US 20190133882A1 ( 19 ) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2019 /0133882 A1 Weikart et al. ( 43) Pub . Date: May 9, 2019
(54 ) COATED PACKAGING C23C 16 / 455 (2006 .01 ) A61 ) 1 /03 ( 2006 .01 ) ( 71) Applicant: SIO2 MEDICAL PRODUCTS , INC . , A61 ) 1 /05 ( 2006 . 01 ) Auburn , AL (US ) C23C 16 / 50 (2006 .01 ) A61L 31/ 08 ( 2006 . 01 ) (72 ) Inventors : Christopher Weikart, Auburn , AL A61L 31/ 14 (2006 . 01) (US ); Becky L . Clark , Auburn , AL (52 ) U . S . CI. ( US ) ; Adam Stevenson , Opelika , AL CPC ...... A61J 1/ 1468 ( 2015 . 05 ) ; A61L 2420 /08 (US ) ; John T . Felts , Alameda , CA (US ) ( 2013 . 01 ); C23C 16 /029 ( 2013 . 01 ) ; A61M 5 /3129 (2013 .01 ); A61L 31/ 16 (2013 .01 ) ; (21 ) Appl . No. : 16 /121 , 046 A61L 31/ 04 (2013 .01 ); B650 25 / 14 (2013 . 01 ) ; C23C 16 / 045 ( 2013 . 01 ) ; C23C 16 / 401 ( 22 ) Filed : Sep . 4, 2018 ( 2013 .01 ) ; C23C 16 / 45523 ( 2013 .01 ) ; A61J 1 /035 ( 2013 .01 ) ; A61J 1 /05 ( 2013 .01 ) ; C23C Related U . S . Application Data 16 /50 (2013 . 01 ); A61L 31/ 08 ( 2013 .01 ) ; AGIL (63 ) Continuation of application No. 14 / 774 , 073, filed on 31/ 088 (2013 . 01 ) ; A61L 31/ 143 ( 2013 . 01 ) ; Sep . 9 , 2015 , filed as application No . PCT/ US2014 / A61M 2005 /3131 ( 2013 .01 ) ; A61M 2205 / 0238 023813 on Mar . 11 , 2014 . ( 2013 .01 ) ; A61L 2420 /02 (2013 .01 ) ; A61J (60 ) Provisional application No. 61/ 776 ,733 , filed on Mar. 1700 ( 2013 .01 ) 11 , 2013 , provisional application No. 61/ 800 , 746 , (57 ) ABSTRACT filed on Mar. 15 , 2013 . A vessel has an interior surface facing a lumen . The interior surface includes a tie coating or layer, a barrier coating or Publication Classification layer, and a pH protective coating or layer. The tie coating (51 ) Int. Ci. or layer can comprise SiO , C ,, or SiN , C ,, , where x is from A61 ) 1 / 14 ( 2006 .01 ) about 0 . 5 to about 2 . 4 and y is from about 0 . 6 to about 3 . The A61 ) 1 / 00 ( 2006 .01 ) barrier coating or layer can comprise SiO . , wherein x is from C23C 16 / 02 ( 2006 .01 ) 1 .5 to 2 .9 . The barrier coating or layer reduces the ingress of A61M 5 /31 ( 2006 .01 ) atmospheric gas into the lumen . The pH protective coating A61L 31/ 16 ( 2006 .01 ) or layer can comprise Sio C , or SiN _ C », as well . In an A61L 31 /04 ( 2006 . 01 ) embodiment, in the presence of a fluid composition con B650 25 / 14 ( 2006 . 01 ) tained in the lumen and having a pH between 5 and 9 , the C23C 16 / 04 ( 2006 .01 ) calculated shelf life of the package can be more than six C23C 16 / 40 ( 2006 .01 ) months at a storage temperature of 4° C .
- 260
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286 -288 H 289 - 214 FIG . 2 Patent Application Publication May 9 , 2019 Sheet 2 of 21 US 2019 /0133882 A1
260 286 216 - 212 - 218 HTT! - 254 - 214 m 289 _ 250 258 NEZIN288
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FIG . 3 Patent Application Publication May 9 , 2019 Sheet 3 of 21 US 2019 /0133882 A1
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Si DISSOLUTION , PH 6 GLASS O1 SIO2 O
(qdd)IS
888900 10000 20000 30000 40000 EXPOSURE TIME (MIN .) @ 20 - 25C FIG . 6
SI DISSOLUTION , pH 7 5000 • GLASS 4500 + SIO2
LOOOUL. )ppbSi(Conc. vona O0000 1000OC + BOL 00 10000 20000 30000 40000 EXPOSURE TIME (MIN . ) @ 20 - 25C FIG . 7 Patent Application Publication May 9 , 2019 Sheet 5 of 21 US 2019 /0133882 A1
Si DISSOLUTION , pH 8 25000 • GLASS - 20500 S102 Conc.Si(ppb) 15000 10000 5000 o 10000 20000 30000 40000 EXPOSURE TIME (MIN . ) @ 20 -25C FIG . 8
SiOx COATING THICKNESS IF FUNCTIONAL COATING THICKNESS IS 30 nm - 2, 622 COATINGTHICKNESS(nm)
36 78 227 4 DH??10. 6 FIG . 9 Patent Application Publication May 9 , 2019 Sheet 6 of 21 US 2019 /0133882 A1
SILICON DISSOLUTION WITH pH 8 SOLVENT AT 40°C
SiCONCENTRATION(ppb)
SIO2 MADE SNOxHyOz SIO2 MADE SIO2 MADE SIWOXHyCZMADE WITH AMOSO MADE WITH WTHAMOSO WITH HMDSO WITH HIMOSO PLASMA +S 'WOxty©z OMCTS PLASMA PLASMA PLASMA+ SlwOxHyCZ PLASMA MADE WITH MADE WITH OMCTSPLASMA HMOSO PLASMA VIALS WITH PLASMA COATING FIG. 10 Patent Application Publication May 9 , 2019 Sheet 7 of 21 US 2019 /0133882 A1
RATIOSI-O(SYM/ASYM)
0 10000 20000 30000 40000 50000 60000 70000 W /FM (kJ / kg ) FIG . 11 1500 1250 1000 + SHELF-LIFEDAYS()
0 10000 20000 30000 40000 50000 60000 70000 W /FM (kJ / kg ) FIG . 12 Patent Application Publication May 9 , 2019 Sheet 8 of 21 US 2019 /0133882 A1
SAMPLE 2 0 .2 0 . 18 0. 16 0 . 14 0 . 12 0.14 ...... 0. 08 ABSORBANCE20 . 06 0 .04 0. 02 O h j eepakpapp hampa spreman sampai kepuasan pertama yang 4000 3500 3000 2500 2000 1500 1000 500 WAVE NUMBER ( cm - 1) FIG . 13
SAMPLE 3 0 . 2 0 . 18 0 . 16 0 . 14 0 . 12 0 . 1 20. 08 ABSORBANCE20 .06 0. 04 0. 02 yangperempuannya menyampaianp ngunan nyawanyament necesario 4000 3500 swingine wapannya3000 menyerangan warna 2500 2000 mb1500 a 1000 500 WAVE NUMBER ( cm - 1 ) FIG . 14 Patent Application Publication May 9 , 2019 Sheet 9 of 21 US 2019 /0133882 A1
SAMPLE 5 0. 2 0 . 18 0 . 16 0 .14 0 . 12 0 . 1 0 . 08 ABSORBANCE 0 . 06 0. 04 + 0 .02 + O te 4000 3500 3000 2500 2000 1500 1000 500 WAVE NUMBER (cm - 1) FIG . 15 SAMPLE 6 0 . 2 0 . 18 0 . 16 0 . 14 0 . 12 0. 1 0 . 08 ABSORBANCE 0 .06 0 .04 0. 02
. 4000 3500 3000 2500 2000 1500 1000 500 WAVE NUMBER (cm -1 ) FIG . 16 Patent Application Publication May 9 , 2019 Sheet 10 of 21 US 2019 /0133882 A1
1300 1253 1200
0 . 10 TIIIIII - - - - 45 % HMDSO 0 . 08 –
0 . 064 0 . 05 0 .0424 ABSORBANCE 0 .04 www 0. 02 0. 00T he 1400 1300 1200 1100 1 000 900 800 700 WAVE NUMBER [ cm - 11
FIG . 17 PRIOR ART (ANNOTATED ) Patent Application Publication May 9 , 2019 Sheet 11 of 21 US 2019 /0133882 A1
FIG . 18 Patent Application Publication May 9 , 2019 Sheet 12 of 21 US 2019 /0133882 A1
W < = 450 DAv < = 500 AN < = 700 < = 550 < = 750 < = 600 FILMETRICS < = 700 < = 450 ( TRI- LAYER STACK) - < = 750 50
HEIGHT ????????? :
V 53650
50 100 150DEGREES 200 250 300 350 FIG . 19 Patent Application Publication May 9 , 2019 Sheet 13 of 21 US 2019 /0133882 A1
COP SiOx Si01C1 BARRIER PROTECTION 273 nm 55 nm 38 nm
Si01C1 ADHESION RODHS575 EAG HD2300 200KV x250K TE 100nm FIG . 20 Patent Application Publication May 9 , 2019 Sheet 14 of 21 US 2019 /0133882 A1
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CAVITY FIG . 22 Patent Application Publication May 9 , 2019 Sheet 15 of 21 US 2019 /0133882 A1
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DEFECTS FIG . 24A Patent Application Publication May 9 , 2019 Sheet 17 of 21 US 2019 /0133882 A1
SIOC 286 SiOx 288 SIOC 289
COP 214
FIG . 25 Patent Application Publication May 9 , 2019 Sheet 18 of 21 US 2019 /0133882 A1
PROTECTIVE 153. 0 LAYER 286 BARRIER LAYER 288 TIE LAYER SEN Z72 289 WWW WWW COP 214 Ohrs KOH 100um
100 um 13 .0 FIG . 26 286 . 0 UNE
3hrs KOH
100pm
100 um 16 . 0 FIG . 27 Patent Application Publication May 9 , 2019 Sheet 19 of 21 US 2019 /0133882 A1
26 .0 WHITE EU 6 .5hrs KOH
100um
Sec. 100 um FIG . 28 ? AREA 2 , 0 hrs koh
...... CARBON OXYGEN SIO2 SIOC
SOC Si
f O/ SinC 200 1 400 600 800 1000 288 286 288 289 214 289 DISTANCE (um ) FIG . 29 Patent Application Publication May 9 , 2019 Sheet 20 of 21 US 2019 /0133882 A1
CARBON OXYGEN AREA 2 , 3HRS koh SiO2 O SIOC SIOC Si dhe hymninga * O / . Samsung SIAL 200 ) 400 600 289 800 1000 1200 288 214 288 286 289 DISTANCE (um ) FIG . 30 COP 214 CARBON BARRIER OXYGEN LAYER Si02 288 SIOC PROTECTIVE LAYER 286
SioC 289
© 200 \ 400 600 800 1000 286 288 do 214 289 288 286 DISTANCE (um ) FIG . 31 Patent Application Publication May 9 , 2019 Sheet 21 of 21 US 2019 /0133882 A1
302 304 US 2019 /0133882 A1 May 9 , 2019
COATED PACKAGING presence of glass particles has led to many FDA Warning Letters and to product recalls . [ 0001 ] This application is a continuation of U . S . applica 10008 ] As a result , some companies have turned to plastic tion Ser. No. 14 /774 ,073 , filed Sep . 9 , 2015 , which is a 371 pharmaceutical packages or other vessels , which provide of International Application No . PCT/ US2014 / 023813 filed greater dimensional tolerance and less breakage than glass, Mar . 11 , 2014 , which claims priority to U . S . Provisional but its use for primary pharmaceutical packaging remains Applications 61 / 776 , 733 , filed Mar . 11 , 2013 , and 61/ 800 , limited due to its gas (oxygen ) permeability : Plastic allows 746 , filed Mar . 15, 2013 . The entire specification and all the small molecule gases to permeate into ( or out of) the article . drawings of each of these provisional applications is incor The permeability of plastics to gases is significantly greater porated here by reference to provide continuity of disclo than that of glass and , in many cases (as with oxygen sure . sensitive drugs such as epinephrine ), plastics have been [0002 ] The specification and drawings of U . S . Pat. No . unacceptable for that reason . 7 , 985 , 188 are incorporated here by reference in their [0009 ] The problem of permeability has been addressed by entirety . That patent describes apparatus, vessels , precursors , adding a barrier coating or layer to the plastic pharmaceu coatings or layers and methods ( in particular coating meth tical package where it contacts fluid contents of the package . ods and test methods for examining the coatings or layers ) One such barrier layer is a very thin coating of Sior, as which can generally be used in performing the present defined below , applied by plasma enhanced chemical vapor invention , unless stated otherwise herein . They also describe deposition . But , current SiO , barrier layers deposited on a Sio , barrier coatings or layers and SiO C , coatings to which package by PECVD are etched off by aqueous contents of reference is made herein . the package having pH - values greater than 4 , particularly at higher pH values. This reduces the useful shelf life of the FIELD OF THE INVENTION package as its barrier efficacy is reduced . [0003 ] The present invention relates to the technical field of barrier coated surfaces, for example interior surfaces of SUMMARY OF THE INVENTION pharmaceutical packages or other vessels for storing or other contact with fluids. Examples of suitable fluids include [0010 ] An aspect of the invention is a vessel comprising or foods, nutritional supplements , drugs , inhalation anaesthet consisting of: a thermoplastic wall having an interior surface ics , diagnostic test materials , biologically active compounds enclosing at least a portion of a lumen . or body fluids, for example blood . The present invention also [0011 ] The tie coating or layer comprises or consists of SiOXV C , H , or Sin C ,V H , in which x is from about 0 . 5 to about relates to a pharmaceutical package or other vessel and to a 2 . 4 as measured by X - ray photoelectron spectroscopy method for making a pharmaceutical package with a pH (XPS ) , y is from about 0 . 6 to about 3 as measured by XPS , protective coating or layer between the contents and the and z is from about 2 to about 9 asmeasured by at least one barrier coating or layer. The present invention also relates of Rutherford backscattering spectrometry (RBS ) or hydro more generally to medical articles , including articles other gen forward scattering (HFS ). The tie coating or layer has an than packages or vessels , for example catheters . outer surface facing the wall surface and an interior surface . [ 0004 ). The present disclosure also relates to improved [0012 ] The barrier coating or layer comprises or consists methods for processing pharmaceutical packages or other of SiOx, in which x is from about 1 . 5 to about 2 . 9 as vessels , for example multiple identical pharmaceutical pack measured by XPS . The barrier coating or layer is positioned ages or other vessels used for pharmaceutical preparation between the interior surface of the tie coating or layer and storage and delivery , venipuncture and other medical sample the lumen . collection , and other purposes . [0013 ] The pH protective coating or layer comprises or [ 0005 ] The resulting packages are also claimed . Such consists of SiO _ C _ H ,, in which x is from about 0 . 5 to about pharmaceutical packages or other vessels are used in large 2 . 4 as measured by XPS , y is from about 0 . 6 to about 3 as numbers for these purposes, and must be relatively eco measured by XPS , and z is from about 2 to about 9 as nomical to manufacture and yet highly reliable in storage measured by at least one of RBS or HFS . The pH protective and use . coating or layer is positioned between the barrier coating or layer and the lumen . BACKGROUND OF THE INVENTION [ 0014 ] The pH protective coating or layer and tie coating [ 0006 ] One important consideration in manufacturing or layer together are effective to keep the barrier coating or pharmaceutical packages or other vessels for storing or other layer at least substantially undissolved as a result of attack contact with fluids, for example vials and pre - filled syringes, by a fluid contained in the lumen having a pH greater than is that the contents of the pharmaceutical package or other 5 for a period of at least six months. vessel desirably will have a substantial shelf life . During this [0015 ] Another aspect of the invention is the use of such shelf life , it is important to isolate the material filling the a vessel for storing a fluid having a pH greater than 5 . pharmaceutical package or other vessel from the vessel wall [ 0016 ] Still another aspect of the invention is a process for containing it, or from barrier layers or other functional layers making such a vessel comprising or consisting of the steps applied to the pharmaceutical package or other vessel wall of forming a tie coating or layer on the vessel interior wall ; to avoid leaching material from the pharmaceutical package forming a barrier coating or layer over at least a portion of or other vessel wall, barrier layer , or other functional layers the tie coating or layer ; and forming a pH protective coating into the prefilled contents or vice versa . or layer positioned between the barrier coating or layer and [ 0007 ] The traditional glass pharmaceutical packages or the lumen . other vessels are prone to breakage or degradation during [0017 ] The pH protective coating or layer and tie coating manufacture , filling operations , shipping and use , which or layer together are effective to keep the barrier coating or means that glass particulates may enter the drug . The layer at least substantially undissolved as a result of attack US 2019 /0133882 A1 May 9 , 2019 by a fluid contained in the lumen having a pH greater than [0046 ] In any embodiment of the invention , The vessel of 5 for a period of at least six months . any preceding claim , having a shelf life , while directly 10018 ] Even another aspect of the invention is a vessel contacted by a fluid contained in the lumen having a pH processing system adapted for making such a vessel. greater than 5 , of at least two years. [0019 ] In any embodiment of the invention , the tie coating [0047 ] In any embodiment of the invention , the shelf life or layer optionally can be applied by plasma enhanced optionally can be based on storage of the vessel containing chemical vapor deposition (PECVD ) . the fluid at 20° C . [ 0020 ] In any embodiment of the invention , the barrier [ 0048 ] In any embodiment of the invention , the shelf life coating or layer optionally can be applied by PECVD . optionally can be based on storage of the vessel containing [0021 ] In any embodiment of the invention , the pH pro the fluid at 40° C . tective coating or layer optionally can be applied by [0049 ] In any embodiment of the invention , a fluid con PECVD . tained in the lumen having a pH greater than 5 optionally can (0022 ] In any embodiment of the invention , the vessel can comprise or consist of a syringe barrel , a vial, cartridge or a remove the pH protective coating or layer at a rate of 1 nm blister package . or less of pH protective coating or layer thickness per 88 [0023 ] In any embodiment of the invention , at least a hours of contact with the fluid . portion of the thermoplastic wall comprises or consists of: [0050 ] In any embodiment of the invention , an FTIR [0024 ] a polyolefin , absorbance spectrum of the pH protective coating or layer [0025 ] a polyvinylalcohol optionally can have a ratio greater than 0 .75 between : [0026 ] a polymethacrylate ether [0051 ] the maximum amplitude of the Si — 0 — Si sym [0027 ] a polyacrylic acid metrical stretch peak between about 1000 and 1040 [0028 ] a polyamide cm - 1 , and 10029 ] a polyimide [0052 ] the maximum amplitude of the Si— 0 Si [0030 ] a polysulfone asymmetric stretch peak between about 1060 and about 0031 ] a polylactic acid 1100 cm - 1 . [0032 ] a cyclic olefin polymer or copolymer 10053 ] In any embodiment of the invention , the silicon [0033 ] a polyester dissolution rate by a 50 mM potassium phosphate buffer [0034 ] a combination of a polyolefin and a polyester or diluted in water for injection , adjusted to pH 8 with con [0035 ] a combination of any one of the foregoing . centrated nitric acid , and containing 0 . 2 wt. % polysorbate [ 0036 ]. In any embodiment of the invention , for the pH 80 surfactant, from the vessel optionally can be less than 170 protective coating or layer , x optionally can be from about ppb /day . 1 to about 2 as measured by XPS , y optionally can be from [0054 ] In any embodiment of the invention , the total about 0 . 6 to about 1 . 5 as measured by XPS , and z optionally silicon content of the pH protective coating or layer, barrier can be from about 2 to about 5 as measured by RBS or HFS . coating or layer , and tie coating or layer, as measured by [0037 ] In any embodiment of the invention , the pH pro dissolution of the pH protective coating or layer , barrier tective coating or layer has been applied by PECVD of a coating or layer, and tie coating or layer into 0 . 1 N potassium precursor feed comprising an organosilicon precursor. hydroxide aqueous solution at 40° C . from the vessel, [0038 ] In any embodiment of the invention , the organo optionally can be less than 66 ppm . silicon precursor comprises or consists of hexamethyldisi [0055 ] In any embodiment of the invention , the calculated loxane (HMDSO ) , trimethylsilane ( TriMS ) , tetramethylsi shelf life optionally can be more than 2 years. lane ( TetraMS ) , tetramethyldisiloxane ( TMDSO ) , [0056 ] In any embodiment of the invention , after forma octamethylcyclotetrasiloxane (OMCTS ) or a combination of tion of a groove by focused ion beam through the pH two or more of them . protective coating or layer, the barrier coating or layer, the 100391 In any embodiment of the invention , the precursor tie coating or layer , and into the lumen wall , and exposure feed for the pH protective coating or layer comprises or of the groove with 1N aqueous potassium hydroxide (KOH ) consists of: solution maintained at 40° C . in the lumen for 6 .5 hours, the [0040 ] from 0 . 5 to 10 standard volumes of the organo barrier coating or layer optionally can be detectable by XPS silicon precursor; and optionally can have atomic percentages of oxygen and 10041 ] from 0 . 1 to 10 standard volumes of oxygen ; and silicon within 10 atomic percent of their values before 0042 ] from 1 to 100 standard volumes of a carrier gas. treatment of the groove with the KOH solution . [ 0043 ] In any embodiment of the invention , the pH pro [0057 ] In any embodiment of the invention , the pH pro tective coating or layer optionally can be from about 10 to tective coating or layer optionally can show an O -Parameter about 1000 nm thick . measured with attenuated total reflection ( ATR ) of less than [0044 ] In any embodiment of the invention , the pH pro tective coating or layer contacting the fluid composition 0 . 4 , measured as : optionally can be from about 10 to about 1000 nm thick after contact with a fluid contained in the lumen having a pH Intensity at 1253 cm - 1 greater than 5 for a period of two years . O - Parameter = Maximum intensity in the range from 1000 to 1100 cm - 1 . 10045 ] In any embodiment of the invention , the rate of erosion of the pH protective coating or layer, if directly contacted by a fluid contained in the lumen having a pH [0058 ] In any embodiment of the invention , the pH pro greater than 5 , optionally can be less than 20 % of the rate of tective coating or layer optionally can show an N -Parameter erosion of the barrier coating or layer, if directly contacted measured with attenuated total reflection ( ATR ) of less than by the same fluid under the same conditions. 0 . 7 , measured as : US 2019 /0133882 A1 May 9 , 2019
BRIEF DESCRIPTION OF THE DRAWINGS Intensity at 840 cm - 1 N - Parameter = [0075 ] FIG . 1 is a schematic sectional view of a vessel Intensity at 799 cm -1 . according to any embodiment of the invention . [0076 ] FIG . 2 is an enlarged detail view of a portion of the [ 0059 ] In any embodiment of the invention , the pH pro vessel wall and coatings of FIG . 1 . tective coating or layer optionally can be applied by PECVD [0077 ] FIG . 3 is a schematic view of a pharmaceutical at a power level per of more than 22, 000 kJ/ kg of mass of package in the form of a syringe barrel as the vessel of FIGS . polymerizing gases in the PECVD reaction chamber. 1 and 2 , containing a fluid and closed with a closure in the [0060 ] In any embodiment of the invention , the pH pro form of a plunger. tective coating or layer optionally can be applied by PECVD [0078 ] FIG . 4 is a schematic view of a pharmaceutical at a power level per of from 1 to 200 W . package in the form of a vial as the vessel of FIGS . 1 and [0061 ] In any embodiment of the invention , for formation 2 containing a fluid and closed with a closure . of the pH protective coating or layer the ratio of the [0079 ] FIG . 5 is a schematic view of a pharmaceutical electrode power applied by PECVD to the plasma volume package in the form of a blister package as the vessel of optionally can be from 5 W /ml to 75 W /ml . FIGS . 1 and 2 containing a fluid and closed with a closure [0062 ] In any embodiment of the invention , for the tie in the form of a coated sheet defining an additional vessel coating or layer, x optionally can be from about 1 to about wall . 2 as measured by X - ray photoelectron spectroscopy (XPS ) , [0080 ] FIG . 6 is a plot of silicon dissolution versus expo y optionally can be from about 0 . 6 to about 1 . 5 as measured sure time at pH 6 for a glass container versus a plastic container having an SiO , barrier layer coated in the inside by XPS , and z optionally can be from about 2 to about 5 as wall . measured by Rutherford backscattering spectrometry (RBS ) [0081 ] FIG . 7 is a plot of silicon dissolution versus expo or hydrogen forward scattering (HFS ) . sure time at pH 7 for a glass container versus a plastic [0063 ] In any embodimentof the invention , the tie coating container having an SiO barrier layer coated in the inside or layer optionally can be applied by PECVD of a precursor wall . feed comprising an organosilicon precursor. [ 0082 ] FIG . 8 is a plot of silicon dissolution versus expo [0064 ] In any embodiment of the invention , the organo sure time at pH 8 for a glass container versus a plastic silicon precursor optionally can be tetramethylsilane ( Te container having an Sio , barrier layer coated in the inside traMS) , trimethylsilane ( TriMS) , hexamethyldisiloxane wall . (HMDSO ) , octamethylcyclotetrasiloxane (OMCTS ) , 10083 ] FIG . 9 is a plot of the SiO , coating thickness tetramethyldisiloxane ( TMDSO ), or a combination of two or necessary initially to leave a 30 nm residual coating thick more of these . ness when stored with solutions at different nominal pH [0065 ] In any embodiment of the invention , the precursor values from 3 to 9 . feed for the tie coating or layer optionally comprises or [0084 ] FIG . 10 shows the silicon dissolution rates at pH 8 consists of: and 40° C . of various PECVD coatings . 100661 from 0 . 5 to 10 standard volumes of the organo [0085 ) FIG . 11 is a plot of the ratio of Si- O _ Si sym silicon precursor; metric / asymmetric stretching mode versus energy input per [0067 ] from 0 . 1 to 10 standard volumes of oxygen ; and unit mass ( W / FM or KJ/kg ) of a PECVD coating using as [ 0068 ] from 1 to 120 standard volumes of a carrier gas . the reactive precursor gases OMCTS and oxygen . 10069 ] In any embodiment of the invention , the tie coating 0086 ]. FIG . 12 is a plot of silicon shelf life (days ) versus or layer optionally can be on average from about 5 to about energy input per unit mass ( W / FM or KJ/kg ) of a PECVD 200 nm thick . coating using as the reactive precursor gases OMCTS and [0070 ] Any embodiment of the invention optionally can oxygen . further comprise a lubricity coating or layer applied between [0087 ] FIG . 13 is a Fourier Transform Infrared Spectro the pH protective coating or layer and the lumen . photometer (FTIR ) absorbance spectrum of a PECVD coat [ 0071] In any embodiment of the invention , the vessel of ing . any preceding claim optionally can be a prefilled syringe [0088 ] FIG . 14 is a Fourier Transform Infrared Spectro having a syringe barrel coated on its interior wall with the tie photometer (FTIR ) absorbance spectrum of a PECVD coat coating or layer , barrier coating or layer, and pH protective ing. coating or layer . It optionally can further have a plunger [0089 ] FIG . 15 is a Fourier Transform Infrared Spectro seated in the barrel . photometer (FTIR ) absorbance spectrum of a PECVD coat [ 0072 ] In any embodiment of the invention , the vessel of ing . any preceding claim optionally can contain a pharmaceutical [0090 ) FIG . 16 is a Fourier Transform Infrared Spectro composition having a pH greater than 5 contained in the photometer (FTIR ) absorbance spectrum of a PECVD coat lumen , the prefilled syringe having a shelf life of at least six ing . months . 10091 ] FIG . 17 is a Fourier Transform Infrared Spectro 10073 ] In any embodiment of the invention , the vessel of photometer (FTIR ) absorbance spectrum of a PECVD coat claim 34 optionally can further comprise a lubricity coating ing , originally presented as FIG . 5 of U . S . Pat. No. 8 ,067 , or layer on at least a portion of the plunger and / or syringe 070 , annotated to show the calculation of the O - Parameter barrel wall . referred to in that patent. [0074 ] Many additional and alternative aspects and [0092 ] FIG . 18 is a schematic view of a syringe with a embodiments of the invention are also contemplated , and are trilayer coating according to FIGS . 1 , 2 , and 3 , showing a described in the specification and claims that follow . cylindrical region and specific points where data was taken . US 2019 /0133882 A1 May 9 , 2019
