. Sea/ability
`
`It has been observed in industrial manufacturing pro(cid:173)
`cesses that the integrity of the closure/vial seal is im(cid:173)
`proved by the siliconization of the closure.
`
`D. Minimize Break/oose and Extrusion Force
`
`As with stoppers, lubrication of syringe plungers
`through siliconization reduces the coefficient of friction
`on the surface of the plunger. This reduced friction mini(cid:173)
`mizes the energy required to overcome the static force
`between the plunger and the barrel. Lubrication of the
`plunger also lowers the extrusion or dynamic forces need(cid:173)
`ed to smoothly expel the drug product from the syringe. In .
`order to keep potential functional problems to a mini(cid:173)
`mum, breakloose and ext rusion values should be low.
`
`E. Syringe Barrel Lubrication
`
`Syringe barrel lubrication is closely related.to break(cid:173)
`loose and extrusion values for plungers. Any luBricant
`present on the plunger or the barrel will greatly reduce the
`amount of friction between the two. The decrease in the
`friction will result in a reduction of force necessary to
`assure the proper operation. Siliconization of syringes will
`also aid in the initial insertion of the plunger into the
`syringe barrel during assembly.
`
`F. Hypodermic Needle Lubrication
`
`By utilizing a process of lubricating needles, a small
`residual amount of silicone is left on the surface. This
`silicone film on a hypodermic needle reduces frictional
`drag resulting in less pain during skin and muscle penetra(cid:173)
`tion (7). Lubrication of the needle surface also minimizes
`the force needed to pierce a rubber closure. In addition to
`enhanced penetration characteristics, siliconizing needles
`also improves the process of needle insertion into the pro(cid:173)
`tective sheath.
`
`G. Drainage of Vial Contents
`
`Siliconization of vials results in a: thin water repellent
`film being applied to the inner surface of the vial. Aqueous
`
`54
`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Journal of Parenteral Science and Technology
`
`Exh. 1004
`
`

`
`solutions tend to bead up on these surfaces since they do
`not wet the silicone film. This leads to characteristic im(cid:173)
`provements of the drainage of the vial (8). Siliconization
`of glass is also used to improve the handling of suspension
`products and to facilitate resuspension following storage.
`
`IV. Compendia! References
`
`A. Medical Grade Silicone
`
`The widely used term, Medical Grade Silicone, has no
`official compendia! or regulatory status. The term Medi(cid:173)
`cal Grade was introduced! by one manufacturer of silicone
`products. That producer, Dow Corning, attach~ the fol(cid:173)
`lowing criteria to these products:
`
`The biocompatibility of the material has been evaluated
`and a profile established. This profile is based on a series
`of tests performed by this manufacturer. Results of these
`tests are a part of the product information..
`Medical Grade by this-defmition does not imply that
`the material has absolute biocompatibility or lack of tox(cid:173)
`icity~only that the level has been established by the tests.
`Further testing of the material by the user may be neces(cid:173)
`sary to establish safety and efficiency for many specific
`uses .
`..
`
`B. USP XXI, NF XVI
`
`The United States Pharmacopeia (USP) contains no
`monograph on polydimethylsiloxane fluids. However, the
`USP furnishes a Reference Standard Poiydimethylsilox(cid:173)
`ane, catalog number 54630. This reference standard is
`referred to in the National Formulary (NF) Monograph
`on Dimethicone. The original NF monograph on Dimethi(cid:173)
`cone has been supplemented more than once and the most
`current version is listed in the 5th Supplement of The
`United States Pharmacopeia Volume XXI and The Na(cid:173)
`t ional Formulary Volume XVI (9).
`The NF has as its goal to provide monographs for those
`pharmaceutical ingredients, which a re not included in the
`USP, as a means of characterizing their composition by
`providing tests and stating testing limits. While some
`polydimethylsiloxane manufacturers perform tests neces(cid:173)
`sary to document their adherence to NF specifications, it
`is necessary for the pharmaceutical end-user of untested
`fluid to perform the necessary analyses.
`
`C. Cosmetic, Toiletry, and Fragrance Association
`(CFTA)
`
`The term " Dimethicone" is defined ( 1 0) as a mixture of
`fully methylated linear siloxane polymers containing re(cid:173)
`peating units of the formula [(CH3)2SIO-], units. These
`fluids possess tbe following general structure:
`
`(CH3) 3Si0 [~i] Si(CH3) 3
`
`CH3 X
`
`This definition is used by both the Cosmetic, Toiletry
`and Fragrance Association (CTFA) and by the National
`Formulary (NF). There is however, a different intent
`associated with these two systems of nomenclature.