[0093 ] FIG . 19 is a Trimetric map of the overall trilayer -continued coating thickness versus position in the cylindrical region of a syringe illustrated by FIGS . 18 , 1 , 2 , and 3 . 262 Closure 264 Inner or interior surface ( of [0094 ] FIG . 20 is a photomicrograhic sectional view 262 ) showing the substrate and coatings of the trilayer coating at 268 Vessel position 2 shown in FIG . 18 . 270 Closure [ 0095 ] FIG . 21 is another Trimetric map of the overall 272 Interior facing surface 274 Lumen trilayer coating thickness versus position in the cylindrical 276 Wall - contacting surface region of a syringe illustrated by FIGS. 18 , 1, 2 , and 3. 278 Inner or interior surface (of 0096 ] FIG . 22 is a plot of coating thickness , representing 280 ) the same coating as FIG . 21 , at Positions 1 , 2 , 3 , and 4 shown 280 Vessel wall 281 Lubricity coating or layer in FIG . 18 . 282 Stopper [0097 ] FIG . 23 is a schematic illustration of a syringe , 283 PH protective coating or layer showing points on its surface where measurements were 284 Shield made in a working example . 285 Vessel coating or layer set pH protective coating or layer [ 0098 ] FIG . 24 is a photograph showing the benefit of the Deposit of lubricant present trilayer coating in preventing pinholes after attack by 288 Barrier layer an alkaline reagent, as discussed in the working examples . 289 Tie coating or layer 290 Apparatus for coating , for (0099 ] FIG . 24A is an enlarged detail view of the indicated example , 250 portion of FIG . 24. 292 Inner or interior surface ( of [0100 ] FIG . 25 is a schematic sectional view of a lateral 294 ) trench cut into a vessel wall and coating set as shown in FIG . 294 Restricted opening (of 250 ) 296 Processing vessel 2 for Example NN . 298 Outer surface (of 250 ) [0101 ] FIG . 26 is a photomicrographic plan view of the 302 Tie coater trench of FIG . 25 before KOH treatment, as referred to in 304 Barrier coater Example NN . 306 pH protective coater 10102 ] FIG . 27 is a photomicrographic plan view of the 308 Fluid filler 310 Fluid supply trench of FIG . 25 after 3 hours ofKOH treatment, as referred 312 Closure installer to in Example NN . 314 Closure supply 10103 ] FIG . 28 is a photomicrographic plan view of the trench of FIG . 25 after 6 . 5 hours of KOH treatment, as [0109 ] In the context of the present invention , the follow referred to in Example NN . ing definitions and abbreviations are used : 0104 FIG . 29 is an XPS plot resulting from a lateral scan [ 0110 ] The term “ at least ” in the context of the present across the trench of FIG . 25 before KOH treatment, as invention means “ equal or more than the integer following referred to in Example NN . the term . The word " comprising ” does not exclude other 0105 ) FIG . 30 is an XPS plot resulting from a lateral scan elements or steps , and the indefinite article “ a” or “ an ” does across the trench of FIG . 25 after 3 hours of KOH treatment, not exclude a plurality unless indicated otherwise . When as referred to in Example NN . ever a parameter range is indicated , it is intended to disclose f01061 FIG . 31 is an XPS plot resulting from a lateral scan the parameter values given as limits of the range and all across the trench of FIG . 25 after 6 hours of KOH treatment, values of the parameter falling within said range . as referred to in Example NN . [ 0111 ] " First” and " second " or similar references to , for example , deposits of lubricant, processing stations or pro [0107 ] FIG . 32 is a schematic view of a system for making cessing devices refer to the minimum number of deposits , the vessels and carrying out processes for making them . processing stations or devices that are present, but do not [0108 ] The following reference characters are used in the necessarily represent the order or total number of deposits , drawing figures : processing stations and devices or require additional depos its , processing stations and devices beyond the stated num ber. These terms do not limit the number of processing 210 Pharmaceutical package 212 Lumen stations or the particular processing carried out at the 214 Wall respective stations. For example , a “ first ” deposit in the 216 Outer surface context of this specification can be either the only deposit or 218 Fluid any one of plural deposits, without limitation . In other 220 Interior surface (of 288 ) words, recitation of a " first ” deposit allows but does not Outer surface (of 288 ) ANS Interior surface (of 286 ) require an embodiment that also has a second or further Outer surface (of 286 ) deposit. 228 Vial [0112 ] For purposes of the present invention , an " organo 230 Blister package silicon precursor ” is a compound having at least one of the 250 Syringe barrel linkages: 252 Syringe 254 Inner or interior surface (of 250 ) 256 Back end (of 250 ) 258 Plunger (of 252 ) ( relatively sliding part ) - 0 - Si - C - H or NH - Si - C - H 259 Lubricant 260 Front end (of 250 ) US 2019 /0133882 A1 May 9 , 2019 which is a tetravalent silicon atom connected to an oxygen the term . Thus , a vessel in the context of the present or nitrogen atom and an organic carbon atom ( an organic invention has one or more openings. One or two openings, carbon atom being a carbon atom bonded to at least one like the openings of a sample tube (one opening ) or a syringe hydrogen atom ) . A volatile organosilicon precursor, defined barrel ( two openings ) are preferred . If the vessel has two as such a precursor that can be supplied as a vapor in a openings , they can be of same or different size . If there is PECVD apparatus , is an optional organosilicon precursor. more than one opening , one opening can be used for the gas Optionally , the organosilicon precursor is selected from the inlet for a PECVD coating method according to the present group consisting of a linear siloxane , a monocyclic siloxane , invention , while the other openings are either capped or a polycyclic siloxane, a polysilsesquioxane, an alkyl open . A vessel according to the present invention can be a trimethoxysilane, a linear silazane, a monocyclic silazane , a sample tube, for example for collecting or storing biological polycyclic silazane , a polysilsesquiazane , and a combination fluids like blood or urine , a syringe (or a part thereof, for of any two or more of these precursors . example a syringe barrel) for storing or delivering a bio [0113 ] The feed amounts of PECVD precursors , gaseous logically active compound or composition , for example a reactant or process gases , and carrier gas are sometimes medicament or pharmaceutical composition , a vial for stor expressed in “ standard volumes” in the specification and ing biological materials or biologically active compounds or claims. The standard volume of a charge or other fixed compositions, a pipe , for example a catheter for transporting amount of gas is the volume the fixed amount of the gas biological materials or biologically active compounds or would occupy at a standard temperature and pressure (with compositions, or a cuvette for holding fluids , for example for out regard to the actual temperature and pressure of deliv holding biological materials or biologically active com ery ) . Standard volumes can be measured using different pounds or compositions . units of volume, and still be within the scope of the present 10117 ] A vessel can be of any shape , a vessel having a disclosure and claims. For example , the same fixed amount substantially cylindrical wall adjacent to at least one of its of gas could be expressed as the number of standard cubic open ends being preferred . Generally , the interior wall of the centimeters , the number of standard cubic meters , or the vessel is cylindrically shaped , like, for example in a sample number of standard cubic feet. Standard volumes can also be tube or a syringe barrel . Sample tubes and syringes or their defined using different standard temperatures and pressures , parts ( for example syringe barrels ) are contemplated . and still be within the scope of the present disclosure and 10118 ] A “ hydrophobic layer " in the context of the present claims. For example , the standard temperature might be 0° invention means that the coating or layer lowers the wetting C . and the standard pressure might be 760 Torr ( as is tension of a surface coated with the coating or layer, conventional ) , or the standard temperature might be 20° C . compared to the corresponding uncoated surface . Hydro and the standard pressure might be 1 Torr . But whatever phobicity is thus a function of both the uncoated substrate standard is used in a given case , when comparing relative and the coating or layer. The same applies with appropriate amounts of two or more different gases without specifying alterations for other contexts wherein the term “ hydropho particular parameters , the same units of volume, standard bic ” is used . The term “hydrophilic ” means the opposite , i .e . temperature , and standard pressure are to be used relative to that the wetting tension is increased compared to reference each gas, unless otherwise indicated . sample . The present hydrophobic layers are primarily [0114 ] The corresponding feed rates of PECVD precur defined by their hydrophobicity and the process conditions sors , gaseous reactant or process gases , and carrier gas are providing hydrophobicity expressed in standard volumes per unit of time in the [0119 ] . In the empirical composition Si- O _CH , or the specification . For example , in the working examples the equivalent composition SiO , C , , the values of w , x , y , and z flow rates are expressed as standard cubic centimeters per used throughout this specification should be understood as minute , abbreviated as sccm . As with the other parameters , ratios or an empirical formula ( for example for a coating or other units of time can be used , such as seconds or hours , but layer ), rather than as a limit on the number or type of atoms consistent parameters are to be used when comparing the in a molecule . For example , octamethylcyclotetrasiloxane , flow rates of two or more gases , unless otherwise indicated . which has the molecular composition Si_ 04C2H24 , can be [0115 ] A “ vessel” in the context of the present invention described by the following empirical formula , arrived at by can be any type of vessel with at least one opening and a wall dividing each of w , x , y , and z in the molecular formula by defining an inner or interior surface . The substrate can be the 4 , the largest common factor : Si, 0 , C Ho. The values of w , wall of a vessel having a lumen . Though the invention is not x , y , and z are also not limited to integers . For example , necessarily limited to pharmaceutical packages or other (acyclic ) octamethyltrisiloxane, molecular composition vessels of a particular volume, pharmaceutical packages or Siz02C2H24 , is reducible to Si, 00 . 67C2. 67Hg . Also , although other vessels are contemplated in which the lumen has a void SIO C , H , is described as equivalent to SiO , Cu, it is not volume of from 0 . 5 to 50 mL , optionally from 1 to 10 mL , necessary to show the presence of hydrogen in any propor optionally from 0 .5 to 5 mL , optionally from 1 to 3 mL . The tion to show the presence of Sio Cy. substrate surface can be part or all of the inner or interior [0120 ] “ Wetting tension ” is a specific measure for the surface of a vessel having at least one opening and an inner hydrophobicity or hydrophilicity of a surface . An optional or interior surface . Some examples of a pharmaceutical wetting tension measurement method in the context of the package include, but are not limited to , a vial, a plastic present invention is ASTM D 2578 or a modification of the coated vial, a syringe, a plastic coated syringe , a blister pack , method described in ASTM D 2578 . This method uses an ampoule , a plastic coated ampoule, a cartridge , a bottle , standard wetting tension solutions (called dyne solutions) to a plastic coated bottle , a pouch , a pump , a sprayer , a stopper, determine the solution that comes nearest to wetting a plastic a needle , a plunger , a cap , a stent, a catheter or an implant. film surface for exactly two seconds. This is the film ' s [0116 ] The term “ at least ” in the context of the present wetting tension . The procedure utilized is varied herein from invention means “ equal or more” than the integer following ASTM D 2578 in that the substrates are not flat plastic films, US 2019 /0133882 A1 May 9 , 2019 but are tubes made according to the Protocol for Forming polyester, for example polyethylene terephthalate , a poly PET Tube and ( except for controls ) coated according to the carbonate, or any combination or copolymer of any of these . Protocol for coating Tube Interior with Hydrophobic Coat- Optionally , at least a portion of the wall 214 of the vessel ing or Layer ( see Example 9 of EP2251671 A2) . 250 comprises or consists essentially of glass, for example [ 0121 ] The atomic ratios of silicon , oxygen , and carbon borosilicate glass . A combination of any two or more of the can be determined by XPS . The atomic ratio of H atoms materials in this paragraph can also be used . cannot be measured by XPS , which does not detect hydro [0129 ] The wall 214 has an interior surface facing the gen . Optionally , the proportion of H atoms can be deter lumen , an outer surface , and a vessel coating set 285 on at mined separately , for example by Rutherford backscattering least a portion of the wall 214 facing the lumen 212 . The or hydrogen forward scattering, preferably the former . Also , interior surface comprises a tie coating or layer 289 , a barrier unless otherwise indicated here , the value of w is normalized coating or layer 288 , and a pH protective coating or layer to 1 , and the subscript w is then conventionally omitted . The 286 . This embodiment of the vessel coating or layer set 285 coating or layer may thus in one aspect have the formula is sometimes known as a " trilayer coating" in which the SiO C , H , , for example where w is 1 , x is from about 0 . 5 barrier coating or layer 288 of SiOx optionally is protected to about 2 . 4 , y is from about 0 . 6 to about 3 , and z is from against contents having a pH otherwise high enough to about 2 to about 9 . The same coating or layer, with the same remove it by being sandwiched between the pH protective determination of w , x , and y , may thus in another aspect have coating or layer 286 and the tie coating or layer 289 , each an the formula Sio C , for example where x is from about 0 . 5 organic layer of SiO C , as defined in this specification . to about 2 . 4 , y is from about 0 .6 to about 3 , and w and z are omitted . Typically , such coating or layer would hence con [0130 ] FIGS . 1 and 2 show a vessel having at least a single tain 36 % to 41 % carbon normalized to 100 % carbon plus opening , and should be understood to include a vessel oxygen plus silicon . having two or more openings, such as a syringe , or a vessel [0122 ] The term “ syringe” is broadly defined to include having no openings , such as a pouch , blister pack , or cartridges, injection “ pens, ” and other types of barrels or ampoule . reservoirs adapted to be assembled with one or more other components to provide a functional syringe . “ Syringe ” is Tie Coating or Layer also broadly defined to include related articles such as auto - injectors , which provide a mechanism for dispensing [0131 ] Referring to FIGS. 1 and 2 , the tie coating or layer the contents. 289 is provided , sometimes referred to as an adhesion [ 0123 ] A coating or layer or treatment is defined as coating or layer . The tie coating or layer 289 optionally “ hydrophobic ” if it lowers the wetting tension of a surface , functions to improve adhesion of a barrier coating or layer compared to the corresponding uncoated or untreated sur 288 to a substrate , in particular a thermoplastic substrate , face . Hydrophobicity is thus a function of both the untreated although a tie layer can be used to improve adhesion to a substrate and the treatment. glass substrate or to another coating or layer. [0124 ] the word “ comprising ” does not exclude other [0132 ] Optionally , the tie coating or layer 289 improves elements or steps, adhesion of the barrier coating or layer 288 to the substrate [0125 ] the indefinite article “ a ” or “ an ” does not exclude or wall 214 . For example , the tie coating or layer 289 , also a plurality . referred to as an adhesion layer or coating, can be applied to the substrate and the barrier layer can be applied to the DETAILED DESCRIPTION adhesion layer to improve adhesion of the barrier layer or coating to the substrate . Optionally , the adhesion or tie [0126 ] The present invention will now be described more coating or layer 289 is also believed to relieve stress on the fully, with reference to the accompanying drawings, in barrier coating or layer 288 , making the barrier layer less which several embodiments are shown . This invention can , subject to damage from thermal expansion or contraction or however, be embodied in many different forms and should mechanical shock . not be construed as limited to the embodiments set forth here. Rather, these embodiments are examples of the inven [0133 ] Optionally , the tie coating or layer 289 applied tion , which has the full scope indicated by the language of under a barrier coating or layer 288 can improve the function the claims. Like numbers refer to like or corresponding of a pH protective coating or layer 286 applied over the elements throughout. The following disclosure relates to all barrier coating or layer 288 . embodiments unless specifically limited to a certain embodi [0134 ] Optionally , the adhesion or tie coating or layer 289 ment . is also believed to decouple defects between the barrier [0127 ] Referring to FIGS. 1 and 2 , a vessel , here in the coating or layer 288 and the COP substrate . This is believed form of a pharmaceutical package 210 is shown. Several to occur because any pinholes or other defects that may be non - limiting examples of such vessels are a syringe barrel , formed when the adhesion or tie coating or layer 289 is a vial, a blister pack or package , an ampoule , a cartridge , a applied tend not to be continued when the barrier coating or bottle , a pouch , a pump, a sprayer, a stopper, a needle , a layer 288 is applied , so the pinholes or other defects in one plunger, a cap , a stent, a catheter or an implant, or any other coating do not line up with defects in the other. Optionally , type of container or conduit for a fluid . the adhesion or tie coating or layer 289 has some efficacy as 0128 ] The vessel 210 of FIGS. 1 and 2 has a lumen 212 a barrier layer , so even a defect providing a leakage path defined at least in part by a wall 214 . At least a portion of extending through the barrier coating or layer 289 is blocked the wall 214 optionally comprises a cyclic olefin polymer. by the adhesion or tie coating or layer 289 . More generally , the suitable materials for the wall 214 of the [0135 ] Optionally , the tie coating or layer 289 comprises vessel 250 include a polyolefin (for example a cyclic olefin SiO2C , or SiN Cy preferably can be composed of , comprise , polymer, a cyclic olefin copolymer , or polypropylene ), a or consist essentially of SiO _ C _ , wherein x is from about 0 . 5 US 2019 /0133882 A1 May 9 , 2019 to about 2 . 4 and y is from about 0 .6 to about 3 . The atomic described elsewhere in this specification , or in U . S . Pat . No . ratios of Si, O , and C in the tie coating or layer 289 7 ,985 , 188 , can be used in any embodiment. optionally can be : 10147 ] The barrier layer optionally is characterized as an [0136 ] Si 100 : 0 50 - 150 : C 90 - 200 ( i .e . x = 0 . 5 to 1 . 5 , y = 0 . 9 “ SiOx” coating , and contains silicon , oxygen , and optionally to 2 ); other elements, in which x , the ratio of oxygen to silicon [0137 ] Si 100 : 0 70 - 130 : C 90 - 200 (i .e . x = 0 . 7 to 1 . 3 , y = 0 . 9 atoms, is from about 1 . 5 to about 2 . 9 , or 1 . 5 to about 2 .6 , or to 2 ) about 2 . One suitable barrier composition is one where x is 2 . 3 , for example . [ 0138 ] Si 100 :0 80 - 120 :C 90 - 150 (i . e . x = 0 . 8 to 1. 2 , y = 0 .9 [0148 ] Optionally , the barrier coating or layer 288 is from to 1 . 5 ) 2 to 1000 nm thick , optionally from 4 nm to 500 nm thick , [0139 ] Si 100 :0 90 - 120 :C 90 - 140 (i . e . x = 0 . 9 to 1. 2 , y = 0 .9 optionally between 10 and 200 nm thick , optionally from 20 to 1 .4 ), or to 200 nm thick , optionally from 20 to 30 nm thick , and [ 0140 ] Si 100 : 0 92 - 107 : C 116 - 133 ( i. e . x = 0 .92 to 1 . 07 , comprises SiOx , wherein x is from 1 . 5 to 2 . 9 . The barrier y = 1 .16 to 1 .33 ). coating or layer 288 of SiO has an interior surface 220 [0141 ] The atomic ratio can be determined by XPS . Tak facing the lumen 212 and an outer surface 222 facing the ing into account the H atoms, which are not measured by interior surface of the tie coating or layer 289 . For example , XPS , the tie coating or layer 289 may thus in one aspect have the barrier coating or layer such as 288 of any embodiment the formula Si- O _ C , H , (or its equivalent SiO , C ,, ) , for can be applied at a thickness of at least 2 nm , or at least 4 example where w is 1 , x is from about 0 . 5 to about 2 . 4 , y is nm , or at least 7 nm , or at least 10 nm , or at least 20 nm , or from about 0 .6 to about 3 , and z is from about 2 to about 9 . at least 30 nm , or at least 40 nm , or at least 50 nm , or at least Typically , tie coating or layer 289 would hence contain 36 % 100 nm , or at least 150 nm , or at least 200 nm , or at least 300 to 41 % carbon normalized to 100 % carbon plus oxygen plus nm , or at least 400 nm , or at least 500 nm , or at least 600 nm , silicon . or at least 700 nm , or at least 800 nm , or at least 900 nm . The [ 0142 ] Optionally , the tie coating or layer can be similar or barrier coating or layer can be up to 1000 nm , or at most 900 identical in composition with the pH protective coating or nm , or at most 800 nm , or at most 700 nm , or at most 600 layer 286 described elsewhere in this specification , although nm , or at most 500 nm , or at most 400 nm , or at most 300 this is not a requirement. nm , or at most 200 nm , or at most 100 nm , or at most 90 nm , [0143 ] Optionally, the tie coating or layer 289 is on or at most 80 nm , or atmost 70 nm , or at most 60 nm , or at average between 5 and 200 nm ( nanometers ) , optionally most 50 nm , or at most 40 nm , or atmost 30 nm , or at most between 5 and 100 nm , optionally between 5 and 20 nm 20 nm , or at most 10 nm , or at most 5 nm thick . thick . These thicknesses are not critical. Commonly but not 10149 ) Ranges of from 4 nm to 500 nm thick , optionally necessarily , the tie coating or layer 289 will be relatively from 7 nm to 400 nm thick , optionally from 10 nm to 300 thin , since its function is to change the surface properties of nm thick , optionally from 20 nm to 200 nm thick , optionally the substrate . from 20 to 30 nm thick , optionally from 30 nm to 100 nm [ 0144 The tie coating or layer 289 has an interior surface thick are contemplated . Specific thickness ranges composed facing the lumen 212 and an outer surface facing the wall of any one of the minimum thicknesses expressed above , 214 interior surface . Optionally , the tie coating or layer 286 plus any equal or greater one of the maximum thicknesses is at least coextensive with the barrier coating or layer . expressed above , are expressly contemplated . Optionally , the tie coating or layer is applied by PECVD , for [0150 ] The thickness of the SiOc or other barrier coating or example of a precursor feed comprising octamethylcyclo layer can be measured , for example , by transmission elec tetrasiloxane (OMCTS ) , tetramethyldisiloxane ( TMDSO ) , tron microscopy ( TEM ) , and its composition can be mea or hexamethyldisiloxane (HMDSO ) . sured by X - ray photoelectron spectroscopy (XPS ). [0151 ] Optionally , the barrier coating or layer 288 is Barrier Coating or Layer effective to reduce the ingress of atmospheric gas into the [0145 ] Referring to FIGS. 1 and 2 , a barrier coating or lumen compared to a vessel without a barrier coating or layer 288 optionally can be deposited by plasma enhanced layer. Optionally , the barrier coating or layer 288 provides a chemical vapor deposition (PECVD ) or other chemical barrier to oxygen that has permeated the wall 214 . Option vapor deposition processes on the vessel of a pharmaceutical ally , the barrier coating or layer 288 is a barrier to extraction package , for example a thermoplastic package, to prevent of the composition of the wall 214 by the contents of the oxygen , carbon dioxide , or other gases from entering the lumen 212 . vessel, the barrier coating 288 optionally being effective to reduce the ingress of atmospheric gas into the lumen 210 pH Protective Coating or Layer compared to an uncoated vessel 210 , and /or to prevent [0152 ] Certain barrier coatings or layers 286 such as SiO , leaching of the pharmaceutical material into or through the as defined here have been found to have the characteristic of package wall. being subject to being measurably diminished in barrier [0146 ] The barrier coating or layer 286 optionally can be improvement factor in less than six months as a result of applied directly or indirectly to the thermoplastic wall 214 attack by certain relatively high pH contents of the coated ( for example the tie coating or layer 289 can be interposed vessel as described elsewhere in this specification , particu between them ) so that in the filled pharmaceutical package larly where the barrier coating or layer directly contacts the or other vessel 210 the barrier coating or layer 286 is located contents . The inventors have found that barrier layers or between the inner or interior surface of the wall 214 and the coatings of SiO , are eroded or dissolved by some fluids , for lumen 212 that is adapted to contain a fluid to be stored . The example aqueous compositions having a pH above about 5 . barrier coating or layer 286 of SiO , is supported by the Since coatings applied by chemical vapor deposition can be thermoplastic wall 214 . The barrier coating or layer 286 as very thin — tens to hundreds of nanometers thick — even a US 2019 /0133882 A1 May 9 , 2019 relatively slow rate of erosion can remove or reduce the sors , for example hexamethyldisiloxane (HMDSO ) or effectiveness of the barrier layer in less time than the desired tetramethyldisiloxane ( TMDSO ) . shelf life of a product package . This is particularly a problem 0156 ] The inventors offer the following theory of opera for aqueous fluid pharmaceutical compositions , since many tion of the pH protective coating or layer described here . The of them have a pH of roughly 7 , or more broadly in the range invention is not limited by the accuracy of this theory or to of 4 to 8 , alternatively from 5 to 9 , similar to the pH of blood the embodiments predictable by use of this theory . and other human or animal fluids. The higher the pH of the 101571. The dissolution rate of the SiO , barrier layer is pharmaceutical preparation , the more quickly it erodes or believed to be dependent on SiOx bonding within the layer. dissolves the SiOc coating . Optionally , this problem can be Oxygen bonding sites ( silanols ) are believed to increase the addressed by protecting the barrier coating or layer 288 , or dissolution rate . other pH sensitive material , with a pH protective coating or [0158 ] It is believed that the OMCTS -based pH protective layer 286 . coating or layer bonds with the silanol sites on the SiOx [0153 ] The pH protective coating or layer 286 optionally barrier layer to " heal” or passivate the SiO surface and thus provides protection of the underlying barrier coating or layer dramatically reduces the dissolution rate . In this hypothesis , 288 against contents of the vessel 210 having a pH from 4 the thickness of the OMCTS layer is not the primary means to 8 , including where a surfactant is present. For a prefilled of protection — the primary means is passivation of the SiO , pharmaceutical package that is in contact with the contents surface . It is contemplated that a pH protective coating or of the lumen 212 from the time it is manufactured to the time layer as described in this specification can be improved by it is used , the pH protective coating or layer 286 optionally increasing the crosslink density of the pH protective coating prevents or inhibits attack of the barrier coating or layer 288 or layer. sufficiently to maintain an effective oxygen barrier over the [0159 ] The pH protective coating or layer 286 optionally intended shelf life of the prefilled syringe . The rate of is effective to keep the barrier coating or layer 288 at least erosion , dissolution , or leaching (different names for related substantially undissolved as a result of attack by the fluid concepts ) of the pH protective coating or layer 286 , if 218 for a period of at least six months. directly contacted by a fluid , is less than the rate of erosion [ 0160 ] The pH protective coating or layer optionally can of the barrier coating or layer 288 , if directly contacted by prevent or reduce the precipitation of a compound or com the fluid having a pH of from 5 to 9 . The pH protective ponent of a composition in contact with the pH protective coating or layer 286 is effective to isolate a fluid 218 having coating or layer , in particular can prevent or reduce insulin a pH between 5 and 9 from the barrier coating or layer 288 , precipitation or blood clotting , in comparison to the at least for sufficient time to allow the barrier coating to act uncoated surface and /or to a barrier coated surface using as a barrier during the shelf life of the pharmaceutical HMDSO as precursor . package or other vessel 210 . [0161 ] Referring to FIGS . 1 and 2 , the pH protective [0154 ] The inventors have further found that certain pH coating or layer 286 can be composed of, comprise , or protective coatings or layers of SiO C , or Sin C , formed consist essentially of SiO _ C _ H , (or its equivalent SiO C ,) from polysiloxane precursors, which pH protective coatings or Si„ N _CH , or its equivalent SiN _ Cu) , each as defined or layers have a substantial organic component, do not erode previously, preferably SiO , C ,, , wherein x is from about 0 . 5 quickly when exposed to fluids, and in fact erode or dissolve to about 2 . 4 and y is from about 0 . 6 to about 3 . The atomic more slowly when the fluids have pHs within the range of 4 ratios of Si, O , and C in the pH protective coating or layer to 8 or 5 to 9 . For example , at pH 8 , the dissolution rate of 286 optionally can be: a pH protective coating or layer made from the precursor [0162 ] Si 100 :0 50 -150 :C 90 - 200 (i . e . x = 0 .5 to 1. 5 , y = 0 .9 octamethylcyclotetrasiloxane , or OMCTS , is quite slow . to 2) ; These pH protective coatings or layers of SiO _ C or Sin C , [0163 ] Si 100 :0 70 - 130 :C 90 -200 (i . e . x = 0 . 7 to 1 .3 , y = 0. 9 can therefore be used to cover a barrier layer of Sio to 2 ) retaining the benefits of the barrier layer by protecting it [0164 ] Si 100 : 80 - 120 : C 90 - 150 ( i. e . x = 0 . 8 to 1 . 2 , y = 0 . 9 from the fluid in the pharmaceutical package . The protective to 1 . 5 ) layer is applied over at least a portion of the SiO , layer to [0165 ] Si 100 : 0 90 - 120 :C 90 -140 (i . e. x = 0 .9 to 1. 2 , y = 0 . 9 protect the SiOx layer from contents stored in a vessel, where to 1 . 4 ) , or the contents otherwise would be in contact with the SiO , [016 ] Si 100 : 0 92 - 107 :C 116 - 133 (i . e . x = 0 .92 to 1. 07 , layer. y = 1 . 16 to 1 . 33 ) or [0155 ] Although the present invention does not depend 0167] Si 100 : 0 80 - 130 : C 90 - 150 . upon the accuracy of the following theory , it is further [0168 ] Alternatively, the pH protective coating or layer believed that effective pH protective coatings or layers for can have atomic concentrations normalized to 100 % carbon , avoiding erosion can be made from siloxanes and silazanes oxygen , and silicon , as determined by X - ray photoelectron as described in this disclosure . SiO , C , or SiN , C ,, coatings spectroscopy (XPS ) of less than 50 % carbon and more than deposited from cyclic siloxane or linear silazane precursors , 25 % silicon . Alternatively , the atomic concentrations are for example octamethylcyclotetrasiloxane (OMCTS ) , are from 25 to 45 % carbon , 25 to 65 % silicon , and 10 to 35 % believed to include intact cyclic siloxane rings and longer oxygen . Alternatively , the atomic concentrations are from 30 series of repeating units of the precursor structure . These to 40 % carbon , 32 to 52 % silicon , and 20 to 27 % oxygen . coatings are believed to be nanoporous but structured and Alternatively, the atomic concentrations are from 33 to 37 % hydrophobic , and these properties are believed to contribute carbon , 37 to 47 % silicon , and 22 to 26 % oxygen . to their success as pH protective coatings or layers, and also 101691 Optionally , the atomic concentration of carbon in protective coatings or layers . This is shown , for example , in the pH protective coating or layer , normalized to 100 % of U . S . Pat. No . 7 , 901, 783 . SiO , C ,, or SiN , C ,, coatings also can carbon , oxygen , and silicon , as determined by X - ray pho be deposited from linear siloxane or linear silazane precur toelectron spectroscopy (XPS ), can be greater than the US 2019 /0133882 A1 May 9 , 2019 atomic concentration of carbon in the atomic formula for the the density of a pH protective coating or layer made from organosilicon precursor. For example, embodiments are HMDSO as the organosilicon compound under the same contemplated in which the atomic concentration of carbon PECVD reaction conditions . increases by from 1 to 80 atomic percent, alternatively from [0176 ] The pH protective coating or layer optionally can 10 to 70 atomic percent, alternatively from 20 to 60 atomic have an RMS surface roughness value (measured by AFM ) percent, alternatively from 30 to 50 atomic percent, alter of from about 5 to about 9 , optionally from about 6 to about natively from 35 to 45 atomic percent, alternatively from 37 8 , optionally from about 6 . 4 to about 7 . 8 . The R , surface to 41 atomic percent. roughness value of the pH protective coating or layer, [0170 ] Optionally , the atomic ratio of carbon to oxygen in measured by AFM , can be from about 4 to about 6 , option the pH protective coating or layer can be increased in ally from about 4 . 6 to about 5 . 8 . The Rmor surface roughness comparison to the organosilicon precursor, and / or the atomic value of the pH protective coating or layer, measured by ratio of oxygen to silicon can be decreased in comparison to AFM , can be from about 70 to about 160, optionally from about 84 to about 142 , optionally from about 90 to about the organosilicon precursor. 130 . [ 0171] Optionally , the pH protective coating or layer can [0177 ] The interior surface of the pH protective optionally have an atomic concentration of silicon , normalized to 100 % can have a contact angle (with distilled water ) of from 90° of carbon , oxygen , and silicon , as determined by X - ray to 110° , optionally from 80° to 120° , optionally from 70° to photoelectron spectroscopy (XPS ) , less than the atomic 130° , as measured by Goniometer Angle measurement of a concentration of silicon in the atomic formula for the feed water droplet on the pH protective surface , per ASTM gas . For example , embodiments are contemplated in which D7334 -08 “ Standard Practice for Surface Wettability of the atomic concentration of silicon decreases by from 1 to 80 Coatings , Substrates and Pigments by Advancing Contact atomic percent, alternatively by from 10 to 70 atomic Angle Measurement, " percent, alternatively by from 20 to 60 atomic percent, [0178 ] Optionally an FTIR absorbance spectrum of the pH alternatively by from 30 to 55 atomic percent , alternatively protective coating or layer 286 of any embodiment has a by from 40 to 50 atomic percent, alternatively by from 42 to ratio greater than 0 . 75 between the maximum amplitude of 46 atomic percent. the Si — Si symmetrical stretch peak normally located [ 0172 ] As another option , a pH protective coating or layer between about 1000 and 1040 cm - 1 , and the maximum is contemplated in any embodiment that can be character amplitude of the Si - O Si assymmetric stretch peak nor ized by a sum formula wherein the atomic ratio C : 0 can be mally located between about 1060 and about 1100 cm - 1 . increased and /or the atomic ratio Si: O can be decreased in Alternatively in any embodiment, this ratio can be at least comparison to the sum formula of the organosilicon precur 0 .8 , or at least 0 . 9 , or at least 1. 0 , or at least 1 . 1, or at least sor . 1 . 2 . Alternatively in any embodiment, this ratio can be at most 1. 7 , or atmost 1. 6 , or at most 1. 5 , or at most 1. 4 , or at [0173 ] The atomic ratio of Si: O : C or Si: N :C can be most 1 . 3 . Any minimum ratio stated here can be combined determined by XPS (X -ray photoelectron spectroscopy ). with any maximum ratio stated here , as an alternative Taking into account the H atoms, the pH protective coating embodiment of the invention of FIGS. 1 - 5 . or layer may thus in one aspect have the formula Si_ O _ C _ H ,, [0179 ] Optionally , in any embodiment the pH protective or its equivalent SiO C „, for example where w is 1 , x is from coating or layer 286 , in the absence of the medicament, has about 0 . 5 to about 2 . 4 , y is from about 0 . 6 to about 3 , and a non -oily appearance . This appearance has been observed z is from about 2 to about 9 . in some instances to distinguish an effective pH protective [0174 ] The thickness of the pH protective coating or layer coating or layer from a lubricity layer, which in some as applied optionally is between 10 and 1000 nm ; alterna instances has been observed to have an oily ( i. e . shiny ) tively from 10 nm to 900 nm ; alternatively from 10 nm to appearance . 800 nm ; alternatively from 10 nm to 700 nm ; alternatively [0180 ] Optionally , for the pH protective coating or layer from 10 nm to 600 nm ; alternatively from 10 nm to 500 nm ; 286 in any embodiment, the silicon dissolution rate by a 50 alternatively from 10 nm to 400 nm ; alternatively from 10 mM potassium phosphate buffer diluted in water for injec nm to 300 nm ; alternatively from 10 nm to 200 nm ; tion , adjusted to pH 8 with concentrated nitric acid , and alternatively from 10 nm to 100 nm ; alternatively from 10 containing 0 . 2 wt. % polysorbate - 80 surfactant, (measured nm to 50 nm ; alternatively from 20 nm to 1000 nm ; in the absence of the medicament, to avoid changing the alternatively from 50 nm to 1000 nm ; alternatively from 50 dissolution reagent) , at 40° C ., is less than 170 ppb /day . nm to 800 nm ; optionally from 50 to 500 nm ; optionally ( Polysorbate - 80 is a common ingredient of pharmaceutical from 100 to 200 nm ; alternatively from 100 nm to 700 nm ; preparations , available for example as Tween® - 80 from alternatively from 100 nm to 200 nm ; alternatively from 300 Uniqema Americas LLC , Wilmington Del. ) to 600 nm . The thickness does not need to be uniform [0181 ] Optionally , for the pH protective coating or layer throughout the vessel, and will typically vary from the 286 in any embodiment, the silicon dissolution rate is less preferred values in portions of a vessel. than 160 ppb / day , or less than 140 ppb /day , or less than 120 10175 ] The pH protective coating or layer can have a ppb / day , or less than 100 ppb / day , or less than 90 ppb / day , density between 1. 25 and 1. 65 g / cm ", alternatively between or less than 80 ppb /day . Optionally , in any embodiment of 1 . 35 and 1 . 55 g / cm², alternatively between 1 . 4 and 1 . 5 FIGS. 24 - 26 the silicon dissolution rate is more than 10 g / cm°, alternatively between 1 . 4 and 1 . 5 g / cm " , alternatively ppb /day , or more than 20 ppb / day, or more than 30 ppb /day , between 1 .44 and 1 . 48 g / cm ” , as determined by X - ray or more than 40 ppb /day , or more than 50 ppb /day , or more reflectivity ( XRR ) . Optionally , the organosilicon compound than 60 ppb /day . Any minimum rate stated here can be can be octamethylcyclotetrasiloxane and the pH protective combined with any maximum rate stated here for the pH coating or layer can have a density which can be higher than protective coating or layer 286 in any embodiment. US 2019 /0133882 A1 May 9 , 2019
[0182 ] Optionally , for the pH protective coating or layer [0189 ] Optionally , the calculated shelf life of the vessel 286 in any embodiment the total silicon content of the pH 210 ( total Si/ Si dissolution rate ) is more than 2 years . protective coating or layer and barrier coating , upon disso [0190 ] Optionally , the pH protective coating or layer 286 lution into a test composition with a pH of 8 from the vessel , shows an O - Parameter measured with attenuated total is less than 66 ppm , or less than 60 ppm , or less than 50 ppm , reflection ( ATR ) of less than 0. 4 , measured as: or less than 40 ppm , or less than 30 ppm , or less than 20 ppm . [0183 ] The pH protective coating or layer 286 has an Intensity at 1253 cm - 1 interior surface facing the lumen 212 and an outer surface O - Parameter = Maximum intensity in the range from 1000 to 1100 cm - 1 . facing the interior surface of the barrier coating or layer 288 . Optionally , the pH protective coating or layer 286 is at least [0191 ] The O -Parameter is defined in U . S . Pat . No . 8 , 067 , coextensive with the barrier coating or layer 288 . The pH 070 , which claims an O -parameter value of most broadly protective coating or layer 286 alternatively can be less from 0 . 4 to 0 . 9 . It can be measured from physical analysis extensive than the barrier coating , as when the fluid does not of an FTIR amplitude versus wave number plot to find the contact or seldom is in contact with certain parts of the numerator and denominator of the above expression , as barrier coating absent the pH protective coating or layer . The shown in FIG . 6 , which is the same as FIG . 5 of U . S . Pat . pH protective coating or layer 286 alternatively can be more No . 8 , 067, 070 , except annotated to show interpolation of the extensive than the barrier coating , as it can cover areas that wave number and absorbance scales to arrive at an absor are not provided with a barrier coating. bance at 1253 cm - 1 of 0 . 0424 and a maximum absorbance [ 0184 ] The pH protective coating or layer 286 optionally at 1000 to 1100 cm - 1 of 0 . 08 , resulting in a calculated can be applied by plasma enhanced chemical vapor depo O - parameter of 0 .53 . The O -Parameter can also be measured sition (PECVD ) of a precursor feed comprising an acyclic from digital wave number versus absorbance data . siloxane , a monocyclic siloxane , a polycyclic siloxane , a [0192 ] U . S . Pat. No. 8 ,067 ,070 asserts that the claimed polysilsesquioxane , a monocyclic silazane, a polycyclic O -parameter range provides a superior pH protective coating silazane , a polysilsesquiazane , a silatrane , a silquasilatrane , or layer , relying on experiments only with HMDSO and a silproatrane, an azasilatrane , an azasilquasiatrane , an HMDSN , which are both non -cyclic siloxanes. Surprisingly , azasilproatrane , or a combination of any two or more of it has been found by the present inventors that 0 - parameters these precursors . Some particular , non - limiting precursors outside the ranges claimed in U . S . Pat. No. 8 , 067, 070 contemplated for such use include octamethylcyclotetrasi provide even better results than are obtained in U . S . Pat. No . loxane (OMCTS ) . 8 , 067, 070 . Alternatively in the embodiment of FIGS . 1 - 5 , [ 0185 ] Optionally , an FTIR absorbance spectrum of the the O -parameter has a value of from 0 . 1 to 0 .39 , or from 0 . 15 pH protective coating or layer 286 has a ratio greater than to 0 . 37 , or from 0 . 17 to 0 . 35 . 0 .75 between the maximum amplitude of the Si — 0 — Si [0193 ] Optionally , the pH protective coating or layer symmetrical stretch peak between about 1000 and 1040 shows an N -Parameter measured with attenuated total cm - 1 , and the maximum amplitude of the Si - O _ Si assym reflection (ATR ) of less than 0 . 7 , measured as : metric stretch peak between about 1060 and about 1100 cm - . [0186 ] In the presence of a fluid composition having a pH Intensity at 840 cm - 1 between 5 and 9 contained in the lumen 212 , the calculated N - Parameter = Intensity at 799 cm - 1. shelf life of the vessel 210 is more than six months at a storage temperature of 4° C . Optionally, the rate of erosion [0194 ] The N - Parameter is also described in U . S . Pat. No. of the pH protective coating or layer 286 , if directly con 8 ,067 , 070 , and is measured analogously to the O -Parameter tacted by a fluid composition having a pH of 8 , is less than except that intensities at two specific wave numbers are 20 % optionally less than 15 % , optionally less than 10 % , used - neither of these wave numbers is a range . U . S . Pat. optionally less than 7 % , optionally from 5 % to 20 % , option No . 8 , 067 , 070 claims a passivation layer with an N -Param ally 5 % to 15 % , optionally 5 % to 10 % , optionally 5 % to 7 % , eter of 0 . 7 to 1 . 6 . Again , the present inventors have made of the rate of erosion of the barrier coating or layer 288 , if better coatings employing a pH protective coating or layer directly contacted by the same fluid composition under the 286 having an N - Parameter lower than 0 . 7 , as described same conditions. Optionally , the fluid composition removes above . Alternatively , the N - parameter has a value of at least the pH protective coating or layer 286 at a rate of 1 nm or 0 . 3 , or from 0 . 4 to 0 . 6 , or at least 0 .53 . less of pH protective coating or layer thickness per 44 hours [0195 ] The protective coating or layer of Si O _ C , or its of contact with the fluid composition . equivalent SiO C ,, also can have utility as a hydrophobic [0187 ] Optionally , the silicon dissolution rate of the pH layer, independent of whether it also functions as a pH protective coating or layer and barrier coating or layer by a protective coating or layer. Suitable hydrophobic coatings or 50 mM potassium phosphate buffer diluted in water for layers and their application , properties, and use are injection , adjusted to pH 8 with concentrated nitric acid , and described in U . S . Pat . No. 7 , 985 , 188 . Dual functional pro containing 0 . 2 wt. % polysorbate - 80 surfactant from the tective /hydrophobic coatings or layers having the properties vessel is less than 170 parts per billion (ppb )/ day . of both types of coatings or layers can be provided for any [0188 ] Optionally , the total silicon content of the pH embodiment of the present invention . protective coating or layer 286 and the barrier coating or layer 288, upon dissolution into 0 . 1 N potassium hydroxide Graded Composite Layer aqueous solution at 40° C . from the vessel, is less than 66 [0196 ] Another expedient contemplated here , for adjacent ppm . layers of SiOx and a pH protective coating or layer , is a US 2019 /0133882 A1 May 9 , 2019
graded composite of any two or more adjacent PECVD tive coating or layer can have a lower wetting tension than layers, for example the barrier coating or layer 288 and a pH the uncoated surface, optionally a wetting tension of from 20 protective coating or layer 286 and / or a lubricity coating or to 72 dyne/ cm , optionally from 30 to 60 dynes/ cm , option layer 281 . A graded composite can be separate layers of a ally from 30 to 40 dynes/ cm , optionally 34 dyne/ cm . Option protective and / or barrier layer or coating with a transition or ally , the pH protective coating or layer can be more hydro interface of intermediate composition between them , or phobic than the uncoated surface . separate layers of a protective and / or hydrophobic layer and SiO , with an intermediate distinct pH protective coating or Equipment layer of intermediate composition between them , or a single coating or layer that changes continuously or in steps from PECVD Apparatus for Forming PECVD Coating or Layer a composition of a protective and / or hydrophobic layer to a [0200 ) PECVD apparatus , a system and precursor mate composition more like SiOx , going through the primer rials suitable for applying any of the PECVD coatings or coating or layer in a normal direction . layers described in this specification , specifically including [0197 ] The grade in the graded composite can go in either the tie coating or layer 289 , the barrier coating or layer 288 , direction . For example , the composition of SiOx can be or the pH protective coating or layer 286 is described in applied directly to the substrate and graduate to a compo described in U .S . Pat . No . 7 , 985 , 188 , which is incorporated sition further from the surface of a primer coating or layer, by reference . and optionally can further graduate to another type of [0201 ] An overview of these conditions is provided in coating or layer , such as a hydrophobic coating or layer or FIG . 32 , which shows a vessel processing system adapted a lubricity coating or layer. Additionally , in any embodiment for making such a vessel. The vessels having walls 214 can an adhesion coating or layer , for example SiOX1 CV , or its be conveyed to a tie coater 302 , which is suitable apparatus equivalent SiO Cv, optionally can be applied directly to the for applying a tie coating or layer to the interior surface of substrate before applying the barrier layer. A graduated the wall, such as the PECVD apparatus described in U . S . primer coating or layer is particularly contemplated if a layer Pat. No. 7 , 985 , 188 . of one composition is better for adhering to the substrate [0202 ] The vessels can then be conveyed to a barrier than another , in which case the better -adhering composition coater 304 , which is suitable apparatus for applying a barrier can , for example, be applied directly to the substrate . It is coating or layer to the interior surface of the wall , such as the contemplated that the more distant portions of the graded PECVD apparatus described in U . S . Pat. No . 7 , 985 , 188 . primer coating or layer can be less compatible with the [0203 ] The vessels can then be conveyed to a pH protec substrate than the adjacent portions of the graded primer tive coater 306 , which is suitable apparatus for applying a coating or layer , since at any point the primer coating or pH protective coating or layer to the interior surface of the layer is changing gradually in properties , so adjacent por wall , such as the PECVD apparatus described in U . S . Pat . tions at nearly the same depth of the primer coating or layer No . 7 , 985 , 188 . This then completes the coating set . have nearly identical composition , and more widely physi [0204 ] Optionally , further steps can be carried out by the cally separated portions at substantially different depths can system . For example , the coated vessels can be conveyed to have more diverse properties. It is also contemplated that a a fluid filler 308 which places fluid from a fluid supply 310 primer coating or layer portion that forms a better barrier into the lumens of the coated vessels . against transfer of material to or from the substrate can be ?0205 ) For another example the filled vessels can be directly against the substrate , to prevent the more remote conveyed to a closure installer 312 , which takes closures, for primer coating or layer portion that forms a poorer barrier example plungers or stoppers , from a closure supply 314 and from being contaminated with the material intended to be seats them in the lumens of the coated vessels . barred or impeded by the barrier . [0206 ] In any embodiment of the invention , the tie coating [ 0198 ] The applied coatings or layers , instead of being or layer optionally can be applied by plasma enhanced graded , optionally can have sharp transitions between one chemical vapor deposition (PECVD ). layer and the next, without a substantial gradient of com [0207 ] In any embodiment of the invention , the barrier position . Such primer coating or layer can be made , for coating or layer optionally can be applied by PECVD . example , by providing the gases to produce a layer as a [ 0208 ] In any embodiment of the invention , the pH pro steady state flow in a non -plasma state , then energizing the tective coating or layer optionally can be applied by system with a brief plasma discharge to form a coating or PECVD . layer on the substrate . If a subsequent primer coating or [0209 ] In any embodiment of the invention , the vessel can layer is to be applied , the gases for the previous primer comprise or consist of a syringe barrel , a vial , cartridge or a coating or layer are cleared out and the gases for the next blister package . primer coating or layer are applied in a steady -state fashion [0210 ] Reaction conditions for forming the Sio , barrier before energizing the plasma and again forming a distinct layer are described in U .S . Pat . No . 7, 985 , 188 , which is layer on the surface of the substrate or its outermost previous incorporated by reference . primer coating or layer, with little if any gradual transition 0211 ] The tie or adhesion coating or layer can be pro at the interface . duced , for example , using as the precursor tetramethyldisi [019 ] An embodiment can be carried out under condi loxane ( TMDSO ) or hexamethyldisiloxane (HMDSO ) at a tions effective to form a hydrophobic pH protective coating flow rate of 0. 5 to 10 sccm , preferably 1 to 5 sccm ; oxygen or layer on the substrate . Optionally, the hydrophobic char flow of 0 . 25 to 5 sccm , preferably 0 .5 to 2 . 5 sccm ; and argon acteristics of the pH protective coating or layer can be set by flow of 1 to 120 sccm , preferably in the upper part of this setting the ratio of the O2 to the organosilicon precursor in range for a 1 mL syringe and the lower part of this range for the gaseous reactant, and /or by setting the electric power a 5 ml. vial . The overall pressure in the vessel during used for generating the plasma . Optionally , the pH protec PECVD can be from 0 .01 to 10 Torr, preferably from 0 . 1 to US 2019 /0133882 A1 May 9 , 2019