`
`Vol. 42, supplement 1988
`
`The CTF A has adopted names for cosmetic ingredients,
`many taken from the USP or NF nomenclature system, to
`assist this industry in standardizing the labeling of these
`ingredients. The CTIFA names do not, however, imply
`standards ot grades of purity, strict chemical equality, or
`interchangeability of ingredients.
`The difference between the CTF A and NF nomencla(cid:173)
`ture concepts is one of compositional testing and stated
`testing limits. When the designation NF is used in con(cid:173)
`junction with an official name, such as "Dimethicone,
`NF," it indicates that the product is in compliance with
`the NF standards. No such compliance testing or testing
`limits are associated with a CTFA product name, such as
`"Dimethicone."
`
`D. Code of Federal Regulations ( CFR)
`
`Polydimethylsiloxane fluids are listed in the Code of
`Federal Regulations, Title 21-Food and Drugs in
`178.3570-Lubricants with Incidental Food Contact (a)
`(3). The specific listing is Dimethylsiloxane (viscosity
`greater than 300 est).
`
`V. Toxicity of Polydlmethylsiloxane !Fluids
`
`A. Introduction
`
`The linear and cyclic polydimethylsiloxanes (PDMS)
`are materials which are frequently used in cosmetic and
`pharmaceutical applications because of their stability, hy(cid:173)
`drophobicity, lubricity, and low toxicity. They are repre(cid:173)
`sented by the following structural formulas.
`
`CH3]
`(CH3hSiO SiO Si(CH3h
`[
`CH3 X
`CH3]
`s·o
`[
`c~3 x
`
`Linear polymers
`
`Cyclic polymers
`
`The value of x in the linear polymers can be 2 to several
`thousand while x for the cyclic species can he 3 to 14, with
`4 and 5 being used most frequently. The materials are
`clear, colorless, oily liquids that are odorless, tasteless,
`and insoluble in water and highly water repellent. They
`are also stable at high and low temperatures and are
`highly resistant to changes due to ·heat or oxidation. The
`viscosity of these linear polymers can. vary from 0.65 to
`1,000,000 centistokes depending on the average chain
`length (11) . .
`Selected polydimethylsiloxane compounds have been
`extensively studied to assess their suitability for use in
`cosmetic, pharmaceutical, and related applications. It is
`generally believed that data gathered from these selected
`polymers can be. applied to all of the materials except for
`certain compounds of very low molecular weight.
`There is no indication that toxicity would be rela:ted to
`molecular weight or viscosity of these fluids. Calandra et
`al. have summarized their review of the health and envi(cid:173)
`ronmental aspects of polydimethylsiloxane fluids by stat(cid:173)
`ing: "The polydimethylsiloxanes, in a very extensive bat-
`
`S5
`
`Exh. 1004
`
`

`
`tery of studies, have been shown to be rcmakably devoid of
`toxicologic problems (12). No effects have been demon(cid:173)
`strated, even at exposure levels massively exaggerated,
`over any conceivable use except for transient eye irritation
`(13)."
`Specific references concerning the toxicity of linear
`polydimethylsiloxane fluids are summarized in this docu(cid:173)
`ment.
`
`B. Skin
`
`Polydimethylsiloxane (PDMS) was successfully substi(cid:173)
`tuted for the liquid petroleum and oil bases of liniments.
`These compounds were found to be pharmacologically
`similar to the original formulas with the adped penefit of
`being odorless, having their wide viscosity range contrib(cid:173)
`ute to variety in liniment viscosity, and not being subject
`to rancidity (11). Human-repeated insult tests conducted
`with PDMS showed no indication that the materials are
`skin sensitizers (13).
`
`C. Oral
`
`Rowe et al. studied the effect of repeated oral adminis(cid:173)
`tration ofPDMS upon rats. They ut'ilized DC 200 (viscos(cid:173)
`ity = 350 est) in 20 doses in 28 days with dose groups
`consisting of 1.0, 2.0, 5.0, 10.0, and 20.0 gjkg. The follow(cid:173)
`ing results were noted when the experimental group was
`compared with a control group dosed with correlated
`amounts of olive oil (14):
`Growth-no difference.
`Bone marrow-
`total and nucleated cell counts within
`standard deviation.
`Organ weights at autopsy-within normal limits.
`Blood ur,ea nitrogen- within normal limits.