1 .5 Torr . The power level applied can be from 5 to 100 Watts , (0216 ) Alternatively, after formation of the SiO , barrier preferably in the upper part of this range for a 1 mL syringe coating or layer, the vacuum can be broken before dehydra and the lower part of this range for a 5 ml. vial. The tion / vaporization of the HMDZ . Dehydration / vaporization deposition time ( i. e . 14" on ” time for RF power ) is from 0 . 1 to of the HMDZ can then be carried out in either the same 10 seconds, preferably 1 to 3 seconds. The power cycle apparatus used for formation of the SiO , barrier coating or optionally can be ramped or steadily increased from 0 Watts layer or different apparatus . to full power over a short time period , such as 2 seconds , [0217 ] Dehydration / vaporization of HMDZ at an elevated when the power is turned on , which may improve the plasma temperature is also contemplated . The above process can uniformity . The ramp up of power over a period of time is alternatively be carried out at an elevated temperature optional, however. exceeding room temperature up to about 150° C . The [0212 ] The pH protective coating or layer 286 coating or maximum temperature is determined by the material from layer described in this specification can be applied in many which the coated part is constructed . An upper temperature different ways . For one example , the low - pressure PECVD should be selected that will not distort or otherwise damage process described in U . S . Pat. No . 7 , 985 , 188 can be used . the part being coated . For another example , instead of using low -pressure PECVD , [0218 ] Dehydration /vaporization of HMDZ with a plasma atmospheric PECVD can be employed to deposit the pH assist is also contemplated . After carrying out any of the protective coating or layer. For another example , the coating above embodiments of dehydration / vaporization , once the can be simply evaporated and allowed to deposit on the SiOx HMDZ vapor is admitted into the part, a plasma is gener layer to be protected . For another example , the coating can ated . The plasma power can range from a few watts to 100 + be sputtered on the SiO layer to be protected . For still watts (similar powers as used to deposit the SiOx) . The another example , the pH protective coating or layer 286 can above is not limited to HMDZ and could be applicable to be applied from a liquid medium used to rinse or wash the any molecule that will react with hydrogen , for example any Sio layer. of the nitrogen - containing precursors described in this speci [0213 ] Other precursors and methods can be used to apply fication . the pH protective coating or layer or passivating treatment. [0219 ] Another way of applying the pH protective coating For example , hexamethylene disilazane (HMDZ ) can be or layer is to apply as the pH protective coating or layer an used as the precursor. HMDZ has the advantage of contain amorphous carbon or fluorocarbon coating , or a combination ing no oxygen in its molecular structure. This passivation of the two. treatment is contemplated to be a surface treatment of the [0220 ] Amorphous carbon coatings can be formed by Sio barrier layer with HMDZ. To slow down and/ or elimi PECVD using a saturated hydrocarbon , ( e .g . methane or nate the decomposition of the silicon dioxide coatings at propane ) or an unsaturated hydrocarbon ( e . g . ethylene, silanol bonding sites, the coating must be passivated . It is acetylene ) as a precursor for plasma polymerization . Fluo contemplated that passivation of the surface with HMDZ rocarbon coatings can be derived from fluorocarbons (for ( and optionally application of a few mono layers of the example , hexafluoroethylene or tetrafluoroethylene ). Either HMDZ - derived coating ) will result in a toughening of the type of coating , or a combination of both , can be deposited surface against dissolution , resulting in reduced decompo by vacuum PECVD or atmospheric pressure PECVD . It is sition . It is contemplated that HMDZ will react with the contemplated that that an amorphous carbon and/ or fluoro OH sites that are present in the silicon dioxide coating, carbon coating will provide better passivation of an Sio resulting in the evolution of NH3 and bonding of barrier layer than a siloxane coating since an amorphous S - (CH3 ) 3 to the silicon ( it is contemplated that hydrogen carbon and / or fluorocarbon coating will not contain silanol atoms will be evolved and bond with nitrogen from the bonds. HMDZ to produce NH3) . [0221 ] It is further contemplated that fluorosilicon precur [0214 ] It is contemplated that this HMDZ passivation can sors can be used to provide a pH protective coating or layer be accomplished through several possible paths. over an SiO , barrier layer. This can be carried out by using [ 0215 ] One contemplated path is dehydration / vaporization as a precursor a fluorinated silane precursor such as of the HMDZ at ambient temperature . First , an SiO surface hexafluorosilane and a PECVD process. The resulting coat is deposited , for example using hexamethylene disiloxane ing would also be expected to be a non -wetting coating . (HMDSO ). The as - coated silicon dioxide surface is then [0222 ] It is further contemplated that any embodiment of reacted with HMDZ vapor. In an embodiment, as soon as the the pH protective coating or layer processes described in this SiOx surface is deposited onto the article of interest , the specification can also be carried out without using the article vacuum is maintained . The HMDSO and oxygen are to be coated to contain the plasma . For example, external pumped away and a base vacuum is achieved . Once base surfaces of medical articles , for example catheters, surgical vacuum is achieved , HMDZ vapor is flowed over the surface instruments , closures, and others can be protected or passi of the silicon dioxide (as coated on the part of interest ) at vated by sputtering the coating , employing a radio frequency pressures from the mTorr range to many Torr. The HMDZ is target. then pumped away (with the resulting NH3 that is a byprod [0223 ] Yet another coating modality contemplated for uct of the reaction ) . The amount of NH3 in the gas stream protecting or passivating an SiO , barrier layer is coating the can be monitored (with a residual gas analyzer — RGA as barrier layer using a polyamidoamine epichlorohydrin resin . an example ) and when there is no more NH3 detected , the For example , the barrier coated part can be dip coated in a reaction is complete . The part is then vented to atmosphere fluid polyamidoamine epichlorohydrin resin melt, solution (with a clean dry gas or nitrogen ). The resulting surface is or dispersion and cured by autoclaving or other heating at a then found to have been passivated . It is contemplated that temperature between 60 and 100° C . It is contemplated that this method optionally can be accomplished without form a coating of polyamidoamine epichlorohydrin resin can be ing a plasma . preferentially used in aqueous environments between pH US 2019 /0133882 A1 May 9 , 2019
5 - 8 , as such resins are known to provide high wet strength in paper in that pH range . Wet strength is the ability to PECVD Trilayer Process General Parameters Table ( 1 mL syring maintain mechanical strength of paper subjected to complete water soaking for extended periods of time, so it is contem Parameter Units Tie Barrier pH Protective plated that a coating of polyamidoamine epichlorohydrin Power W 40 - 90 140 40 - 90 resinon an Sio , barrier layer will have similar resistance to (60 - 80 ) (60 - 80 ) TMDSO Flow sccm 1 - 10 None 1 - 10 dissolution in aqueous media . It is also contemplated that, ( 3 - 5 ) ( 3 - 5 ) because polyamidoamine epichlorohydrin resin imparts a HMDSO Flow sccm None 1 . 56 None lubricity improvement to paper, it will also provide lubricity 0 Flow sccm 0 . 5 - 5 20 0 . 5 - 5 in the form of a coating on a thermoplastic surface made of , ( 1 . 5 - 2 . 5 ) ( 1 . 5 - 2 . 5 ) Argon Flow sccm 40 - 120 O 40 - 120 for example , COC or COP. ( 70 - 90 ) ( 70 - 90 ) [ 0224 ] Even another approach for protecting an SiO2 layer Ramp Time seconds None None None is to apply as a pH protective coating or layer a liquid Deposition seconds 0 . 1 - 10 20 0 . 1 - 40 applied coating of a polyfluoroalkyl ether, followed by Time ( 1 - 3 ) ( 15 - 25 ) atmospheric plasma curing the pH protective coating or Tube Pressure Torr 0 . 01 - 10 0 .59 0 .01 - 10 layer . For example , it is contemplated that the process ( 0 . 1 - 1 . 5 ) ( 0 . 1 - 1 . 5 ) practiced under the trademark TriboGlide® , described in this specification , can be used to provide a pH protective coating or layer that is also a lubricity layer , as TriboGlide® is conventionally used to provide lubricity . PECVD Trilayer Process General Parameters Table ( 5 mL vial) [ 0225 ] Exemplary PECVD reaction conditions for prepar Parameter Units Adhesion Barrier Protection ing a pH protective coating or layer 286 in a 3 ml sample size Power W 40 - 90 140 40 - 90 syringe with a 1/ 8 " diameter tube (open at the end ) are as (60 -80 ) (60 - 80 ) follows : TMDSO Flow sccm 1 - 10 None 1 - 10 ( 3 - 5 ) ( 3 - 5 ) [ 0226 ] For depositing a pH protective coating or layer, a HMDSO Flow sccm None 1 . 56 None precursor feed or process gas can be employed having a O2 Flow sccm 0 . 5 - 5 20 0 . 5 - 5 standard volume ratio of, for example : ( 1 . 5 - 2 . 5 ) ( 1 . 5 - 2 . 5 ) Argon Flow sccm 40 - 120 40 - 120 [0227 ] from 0 .5 to 10 standard volumes , optionally ( 70 - 90 ) ( 70 - 90 ) from 1 to 6 standard volumes , optionally from 2 to 4 Ramp Time seconds None None None standard volumes , optionally equal to or less than 6 Deposition Time seconds 0 . 1 - 10 20 0 . 1 - 40 standard volumes , optionally equal to or less than 2 . 5 ( 1 - 3 ) ( 15 - 25 ) standard volumes , optionally equal to or less than 1 . 5 Tube Pressure Torr 0 .01 - 10 0 . 59 0 .01 - 10 standard volumes, optionally equal to or less than 1. 25 (0 . 1- 1 .5 ) ( 0 . 1 - 1 . 5 ) standard volumes of the precursor, for example OMCTS or one of the other precursors of any embodi [0231 ] Examples of specific coating parameters that have ment ; been used for a 1 mL syringe and 5 mL vial are shown in the [0228 ] from 0 to 100 standard volumes , optionally from PECVD Trilayer Process Specific Parameters Tables ( 1 mL 1 to 200 standard volumes, optionally from 1 to 80 syringe and 5 mL vial ): standard volumes , optionally from 5 to 100 standard volumes, optionally from 10 to 70 standard volumes, of a carrier gas of any embodiment, for example argon . PECVD Trilayer Process [0229 ] from 0. 1 to 10 standard volumes, optionally Specific Parameters Table ( 1 mL syringe ) from 0 . 1 to 2 standard volumes, optionally from 0 . 2 to Parameter Units Tie Barrier Protection 1. 5 standard volumes, optionally from 0 . 2 to 1 standard Power W 70 140 70 volumes, optionally from 0 . 5 to 1 .5 standard volumes , TMDSO Flow sccm 4 None 4 . optionally from 0 . 8 to 1 .2 standard volumes of an HMDSO Flow sccm None 1 . 56 None oxidizing agent. O , Flow sccm 2 20 2 Argon Flow sccm 80 80 The power level can be , for example , from 0 .1 -500 watts . Ramp Time seconds None None None Deposition Time seconds 2 .5 20 10 Specific Flow rates and power levels contemplated include: Tube Pressure Torr 1 0 591. OMCTS : 2 .0 sccm Oxygen : 0 . 7 sccm Argon : 7 .0 sccm PECVD Trilayer Process Power : 3 .5 watts Specific Parameters Table ( 5 mL vial ) PECVD Process for Trilayer Coating Parameter Units Adhesion Barrier Protection Power 20 4 0 20 TMDSO sccm 200 [ 0230 ] Other general coating parameter ranges , with pre Flow ferred ranges in parentheses, for a trilayer coating for a 1 mL HMDSO sccmscem 0 3 0 syringe barrel are shown in the PECVD Trilayer Process Flow General Parameters Tables ( 1 mL syringe and 5 mL vial) . US 2019 /0133882 A1 May 9 , 2019 14
- continued is a blood collection tube . The tube can also contain an agent for preventing blood clotting or platelet activation , for PECVD Trilayer Process example EDTA or heparin . Specific Parameters Table ( 5 mL vial) [0238 ] Any of the above -described embodiments can be Parameter Units Adhesion Barrier Protection made , for example , by providing as the vessel a length of tubing from about 1 cm to about 200 cm , optionally from O2 Flow sccm 1 about 1 cm to about 150 cm , optionally from about 1 cm to Argon Flow sccm 20 20 Ramp Time seconds 0 about 120 cm , optionally from about 1 cm to about 100 cm , Deposition seconds 510102 . optionally from about 1 cm to about 80 cm , optionally from Time about 1 cm to about 60 cm , optionally from about 1 cm to Tube Torr 0 . 85 1 . 29 0 . 85 about 40 cm , optionally from about 1 cm to about 30 cm Pressure long , and processing it with a probe electrode as described below . Particularly for the longer lengths in the above [0232 ] The O -parameter and N -parameter values for the ranges , it is contemplated that relative motion between the pH protective coating or layer applied to the 1 mL syringe probe and the vessel can be useful during primer coating or as described above are 0 . 34 and 0 .55 , respectively . layer formation . This can be done , for example , by moving [0233 ] The O -parameter and N -parameter values for the the vessel with respect to the probe or moving the probe with pH protective coating or layer applied to the 5 mL vial are respect to the vessel . [02391 . In these embodiments, it is contemplated that the 0 . 24 and 0 .63 , respectively . barrier coating or layer can be thinner or less complete than would be preferred to provide the high gas barrier integrity Vessels Generally needed in an evacuated blood collection tube . In these [ 0234 ] Avessel with a primer coating or layer as described embodiments , it is contemplated that the primer coating or herein and /or prepared according to a method described layer can be thinner or less complete than would be preferred herein can be used for reception and /or storage and /or to provide the long shelf life needed to store a liquid material delivery of a compound or composition . The compound or in contact with the barrier layer for an extended period . composition can be sensitive , for example air - sensitive, 10240 ] As an optional feature of any of the foregoing oxygen -sensitive , sensitive to humidity and /or sensitive to embodiments the vessel has a central axis . mechanical influences. It can be a biologically active com [0241 ] As an optional feature of any of the foregoing pound or composition , for example a pharmaceutical prepa embodiments the vessel wall is sufficiently flexible to be ration or medicament like insulin or a composition compris flexed at least once at 20° C ., without breaking the wall, over ing insulin . In another aspect , it can be a biological fluid , a range from at least substantially straight to a bending optionally a bodily fluid , for example blood or a blood radius at the central axis of notmore than 100 times as great fraction . In certain aspects of the present invention , the as the outer diameter of the vessel. compound or composition can be a product to be adminis [0242 ] As an optional feature of any of the foregoing trated to a subject in need thereof, for example a product to embodiments the bending radius at the central axis is not be injected , like blood (as in transfusion of blood from a more than 90 times as great as , or not more than 80 times as donor to a recipient or reintroduction of blood from a patient great as , or not more than 70 times as great as , or not more back to the patient) or insulin . than 60 times as great as , or not more than 50 times as great [0235 ] Avessel with a primer coating or layer as described as, or not more than 40 times as great as , or not more than herein and /or prepared according to a method described 30 times as great as, or not more than 20 times as great as , herein can further be used for protecting a compound or or not more than 10 times as great as, or not more than 9 composition contained in its interior space against mechani times as great as , or not more than 8 times as great as , or not cal and /or chemical effects of the surface of the vessel more than 7 times as great as , or not more than 6 times as material. For example , it can be used for preventing or great as , or not more than 5 times as great as , or not more reducing precipitation and /or clotting or platelet activation than 4 times as great as, or not more than 3 times as great of the compound or a component of the composition , for as , or not more than 2 times as great as , or not more than , example insulin precipitation or blood clotting or platelet the outer diameter of the vessel. activation . [0243 ] As an optional feature of any of the foregoing [0236 ] It can further be used for protecting a compound or embodiments the vessel wall can be a fluid - contacting composition contained in its interior against the environment surface made of flexible material. outside of the pharmaceutical package or other vessel , for 10244 ] As an optional feature of any of the foregoing example by preventing or reducing the entry of one ormore embodiments the vessel lumen can be the fluid flow passage compounds from the environment surrounding the vessel of a pump. into the interior space of the vessel . Such environmental [0245 ] As an optional feature of any of the foregoing compound can be a gas or liquid , for example an atmo embodiments the vessel can be a blood bag adapted to spheric gas or liquid containing oxygen , air , and /or water maintain blood in good condition for medical use . vapor. [ 0246 ] As an optional feature of any of the foregoing [ 0237 ] Avessel with a primer coating or layer as described embodiments the polymeric material can be a silicone herein can also be evacuated and stored in an evacuated elastomer or a thermoplastic polyurethane , as two examples , state . For example, the primer coating or layer allows better or any material suitable for contact with blood , or with maintenance of the vacuum in comparison to a correspond insulin . ing vessel without a primer coating or layer. In one aspect of [0247 ] In an optional embodiment, the vessel has an inner this embodiment, the vessel with a primer coating or layer diameter of at least 2 mm , or at least 4 mm . US 2019 /0133882 A1 May 9 , 2019 15
[ 0248 ] As an optional feature of any of the foregoing layer protected by the plunger seal( s ) from the fluid 218 will embodiments the vessel is a tube . remain in place and further reduce the Fi experienced when [ 0249 ] As an optional feature of any of the foregoing the syringe is used . embodiments the lumen has at least two open ends . 10258 ] Optionally for any of the embodiments of FIGS . 1 -5 , the pH of the fluid 218 is between 5 and 6 and the Pharmaceutical Package thickness by TEM of the pH protective coating or layer 286 [0250 ] The vessel 210 illustrated most broadly by FIG . 1 is at least 80 nm at the end of the shelf life . Alternatively , the and FIG . 2 , is ontemplated for use as a pharmaceutical pH of the fluid 218 is between 6 and 7 and the thickness by package . TEM of the pH protective coating or layer 286 is at least 80 0251] FIGS . 1 - 5 illustrate several exemplary pharmaceu nm at the end of the shelf life . Alternatively , the pH of the tical packages or other vessels 210 including a wall 214 fluid 218 is between 7 and 8 and the thickness by TEM of enclosing a lumen 212 , a fluid 218 in the lumen 212 , and a the pH protective coating or layer 286 is at least 80 nm at the vessel coating or layer set 285 a barrier coating or layer 288 , end of the shelf life . Alternatively, the pH of the fluid 218 is and a pH protective coating or layer 286 . The fluid 218 is between 8 and 9 and the thickness by TEM of the pH contained in the lumen 212 . Optionally for any of the protective coating or layer 286 is at least 80 nm at the end embodiments of FIGS. 1 - 5 , the fluid 218 is an aqueous fluid of the shelf life . Alternatively , the pH of the fluid 218 is having a pH between 5 and 6 , optionally between 6 and 7 , between 5 and 6 and the thickness by TEM of the pH optionally between 7 and 8 , optionally between 8 and 9 , protective coating or layer 286 is at least 150 nm at the end optionally between 6 .5 and 7 .5 , optionally between 7 .5 and of the shelf life . Alternatively , the pH of the fluid 218 is 8 .5 , optionally between 8 .5 and 9 . Optionally , the pH between 6 and 7 and the thickness by TEM of the pH protective coating or layer 286 is effective to isolate a fluid protective coating or layer 286 is at least 150 nm at the end 218 from the barrier coating 288 . Optionally , the rate of of the shelf life . Alternatively , the pH of the fluid 218 is erosion of the pH protective coating or layer 286 , if directly between 7 and 8 and the thickness by TEM of the pH contacted by an aqueous fluid 218 having a pH between 5 protective coating or layer 286 is at least 150 nm at the end and 9 , is less than the rate of erosion of the barrier coating of the shelf life . Alternatively , the pH of the fluid 218 is 288 , if directly contacted by an aqueous fluid 218 having a between 8 and 9 and the thickness by TEM of the pH pH between 5 and 9 . Optionally for any of the embodiments protective coating or layer 286 is at least 150 nm at the end of FIGS . 1 - 5 , the pharmaceutical package 210 can have a of the shelf life. shelf life , after the pharmaceutical package 210 is [0259 ] Optionally for any of the embodiments of FIGS . assembled , of at least one year , alternatively at least two 1 - 5 , the fluid 218 removes the pH protective coating or layer years . 286 at a rate of 1 nm or less of pH protective coating or layer [ 0252 ] Optionally for any of the embodiments of FIGS. thickness per 44 hours of contact with the fluid 218 (200 nm 1 - 5 , the shelf life is measured at 3° C . , alternatively at 4° C . per year ), alternatively 1 nm or less of pH protective coating or higher, alternatively at 20° C . or higher , alternatively at or layer thickness per 88 hours of contact with the fluid 218 23° C ., alternatively at 40° C . ( 100 nm per year ) , alternatively 1 nm or less of pH protec [0253 ] Optionally for any of the embodiments of FIGS. tive coating or layer thickness per 175 hours of contact with 1 - 5 , the fluid 218 is a liquid at 20° C . and ambient pressure the fluid 218 ( 50 nm per year ) , alternatively 1 nm or less of at sea level , which is defined as a pressure of 760 mm Hg. pH protective coating or layer thickness per 250 hours of [0254 ] Optionally for any of the embodiments of FIGS . contact with the fluid 218 (35 nm per year ) , alternatively 1 1 -5 , the fluid 218 is an aqueous liquid . nm or less of pH protective coating or layer thickness per 102551 Optionally for any of the embodiments of FIGS . 350 hours of contact with the fluid 218 (25 nm per year ) . The 1 - 5 , the pH protective coating or layer 286 contacting the rate of removing the pH protective coating or layer can be fluid 218 is between 10 and 1000 nm thick , optionally determined by TEM from samples exposed to the fluid for between 50 and 500 nm thick , optionally between 100 and known periods. 400 nm thick , optionally between 150 and 300 nm thick two years after the pharmaceutical package 210 is assembled . [0260 ] Optionally , in any embodiment of FIGS. 24 - 26 the [0256 ] Referring to FIG . 19, the syringe such as 252 calculated shelf life of the package ( total Si/ Si dissolution optionally comprises a plunger 258 having a plunger tip rate ) is more than six months, or more than 1 year, or more inserted in the barrel 250 and a push rod . The plunger 258 than 18 months, or more than 2 years , or more than 21/ 2 optionally is provided with a lubricity layer, at least on its years , or more than 3 years , or more than 4 years , or more surface in contact with the barrel interior surface 264 . The than 5 years , or more than 10 years , or more than 20 years . lubricity coating or layer on the plunger tip is in the right Optionally , in any embodiment of FIGS . 24 - 26 the calcu position to prevent “ sticktion ” during storage and to con lated shelf life of the package ( total Si/ Si dissolution rate) is tinue to lower the friction between the plunger tip and barrel less than 60 years. when the plunger is advanced , and if applied by CVD is 10261 ] Any minimum time stated here can be combined contemplated to be less subject to displacement by the force with any maximum time stated here , as an alternative exerted by the plunger tip on the barrel than traditional embodiment of the invention of FIGS. 1 - 5 . silicon oil coatings or layers and more uniformly applied as [0262 ] Optionally for any of the embodiments of FIGS . a uniform coating rather than as isolated droplets of liquid . 1 - 5 , the fluid 218 comprises a member or a combination of [ 0257] Optionally , a hydrophilic further primer layer of two or more members selected from any of the materials SiO , can be applied on top of the primer coating or layer 286 recited below . As several examples , the fluid 218 can be a made of SiO C , or SiN Cy. Although the portions of this material selected from the group consisting of inhalation further primer layer exposed to the fluid 218 will erode , if anesthetics , injectable drugs , liquid drugs (non - injectable ) , the pH is high enough , the portions of this further primer drugs in a variety of classes, and diagnostic tests . US 2019 /0133882 A1 May 9 , 2019