`Histopat hology-microscopic examination showed no
`pathologic changes in the heart, spleen, liver, kidney,
`adrenals, pancreas, bone marrow, stomach, and in(cid:173)
`testine.
`McDonald et al. corroborated these findings in their
`studies utilizing poly.dimethylsiloxane (various viscosity)
`as 1 percent of a rat's diet over a 90-day period (15). They
`noted no changes in organ weights, body weights, hemato(cid:173)
`crit, hemoglobin, white blood cell count, and differential.
`However, they did see some pneumonitis and consolida(cid:173)
`tion with formation of caseous-centered abscesses in the
`lungs in many of the different groups, including the five
`control animals.
`
`D. Intraperitoneal
`
`Rowe et al. investigated a single intraperit oneal injec(cid:173)
`tion of PDMS in rats. They utilized 0.1, 0.3, 1.0, 3.0, and
`10.0 mL/kg dose of varying silicone fluids. The only
`deaths noted were -in the usc of hcxamethyldisiloxane in
`the three higher doses. This substance produced a consid(cid:173)
`erable amount of local irritation and extensive visceral
`adhesions. In the subjects utilizing PDMS, the reaction
`noted was that of a nonirritating foreign body. Also found
`at autopsy were body fluid containing nodules on omental
`tissue and surfaces of the liver, spleen, and diaphragm.
`However, no inflammation was noted (14).
`'
`Hawthorne et al. showed that with subcutaneous or
`
`intraperitoneal injections, the silicone fluid deposition was
`subjected to phagocytosis and systemic deposition into the
`reticuloendothelial system. fn mice receiving subcutane(cid:173)
`ous or intraperitoneal injections greater than 7 mL/
`mouse, Hawthorne noted an accumulation of histocytes
`containing ingested silicone in the regional lymph nodes.
`Also clusters of macrophages with vacuolated cytoplasm
`were seen in distant organs, i.e., liver, spleen, kidney,·
`pancreas, and ovary (16).
`Rees et al. demonstrated that PDMS fluid introduced
`intraperitoneal or subcutaneous injection produced a gen(cid:173)
`eralized alteration of abdominal and epicardial adipose
`tissue. The fat cells appeared smaller and the cytoplasm
`contained vacuoles. There was macrophage clustering as
`noted above. The liver showed lesions in all parts of the
`hepatic lobule, and the kidney demonstrated interstitial
`renal k.sions in which the glomerular capillal'ies were
`dilated by a clear, unidentified material (17).
`Bischoff noted that, in rabbits, PDMS fluid (viscosity =
`360 cs) could augment postoperative pelvic adhesions
`evaluated 2- 4 weeks post-silicone administrations. Bis(cid:173)
`choff also demonstrated, utilizing male and female rats
`and mice, that 8/34 of the silicone-dosed females showed
`reticulum cell sarcoma in the lung or peritoneal cavity
`during the 17-month study. His doses were 2.0 mL for
`male rats, and 0.4 mL for female mice. This trend was not
`seen in the males which was comparable to control. He
`also noted in the female rat and the male mouse an in(cid:173)
`crease in lung and peritoneal lymphoid tumors (18).
`
`E. Eye
`
`The effects of various types of silicones upon the eye
`were investigated by Rowe et al., utilizing rabbits. They
`observed the eyes immediately upon exposure and at 1, 4,
`8, 14, and 48 hours post-exposure. The irritation produced
`was transitory and was eliminated within 24- 48 hours.
`Fluorescein staining failed to show any corneal damage.
`According to Rowe the human response to these com(cid:173)
`pounds is similar to that of rabbits. The humai1 i·esponse
`demonstrated erythema of conjunctival membranes and
`edema of the lids is frequently seen (14).
`
`F. Subcutaneous Administration
`
`Andrews noted, in his albino mice studies of the injec(cid:173)
`tion site and underlying tissue following a 5 mL subcuta(cid:173)
`neous injection of DC 360 fluid, a tissue reaction at 1- 3
`days. T~is consisted of the mild exudative phase of the
`inflammatory process with polymorphonuclear cell infil(cid:173)
`tration and plasma cells and macrophages surrounding
`the silicone fluid. During 4- 10 days, polymorphonuclear
`cells decreased in number and a predominance of lympho(cid:173)
`cytes, fibroblasts, and plas~a cells were seen. · M acro·
`phages with clear vacuoles formed a capsule around the
`encountered cyst. Deposition of collagen fibers around
`fibroblasts was also noted after 18 months at the injection
`site, or in the lung, kidney, intestine, and spleen as well.
`Andrews also noted neutrophils contain£ng vacuoles due
`to their phagocytizing the silicone (19).