[ 0263] Examples of suitable inhalation anesthetics to be Sodium Injection ) ; Botox Cosmetic (Onabotulinumtoxin A contained in the lumen 212 of FIGS. 1 and 2 include : for Injection ) ; BR3- FC ; Bravelle (Urofollitropin Injection ); Aliflurane ; Chloroform ; Cyclopropane; Desflurane (Su Bretylium (Bretylium Tosylate Injection ); Brevital Sodium prane ); Diethyl Ether; Enflurane ( Ethrane ) ; Ethyl Chloride ; (Methohexital Sodium for Injection ); Brethine ; Briobacept; Ethylene ; Halothane (Fluothane ); Isoflurane (Forane , Iso BTT- 1023 ; Bupivacaine HCl; Byetta ; Ca -DTPA (Pentetate flo ) ; Isopropenyl vinyl ether ; Methoxyflurane ; methoxyflu Calcium Trisodium Inj) ; Cabazitaxel Injection ( Jevtana ) ; rane ; Methoxypropane; Nitrous Oxide ; Roflurane ; Sevoflu Caffeine Alkaloid (Caffeine and Sodium Benzoate Injec rane (Sevorane , Ultane , Sevoflo ) ; Teflurane ; tion ) ; Calcijex Injection (Calcitrol ) ; Calcitrol (Calcijex Trichloroethylene; Vinyl Ether ; Xenon . Injection ); Calcium Chloride ( Calcium Chloride Injection [ 0264 ] Examples of suitable injectable drugs to be con 10 % ) ; Calcium Disodium Versenate ( Edetate Calcium Diso tained in the lumen 212 of FIGS . 1 and 2 include : Ablavar dium Injection ) ; Campath (Altemtuzumab ) ; Camptosar (Gadofosveset Trisodium Injection ) ; Abarelix Depot; Abo Injection ( Irinotecan Hydrochloride ) ; Canakinumab Injec botulinumtoxin A Injection (Dysport ) ; ABT- 263 ; ABT- 869; tion ( Ilaris ); Capastat Sulfate (Capreomycin for Injection ); ABX - EFG ; Accretropin (Somatropin Injection ); Acetadote Capreomycin for Injection ( Capastat Sulfate ); Cardiolite ( Acetylcysteine Injection ) ; Acetazolamide Injection ( Aceta (Prep kit for Technetium Tc99 Sestamibi for Injection ); zolamide Injection ); Acetylcysteine Injection (Acetadote ) ; Carticel; Cathflo ; Cefazolin and Dextrose for Injection (Ce Actemra ( Tocilizumab Injection ); Acthrel ( Corticorelin fazolin Injection ) ; Cefepime Hydrochloride ; Cefotaxime; Ovine Triflutate for Injection ) ; Actummune ; Activase ; Acy Ceftriaxone ; Cerezyme ; Carnitor Injection ; Caverject ; Cele clovir for Injection ( Zovirax Injection ) ; Adacel; Adalim stone Soluspan ; Celsior; Cerebyx ( Fosphenytoin Sodium umab ; Adenoscan (Adenosine Injection ); Adenosine Injec Injection ); Ceredase ( Alglucerase Injection ); Ceretec ( Tech tion ( Adenoscan ); Adrenaclick ; AdreView ( lobenguane 1 netium Tc99m Exametazime Injection ) ; Certolizumab ; 123 Injection for Intravenous Use ); Afluria ; Ak -Fluor (Fluo CF - 101; Chloramphenicol Sodium Succinate ( Chloram rescein Injection ); Aldurazyme (Laronidase ) ; Alglucerase phenicol Sodium Succinate Injection ); Chloramphenicol Injection (Ceredase ); Alkeran Injection (Melphalan Hel Sodium Succinate Injection (Chloramphenicol Sodium Suc Injection ); Allopurinol Sodium for Injection ( Aloprim ); cinate ) ; Cholestagel (Colesevelam HCL ) ; Choriogonadotro Aloprim ( Allopurinol Sodium for Injection ) ; Alprostadil ; pin Alfa Injection (Ovidrel ) ; Cimzia ; Cisplatin (Cisplatin Alsuma (Sumatriptan Injection ) ; ALTU - 238 ; Amino Acid Injection ) ; Clolar (Clofarabine Injection ) ; Clomiphine Cit Injections ; Aminosyn ; Apidra ; Apremilast ; Alprostadil Dual rate ; Clonidine Injection (Duraclon ) ; Cogentin (Benztropine Chamber System for Injection (Caverject Impulse ) ; AMG Mesylate Injection ) ; Colistimethate Injection (Coly -Mycin 009; AMG 076 ; AMG 102 ; AMG 108 ; AMG 114 ; AMG M ) ; Coly -Mycin M ( Colistimethate Injection ) ; Compath ; 162 ; AMG 220 ; AMG 221 ; AMG 222; AMG 223 ; AMG Conivaptan Hcl Injection (Vaprisol ) ; Conjugated Estrogens 317 ; AMG 379 ; AMG 386 ; AMG 403 ; AMG 477 ; AMG for Injection ( Premarin Injection ) ; Copaxone ; Corticorelin 479 ; AMG 517 ; AMG 531 ; AMG 557 ; AMG 623 ; AMG Ovine Triflutate for Injection (Acthrel ) ; Corvert ( Ibutilide 655 ; AMG 706 ; AMG 714 ; AMG 745 ; AMG 785 ; AMG Fumarate Injection ); Cubicin (Daptomycin Injection ) ; 811 ; AMG 827 ; AMG 837 ; AMG 853 ; AMG 951; Amio CF - 101; Cyanokit (Hydroxocobalamin for Injection ) ; Cyt darone HCl Injection ( Amiodarone HCl Injection ); Amo arabine Liposome Injection (DepoCyt ) ; Cyanocobalamin ; barbital Sodium Injection ( Amytal Sodium ) ; Amytal Cytovene ( ganciclovir ) ; D . H . E . 45 ; Dacetuzumab ; Dacogen Sodium ( Amobarbital Sodium Injection ) ; Anakinra ; Anti (Decitabine Injection ) ; Dalteparin ; Dantrium IV (Dantrolene Abeta ; Anti -Beta7 ; Anti -Beta20 ; Anti -CD4 ; Anti -CD20 ; Sodium for Injection ); Dantrolene Sodium for Injection Anti - CD40 ; Anti -IFNalpha ; Anti - IL13 ; Anti- OX40L ; Anti (Dantrium IV ); Daptomycin Injection (Cubicin ); Darbepoi oxLDS ; Anti -NGF ; Anti -NRP1 ; Arixtra ; Amphadase (Hy etin Alfa ; DDAVP Injection (Desmopressin Acetate Injec aluronidase Inj) ; Ammonul (Sodium Phenylacetate and tion ) ; Decavax ; Decitabine Injection (Dacogen ) ; Dehydrated Sodium Benzoate Injection ) ; Anaprox ; Anzemet Injection Alcohol (Dehydrated Alcohol Injection ) ; Denosumab Injec (Dolasetron Mesylate Injection ) ; Apidra (Insulin Glulisine tion (Prolia ) ; Delatestryl; Delestrogen ; Delteparin Sodium ; [rDNA origin ] Inj) ; Apomab ; Aranesp (darbepoetin alfa ) ; Depacon ( Valproate Sodium Injection ); Depo Medrol Argatroban (Argatroban Injection ); Arginine Hydrochloride (Methylprednisolone Acetate Injectable Suspension ) ; Depo Injection (R -Gene 10 ) ; Aristocort ; Aristospan ; Arsenic Tri Cyt (Cytarabine Liposome Injection ); DepoDur (Morphine oxide Injection ( Trisenox ) ; Articane HCl and Epinephrine Sulfate XR Liposome Injection ) ; Desmopressin Acetate Injection ( Septocaine ); Arzerra (Ofatumumab Injection ) ; Injection (DDAVP Injection ) ; Depo - Estradiol; Depo - Pro Asclera (Polidocanol Injection ) ; Ataluren ; Ataluren - DMD ; vera 104 mg/ ml ; Depo - Provera 150 mg/ ml ; Depo - Testoster Atenolol Inj ( Tenormin I . V . Injection ); Atracurium Besylate one ; Dexrazoxane for Injection , Intravenous Infusion Only Injection ( Atracurium Besylate Injection ) ; Avastin ; Azactam ( Totect ) ; Dextrose / Electrolytes ; Dextrose and Sodium Chlo Injection ( Aztreonam Injection ); Azithromycin (Zithromax ride Inj ( Dextrose 5 % in 0 . 9 % Sodium Chloride ) ; Dextrose ; Injection ) ; Aztreonam Injection (Azactam Injection ) ; Diazepam Injection (Diazepam Injection ); Digoxin Injection Baclofen Injection (Lioresal Intrathecal) ; Bacteriostatic (Lanoxin Injection ) ; Dilaudid - HP (Hydromorphone Hydro Water (Bacteriostatic Water for Injection ) ; Baclofen Injec chloride Injection ) ; Dimercarprol Injection (Bal in Oil tion (Lioresal Intrathecal) ; Bal in Oil Ampules (Dimercar Ampules ) ; Diphenhydramine Injection ( Benadryl Injection ) ; prol Injection ) ; BayHepB ; Bay Tet; Benadryl ; Bendamustine Dipyridamole Injection (Dipyridamole Injection ) ; Hydrochloride Injection ( Treanda ) ; Benztropine Mesylate DMOAD ; Docetaxel for Injection ( Taxotere ); Dolasetron Injection (Cogentin ) ; Betamethasone Injectable Suspension Mesylate Injection (Anzemet Injection ); Doribax (Dorip (Celestone Soluspan ) ; Bexxar; Bicillin C - R 900 /300 (Peni enem for Injection ) ; Doripenem for Injection (Doribax ) ; cillin G Benzathine and Penicillin G Procaine Injection ) ; Doxercalciferol Injection (Hectorol Injection ) ; Doxil (Doxo Blenoxane (Bleomycin Sulfate Injection ) ; Bleomycin Sul rubicin Hcl Liposome Injection ) ; Doxorubicin Hcl Lipo fate Injection (Blenoxane ); Boniva Injection ( Ibandronate some Injection ( Doxil ) ; Duraclon ( Clonidine Injection ) ; US 2019 /0133882 A1 May 9 , 2019 17
Duramorph (Morphine Injection ) ; Dysport (Abobotulinum Injection ); Iprivask ; Irinotecan Hydrochloride (Camptosar toxin A Injection ); Ecallantide Injection (Kalbitor ) ; EC Injection ) ; Iron Sucrose Injection ( Venofer) ; Istodax (Ro Naprosyn (naproxen ); Edetate Calcium Disodium Injection midepsin for Injection ); Itraconazole Injection (Sporanox ( Calcium Disodium Versenate ) ; Edex (Alprostadil for Injec Injection ) ; Jevtana ( Cabazitaxel Injection ) ; Jonexa ; Kalbitor tion ) ; Engerix ; Edrophonium Injection (Enlon ); Eliglustat ( Ecallantide Injection ) ; KCL in D5NS ( Potassium Chloride Tartate ; Eloxatin (Oxaliplatin Injection ); Emend Injection in 5 % Dextrose and Sodium Chloride Injection ) ; KCL in ( Fosaprepitant Dimeglumine Injection ); Enalaprilat Injec D5W ; KCL in NS ; Kenalog 10 Injection ( Triamcinolone tion ( Enalaprilat Injection ) ; Enlon ( Edrophonium Injection ) ; Acetonide Injectable Suspension ); Kepivance (Palifermin ) ; Enoxaparin Sodium Injection (Lovenox ) ; Eovist (Gadox Keppra Injection (Levetiracetam ); Keratinocyte; KFG ; etate Disodium Injection ) ; Enbrel ( etanercept) ; Enoxaparin ; Kinase Inhibitor ; Kineret (Anakinra ) ; Kinlytic (Urokinase Epicel ; Epinepherine ; Epipen ; Epipen Jr. ; Epratuzumab ; Injection ); Kinrix ; Klonopin (clonazepam ); Kytril Injection Erbitux ; Ertapenem Injection ( Invanz ) ; Erythropoieten ; (Granisetron Hydrochloride ) ; lacosamide Tablet and Injec Essential Amino Acid Injection (Nephramine ) ; Estradiol tion (Vimpat ) ; Lactated Ringer’ s ; Lanoxin Injection Cypionate ; Estradiol Valerate ; Etanercept; Exenatide Injec (Digoxin Injection ) ; Lansoprazole for Injection ( Prevacid tion (Byetta ) ; Evlotra ; Fabrazyme (Adalsidase beta ); Famo I . V .) ; Lantus; Leucovorin Calcium (Leucovorin Calcium tidine Injection ; FDG ( Fludeoxyglucose F 18 Injection ) ; Injection ) ; Lente ( L ) ; Leptin ; Levemir ; Leukine Sargra Feraheme (Ferumoxytol Injection ); Feridex I . V . (Ferumox mostim ; Leuprolide Acetate ; Levothyroxine; Levetiracetam ides Injectable Solution ) ; Fertinex ; Ferumoxides Injectable (Keppra Injection ) ; Lovenox ; Levocarnitine Injection (Car Solution (Feridex I. V . ) ; Ferumoxytol Injection (Feraheme ) ; nitor Injection ) ; Lexiscan (Regadenoson Injection ) ; Lioresal Flagyl Injection (Metronidazole Injection ); Fluarix ; Fludara Intrathecal (Baclofen Injection ); Liraglutide [rDNA ] Injec ( Fludarabine Phosphate ) ; Fludeoxyglucose F 18 Injection tion (Victoza ) ; Lovenox (Enoxaparin Sodium Injection ) ; (FDG ) ; Fluorescein Injection ( Ak - Fluor ) ; Follistim AQ Car Lucentis (Ranibizumab Injection ); Lumizyme; Lupron tridge ( Follitropin Beta Injection ) ; Follitropin Alfa Injection (Leuprolide Acetate Injection ) ; Lusedra (Fospropofol Diso (Gonal - f RFF ) ; Follitropin Beta Injection ( Follistim AO dium Injection ) ; Maci ; Magnesium Sulfate (Magnesium Cartridge ); Folotyn ( Pralatrexate Solution for Intravenous Sulfate Injection ) ; Mannitol Injection (Mannitol IV ) ; Mar Injection ) ; Fondaparinux ; Forteo ( Teriparatide ( rDNA ori caine (Bupivacaine Hydrochloride and Epinephrine Injec gin ) Injection ) ; Fostamatinib ; Fosaprepitant Dimeglumine tion ) ; Maxipime (Cefepime Hydrochloride for Injection ) ; Injection (Emend Injection ); Foscarnet Sodium Injection MDP Multidose Kit of Technetium Injection ( Technetium ( Foscavir ) ; Foscavir (Foscarnet Sodium Injection ) ; Fosphe Tc99m Medronate Injection ) ; Mecasermin frDNA origin ] nytoin Sodium Injection ( Cerebyx ); Fospropofol Disodium Injection ( Increlex ) ; Mecasermin Rinfabate [ rDNA origin ] Injection (Lusedra ) ; Fragmin ; Fuzeon ( enfuvirtide ) ; GA101 ; Injection ( Iplex ); Melphalan Hel Injection ( Alkeran Injec Gadobenate Dimeglumine Injection (Multihance ) ; Gadofos tion ) ; Methotrexate ; Menactra ; Menopur Menotropins( veset Trisodium Injection ( Ablavar ) ; Gadoteridol Injection Injection ); Menotropins for Injection (Repronex ) ; Metho Solution (ProHance ); Gadoversetamide Injection (Opti hexital Sodium for Injection (Brevital Sodium ) ; Methyldo MARK ) ;Gadoxetate Disodium Injection ( Eovist ); Ganirelix pate Hydrochloride Injection , Solution (Methyldopate Hcl) ; (Ganirelix Acetate Injection ) ; Gardasil ; GC1008 ; GDFD ; Methylene Blue (Methylene Blue Injection ) ; Methylpredni Gemtuzumab Ozogamicin for Injection (Mylotarg ); Geno solone Acetate Injectable Suspension (Depo Medrol) ; Met tropin ; Gentamicin Injection ; GENZ - 112638 ; Golimumab Mab ; Metoclopramide Injection (Reglan Injection ) ; Injection (Simponi Injection ) ; Gonal- f RFF ( Follitropin Alfa Metrodin (Urofollitropin for Injection ) ; Metronidazole Injection ) ; Granisetron Hydrochloride (Kytril Injection ) ; Injection (Flagyl Injection ); Miacalcin ; Midazolam (Mida Gentamicin Sulfate ; Glatiramer Acetate ; Glucagen ; Gluca zolam Injection ) ; Mimpara (Cinacalet ); Minocin Injection gon ; HAE1 ; Haldol ( Haloperidol Injection ) ; Havrix ; Hec (Minocycline Inj) ; Minocycline Inj (Minocin Injection ) ; torol Injection (Doxercalciferol Injection ) ; Hedgehog Path Mipomersen ; Mitoxantrone for Injection Concentrate (No way Inhibitor ; Heparin ; Herceptin ; hG -CSF ; Humalog ; vantrone ) ; Morphine Injection (Duramorph ) ; Morphine Sul Human Growth Hormone ; Humatrope; HuMax ; Humegon ; fate XR Liposome Injection (DepoDur ) ; Morrhuate Sodium Humira ; Humulin ; Ibandronate Sodium Injection (Boniva (Morrhuate Sodium Injection ) ; Motesanib ; Mozobil Injection ); Ibuprofen Lysine Injection (NeoProfen ); Ibutilide ( Plerixafor Injection ); Multihance (Gadobenate Dimeglu Fumarate Injection ( Corvert) ; Idamycin PFS ( Idarubicin mine Injection ); Multiple Electrolytes and Dextrose Injec Hydrochloride Injection ) ; Idarubicin Hydrochloride Injec tion ; Multiple Electrolytes Injection ; Mylotarg (Gemtu tion ( Idamycin PFS ); Ilaris ( Canakinumab Injection ); Imi zumab Ozogamicin for Injection ) ;Myozyme ( Alglucosidase penem and Cilastatin for Injection ( Primaxin I . V . ) ; Imitrex ; alfa ); Nafcillin Injection (Nafcillin Sodium ) ; Nafcillin Incobotulinumtoxin A for Injection (Xeomin ) ; Increlex (Me Sodium (Nafcillin Injection ) ; Naltrexone XR Inj (Vivitrol ) ; casermin [rDNA origin ] Injection ) ; Indocin IV ( Indometha Naprosyn ( naproxen ) ; NeoProfen (Ibuprofen Lysine Injec cin Inj ) ; Indomethacin Inj ( Indocin IV ) ; Infanrix : Innohep ; tion ) ; Nandrol Decanoate ; Neostigmine Methylsulfate (Neo Insulin ; Insulin Aspart [rDNA origin ] Inj (NovoLog ); Insulin stigmine Methylsulfate Injection ) ; NEO -GAA ; NeoTect Glargine [rDNA origin ] Injection (Lantus ) ; Insulin Glulisine ( Technetium Tc 99m Depreotide Injection ) ; Nephramine [rDNA origin ] Inj ( Apidra ) ; Interferon alfa - 2b , Recombinant (Essential Amino Acid Injection ) ; Neulasta (pegfilgrastim ); for Injection ( Intron A ) ; Intron A (Interferon alfa - 2b , Recom Neupogen (Filgrastim ) ; Novolin ; Novolog ; NeoRecormon ; binant for Injection ); Invanz (Ertapenem Injection ); Invega Neutrexin ( Trimetrexate Glucuronate Inj ); NPH (N ); Nex Sustenna (Paliperidone Palmitate Extended -Release Inject terone ( Amiodarone HCl Injection ) ; Norditropin ( Somatro able Suspension ) ; Invirase (saquinavir mesylate ); loben pin Injection ); Normal Saline (Sodium Chloride Injection ); guane 1123 Injection for Intravenous Use ( AdreView ) ; Novantrone (Mitoxantrone for Injection Concentrate ) ; Iopromide Injection (Ultravist ); Ioversol Injection (Optiray Novolin 70 / 30 Innolet ( 70 % NPH , Human Insulin Isophane Injection ); Iplex (Mecasermin Rinfabate [ rDNA origin ] Suspension and 30 % Regular , Human Insulin Injection ); US 2019 /0133882 A1 May 9 , 2019
NovoLog ( Insulin Aspart [ rDNA origin ] Inj) ; Nplate ( romi gin ) Injection ) ; Simponi Injection (Golimumab Injection ) ; plostim ) ; Nutropin (Somatropin (rDNA origin ) for Inj) ; Sodium Acetate (Sodium Acetate Injection ); Sodium Bicar Nutropin AQ ; Nutropin Depot (Somatropin (rDNA origin ) bonate (Sodium Bicarbonate 5 % Injection ) ; Sodium Lactate for Inj) ; Octreotide Acetate Injection (Sandostatin LAR ); (Sodium Lactate Injection in AVIVA ) ; Sodium Phenylac Ocrelizumab ; Ofatumumab Injection ( Arzerra ) ; Olanzapine etate and Sodium Benzoate Injection ( Ammonul) ; Somatro Extended Release Injectable Suspension (Zyprexa Rel pin ( rDNA origin ) for Inj (Nutropin ) ; Sporanox Injection prevv ) ; Omnitarg ; Omnitrope (Somatropin [ rDNA origin ] ( Itraconazole Injection ); Stelara Injection (Ustekinumab ); Injection ) ; Ondansetron Hydrochloride Injection (Zofran Stemgen ; Sufenta (Sufentanil Citrate Injection ); Sufentanil Injection ); OptiMARK (Gadoversetamide Injection ); Opti Citrate Injection ( Sufenta ) ; Sumavel; Sumatriptan Injection ray Injection (Ioversol Injection ); Orencia ; Osmitrol Injec ( Alsuma ); Symlin ; Symlin Pen ; Systemic Hedgehog tion in Aviva (Mannitol Injection in Aviva Plastic Vessel) ; Antagonist ; Synvisc -One (Hylan G - F 20 Single Intra - articu Osmitrol Injection in Viaflex (Mannitol Injection in Viaflex lar Injection ) ; Tarceva ; Taxotere (Docetaxel for Injection ) ; Plastic Vessel) ; Osteoprotegrin ; Ovidrel ( Choriogonadotro Technetium Tc 99m ; Telavancin for Injection (Vibativ ); pin Alfa Injection ); Oxacillin (Oxacillin for Injection ) ; Oxa Temsirolimus Injection ( Torisel) ; Tenormin I . V . Injection liplatin Injection (Eloxatin ); Oxytocin Injection (Pitocin ); ( Atenolol Inj) ; Teriparatide ( rDNA origin ) Injection (For Paliperidone Palmitate Extended - Release Injectable Sus teo ) ; Testosterone Cypionate ; Testosterone Enanthate ; Tes pension ( Invega Sustenna ); Pamidronate Disodium Injection tosterone Propionate ; Tev - Tropin ( Somatropin , rDNA Ori ( Pamidronate Disodium Injection ) ; Panitumumab Injection gin , for Injection ) ; tgAAC94 ; Thallous Chloride ; for Intravenous Use (Vectibix ) ; Papaverine Hydrochloride Theophylline ; Thiotepa ( Thiotepa Injection ) ; Thymoglobu Injection (Papaverine Injection ); Papaverine Injection (Pa lin (Anti - Thymocyte Globulin (Rabbit ); Thyrogen ( Thy paverine Hydrochloride Injection ) ; Parathyroid Hormone ; rotropin Alfa for Injection ); Ticarcillin Disodium and Cla Paricalcitol Injection Fliptop Vial (Zemplar Injection ); vulanate Potassium Galaxy ( Timentin Injection ) ; Tigan PARP Inhibitor; Pediarix ; PEGIntron ; Peginterferon ; Pegfil Injection ( Trimethobenzamide Hydrochloride Injectable ); grastim ; Penicillin G Benzathine and Penicillin G Procaine ; Timentin Injection ( Ticarcillin Disodium and Clavulanate Pentetate Calcium Trisodium Inj (Ca -DTPA ); Pentetate Zinc Potassium Galaxy ) ; TNKase ; Tobramycin Injection ( To Trisodium Injection ( Zn -DTPA ) ; Pepcid Injection ( Famoti bramycin Injection ) ; Tocilizumab Injection ( Actemra ) ; Tori dine Injection ) ; Pergonal ; Pertuzumab ; Phentolamine Mesy sel ( Temsirolimus Injection ) ; Totect (Dexrazoxane for Injec late (Phentolamine Mesylate for Injection ) ; Physostigmine tion , Intravenous Infusion Only ) ; Trastuzumab - DM1; Salicylate (Physostigmine Salicylate ( injection ) ); Physostig Travasol ( Amino Acids ( Injection ) ) ; Treanda ( Bendamustine mine Salicylate ( injection ) ( Physostigmine Salicylate ) ; Pip Hydrochloride Injection ) ; Trelstar ( Triptorelin Pamoate for eracillin and Tazobactam Injection (Zosyn ) ; Pitocin ( Oxy Injectable Suspension ) ; Triamcinolone Acetonide ; Triamci tocin Injection ) ; Plasma- Lyte 148 (Multiple Electrolytes nolone Diacetate ; Triamcinolone Hexacetonide Injectable Inj) ; Plasma- Lyte 56 and Dextrose (Multiple Electrolytes Suspension ( Aristospan Injection 20 mg) ; Triesence ( Triam and Dextrose Injection in Viaflex Plastic Vessel) ; Plasma cinolone Acetonide Injectable Suspension ) ; Trimethobenz Lyte ; Plerixafor Injection (Mozobil ) ; Polidocanol Injection amide Hydrochloride Injectable ( Tigan Injection ) ; Trime ( Asclera ) ; Potassium Chloride ; Pralatrexate Solution for trexate Glucuronate Inj (Neutrexin ); Triptorelin Pamoate for Intravenous Injection (Folotyn ) ; Pramlintide Acetate Injec Injectable Suspension ( Trelstar ); Twinject; Trivaris ( Triam tion (Symlin ) ; Premarin Injection (Conjugated Estrogens for cinolone Acetonide Injectable Suspension ) ; Trisenox ( Arse Injection ); Prep kit for Technetium Tc99 Sestamibi for nic Trioxide Injection ) ; Twinrix ; Typhoid Vi; Ultravist ( Io Injection (Cardiolite ) ; Prevacid I . V . (Lansoprazole for Injec promide Injection ); Urofollitropin for Injection (Metrodin ); tion ) ; Primaxin I . V . ( Imipenem and Cilastatin for Injection ) ; Urokinase Injection (Kinlytic ) ; Ustekinumab (Stelara Injec Prochymal; Procrit ; Progesterone; ProHance (Gadoteridol tion ) ; Ultralente ( U ) ; Valium ( diazepam ) ; Valproate Sodium Injection Solution ); Prolia (Denosumab Injection ); Promet Injection (Depacon ) ; Valtropin ( Somatropin Injection ) ; Van hazine HC1 Injection (Promethazine Hydrochloride Injec comycin Hydrochloride ( Vancomycin Hydrochloride Injec tion ); Propranolol Hydrochloride Injection ( Propranolol tion ) ; Vancomycin Hydrochloride Injection (Vancomycin Hydrochloride Injection ) ; Quinidine Gluconate Injection Hydrochloride ) ; Vaprisol (Conivaptan Hel Injection ) ; (Quinidine Injection ) ; Quinidine Injection (Quinidine Glu VAQTA ; Vasovist (Gadofosveset Trisodium Injection for conate Injection ) ; R -Gene 10 ( Arginine Hydrochloride Intravenous Use ) ; Vectibix (Panitumumab Injection for Injection ) ; Ranibizumab Injection (Lucentis ) ; Ranitidine Intravenous Use ) ; Venofer ( Iron Sucrose Injection ); Verte Hydrochloride Injection ( Zantac Injection ); Raptiva ; Reclast porfin Inj ( Visudyne ) ; Vibativ ( Telavancin for Injection ) ; ( Zoledronic Acid Injection ) ; Recombivarix HB ; Regadeno Victoza (Liraglutide [ rDNA ] Injection ) ; Vimpat ( lacosamide son Injection (Lexiscan ) ; Reglan Injection (Metoclopramide Tablet and Injection ) ; Vinblastine Sulfate ( Vinblastine Sul Injection ) ; Remicade; Renagel ; Renvela (Sevelamer Car fate Injection ) ; Vincasar PFS ( Vincristine Sulfate Injection ) ; bonate ) ; Repronex (Menotropins for Injection ) ; Retrovir IV Victoza ; Vincristine Sulfate (Vincristine Sulfate Injection ) ; ( Zidovudine Injection ); rhApo2L / TRAIL ; Ringer 's and 5 % Visudyne ( Verteporfin Inj) ; Vitamin B - 12 ; Vivitrol (Naltrex Dextrose Injection (Ringers in Dextrose ) ; Ringer ' s Injection one XR Inj) ; Voluven (Hydroxyethyl Starch in Sodium ( Ringers Injection ); Rituxan ; Rituximab ; Rocephin ( ceftri Chloride Injection ) ; Xeloda ; Xenical (orlistat ) ; Xeomin ( In axone ) ; Rocuronium Bromide Injection ( Zemuron ) ; Rof cobotulinumtoxin A for Injection ) ; Xolair ; Zantac Injection eron - A ( interferon alfa - 2a ) ; Romazicon ( flumazenil ) ; (Ranitidine Hydrochloride Injection ); Zemplar Injection Romidepsin for Injection ( Istodax ) ; Saizen (Somatropin (Paricalcitol Injection Fliptop Vial ); Zemuron (Rocuronium Injection ) ; Sandostatin LAR (Octreotide Acetate Injection ) ; Bromide Injection ) ; Zenapax ( daclizumab ); Zevalin ; Zido Sclerostin Ab ; Sensipar ( cinacalcet) ; Sensorcaine ( Bupiva vudine Injection (Retrovir IV ) ; Zithromax Injection caine HCl Injections ) ; Septocaine ( Articane HCl and Epi ( Azithromycin ) ; Zn -DTPA (Pentetate Zinc Trisodium Injec nephrine Injection ); Serostim LQ ( Somatropin (rDNA ori tion ) ; Zof ran Injection (Ondansetron Hydrochloride Injec US 2019 /0133882 A1 May 9 , 2019 tion ) ; Zingo ; Zoledronic Acid for Inj (Zometa ) ; Zoledronic Oral Solution ); Eurax ; Extraneal ( Icodextrin Peritoneal Acid Injection (Reclast ) ; Zometa (Zoledronic Acid for Inj) ; Dialysis Solution ); Felbatol; Feridex I. V . (Ferumoxides Zosyn (Piperacillin and Tazobactam Injection ) ; Zyprexa Injectable Solution ) ; Flovent; Floxin Otic (Ofloxacin Otic Relprevv (Olanzapine Extended Release Injectable Suspen Solution ); Flo - Pred (Prednisolone Acetate Oral Suspension ); sion ). Fluoroplex ; Flunisolide Nasal Solution ( Flunisolide Nasal [ 0265 ] Examples of suitable liquid drugs ( non - injectable ) Spray 0 .025 % ); Fluorometholone Ophthalmic Suspension to be contained in the lumen 212 of FIGS. 1 and 2 include : (FML ) ; Flurbiprofen Sodium Ophthalmic Solution Abilify ; AccuNeb (Albuterol Sulfate Inhalation Solution ) ; (Ocufen ) ; FML; Foradil ; Formoterol Fumarate Inhalation Actidose Aqua ( Activated Charcoal Suspension ) ; Activated Solution ( Perforomist ) ; Fosamax ; Furadantin (Nitrofuran Charcoal Suspension (Actidose Aqua ); Advair ; Agenerase toin Oral Suspension ) ; Furoxone ; Gammagard Liquid ( Im Oral Solution ( Amprenavir Oral Solution ) ; Akten (Lido mune Globulin Intravenous (Human ) 10 % ) ; Gantrisin caine Hydrochloride Ophthalmic Gel) ; Alamast (Pemirolast (Acetyl Sulfisoxazole Pediatric Suspension ) ; Gatifloxacin Potassium Ophthalmic Solution ); Albumin (Human ) 5 % Ophthalmic Solution (Zymar ) ; Gengraf Oral Solution (Cy Solution (Buminate 5 % ) ; Albuterol Sulfate Inhalation Solu closporine Oral Solution ); Glycopyrrolate Oral Solution tion ; Alinia ; Alocril ; Alphagan ; Alrex ; Alvesco ; Amprenavir (Cuvposa ) ; Halcinonide Topical Solution (Halog Solution ) ; Oral Solution ; Analpram -HC ; Arformoterol Tartrate Inhala Halog Solution (Halcinonide Topical Solution ); HEP -LOCK tion Solution (Brovana ) ; Aristospan Injection 20 mg ( Tri U / P (Preservative - Free Heparin Lock Flush Solution ) ; amcinolone Hexacetonide Injectable Suspension ) ; Asacol; Heparin Lock Flush Solution (Hepflush 10 ) ; Hexaminole Asmanex ; Astepro ; Astepro (Azelastine Hydrochloride vulinate Hydrochloride Intravesical Solution (Cysview ) ; Nasal Spray ) ; Atrovent Nasal Spray ( Ipratropium Bromide Hydrocodone Bitartrate and Acetaminophen Oral Solution Nasal Spray ) ; Atrovent Nasal Spray 0 . 