`Hawthorne et al. also noted a similar progression of
`tissue reaction .. He noted that the silicone appeared un-
`
`S6
`
`Journal of Parenteral Science and Technology
`
`Exh. 1004
`
`

`
`changed. This group also reported a mild degree of fibro(cid:173)
`s!§ pre$ent around the cyst with an occasional giant cell
`seen. This was noted at six months post-injection. Howev(cid:173)
`er, Hawthorne <'inly noted tllis cyst formation with massive
`doses of silicone fluid (16).
`Hawthorne also reported that, in rats, small multiple
`vacuoles at the periphery of the cytoplasm of the red blood
`cells caused no toxic effects on blood values. This vacuo(cid:173)
`lated red blood cell was seen at 9 months in the groups that
`had received 14, 21, and 24 mL of silicone fluid subcuta(cid:173)
`neously.,No effect was seen on the white blood cells or the
`differeniial count (16) . Hawthorne was also unable to
`prove Andrews' statement that PDMS is transported in
`the leukocytes in the blood (16, 19).
`Rees et al. noted in studies using massive subcutaneous
`doses of .PDMS, an alteration of the tissue structure of the
`subcutis. Fat cells showed! varying degrees of atrophy with
`".Y •vy~u.,,u:v •"'-'uoles. A large number of clear cells was
`seen throughout the injection site. These were phagocytes
`with eccentric nuclei. Rees also noted that administration
`of 7 mL or greater subcutaneously showed a greater than
`50 percent mortality rate of mice at 3 months (1 7).
`
`G . Intravenous Administration
`
`The.now Chemical Company has placed the intrave(cid:173)
`nous LD 50 for the DC 200 (350 est) fluid in rabbits at
`about 0.5 gjkg. Cause of death appeared to be the accu(cid:173)
`mulation of silicone fluid in the lungs. lt was possible to
`inject 0.1 gjkg daily for 25 days without obvious ill effects
`(20).
`
`H. Inhalation
`
`Calandra et al. reported that rats, dogs, and guinea pigs
`exposed to 300 centiskokes PDMS fluid at a concentration
`of 2.1 mg/L for 6 hours demonstrated no ill effects (12).
`
`I. Reproduction
`
`Kennedy et al. showed in studies utilizing 20 mgjkg,
`200 mgjkg, and 1,000 mg/kg PDMS subcutaneously
`(DC 360 fluid) in rats that there was no alteration of
`weight gain, food consumption, or genital development in
`male rats. In female studies during gestation, the average
`length of gestation, as well as the mean body weight of the
`pups, was comparable to the control. No abnormal pat(cid:173)
`terns of behavior nor gross abnormality of dams and pups
`were noted at 21 days when sacrificed (13).
`He also noted a slightly greater number of fetuses de(cid:173)
`rived from dams tested with either 200 or 1,000 mgjkg
`DC 360 fluid with incompletely developed sternebrae,
`than fetuses from the control group of the low-dose group.
`They also noted a slight increase in lack of cranial closure
`in the 1,000 mgjkg group. He showed that there was an
`irtcreased incidence of in utero mortality at the 200 and
`1,000 mgjkg dose groups during the third trimester as
`compared to control. They also noted that there was no
`evidence of teratogenic activity in either rats or rabbits.
`Kennedy et al. also noted there was no evidence of
`fetotoxicity in rats caused by DC 360 fluid when adminis(cid:173)
`tered during the third trimester of pregnancy. There were
`no adverse effects on reproductive performance, or on
`
`Vol. 42, Supplement 1988
`
`weights, numbers, or survival of the progeny. Kennedy
`also stated that they rioted no teratogenic effects in rabbits
`using DC 225 fluid (13).
`
`J. Human,
`
`Rees et a!. noted that liquid or solid silicone conforms
`fairly well to the perfect implant material. Elastomeric
`silicone rubber can be used to replace bone or cartilage in
`the chin, nose, ear, and related soft tissue reconstruction.
`Liquid silicone is injected subcutaneously to restore lost
`tissue contours. They note that there are virtually no
`complications . .Tissue tolerance is high and infection and
`exposure only occur with solid implant s in areas of high
`tension or gross contamination (21).
`Selmanowitz and Orentreich note tl1at in patients fol(cid:173)
`lowed after having PDMS injected subcutaneously for
`cosmesis, no alterations were noted in complete blood
`count with differential, blood chemistry (glucose, BUN,
`urate, cholesterol, total protein, albumin, bilirubin, alka(cid:173)
`line phosphatase, SGOT, LDH, calcium and phosphorus),
`and urinalysis {22)".