06 ; Augmentin (Lortab Elixir ) ; Hydroquinone 3 % Topical Solution ES -600 ; Azasite ( Azithromycin Ophthalmic Solution ) ; Aze (Melquin - 3 Topical Solution ); IAP Antagonist; Isopto ; Ipra laic Acid (Finacea Gel) ; Azelastine Hydrochloride Nasalasd tropium Bromide Nasal Spray ( Atrovent Nasal Spray ) ; Itra Spray ( Astepro ) ; Azelex (Azelaic Acid Cream ) ; Azopt ( Brin conazole Oral Solution (Sporanox Oral Solution ); Ketorolac zolamide Ophthalmic Suspension ) ; Bacteriostatic Saline ; Tromethamine Ophthalmic Solution ( Acular LS ) ; Kaletra ; Balanced Salt; Bepotastine; Bactroban Nasal; Bactroban ; Lanoxin ; Lexiva ; Leuprolide Acetate for Depot Suspension Beclovent; Benzac W ; Betimol; Betoptic S ; Bepreve ; (Lupron Depot 11 . 25 mg) ; Levobetaxolol Hydrochloride Bimatoprost Ophthalmic Solution ; Bleph 10 ( Sulfacetamide Ophthalmic Suspension (Betaxon ) ; Levocarnitine Tablets , Sodium Ophthalmic Solution 10 % ) ; Brinzolamide Ophthal Oral Solution , Sugar- Free (Carnitor ) ; Levofloxacin Ophthal mic Suspension ( Azopt) ; Bromfenac Ophthalmic Solution mic Solution 0 .5 % ( Quixin ) ; Lidocaine HCI Sterile Solution ( Xibrom ); Bromhist ; Brovana ( Arformoterol Tartrate Inha (Xylocaine MPF Sterile Solution ) ; Lok Pak (Heparin Lock lation Solution ) ; Budesonide Inhalation Suspension ( Pulmi Flush Solution ) ; Lorazepam Intensol; Lortab Elixir (Hydro cort Respules ); Cambia (Diclofenac Potassium for Oral codone Bitartrate and Acetaminophen Oral Solution ) ; Solution ); Capex ; Carac ; Carboxine -PSE ; Carnitor ; Cayston Lotemax (Loteprednol Etabonate Ophthalmic Suspension ) ; ( Aztreonam for Inhalation Solution ) ; Cellcept; Centany ; Loteprednol Etabonate Ophthalmic Suspension ( Alrex ) ; Cerumenex ; Ciloxan Ophthalmic Solution (Ciprofloxacin Low Calcium Peritoneal Dialysis Solutions (Dianeal Low HCL Ophthalmic Solution ) ; Ciprodex ; Ciprofloxacin HCL Calcium ) ; Lumigan (Bimatoprost Ophthalmic Solution Ophthalmic Solution (Ciloxan Ophthalmic Solution ); Cle 0 .03 % for Glaucoma ) ; Lupron Depot 11 . 25 mg (Leuprolide mastine Fumarate Syrup ( Clemastine Fumarate Syrup ) ; Acetate for Depot Suspension ) ; Megestrol Acetate Oral CoLyte (PEG Electrolytes Solution ); Combiven ; Comtan ; Suspension (Megestrol Acetate Oral Suspension ) ; MEK Condylox ; Cordran ; Cortisporin Ophthalmic Suspension ; Inhibitor; Mepron ; Mesnex ; Mestinon ; Mesalamine Rectal Cortisporin Otic Suspension ; Cromolyn Sodium Inhalation Suspension Enema (Rowasa ); Melquin - 3 Topical Solution Solution ( Intal Nebulizer Solution ); Cromolyn Sodium Oph (Hydroquinone 3 % Topical Solution ) ; MetMab ; Methyldo thalmic Solution (Opticrom ) ; Crystalline Amino Acid Solu pate Hel (Methyldopate Hydrochloride Injection , Solution ) ; tion with Electrolytes ( Aminosyn Electrolytes ) ; Cutivate ; Methylin Oral Solution (Methylphenidate HCl Oral Solution Cuvposa (Glycopyrrolate Oral Solution ) ; Cyanocobalamin 5 mg/ 5 mL and 10 mg/ 5 mL ); Methylprednisolone Acetate ( CaloMist Nasal Spray ) ; Cyclosporine Oral Solution (Gen Injectable Suspension (Depo Medrol) ;Methylphenidate HC1 graf Oral Solution ) ; Cyclogyl; Cysview (Hexaminolevuli Oral Solution 5 mg/ 5 mL and 10 mg/ 5 mL (Methylin Oral nate Hydrochloride Intravesical Solution ) ; DermOtic Oil Solution ) ; Methylprednisolone sodium succinate ( Solu ( Fluocinolone Acetonide Oil Ear Drops ) ; Desmopressin Medrol) ; Metipranolol Ophthalmic Solution (Optipranolol ) ; Acetate Nasal Spray ; DDAVP ; Derma - Smoothe / FS ; Dex Migranal ; Miochol- E ( Acetylcholine Chloride Intraocular amethasone Intensol; Dianeal Low Calcium ; Dianeal PD ; Solution ) ; Micro - K for Liquid Suspension (Potassium Chlo Diclofenac Potassium for Oral Solution (Cambia ); Didanos ride Extended Release Formulation for Liquid Suspension ) ; ine Pediatric Powder for Oral Solution (Videx ) ; Differin ; Minocin (Minocycline Hydrochloride Oral Suspension ) ; Dilantin 125 (Phenytoin Oral Suspension ); Ditropan ; Dor Nasacort; Neomycin and Polymyxin B Sulfates and Hydro zolamide Hydrochloride Ophthalmic Solution ( Trusopt) ; cortisone; Nepafenac Ophthalmic Suspension (Nevanac ) ; Dorzolamide Hydrochloride - Timolol Maleate Ophthalmic Nevanac (Nepafenac Ophthalmic Suspension ) ; Nitrofuran Solution (Cosopt ) ; Dovonex Scalp (Calcipotriene Solution ) ; toin Oral Suspension (Furadantin ) ; Noxafil ( Posaconazole Doxycycline Calcium Oral Suspension ( Vibramycin Oral) ; Oral Suspension ); Nystatin ( oral) (Nystatin Oral Suspen Efudex ; Elaprase (Idursulfase Solution ) ; Elestat (Epinastine sion ) ; Nystatin Oral Suspension (Nystatin (oral ) ) ; Ocufen HC1 Ophthalmic Solution ) ; Elocon ; Epinastine HC1 Oph ( Flurbiprofen Sodium Ophthalmic Solution ) ; Ofloxacin thalmic Solution ( Elestat ) ; Epivir HBV ; Epogen (Epoetin Ophthalmic Solution (Ofloxacin Ophthalmic Solution ) ; alfa ) ; Erythromycin Topical Solution 1 . 5 % ( Staticin ) ; Ethio Ofloxacin Otic Solution ( Floxin Otic ) ; Olopatadine Hydro dol ( Ethiodized Oil) ; Ethosuximide Oral Solution ( Zarontin chloride Ophthalmic Solution (Pataday ) ; Opticrom ( Cromo US 2019 /0133882 A1 May 9 , 2019
lyn Sodium Ophthalmic Solution ) ; Optipranolol (Metipra - aminoglycosides ; aminopenicillins ; aminosalicylates ; amy nolol Ophthalmic Solution ); Patanol; Pediapred ; PerioGard ; lin analogs ; Analgesic Combinations; Analgesics; androgens Phenytoin Oral Suspension ( Dilantin 125 ) ; Phisohex ; Posa and anabolic steroids ; angiotensin converting enzyme conazole Oral Suspension (Noxafil ) ; Potassium Chloride inhibitors ; angiotensin II inhibitors ; anorectal preparations ; Extended Release Formulation for Liquid Suspension (Mi anorexiants; antacids ; anthelmintics ; anti -angiogenic oph cro - K for Liquid Suspension ) ; Pataday (Olopatadine Hydro thalmic agents ; anti -CTLA - 4 monoclonal antibodies; anti chloride Ophthalmic Solution ) ; Patanase Nasal Spray (Olo infectives; antiadrenergic agents , centrally acting; antiadren patadine Hydrochloride Nasal Spray ) ; PEG Electrolytes ergic agents , peripherally acting ; antiandrogens ; antianginal Solution ( CoLyte ); Pemirolast Potassium Ophthalmic Solu agents ; antiarrhythmic agents ; antiasthmatic combinations; tion ( Alamast ) ; Penlac (Ciclopirox Topical Solution ) ; antibiotics /antineoplastics ; anticholinergic antiemetics ; anti PENNSAID (Diclofenac Sodium Topical Solution ) ; Per cholinergic antiparkinson agents ; anticholinergic broncho foromist (Formoterol Fumarate Inhalation Solution ) ; Peri dilators ; anticholinergic chronotropic agents ; anticholin toneal Dialysis Solution ; Phenylephrine Hydrochloride ergics / antispasmodics ; anticoagulants ; anticonvulsants ; Ophthalmic Solution (Neo -Synephrine ); Phospholine lodide antidepressants ; antidiabetic agents ; antidiabetic combina ( Echothiophate Iodide for Ophthalmic Solution ); Podofilox tions ; antidiarrheals ; antidiuretic hormones ; antidotes ; anti (Podofilox Topical Solution ) ; Pred Forte (Prednisolone emetic / antivertigo agents ; antifungals ; antigonadotropic Acetate Ophthalmic Suspension ) ; Pralatrexate Solution for agents ; antigout agents; antihistamines ; antihyperlipidemic Intravenous Injection (Folotyn ) ; Pred Mild ; Prednisone agents ; antihyperlipidemic combinations ; antihypertensive Intensol; Prednisolone Acetate Ophthalmic Suspension combinations; antihyperuricemic agents ; antimalarial (Pred Forte ) ; Prevacid ; PrismaSol Solution ( Sterile Hemo agents ; antimalarial combinations ; antimalarial quinolines ; filtration Hemodiafiltration Solution ) ; ProAir ; Proglycem ; antimetabolites ; antimigraine agents ; antineoplastic detoxi ProHance (Gadoteridol Injection Solution ) ; Proparacaine fying agents ; antineoplastic interferons; antineoplastic Hydrochloride Ophthalmic Solution (Alcaine ); Propine ; monoclonal antibodies ; antineoplastics ; antiparkinson Pulmicort ; Pulmozyme; Quixin (Levofloxacin Ophthalmic agents ; antiplatelet agents ; antipseudomonal penicillins ; Solution 0 . 5 % ) ; QVAR ; Rapamune ; Rebetol; Relacon -HC ; antipsoriatics ; antipsychotics ; antirheumatics ; antiseptic and Rotarix (Rotavirus Vaccine , Live, Oral Suspension ) ; Rota germicides ; antithyroid agents; antitoxins and antivenins ; virus Vaccine , Live , Oral Suspension (Rotarix ) ; Rowasa antituberculosis agents ; antituberculosis combinations; anti (Mesalamine Rectal Suspension Enema ); Sabril ( Vigabatrin tussives; antiviral agents ; antiviral combinations ; antiviral Oral Solution ) ; Sacrosidase Oral Solution (Sucraid ) ; Sand interferons; anxiolytics , sedatives , and hypnotics ; aromatase immune; Sepra ; Serevent Diskus; Solu Cortef ( Hydrocorti inhibitors ; atypical antipsychotics ; azole antifungals ; bacte sone Sodium Succinate ) ; Solu Medrol (Methylprednisolone rial vaccines; barbiturate anticonvulsants ; barbiturates ; sodium succinate ) ; Spiriva ; Sporanox Oral Solution ( Itra BCR - ABL tyrosine kinase inhibitors ; benzodiazepine anti conazole Oral Solution ); Staticin (Erythromycin Topical convulsants ; benzodiazepines ; beta - adrenergic blocking Solution 1 . 5 % ); Stalevo ; Starlix ; Sterile Hemofiltration agents ; beta - lactamase inhibitors ; bile acid sequestrants ; Hemodiafiltration Solution (PrismaSol Solution ); Stimate; biologicals ; bisphosphonates ; bone resorption inhibitors ; Sucralfate ( Carafate Suspension ) ; Sulfacetamide Sodium bronchodilator combinations ; bronchodilators ; calcitonin ; Ophthalmic Solution 10 % (Bleph 10 ) ; Synarel Nasal Solu calcium channel blocking agents ; carbamate anticonvul tion (Nafarelin Acetate Nasal Solution for Endometriosis ) ; sants ; carbapenems; carbonic anhydrase inhibitor anticon Taclonex Scalp (Calcipotriene and Betamethasone Dipropi vulsants ; carbonic anhydrase inhibitors ; cardiac stressing onate Topical Suspension ); Tamiflu ; Tobi; TobraDex ; Tobra agents ; cardioselective beta blockers ; cardiovascular agents ; dex ST ( Tobramycin /Dexamethasone Ophthalmic Suspen catecholamines ; CD20 monoclonal antibodies ; CD33mono sion 0 . 3 % / 0 . 05 % ) ; Tobramycin /Dexamethasone clonal antibodies; CD52 monoclonal antibodies; central Ophthalmic Suspension 0 . 3 % / 0 .05 % ( Tobradex ST) ; nervous system agents ; cephalosporins; cerumenolytics ; Timolol; Timoptic ; Travatan Z ; Treprostinil Inhalation Solu chelating agents ; chemokine receptor antagonist; chloride tion ( Tyvaso ) ; Trusopt ( Dorzolamide Hydrochloride Oph channel activators ; cholesterol absorption inhibitors ; cholin thalmic Solution ) ; Tyvaso ( Treprostinil Inhalation Solution ) ; ergic agonists ; cholinergic muscle stimulants ; cholinesterase Ventolin ; Vfend ; Vibramycin Oral (Doxycycline Calcium inhibitors; CNS stimulants ; coagulation modifiers; colony Oral Suspension ) ; Videx (Didanosine Pediatric Powder for stimulating factors ; contraceptives; corticotropin ; coumarins Oral Solution ) ; Vigabatrin Oral Solution (Sabril ) ; Viokase ; and indandiones; cox - 2 inhibitors ; decongestants ; dermato Viracept; Viramune ; Vitamin K1 ( Fluid Colloidal Solution logical agents , diagnostic radiopharmaceuticals ; diben of Vitamin K1) ; Voltaren Ophthalmic (Diclofenac Sodium zazepine anticonvulsants ; digestive enzymes ; dipeptidyl Ophthalmic Solution ) ; Zarontin Oral Solution ( Ethosuxim peptidase 4 inhibitors ; diuretics ; dopaminergic antiparkin ide Oral Solution ); Ziagen ; Zyvox ; Zymar (Gatifloxacin sonism agents ; drugs used in alcohol dependence ; echi Ophthalmic Solution ) ; Zymaxid (Gatifloxacin Ophthalmic nocandins; EGFR inhibitors ; estrogen receptor antagonists ; Solution ) . estrogens; expectorants ; factor Xa inhibitors ; fatty acid [ 0266 ] Examples of suitable drug classes to be contained derivative anticonvulsants ; fibric acid derivatives ; first gen in the lumen 212 of FIGS . 1 and 2 include : 5 - alpha eration cephalosporins ; fourth generation cephalosporins ; reductase inhibitors ; 5 - aminosalicylates ; 5HT3 receptor functional bowel disorder agents ; gallstone solubilizing antagonists ; adamantane antivirals ; adrenal cortical steroids ; agents ; gamma- aminobutyric acid analogs ; gamma - amin adrenal corticosteroid inhibitors ; adrenergic bronchodila obutyric acid reuptake inhibitors ; gamma - aminobutyric acid tors , agents for hypertensive emergencies; agents for pul transaminase inhibitors ; gastrointestinal agents ; general monary hypertension ; aldosterone receptor antagonists ; anesthetics ; genitourinary tract agents; GI stimulants ; glu alkylating agents ; alpha -adrenoreceptor antagonists ; alpha cocorticoids; glucose elevating agents ; glycopeptide antibi glucosidase inhibitors ; alternative medicines ; amebicides ; otics ; glycoprotein platelet inhibitors ; glycylcyclines; US 2019 /0133882 A1 May 9 , 2019 21 gonadotropin releasing hormones ; gonadotropin - releasing supplements ; otic anesthetics ; otic anti- infectives; otic hormone antagonists ; gonadotropins; group I antiarrhyth preparations; otic steroids ; otic steroids with anti -infectives ; mics; group II antiarrhythmics; group III antiarrhythmics ; oxazolidinedione anticonvulsants ; parathyroid hormone and group IV antiarrhythmics ; group V antiarrhythmics ; growth analogs ; penicillinase resistant penicillins ; penicillins ; hormone receptor blockers ; growth hormones; H . pylori peripheral opioid receptor antagonists ; peripheral vasodila eradication agents ; H2 antagonists ; hematopoietic stem cell tors; peripherally acting antiobesity agents ; phenothiazine mobilizer ; heparin antagonists ; heparins ; HER2 inhibitors ; antiemetics; phenothiazine antipsychotics ; phenylpiperazine herbal products ; histone deacetylase inhibitors ; hormone antidepressants ; plasma expanders ; platelet aggregation replacement therapy ; hormones ; hormones/ antineoplastics ; inhibitors ; platelet - stimulating agents ; polyenes; potassium sparing diuretics ; probiotics ; progesterone receptor modu hydantoin anticonvulsants ; illicit ( street ) drugs; immune lators ; progestins; prolactin inhibitors ; prostaglandin D2 globulins; immunologic agents ; immunosuppressive agents ; antagonists; protease inhibitors; proton pump inhibitors ; impotence agents ; in vivo diagnostic biologicals ; incretin psoralens; psychotherapeutic agents ; psychotherapeutic mimetics ; inhaled anti -infectives ; inhaled corticosteroids ; combinations ; purine nucleosides ; pyrrolidine anticonvul inotropic agents ; insulin ; insulin - like growth factor; inte sants ; quinolones; radiocontrast agents ; radiologic adjuncts ; grase strand transfer inhibitor ; interferons ; intravenous radiologic agents ; radiologic conjugating agents ; radiophar nutritional products; iodinated contrast media ; ionic iodi maceuticals ; RANK ligand inhibitors ; recombinant human nated contrast media ; iron products ; ketolides; laxatives ; erythropoietins ; renin inhibitors ; respiratory agents ; respi leprostatics ; leukotriene modifiers ; lincomycin derivatives ; ratory inhalant products; rifamycin derivatives ; salicylates ; lipoglycopeptides; local injectable anesthetics ; loop diuret sclerosing agents ; second generation cephalosporins; selec ics ; lung surfactants ; lymphatic staining agents ; lysosomal tive estrogen receptor modulators ; selective serotonin enzymes ; macrolide derivatives; macrolides; magnetic reso reuptake inhibitors ; serotonin - norepinephrine reuptake nance imaging contrastmedia ; mast cell stabilizers ; medical inhibitors ; serotoninergic neuroenteric modulators ; sex hor gas; meglitinides ; metabolic agents ; methylxanthines ; min mone combinations , sex hormones ; skeletal muscle relaxant eralocorticoids; minerals and electrolytes ; miscellaneous combinations ; skeletal muscle relaxants ; smoking cessation agents ; miscellaneous analgesics ; miscellaneous antibiotics ; agents ; somatostatin and somatostatin analogs; spermicides ; miscellaneous anticonvulsants ; miscellaneous antidepres statins ; sterile irrigating solutions , streptomyces derivatives ; sants ; miscellaneous antidiabetic agents ; miscellaneous anti succinimide anticonvulsants ; sulfonamides ; sulfonylureas ; emetics ; miscellaneous antifungals ; miscellaneous antihy synthetic ovulation stimulants ; tetracyclic antidepressants ; perlipidemic agents ; miscellaneous antimalarials ; tetracyclines ; therapeutic radiopharmaceuticals ; thiazide miscellaneous antineoplastics ; miscellaneous antiparkinson diuretics ; thiazolidinediones ; thioxanthenes ; third genera agents ; miscellaneous antipsychotic agents ; miscellaneous tion cephalosporins; thrombin inhibitors ; thrombolytics; antituberculosis agents ; miscellaneous antivirals ; miscella thyroid drugs ; tocolytic agents ; topical acne agents ; topical neous anxiolytics , sedatives and hypnotics ; miscellaneous biologicals ; miscellaneous bone resorption inhibitors ; mis agents ; topical anesthetics ; topical anti - infectives; topical cellaneous cardiovascular agents ; miscellaneous central ner antibiotics ; topical antifungals ; topical antihistamines ; topi vous system agents ; miscellaneous coagulation modifiers ; cal antipsoriatics ; topical antivirals ; topical astringents ; topi miscellaneous diuretics ; miscellaneous genitourinary tract cal debriding agents ; topical depigmenting agents ; topical agents ; miscellaneous GI agents ; miscellaneous hormones ; emollients ; topical keratolytics ; topical steroids ; topical ste miscellaneous metabolic agents ; miscellaneous ophthalmic roids with anti - infectives ; toxoids ; triazine anticonvulsants ; agents ; miscellaneous otic agents; miscellaneous respiratory tricyclic antidepressants ; trifunctional monoclonal antibod agents ; miscellaneous sex hormones ; miscellaneous topical ies ; tumor necrosis factor ( TNF ) inhibitors ; tyrosine kinase agents ; miscellaneous uncategorized agents ; miscellaneous inhibitors ; ultrasound contrast media ; upper respiratory vaginal agents ; mitotic inhibitors ; monoamine oxidase combinations ; urea anticonvulsants ; urinary anti - infectives ; inhibitors ; monoclonal antibodies ; mouth and throat prod urinary antispasmodics ; urinary pH modifiers ; uterotonic ucts ; mTOR inhibitors ; mTOR kinase inhibitors ; mucolyt agents ; vaccine ; vaccine combinations; vaginal anti - infec ics ; multikinase inhibitors ; muscle relaxants ; mydriatics ; tives ; vaginal preparations ; vasodilators ; vasopressin narcotic analgesic combinations ; narcotic analgesics ; nasal antagonists ; vasopressors ; VEGF/ VEGFR inhibitors ; viral anti - infectives; nasal antihistamines and decongestants ; vaccines ; viscosupplementation agents ; vitamin and mineral nasal lubricants and irrigations; nasal preparations; nasal combinations ; vitamins . steroids ; natural penicillins ; neuraminidase inhibitors ; neu [0267 ] Examples of suitable diagnostic tests to be con romuscular blocking agents ; next generation cepha tained in the lumen 212 of FIGS . 1 and 2 include : 17 -Hy losporins ; nicotinic acid derivatives ; nitrates ; NNRTIs ; non droxyprogesterone ; ACE ( Angiotensin I converting cardioselective beta blockers ; non - iodinated contrast media ; enzyme) ; Acetaminophen ; Acid phosphatase ; ACTH ; Acti non - ionic iodinated contrast media ; non -sulfonylureas ; non vated clotting time; Activated protein C resistance ; Adreno steroidal anti - inflammatory agents ; norepinephrine reuptake corticotropic hormone (ACTH ); Alanine aminotransferase inhibitors ; norepinephrine -dopamine reuptake inhibitors; (ALT ) ; Albumin ; Aldolase ; Aldosterone ; Alkaline phos nucleoside reverse transcriptase inhibitors (NRTIS ) ; nutra phatase; Alkaline phosphatase ( ALP ) ; Alphal - antitrypsin ; ceutical products ; nutritional products ; ophthalmic anesthet Alpha - fetoprotein ; Alpha - fetoprotien ; Ammonia levels ; ics ; ophthalmic anti - infectives ; ophthalmic anti - inflamma Amylase ; ANA ( antinuclear antbodies ); ANA ( antinuclear tory agents ; ophthalmic antihistamines and decongestants ; antibodies ) ; Angiotensin - converting enzyme ( ACE ) ; Anion ophthalmic diagnostic agents ; ophthalmic glaucoma agents ; gap ; Anticardiolipin antibody ; Anticardiolipin antivbodies ophthalmic lubricants and irrigations; ophthalmic prepara (ACA ) ; Anti- centromere antibody ; Antidiuretic hormone ; tions ; ophthalmic steroids; ophthalmic steroids with anti Anti - DNA ; Anti- Dnase - B ; Anti -Gliadin antibody ; Anti infectives; ophthalmic surgical agents ; oral nutritional glomerular basement membrane antibody ; Anti- HBc (Hepa US 2019 /0133882 A1 May 9 , 2019
titis B core antibodies ; Anti- HBs (Hepatitis B surface anti Vessel Containing Viable Blood , Having a Primer Coating or body; Antiphospholipid antibody; Anti- RNA polymerase ; Layer Deposited from an Organosilicon Precursor Anti -Smith (Sm ) antibodies ; Anti -Smooth Muscle antibody ; 10269 ] Even another embodiment is a blood containing vessel. Several non -limiting examples of such a vessel are a Antistreptolysin 0 ( ASO ) ; Antithrombin III; Anti -Xa activ blood transfusion bag , a blood sample collection vessel in ity ; Anti - Xa assay ; Apolipoproteins ; Arsenic ; Aspartate ami which a sample has been collected , the tubing of a heart - lung notransferase ( AST) ; B12 ; Basophil; Beta - 2 -Microglobulin ; machine , a flexible -walled blood collection bag, or tubing Beta - hydroxybutyrate ; B -HCG ; Bilirubin ; Bilirubin , direct; used to collect a patient' s blood during surgery and reintro Bilirubin , indirect; Bilirubin , total; Bleeding time; Blood duce the blood into the patient' s vasculature . If the vessel gases ( arterial) ; Blood urea nitrogen (BUN ) ; BUN ; BUN includes a pump for pumping blood , a particularly suitable (blood urea nitrogen ); CA 125 ; CA 15 - 3 ; CA 19 - 9 ; Calci pump is a centrifugal pump or a peristaltic pump . The vessel tonin ; Calcium ; Calcium ( ionized ) ; Carbon monoxide (CO ) ; has a wall ; the wall has an inner or interior surface defining Carcinoembryonic antigen (CEA ) ; CBC ; CEA ; CEA ( car a lumen . The inner or interior surface of the wall has an at cinoembryonic antigen ) ; Ceruloplasmin ; CH50Chloride ; least partial primer coating or layer of a protective layer, Cholesterol; Cholesterol, HDL ; Clot lysis time ; Clot retrac which optionally also presents a hydrophobic surface . The tion time; CMP; CO2; Cold agglutinins; Complement C3 ; primer coating or layer can be as thin as monomolecular Copper; Corticotrophin releasing hormone (CRH ) stimula thickness or as thick as about 1000 nm . The vessel contains tion test; Cortisol; Cortrosyn stimulation test ; C -peptide ; blood viable for return to the vascular system of a patient CPK ( Total) ; CPK -MB ; C -reactive protein ; Creatinine ; disposed within the lumen in contact with the hydrophobic Creatinine kinase (CK ) ; Cryoglobulins ; DAT (Direct anti layer . globulin test ) ; D - Dimer ; Dexamethasone suppression test ; [0270 ] An embodiment is a blood containing vessel DHEA - S ; Dilute Russell viper venom ; Elliptocytes; Eosino including a wall and having an inner or interior surface defining a lumen . The inner or interior surface has an at least phil ; Erythrocyte sedimentation rate ( ESR ) ; Estradiol; Est partial primer coating or layer that optionally also presents riol; Ethanol ; Ethylene glycol ; Euglobulin lysis ; Factor V a hydrophobic surface . The primer coating or layer can also Leiden ; Factor VIII inhibitor ; Factor VIII level; Ferritin ; comprise or consist essentially of SiO , C ,, where x and y are Fibrin split products ; Fibrinogen ; Folate; Folate ( serum ; as defined in this specification . The thickness of the hydro Fractional excretion of sodium ( FENA ) ; FSH ( follicle phobic coating or layer is within the range from monomo stimulating factor ) ; FTA - ABS ; Gamma glutamyl transferase lecular thickness to about 1000 nm thick on the inner or (GGT ) ; Gastrin ; GGTP (Gamma glutamyl transferase ); Glu interior surface . The vessel contains blood viable for return cose ; Growth hormone ; Haptoglobin ; HBeAg (Hepatitis Be to the vascular system of a patient disposed within the lumen antigen ) ; HBs- Ag (Hepatitis B surface antigen ) ; Helico in contact with the hydrophobic coating or layer. bacter pylori ; Hematocrit; Hematocrit (HCT ); Hemoglobin ; Primer Coating or Layer Deposited from an Organosilicon Hemoglobin A1C ; Hemoglobin electrophoresis ; Hepatitis A Precursor Reduces Clotting or Platelet Activation of Blood antibodies ; Hepatitis C antibodies ; IAT ( Indirect antiglobu in the Vessel lin test) ; Immunofixation ( IFE ) ; Iron ; Lactate dehydroge [0271 ] Another embodiment is a vessel having a wall. The nase (LDH ); Lactic acid (lactate ); LDH ; LH (Leutinizing wall has an inner or interior surface defining a lumen and has hormone ; Lipase ; Lupus anticoagulant; Lymphocyte ; Mag an at least partial primer coating or layer that presents a nesium ; MCH (mean corpuscular hemoglobin ; MCHC hydrophobic surface, where optionally x and y are as pre (mean corpuscular hemoglobin concentration ) ; MCV (mean viously defined . The thickness of the primer coating or layer corpuscular volume) ; Methylmalonate ; Monocyte ; MPV is from monomolecular thickness to about 1000 nm thick on (mean platelet volume) ; Myoglobin ; Neutrophil; Parathy the inner or interior surface . The primer coating or layer is effective to reduce the clotting or platelet activation of blood roid hormone (PTH ) ; Phosphorus ; Platelets (plt ) ; Potassium ; exposed to the inner or interior surface , compared to the Prealbumin ; Prolactin ; Prostate specific antigen (PSA ) ; Pro same type of wall uncoated with a hydrophobic layer . tein C ; Protein S ; PSA (prostate specific antigen ); PT [0272 ] It is contemplated that the incorporation of a hydro ( Prothrombin time) ; PTT (Partial thromboplastin time) ; phobic layer will reduce the adhesion or clot forming RDW ( red cell distribution width ) ; Renin ; Rennin ; Reticu tendency of the blood , as compared to its properties in locyte count ; reticulocytes ; Rheumatoid factor (RF ); Sed contact with an unmodified polymeric or SiO , surface . This Rate ; Serum glutamic -pyruvic transaminase (SGPT ; Serum property is contemplated to reduce or potentially eliminate protein electrophoresis (SPEP ) ; Sodium ; T3 -resin uptake the need for treating the blood with heparin , as by reducing ( T3RU ) ; T4 , Free ; Thrombin time ; Thyroid stimulating the necessary blood concentration of heparin in a patient hormone ( TSH ) ; Thyroxine ( T4 ) ; Total iron binding capac undergoing surgery of a type requiring blood to be removed ity ( TIBC ) ; Total protein ; Transferrin ; Transferrin saturation ; from the patient and then returned to the patient, as when Triglyceride ( TG ) ; Troponin ; Uric acid ; Vitamin B12 ; White using a heart- lung machine during cardiac surgery . It is blood cells (WBC ) ; Widal test . contemplated that this will reduce the complications of surgery involving the passage of blood through such a [ 0268 ] Even another embodiment is a medical or diagnos pharmaceutical package or other vessel , by reducing the tic kit including a vessel having a pH protective coating or bleeding complications resulting from the use of heparin . layer as defined in any embodiment herein on a substrate as [0273 ] Another embodiment is a vessel including a wall defined in any embodiment above. Optionally, the kit addi and having an inner or interior surface defining a lumen . The tionally includes a medicament or diagnostic agent which is inner or interior surface has an at least partial primer coating contained in the vessel ; and / or a hypodermic needle , double or layer that presents a hydrophobic surface , the thickness of ended needle , or other delivery conduit ; and /or an instruc the primer coating or layer being from monomolecular tion sheet. thickness to about 1000 nm thick on the inner or interior US 2019 /0133882 A1 May 9 , 2019 22