`Bischoff also noted some interaction with products con(cid:173)
`taining PDMS and the body's response to these silicones.
`In hllmans ingesting oils containing !>DMS caused a d e(cid:173)
`creased effectiveness on anticoagulants such as warfarin
`or phenindione (18).
`
`VI. Types of Silicone Lubricants
`
`A. Polydimethy/siloxane Fluid ("Silicone oil")
`
`There are three separate types of silicone products
`available for use as a ]ubrication aid for packaging compo(cid:173)
`nents. The most widely used silicone fluid is a clear, color(cid:173)
`less, polydimethylsiloxane fluid, commonly referred to as
`"Silicone oil." Some major suppliers of polydimethysilox(cid:173)
`ane fluid are listed below:
`
`Supplier
`Bayer Chemical Co.
`Dow Corning
`
`General Electric
`Rhone-Poulenc, Inc.
`
`Trade Name Viscosit~ Range
`Full
`Baysilon M
`360 Fluid
`Full
`200 ;Fluid
`Full
`SF18 (350)
`350 est only
`Rhodorsil
`70047 Fluid
`Union Carbide Corp.
`L-45FG
`W acker-Chemie GmbH AKSilicone
`Fluids
`
`Full
`350 est only
`Full
`
`Dow Corning differentiates an industrial grade PDMS
`f1uid (DC 200) from "Medical Grade'' fluid (DC 360) on
`the basis of biocompatibility testing profiles. Rhone-Pou(cid:173)
`lenc, Inc. will also supply biocompatibility data on their
`RhodorsiJ® 70047 line.
`Fluid polysiloxane can be applied to glass, metal, plas(cid:173)
`tic, and elastomeric surfaces either straight or in a diluted
`form as a temporary PDMS fluid in water emulsion.
`When coated on glass or ceramic surfaces, the fluid can be
`"cured" or converted to a highly durable film by heating
`the treated surface at temperatures up to 350 oc. More
`
`S7
`
`Exh. 1004
`
`

`
`. specific application details can be found in the application
`section of this paper.
`
`B. Silicone Emulsions
`
`Another form of silicone product used for lubrication of
`packaging components is a water dilutable emulsion con(cid:173)
`taining approximately 35 percent polymetbylsilo~ane flu(cid:173)
`id. The emulsion may be used as received or it may be
`diluted with water to any desired silicone fluid concentra(cid:173)
`tion. The major suppliers of silicone fluids have emulsions
`available. Specific product information can be obtained
`from each supplier. Dilution of emulsions with water may
`result in the need for a bacteriostat or fungistat to coun(cid:173)
`teract possLble microbial activity. The emulsifying agents
`used in silicone emulsions may support bacterial growth.
`
`C. Air Curable Silicones
`
`There is a silicone product, currently available, which
`cures at room temperature. Not much field experience has
`been generated with this pi·oduct use on pharmaceutical
`packaging. It is listed here as a potential alternative to
`silicone fluids which require higher temperature to
`"cure."
`The product is available from Dow Corning as MDX-
`4159 fluid. It is a solution containing 50 percent polydi(cid:173)
`methylsiloxane which contains an amino functional group
`mixed with aliphatic solvents. The fluid is not soluble in
`water. Organic solvents, including aliphatic a nd aromatic
`hydrocarbon ~olvents such a:; i:;obutanol and lower molec(cid:173)
`ular weight alcohols, can be used to dilute the fluid to a 2
`to 5 percent active silicone level. Since many polymers,
`both plastic and elastomeric, can be adversely affected by
`organic solvents, care should be taken in the selection of
`the diluent. Lower molecular weight alcohols arc recom(cid:173)
`mended for elastomeric closures.
`
`VII. Method of Application ·of Silicones
`
`A. Introduction
`
`The methods of application described in this publica(cid:173)
`tion will be limited to those involving polydimethylsilox(cid:173)
`ane preparations. Other materials such as plastic and
`resin coatings are sometimes used to impart lubricity to
`parenteral package components. However, the applica(cid:173)
`tion of such materials is impractical for the general user as
`a process step.
`One should consider the use of dedicated equipment for
`all operations involving the preparation and application of
`PDMS fluid lubricants. It is very difficult to remove ·all
`residuals ofPDMS fluid during cleaning operations.
`
`B. Prepamtions
`
`Essentially all treatments utilized for the lubrication of
`parenteral components are based on the usc of PDM