surface, the primer coating or layer being effective to reduce the top three photoelectron escape depths are detected . the clotting or platelet activation of blood exposed to the Escape depths are on the order of 15 -35 Å , which leads to inner or interior surface . an analysis depth of - 50 - 100 Å . Typically , 95 % of the signal originates from within this depth . Vessel Containing Viable Blood , Having a Primer Coating or [0280 ] The following analytical parameters are used : Layer of Group III or IV Element [ 0281 ] Instrument: PHI Quantum 2000 [0274 ] Another embodiment is a blood containing vessel [0282 ] X - ray source : Monochromated Alka 1486 . 6 eV having a wall having an inner or interior surface defining a [0283 ] Acceptance Angle + 23° lumen . The inner or interior surface has an at least partial [0284 ] Take -off angle 45° primer coating or layer of a composition comprising one or [ 0285 ] Analysis area 600 um more elements ofGroup III, one or more elements of Group [0286 ] Charge Correction Cls 284 .8 eV IV , or a combination of two or more of these. The thickness [ 0287 ] Ion Gun Conditions Art , 1 keV , 2x2 mm raster of the primer coating or layer is between monomolecular 10288 ] Sputter Rate 15 . 6 Å /min (SiO2 Equivalent) thickness and about 1000 nm thick , inclusive , on the inner [0289 ] Values given are normalized to 100 percent using or interior surface . The vessel contains blood viable for the elements detected . Detection limits are approximately return to the vascular system of a patient disposed within the 0 .05 to 1. 0 atomic percent. lumen in contact with the primer coating or layer. Rutherford Backscattering Spectrometry (RBS ) Primer Coating or Layer of Group III or IV Element [0290 ] RBS spectra are acquired at a backscattering angle Reduces Clotting or Platelet Activation of Blood in the of 160° and an appropriate grazing angle (with the sample Vessel oriented perpendicular to the incident ion beam ) . The sample [ 0275 ] Optionally , in the vessel of the preceding para is rotated or tilted with a small angle to present a random graph , the primer coating or layer of the Group III or IV geometry to the incident beam . This avoids channeling in Element is effective to reduce the clotting or platelet acti both the film and the substrate . The use of two detector vation of blood exposed to the inner or interior surface of the angles can significantly improve the measurement accuracy vessel wall. for composition when thin surface layers need to be ana lyzed . Insulin Vessel [0291 ] When a thin ( < 100 nm ) amorphous or polycrystal [ 027 ] As one option , the compound or a component of line film resides on a single crystal substrate “ ion channel the composition is insulin , and precipitation of the insulin is ing ” may be utilized to reduce the backscattering signal from prevented or reduced . As another option , the compound or a the substrate . This results in improved accuracy in the component of the composition is blood or a blood fraction , composition of layers containing elements that overlay with and blood clotting or platelet activation is prevented or the substrate signal , typically light elements such as oxygen , reduced . As still another option , the vessel with a primer nitrogen and carbon . coating or layer is a blood collection tube. Optionally , the blood collection tube can contain an agent for preventing Analytical Parameters : RBS blood clotting or platelet activation , for example ethylene [0292 ] He + + Ion Beam Energy 2 . 275 MeV diamineteetraacetic acid ( EDTA ) , a sodium salt thereof, or [0293 ] Normal Detector Angle 160° heparin . [0294 ] Grazing Detector Angle - 100° [0277 ] The use of a coated substrate according to any [0295 ] Analysis Mode CC RR described embodiment is contemplated for storing insulin . [0296 ] Spectra are fit by applying a theoretical layer model and iteratively adjusting elemental concentrations and thick Protocols and Test Methods ness until good agreement is found between the theoretical Atomic Composition and the experimental spectra . [0278 ] The atomic compositions of the tie coating or layer , Hydrogen Forward Scattering Spectrometry (HFS ) the barrier coating or layer, and the pH protective coating or [0297 ] In an HFS experiment a detector is placed 30° from layer are characterized using X -Ray Photoelectron Spectros the forward trajectory of the incident He + + ion beam and the copy (XPS ) , to measure silicon , oxygen , and carbon , and sample is rotated so that the incident beam strikes the either Rutherford backscattering (RBS ) or hydrogen forward surfaces 75° from normal. In this geometry it is possible to scattering (HFS ) spectrometry to measure hydrogen . A sepa collect light atoms, namely hydrogen , forward - scattered rate analytical method is used to determine the hydrogen from a sample after collisions with the probing He + + ion content because XPS does not detect hydrogen . The follow beam . A thin absorber foil is placed over the detector to filter ing methods are used , unless otherwise expressly indicated . out He+ + ions that are also forward scattered from the sample . XPS Protocol [0298 ] Hydrogen concentrations are determined by com [0279 ] XPS data is quantified using relative sensitivity paring the number of hydrogen counts obtained from refer factors and a model that assumes a homogeneous layer . The ence samples after normalizing by the stopping powers of analysis volume is the product of the analysis area (spot size the different materials . A hydrogen implanted silicon sample or aperture size ) and the depth of information . Photoelec and a geological sample , muscovite , are used as references . trons are generated within the X -ray penetration depth The hydrogen concentration in the hydrogen implanted ( typically many microns) , but only the photoelectrons within silicon sample is taken to be its stated implant dose of US 2019 /0133882 A1 May 9 , 2019 24
1 .6x1017 + 0 . 2x1017 atoms/ cm². The muscovite (MUSC ) centration for each set of vessels is determined in the same sample is known to have ~ 6 . 5 + 0 .5 atomic percent hydrogen . manner as described above . The difference between the two 10299 ] Samples are checked for hydrogen loss in the Si concentrations is the total Si concentration of the SiO Cv analyzed region . This is done by acquiring spectra for second layer. different acquisition times ( initially a short exposure fol lowed by a longer exposure to the He + + beam ) . Charge Protocol for Measuring Dissolved Silicon in a Vessel accumulations for 5 and 40 °C are used . A lower propor [0308 ] In some of the working examples , the amount of tional signal in the 40 uC spectrum indicates hydrogen loss . silicon dissolved from the wall of the vessel by a test In those cases the shorter exposure is chosen for analysis at solution is determined , in parts per billion (ppb ) , for the expense of higher noise in the spectrum . To account for example to evaluate the dissolution rate of the test solution . surface hydrogen due to residual moisture or hydrocarbon This determination of dissolved silicon is made by storing adsorption a silicon control sample is analyzed together with the test solution in a vessel provided with an SiO , and /or the actual samples and the hydrogen signal from the control Sio C , coating or layer under test conditions, then removing sample is subtracted from each of the spectra obtained from a sample of the solution from the vessel and testing the Si the actual samples . During the HFS acquisition backscatter concentration of the sample . The test is done in the same ing spectra are acquired using the 160° angle detector (with manner as the Protocol for Total Silicon Measurement , the sample in forward scattering orientation ). The RBS except that the digestion step of that protocol is replaced by spectra are used to normalize the total charge delivered to storage of the test solution in the vessel as described in this the sample . protocol. The total Si concentration is reported as parts per Analytical Parameters : HFS billion of Si in the test solution [0300 ] He + + Ion Beam Energy 2. 275 MeV Protocol for Determining Average Dissolution Rate [0301 ] Normal Detector Angle 160° [0309 ] As shown in the working examples, the silicon [0302 ] Grazing Detector Angle - 30° dissolution rate is measured by determining the total silicon [0303 ] Ion Beam to Sample Normal 75° leached from the vessel into its contents , and does not distinguish between the silicon derived from the pH protec Protocol for Total Silicon Measurement tive coating or layer 286 , the lubricity layer 281 , the barrier [ 03041 This protocol is used to determine the total amount coating or layer 288 , or other materials present. of silicon coatings present on the entire vessel wall . A supply [0310 ] The average dissolution rates reported in the work of 0 . 1 N potassium hydroxide (KOH ) aqueous solution is ing examples are determined as follows. A series of test prepared , taking care to avoid contact between the solution vessels having a known total total silicon measurement are or ingredients and glass . The water used is purified water , 18 filled with the desired test solution analogous to the manner M22 quality . A Perkin Elmer Optima Model 7300DV ICP of filling the vials with the KOH solution in the Protocol for OES instrument is used for the measurement except as Total Silicon Measurement. ( The test solution can be a otherwise indicated . physiologically inactive test solution as employed in the [0305 ] Each device ( vial, syringe, tube, or the like ) to be present working examples or a physiologically active phar tested and its cap and crimp ( in the case of a vial) or other maceutical preparation intended to be stored in the vessels to closure are weighed empty to 0 .001 g , then filled completely form a pharmaceutical package ) . The test solution is stored with the KOH solution (with no headspace ) , capped , in respective vessels for several different amounts of time , crimped , and reweighed to 0 .001 g . In a digestion step , each then analyzed for the Si concentration in parts per billion in vial is placed in an autoclave oven ( liquid cycle ) at 121° C . the test solution for each storage time. The respective for 1 hour. The digestion step is carried out to quantitatively storage times and Si concentrations are then plotted . The remove the silicon coatings from the vessel wall into the plots are studied to find a series of substantially linear points KOH solution . After this digestion step , the vials are having the steepest slope . removed from the autoclave oven and allowed to cool to [ 0311 ] The plot of dissolution amount ( ppb Si) versus days room temperature . The contents of the vials are transferred decreases in slope with time, even though it does not appear into ICP tubes . The total Si concentration is run on each that the Si layer has been fully digested by the test solution . solution by ICP /OES following the operating procedure for [0312 ] For the PC194 test data in Table 10 below , linear the ICP / OES . plots of dissolution versus time data are prepared by using [ 0306 ] The total Si concentration is reported as parts per a least squares linear regression program to find a linear plot billion of Si in the KOH solution . This concentration rep corresponding to the first five data points of each of the resents the total amount of silicon coatings that were on the experimental plots . The slope of each linear plot is then vessel wall before the digestion step was used to remove it . determined and reported as representing the average disso [0307 ] The total Si concentration can also be determined lution rate applicable to the test , measured in parts per for fewer than all the silicon layers on the vessel, as when billion of Si dissolved in the test solution per unit of time. an Sio barrier layer is applied , an Sio C , second layer ( for example , a lubricity layer or a pH protective coating or Protocol for Determining Calculated Shelf Life layer ) is then applied , and it is desired to know the total [0313 ] The calculated shelf life values reported in the silicon concentration of just the SiO C , layer. This determi working examples below are determined by extrapolation of nation is made by preparing two sets of vessels , one set to the total silicon measurements and average dissolution rates , which only the SiO , layer is applied and the other set to respectively determined as described in the Protocol for which the same SiO , layer is applied , followed by the Total Silicon Measurement and the Protocol for Determining SIO C , layer or other layers of interest. The total Si con Average Dissolution Rate . The assumption is made that US 2019 /0133882 A1 May 9 , 2019 25 under the indicated storage conditions the SiO _ C , pH pro tective coating or layer will be removed at the average - continued dissolution rate until the coating is entirely removed . Thus, Scanning Transmission Electron the total silicon measurement for the vessel, divided by the Instrument Microscope dissolution rate , gives the period of time required for the test Objective Aperture solution to totally dissolve the SiO , C ,V , coating. This period Condenser Lens 1 Setting 1 .672 of time is reported as the calculated shelf life . Unlike Condenser Lens 2 Setting 1 . 747 commercial shelf life calculations , no safety factor is cal Approximate Objective Lens Setting 5 . 86 ZC Mode Projector Lens 1 . 149 culated . Instead , the calculated shelf life is the calculated TE Mode Projector Lens 0 . 7 time to failure . Image Acquisition [ 0314 ] It should be understood thatbecause the plot of ppb Si versus hours decreases in slope with time, an extrapola Pixel Resolution 1280 x 960 tion from relatively short measurement times to relatively Acquisition Time 20 sec. (x4 long calculated shelf lives is believed to be a " worst case ” test that tends to underestimate the calculated shelf life [0318 ] For TEM analysis the sample grids can be trans actually obtainable . ferred to a Hitachi HF2000 transmission electron micro scope . Transmitted electron images can be acquired at Measurement of Coating Thickness appropriate magnifications. The relevant instrument settings [ 0315 ] The thickness of a PECVD coating or layer such as used during image acquisition can be those given below . the pH protective coating or layer, the barrier coating or layer , the lubricity coating or layer , and /or a composite of any two or more of these layers can be measured , for Instrument Transmission Electron Microscope example, by transmission electron microscopy ( TEM ) . An Manufacturer /Model Hitachi HF2000 Accelerating Voltage 200 kV exemplary TEM image for a pH protective coating or layer Condenser Lens 1 0 .78 is shown in FIG . 17 . An exemplary TEM image for an SiO2 Condenser Lens 2 barrier coating or layer is shown in FIG . 18 . Objective Lens 6 . 34 [ 0316 ] The TEM can be carried out, for example , as Condenser Lens Aperture follows . Samples can be prepared for Focused Ion Beam ( FIB ) cross - sectioning in two ways . Either the samples can be first coated with a thin layer of carbon (50 - 100 nm thick ) and then coated with a sputtered coating or layer of platinum Instrument Transmission Electron Microscope (50 - 100 nm thick ) using a K575X Emitech primer coating or layer system , or the samples can be coated directly with the Objective Lens Aperture for imaging 3 protective sputtered Pt layer. The coated samples can be Selective Area Aperture for SAD N / A placed in an FEI FIB200 FIB system . An additional coating or layer of platinum can be FIB -deposited by injection of an organometallic gas while rastering the 30 kV gallium ion SEM Procedure beam over the area of interest . The area of interest for each [0319 ] SEM Sample Preparation : Each syringe sample sample can be chosen to be a location half way down the was cut in half along its length ( to expose the inner or length of the syringe barrel . Thin cross sections measuring interior surface ). The top of the syringe (Luer end) was cut approximately 15 um (“ micrometers " ) long, 2 um wide and off to make the sample smaller. 15 um deep can be extracted from the die surface using an [0320 ] The sample was mounted onto the sample holder in - situ FIB lift- out technique . The cross sections can be with conductive graphite adhesive , then put into a Denton attached to a 200 mesh copper TEM grid using FIB Desk IV SEM Sample Preparation System , and a thin deposited platinum . One or two windows in each section , ( approximately 50 Å ) gold coating was sputtered onto the measuring about 8 um wide, can be thinned to electron inner or interior surface of the syringe . The gold coating is transparency using the gallium ion beam of the FEI FIB . used to eliminate charging of the surface during measure [ 03171 Cross -sectional image analysis of the prepared ment. samples can be performed utilizing either a Transmission [0321 ] The sample was removed from the sputter system Electron Microscope ( TEM ) , or a Scanning Transmission and mounted onto the sample stage of a Jeol JSM 6390 SEM Electron Microscope (STEM ) , or both . All imaging data can ( Scanning Electron Microscope ) . The sample was pumped be recorded digitally . For STEM imaging , the grid with the down to at least 1x10 -6 Torr in the sample compartment. thinned foils can be transferred to a Hitachi HD2300 dedi Once the sample reached the required vacuum level, the slit cated STEM . Scanning transmitted electron images can be valve was opened and the sample was moved into the acquired at appropriate magnifications in atomic number analysis station . contrast mode ( ZC ) and transmitted electron mode ( TE ). The [0322 ] The sample was imaged at a coarse resolution first , following instrument settings can be used . then higher magnification images were accumulated . The SEM images provided in the Figures are 5 um edge - to - edge Scanning Transmission Electron (horizontal and vertical ). Instrument Microscope AFM (Atomic Force Microscopy ) Procedure . Manufacturer /Model Hitachi HD2300 Accelerating Voltage 200 kV [0323 ] AFM images were collected using a NanoScope III Dimension 3000 machine (Digital Instruments , Santa Bar US 2019 /0133882 A1 May 9 , 2019 bara , Calif. , USA ). The instrument was calibrated against a [0328 ] Mean : The average of all of the Z values in the NIST traceable standard . Etched silicon scanning probe imaged area . This value is not corrected for the tilt in the microscopy (SPM ) tips were used . Image processing pro plane of the image ; therefore , plane fitting or flattening the cedures involving auto - flattening , plane fitting or convolu data will change this value . tion were employed . One 10 umx10 um area was imaged . [0329 ] RMS (Rq ) : This is the standard deviation of the Z Roughness analyses were performed and were expressed in : values ( or RMS roughness ) in the image . It is calculated ( 1 ) Root- Mean - Square Roughness, RMS ; 2 Mean Rough according to the formula : ness , Ra ; and ( 3 ) Maximum Height ( Peak -to - Valley ) , Rmax , Rq = { E (Z1 – Zavg )2 / N } all measured in nm (see Table 5 and FIGS . 8 to 16 . For the [0330 ] where Zavg is the average Z value within the roughness analyses , each sample was imaged over the 10 image ; Z1 is the current value of Z , and N is the number of umx10 um area , followed by three cross sections selected by points in the image . This value is not corrected for tilt in the the analyst to cut through features in the 10 umx10 um plane of the image ; therefore , plane fitting or flattening the images. The vertical depth of the features was measures data will change this value . using the cross section tool. For each cross section , a 0331 Mean roughness (Ra ) : This is the mean value of the Root -Mean -Square Roughness (RMS ) in nanmeters was surface relative to the Center Plane and is calculated using reported . These RMS values along with the average of the the formula : three cross sections for each sample are listed in Table 5 . Ra= [1 / ( LxLy) ] ?oLy?oLx { f ( x , y )} dxdy [ 0324 ] Additional analysis of the 10 umx10 um images represented by FIGS . 8 to 16 (Examples Q , T and V ) was [0332 ] where f ( x , y ) is the surface relative to the Center carried out. For this analysis three cross sections were plane , and Lx and Ly are the dimensions of the surface . extracted from each image . The locations of the cross [0333 ] Max height (Rmax ): This is the difference in height sections were selected by the analyst to cut through features between the highest and lowest points of the surface relative in the images . The vertical depth of the features was mea to the Mean Plane . [0334 ] Surface area : (Optical calculation ): This is the area sured using the cross section tool. of the 3 - dimensional surface of the imaged area . It is [0325 ] The Digital Instruments Nanoscope III AFM /STM calculated by taking the sum of the areas of the triangles acquires and stores 3 - dimensional representations of sur formed by 3 adjacent data points throughout the image . faces in a digital format. These surfaces can be analyzed in [0335 ] Surface area diff: (Optional calculation ) This is the a variety of ways. amount that the Surface area is in excess of the imaged area . [0326 ] The Nanoscope III software can perform a rough It is expressed as a percentage and is calculated according to ness analysis of any AFM or STM image . The product of this analysis is a single page reproducing the selected image in the formula : top view . To the upper right of the image is the “ Image Surface area diff = 100 [ (Surface area / S12 – 1 ] Statistics” box , which lists the calculated characteristics of [0336 ] where S1 is the length ( and width ) of the scanned the whole image minus any areas excluded by a stopband (a area minus any areas excluded by stopbands . box with an X through it ) . Similar additional statistics can be 0337 ] Center Plane : A flat plane that is parallel to the calculated for a selected portion of the image and these are Mean Plane . The volumes enclosed by the image surface listed in the “ Box Statistics ” in the lower right portion of the above and below the center plane are equal . page . What follows is a description and explanation of these [0338 ] Mean Plane : The image data has a minimum vari statistics . ance about this flat plane . It results from a first order least squares fit on the Z data . Image Statistics: EXAMPLES [ 0327 ] Z Range (Rp ) : The difference between the highest Examples 1 - 4 _ Conditions for Production of pH and lowest points in the image. The value is not corrected for Protective Layer tilt in the plane of the image ; therefore , plane fitting or [0339 ] Some conditions used for production of pH Pro flattening the data will change the value . tective Layers are shown in Table 1 . TABLE 1 OMCTS -BASED PLASMA PH PROTECTIVE COATING OR LAYER MADE WITH CARRIER GAS pH protective protective protective Carrier pH protective pH protective coating or OMCTS 02 Gas ( Ar ) coating or coating or PH protective layer Time Flow Rate Flow Rate Flow Rate layer Power Example layer Type Monomer ( sec ) ( sccm ) (sccm ) ( sccm ) (Watts ) 1 Uncoated n / a n / a n / a n / a n / a n / a (Control ) COC 2 Silicon oil n / a n /a nn / a n /a n/ a n /a (Industry on COC Standard ) 3 L3 lubricity OMCTS 10 sec (without coating or Oxygen ) layer over SiO , on COC US 2019 /0133882 A1 May 9 , 2019 27
TABLE 1 - continued OMCTS -BASED PLASMA pH PROTECTIVE COATING OR LAYER MADE WITH CARRIER GAS pH protective protective protective Carrier pH protective pH protective coating or OMCTS O2 Gas ( Ar ) coating or coating or PH protective layer Time Flow Rate Flow Rate Flow Rate layer Power Example layer Type Monomer (sec ) ( sccm ) ( sccm ) ( sccm ) (Watts ) 4 L2 pH OMCTS 10 sec 3 1 65 ( with protective Oxygen ) coating or layer over SiOx on COC
Examples 5 - 8 [0348 ] Next , the fluid recovered from each syringe was [ 0340 ] Syringe samples were produced as follows. A COC tested for extractable silicon using the Protocol for Measur 8007 extended barrel syringe was produced according to the ing Dissolved Silicon in a Vessel. The instrument used was Protocol for Forming COC Syringe Barrel. An SiO , barrier a Perkin Elmer Elan DRC II equipped with a Cetac ASX - 520 coating or layer was applied to the syringe barrels according autosampler . The following ICP -MS conditions were to the Protocol for Coating COC Syringe Barrel Interior with employed : SiOx . A pH protective coating or layer was applied to the [ 0349 ] Nebulizer: Quartz Meinhardt SiO coated syringes according to the Protocol for Coating [ 0350 ) Spray Chamber: Cyclonic COC Syringe Barrel Interior with OMCTS , modified as [0351 ] RF (radio frequency ) power : 1550 Watts follows. Argon carrier gas and oxygen were used where [0352 ] Argon (Ar ) Flow : 15 . 0 L / min noted in Table 2 . The process conditions were set to the [ 0353 ] Auxiliary Ar Flow : 1. 2 L /min following , or as indicated in Table 2 : [0354 ] Nebulizer Gas Flow : 0 . 88 L /min 10341 ] OMCTS3sccm (when used ) 10355 ) Integration time: 80 sec [0342 ] Argon gas — 7 . 8 sccm (when used ) [ 0356 ] Scanning mode: Peak hopping [0343 ] Oxygen 0 . 38 sccm (when used ) [0357 ] RPq ( The RPq is a rejection parameter ) for [0344 ] Power — 3 watts Cerium as CeO ( m / z 156 : < 2 % [ 0345 ] Power on time — 10 seconds 0358 Aliquots from aqueous dilutions obtained from Syringes of Examples 5 , 6 , and 7 were tested to determine Syringes E , F , and G were injected and analyzed for Si in total extractable silicon levels ( representing extraction of the concentration units of micrograms per liter. The results of organosilicon - based PECVD pH protective coating or layer ) this test are shown in Table 2 . While the results are not using the Protocol for Measuring Dissolved Silicon in a quantitative , they do indicate that extractables from the pH Vessel, modified and supplemented as shown in this protective coating or layer are not clearly higher than the example . extractables for the SiO , barrier layer only . Also , the static [0346 ] The silicon was extracted using saline water diges mode produced far less extractables than the dynamic mode, tion . The tip of each syringe plunger was covered with PTFE which was expected . tape to prevent extracting material from the elastomeric tip material , then inserted into the syringe barrel base. The TABLE 2 syringe barrel was filled with two milliliters of 0 . 9 % aque ous saline solution via a hypodermic needle inserted through OMCTS PH PROTECTIVE COATING OR LAYER ( E and F ) the Luer tip of the syringe . This is an appropriate test for OMCTS 02 Ar extractables because many prefilled syringes are used to Example ( sccm ) ( sccm ) ( sccm ) contain and deliver saline solution . The Luer tip was 3 . 0 0 . 38 7. 8 plugged with a piece of PTFE beading of appropriate 3 . 0 0 . 38 7 . 8 diameter . The syringe was set into a PTFE test stand with the n / a n / a n / a Luer tip facing up and placed in an oven at 50° C . for 72 (SiO only) hours . n / a n / a na [0347 ] Then , either a static or a dynamic mode was used ( silicon oil ) to remove the saline solution from the syringe barrel. According to the static mode indicated in Table 2 , the syringe plunger was removed from the test stand , and the Examples 9 - 11 fluid in the syringe was decanted into a vessel. According to the dynamic mode indicated in Table 2 , the Luer tip seal was [0359 ] Syringe Examples 9, 10 , and 11, employing three removed and the plunger was depressed to push fluid different pH protective coatings or layers , were produced in through the syringe barrel and expel the contents into a the same manner as for Examples 5 - 8 except as follows or vessel. In either case , the fluid obtained from each syringe as indicated in Table 3 : barrel was brought to a volume of 50 ml using 18 .2M2 - cm [0360 ] OMCTS2.5 sccm deionized water and further diluted 2x to minimize sodium [ 0361 ] Argon gas — 7 .6 sccm (when used ) background during analysis . The CVH barrels contained two [ 0362 ] Oxygen 0 . 38 sccm (when used ) milliliters and the commercial barrels contained 2 . 32 milli [ 0363 ] Power — 3 watts liters . [0364 ] Power on time — 10 seconds US 2019 /0133882 A1 May 9 , 2019
[0365 ] Syringe Example 9 had a three -component pH Examples 12 - 14 protective coating or layer employing OMCTS , oxygen , and [0367 ] Examples 9 - 11 using an OMCTS precursor gas carrier gas. Syringe Example 10 had a two component pH were repeated in Examples 12 - 14 , except that HMDSO was protective coating or layer employing OMCTS and oxygen , used as the precursor in Examples 12 - 14 . The results are but no carrier gas. Syringe Example 11 had a one - component shown in Table 4 . The coatings produced according to these pH protective coating or layer ( OMCTS only ) . Syringes of working examples are contemplated to function as pH Examples 9 - 11 were then tested for lubricity as described for protective coatings or layers , and also as protective coatings Examples 5 - 8 . or layers to increase the shelf life of the vessels , compared to similar vessels provided with a barrier coating or layer but [0366 ] The pH protective coatings or layers produced no pH protective coating or layer. according to these working examples are also contemplated to function as protective coatings or layers to increase the TABLE 4 shelf life of the vessels, compared to similar vessels pro vided with a barrier coating or layer but no pH protective HMDSO pH protective coating or laver coating or layer . HMDSO 02 Ar Example (sccm ) (sccm ) ( sccm ) TABLE 3 12 2 . 5 0 . 38 7 .6 13 0 . 38 OMCTS PH protective coating or layer 14 OMCTS - 2. 5 sccm Argon gas - 7 . 6 sccm (when used ) [0368 ] The pH protective coatings or layers produced Oxygen 0 . 38 sccm (when used ) according to these working examples are also contemplated Power - 3 watts to function as protective coatings or layers to increase the Power on time - 10 seconds shelf life of the vessels , compared to similar vessels pro vided with a barrier coating or layer but no pH protective coating or layer. TABLE 5 Dep . OMCTS Ar/ O Power Time AFM RMS Example ( sccm ) ( sccm ) (Watts ) ( sec ) (nanometers ) 2 . 0 10/ 0 .38 3. 5 10
19 . 6 , 9 . 9 , 9 . 4 (Average = 13 .0 2 .0 10 / 0 . 38 4 . 5 10 FIG . 7 12. 5 , 8 . 4 , 6 . 1 (Average = 6 . 3 ) 2 .0 10 /0 3 . 4 10 1. 9 , 2 .6 , 3 . 0 (Average = 2 . 3 )
TABLE 6 Siloxane Power Dep . Time SiO / Lub Coater Mode Feed Ar/ O2 ( W ) (Sec .) Example 18 SiOz: Auto - Tube Auto HMDSO O sccm Ar, 37 7 SIO / Baseline 52 . 5 in , 90 sccm 02 OMCTS Lub 133. 4 cm . Lubricity : Auto - S same OMCTS , 10 sccm Ar 3 . 4 2 . 0 sccm 0 . 38 sccm 02 Example 19 SiOz: same same same same 37 SiO / High Pwr OMCTS Lub Lubricity : same same same same 4 .5 Example 20 SiOx: Auto - Tube same same O sccm Ar, 37 SiO /No 0 , 90 sccm 2 OMCTS Lub Lubricity : Auto - S same same 10 sccm Ar 3 . 4 10 O sccm 02 US 2019 /0133882 A1 May 9 , 2019
Summary of Lubricity and / or Protective Measurements Most biotech products and many pharma products are stored [ 0369 ] [ Table 8 shows a summary of the above OMCTS at refrigerated conditions and none are typically recom coatings or layers mended for storage above room temperature . As a general rule of thumb , storage at a lower temperature reduces the TABLE 8 thickness required , all other conditions being equivalent. [03741 . The following conclusions are reached , based on Summary Table of OMCTS PH PROTECTIVE COATING this test . First , the amount of dissolved Si in the SiO coating OR LAYER from Tables 1 , 2 , 3 and 5 or glass increases exponentially with increasing pH . Second , OMCTS 0 Ar Power Dep Time the SiOx coating dissolves more slowly than borosilicate Example (sccm ) (sccm ) (sccm ) (Watt ) (sec ) glass at a pH lower than 8 . The SiO coating shows a linear, 3 . 0 0 .00 65 10 monophasic dissolution over time, whereas borosilicate 3 .0 1 .00 65 10 glass tends to show a more rapid dissolution in the early 3 . 0 0 . 38 7 . 8 10 hours of exposure to solutions, followed by a slower linear 0 . 38 10 0 . 38 10 dissolution . This may be due to surface accumulation of mtinao 0 . 38 0 . 0 10 some salts and elements on borosilicate during the forming 11 0 . 00 0 . 0 10 process relative to the uniform composition of the SiO , 15 mimicinini2 . 0 0 . 38 10 10 coating . This result incidentally suggests the utility of an 16 2 . 0 0 . 38 10 10 16A 0 . 00 10 3 . 4 10 SiO coating on the wall of a borosilicate glass vial to reduce 18 0 . 38 10 dissolution of the glass at a pH lower than 8 . Third , PECVD ooo 0 . 38 10 applied barrier coatings for vials in which pharmaceutical 2 . 0 0 .00 3 . 4 10 preparations are stored will need to be adapted to the specific pharmaceutical preparation and proposed storage conditions ( or vice versa ) , at least in some instances in which the Comparative Example 26 : Dissolution of SiO , pharmaceutical preparation interacts with the barrier coating Coating Versus pH significantly [0370 ] The Protocol for Measuring Dissolved Silicon in a Example 27 Vessel is followed , except as modified here . Test solutions 50 mM buffer solutions at pH 3 , 6 , 7 , 8 , 9 , and 12 are [0375 ] An experiment is conducted with vessels coated prepared . Buffers are selected having appropriate pKa val with SiO , coating + OMCTS PH protective coating or layer, ues to provide the pH values being studied . A potassium to test the pH protective coating or layer for its functionality phosphate buffer is selected for pH 3 , 7 , 8 and 12 , a sodium as a protective coating or layer . The vessels are 5 mL vials citrate buffer is utilized for pH 6 and tris buffer is selected (the vials are normally filled with product to 5 mL; their for pH 9 . 3 ml of each test solution is placed in borosilicate capacity without headspace , when capped , is about 7 . 5 mL ) glass 5 ml pharmaceutical vials and Sio , coated 5 ml composed of cyclic olefin co -polymer (COC , Topas® thermoplastic pharmaceutical vials . The vials are all closed 6013M -07 ) . with standard coated stoppers and crimped . The vials are [0376 ] Sixty vessels are coated on their interior surfaces placed in storage at 20 - 25° C . and pulled at various time with an SiO , coating produced in a plasma enhanced chemi points for inductively coupled plasma spectrometer ( ICP ) cal vapor deposition (PECVD ) process using a HMDSO analysis of Si content in the solutions contained in the vials , precursor gas according to the Protocol for Coating Tube in parts per billion (ppb ) by weight, for different storage Interior with SiOx set forth above, except that equipment times . suitable for coating a vial is used . The following conditions [0371 ] The Protocol for Determining Average Dissolution are used . Rate Si content is used to monitor the rate of glass disso lution , except as modified here. The data is plotted to [0377 ] HMDSO flow rate : 0 . 47 sccm determine an average rate of dissolution of borosilicate glass [ 0378 ] Oxygen flow rate : 7 .5 sccm or SiO coating at each pH condition . Representative plots at [0379 ] RF power: 70 Watts pH 6 through 8 are FIGS. 27 - 29 . [0372 ] The rate of Si dissolution in ppb is converted to a [ 0380 ] Coating time: 12 seconds (includes a 2 - sec RF predicted thickness (nm ) rate of Si dissolution by determin power ramp - up time) ing the total weight of Si removed , then using a surface area [0381 ] Next the SiO coated vials are coated over the SiO calculation of the amount of vial surface ( 11. 65 cm2) with an SiO2C , coating produced in a PECVD process using exposed to the solution and a density of SiO , of 2 .2 g /cm3 . an OMCTS precursor gas according to the Protocol for FIG . 9 shows the predicted initial thickness of the SiO , Coating COC Syringe Barrel Interior with OMCTS Lubric coating required , based on the conditions and assumptions ity Coating set forth above , except that the same coating of this example (assuming a residual SiO coating of at least equipment is used as for the SiO , coating . Thus, the special 30 nm at the end of the desired shelf life of two years, and adaptations in the protocol for coating a syringe are not used . assuming storage at 20 to 25° C . ) . As FIG . 9 shows, the The following conditions are used . predicted initial thickness of the coating is about 36 nm at [0382 ] OMCTS flow rate : 2 .5 sccm pH 5 , about 80 nm at pH 6 , about 230 nm at pH 7 , about 400 [0383 ] Argon flow rate : 10 sccm nm at pH 7 . 5 , about 750 nm at pH 8 , and about 2600 nm at pH 9 . [0384 ] Oxygen flow rate : 0 . 7 sccm [ 0373] The coating thicknesses in FIG . 9 represent atypi [0385 ] RF power: 3 .4 Watts cally harsh case scenarios for pharma and biotech products . [0386 ] Coating time: 5 seconds US 2019 /0133882 A1 May 9 , 2019 30
[ 0387 ] Eight vials are selected and the total deposited - continued quantity of PECVD coating (SiO + SiO _ CV) is determined with a Perkin Elmer Optima Model 7300DV ICP - OES Shelf Life Conditions 4° C . instrument, using the Protocol for Total Silicon Measure Vial SiOx + Lubricity Vial SiOx + Lubricity ment set forth above . This measurement determines the total Coating at pH 4 Coating at pH 8 amount of silicon in both coatings, and does not distinguish Si Dissolution Rate 11 between the respective SiOx and SiO Cy coatings . The (PPB /day ) results are shown below . [0391 ] The observations of Si dissolution versus time for the OMCTS -based coating at pH8 and pH 4 indicate the pH Vial Total Silicon ug/ L 4 rates are higher at ambient conditions . Thus, the pH 4 rates 13844 are used to determine how much material would need to be 14878 initially applied to leave a coating of adequate thickness at 14387 the end of the shelf life , taking account of the amount of the 13731 initial coating that would be dissolved . The results of this 15260 calculation are : 15017 15118 Vial SiOx + Lubricity 12736 Coating at pH 4 Mean 14371 Std Dev 877 Si Dissolution Rate (PPB /day ) 31 Mass of Coating Tested ( Total Si ) 14 , 371 Shelf Life ( days ) at 23° C . 464 Quantity of SiOx + Lubricity layer on Vials Shelf Life ( years ) at 23° C . 1 . 3 Required Mass of Coating ( Total Si) - 2 years 22 ,630 [0388 ] In the following work , except as indicated other Required Mass of Coating ( Total Si ) - 3 years 33, 945 wise in this example , the Protocol for Determining Average Dissolution Rate is followed . Two buffered pH test solutions are used in the remainder of the experiment, respectively at Shelf Life Calculation pH 4 and pH 8 to test the effect of pH on dissolution rate . Both test solutions are 50 mM buffers using potassium [ 0392 ] Based on this calculation , the OMCTS protective phosphate as the buffer, diluted in water for injection (WFI ) layer needs to be about 2 . 5 times thicker - resulting in ( 0 . 1 um sterilized , filtered ) . The pH is adjusted to pH 4 or 8 , dissolution of 33945 ppb versus the 14 , 371 ppb representing respectively , with concentrated nitric acid . the entire mass of coating tested — to achieve a 3 -year [ 0389 ] 25 vials are filled with 7 . 5 ml per vial of pH 4 calculated shelf life . buffered test solution and 25 other vials are filled with 7 . 5 ml per vial of pH 4 buffered test solution (note the fill level is Example 28 to the top of the vial no head space ) . The vials are closed using prewashed butyl stoppers and aluminum crimps. The [0393 ] The results of Comparative Example 26 and vials at each pH are split into two groups. One group at each Example 27 above can be compared as follows, where the pH containing 12 vials is stored at 4° C . and the second “ pH protective coating or layer " is the coating of SiO2C , group of 13 vials is stored at 23° C . referred to in Example BB . [ 0390 ] The vials are sampled at Days 1 , 3 , 6 , and 8 . The Protocol for Measuring Dissolved Silicon in a Vessel is used , Shelf Life Conditions - - pH 8 and 23° C . except as otherwise indicated in this example . The analytical Vial SiOx + Lubricity result is reported on the basis of parts per billion of silicon Coating in the buffered test solutions of each vial. A dissolution rate Vial Sio is calculated in termsof parts per billion per day as described Si Dissolution Rate (PPB /day ) 1, 250 above in the Protocol for Determining Average Dissolution Rate . The results at the respective storage temperatures follow : [0394 ] This data shows that the silicon dissolution rate of SiOx alone is reduced by more than 2 orders of magnitude at pH 8 in vials also coated with SiO Cy coatings. Shelf Life Conditions 23° C . Vial SiOx + Lubricity Vial SiOg + Lubricity Example 29 Coating at pH 4 Coating at pH 8 Si Dissolution Rate 31 [0395 ] Another comparison is shown by the following (PPB /day ) data from several different experiments carried out under similar accelerated dissolution conditions , of which the 1 -day data is also presented in FIG . 10 . US 2019 /0133882 A1 May 9 , 2019 31
Silicon Dissolution with pH 8 at 40° C . (ug / L ) Vial Coating 23471015 Description day days days days days days days A . SIO , made with HMDSO 165 211 226 252 435 850 1, 364 Plasma + Sivo C , or its equivalent Sio C , made with OMCTS Plasma B . Si„ O , C , or its 109 107 76 74 158 198 equivalent SiOC, made with OMCTS Plasma C . Sio made with HMDSO 2 ,504 4 ,228 5 ,226 5 ,650 9 ,292 10 ,177 9 ,551 Plasma D . Sio made with HMDSO 1 , 607 1 ,341 3 , 927 10 , 182 18 ,148 20 ,446 21, 889 Plasma + Si„ O _ C , or its equivalent SiO C , made with HMDSO Plasma E . Si„ O C , or its 1 ,515 1 ,731 1 ,813 1 , 743 2 , 890 3 ,241 3 ,812 equivalent SiOzC , made with HMDSO Plasma
[0396 ] FIG . 10 and Row A ( SiOx with OMCTS coating ) [0401 ] In this test , PECVD processing at high W /FM is versus C (SiO without OMCTS coating ) show that the believed to have resulted in higher monomer fragmentation , OMCTS pH protective coating or layer is also an effective producing organosiloxane coatings with higher cross - link protective coating or layer to the SiO , coating at pH 8 . The density . PECVD processing at low W / FM , by comparison , is OMCTS coating reduced the one -day dissolution rate from bebelieved to have resulted in lower monomer fragmentation 2504 ug / L ( “ u ” or p or the Greek letter " mu” as used herein producing organosiloxane coatings with a relatively lower are identical, and are abbreviations for “ micro ” ) to 165 ug / L . cross -link density . This data also shows that an HMDSO -based Si „ O _ C , (or its [0402 ] The relative cross - link density of samples 5 , 6 , 2, equivalent SiO CV ) overcoat (Row D ) provided a far higher and 3 was compared between different coatings by measur dissolution rate than an OMCTS - based SiO _ C , ( or its ing FTIR absorbance spectra . The spectra of samples 5 , 6 , 2 , equivalent SiO C ) overcoat (Row A ) . This data shows that and 3 are provided in FIGS . 13 to 16 . In each spectrum , the a substantial benefit can be obtained by using a cyclic ratio of the peak absorbance at the symmetric stretching precursor versus a linear one . mode ( 1000 - 1040 cm - 1 ) versus the peak absorbance at the asymmetric stretching mode ( 1060 -1100 cm - 1 ) of the Si — Example 30 0 — Si bond was measured , and the ratio of these two measurements was calculated , all as shown in Table 9 . The [ 0397 ] Samples 1 -6 as listed in Table 9 were prepared as respective ratios were found to have a linear correlation to described in Example AA , with further details as follows . the composite parameter W /FM as shown in FIG . 11. [ 0398 ] A cyclic olefin copolymer (COC ) resin was injec [0403 ] A qualitative relation — whether the coating tion molded to form a batch of 5 ml vials . Silicon chips were appeared oily (shiny , often with irridescence ) or non - oily adhered with double- sided adhesive tape to the internal (non - shiny ) when applied on the silicon chips — was also walls of the vials . The vials and chips were coated with a two found to correlate with the W / FM values in Table 9 . Oily layer coating by plasma enhanced chemical vapor deposition appearing coatings deposited at lower W /FM values, as (PECVD ) . The first layer was composed of SiOx with barrier confirmed by Table 9, are believed to have a lower crosslink properties as defined in the present disclosure , and the density, as determined by their lower sym / asym ratio , rela second layer was an Sio CypH protective coating or layer. tive to the non -oily coatings that were deposited at higher [ 0399 ] A precursor gas mixture comprising OMCTS , W / FM and a higher cross- link density . The only exception to argon , and oxygen was introduced inside each vial. The gas this general rule of thumb was sample 2 in Table 9 . It is inside the vial was excited between capacitively coupled believed that the coating of sample 2 exhibited a non - oily electrodes by a radio - frequency ( 13 . 56 MHz) power source . appearance because it was was too thin to see . Thus, an The monomer flow rate (Fm ) in units of sccm , oxygen flow oilyness observation was not reported in Table 9 for sample rate (Fo ) in units of sccm , argon flowrate in sccm , and power 2 . The chips were analyzed by FTIR in transmission mode , ( W ) in units of watts are shown in Table 9 . with the infrared spectrum transmitted through the chip and [ 0400 ] A composite parameter , W / FM in units of kJ/ kg , sample coating , and the transmission through an uncoated was calculated from process parameters W , Fm , Fo and the null chip subtracted . molecular weight, M in g /mol , of the individual gas species . [0404 ] Non -oily organosiloxane layers produced at higher W /FM is defined as the energy input per unit mass of W /FM values , which protect the underlying SiO , coating polymerizing gases . Polymerizing gases are defined as those from aqueous solutions at elevated pH and temperature , species that are incorporated into the growing coating such were preferred because they provided lower Si dissolution as, but not limited to , the monomer and oxygen . Non and a longer shelf life , as confirmed by Table 9. For polymerizing gases , by contrast, are those species that are example , the calculated silicon dissolution by contents of the not incorporated into the growing coating , such as but not vial at a pH of 8 and 40° C . was reduced for the non -oily limited to argon , helium and neon . coatings, and the resulting shelf life was 1381 days in one US 2019 /0133882 A1 May 9 , 2019 32 case and 1147 days in another , as opposed to the much 22unfavorable characteristic for pH protection and long shelf shorter shelf lives and higher rates of dissolution for oily life . coatings . Calculated shelf life was determined as shown for [0408 ] An organosiloxane , pH pH protective coating or Example AA . The calculated shelf life also correlated lin layer was deposited according to the process conditions of early to the ratio of symmetric to asymmetric stretching sample 3 in Table 9 . The coating was deposited at a high modes of the Si - O _ Si bond in organosiloxane pH pro W / FM . This resulted in a non -oily coating with a high Si - O _ Si sym / asym ratio of 0 . 947, which resulted in a low tective coatings or layers . rate of Si dissolution of 79 . 5 ppb /day ( following the Protocol [0405 ] Sample 6 can be particularly compared to Sample for Determining Average Dissolution Rate ) and long shelf 5 . An organosiloxane, pH protective coating or layer was life of 1381 days ( following the Protocol for Determining deposited according to the process conditions of sample 6 in Calculated Shelf Life ) . The FTIR spectrum of this coating is Table 9 . The coating was deposited at a high W / FM . This shown in FIG . 37 , which exhibits a relatively similar asym resulted in a non - oily coating with a high Si - O Si sym / metric Si — Si peak absorbance compared to the sym asym ratio of 0 . 958 , which resulted in a low rate of disso metric Si - 0 — Si peak absorbance . This is an indication of lution of 84 .1 ppb /day (measured by the Protocol for Deter a higher cross- link density coating , which is a preferred mining Average Dissolution Rate ) and long shelf life of 1147 characteristic for pH protection and long shelf life . TABLE 9 FTIR Absorbance Process Parameters Si Dissoution @ pH 8 / 40° C . Si - 0 — Si Si - O _ Si Flow 02 Total Shelf Rate of sym stretch asym stretch Ratio Rate Flow Power W / FM Si life Dissolution ( 1000 ( 1160 - Sio Si Samples OMCTS Ar Rate (W ) (kJ / kg ) (ppb ) (days ) (ppb /day ) 1040 cm - 1) 1100 cm -1 ) (sym /asym ) Oilyness 385 293 . 18 0 . 153 0 . 700 YES ????? 10 0 . 5 14 21613 43464 0 .219 20 0 . 5 2 3088 7180 107 174 . 08 0 .011 0 .020 0 .582 NA 0 . 5 62533 42252 . 17 1381 79 .53 0 . 093 0 .098 0 . 947 NO 0 . 5 18356 27398 380 187 .63 0 . 106 0 . 141 0 . 748 YES M?? 20 0 . 5 14 21613 24699 271 236 .73 0 . 135 0 . 201 0 .673 YES Antino 10 0 .5 14 62533 37094 1147 84 . 1 0 . 134 0 . 140 0 .958 NO days (measured by the Protocol for Determining Calculated Example 31 Shelf Life ). The FTIR spectra of this coating is shown in FIG . 35 , which exhibits a relatively similar asymmetric [0409 ] An experiment similar to Example 27 was carried Si - 0 — Si peak absorbance compared to the symmetric out , modified as indicated in this example and in Table 10 Si — 0 — Si peak absorbance . This is an indication of a (where the results are tabulated ) . 100 5 mL COP vials were higher cross - link density coating , which is a preferred char made and coated with an SiO , barrier layer and an OMCTS acteristic for pH protection and long shelf life . based pH protective coating or layer as described previously , [ 0406 ] An organosiloxane pH protective coating or layer except that for Sample PC194 only the pH protective coating was deposited according to the process conditions of sample or layer was applied . The coating quantity was again mea 5 in Table 9 . The coating was deposited at a moderate sured in parts per billion extracted from the surfaces of the W / FM . This resulted in an oily coating with a low Si — 0 vials to remove the entire pH protective coating or layer, as Si sym /asym ratio of 0 .673 , which resulted in a high rate of reported in Table 10 . dissolution of 236 . 7 ppb / day ( following the Protocol for [0410 ] In this example , several different coating dissolu Determining Average Dissolution Rate ) and shorter shelf life tion conditions were employed . The test solutions used for of 271 days ( following the Protocol for Determining Cal dissolution contained either 0 . 02 or 0 . 2 wt. % polysorbate culated Shelf Life ) . The FTIR spectrum of this coating is 80 surfactant , as well as a buffer to maintain a pH of 8 . shown in FIG . 13 , which exhibits a relatively high asym Dissolution tests were carried out at either 23° C . or 40° C . metric Si – O Si peak absorbance compared to the sym 10411 ] Multiple syringes were filled with each test solu metric Si – 0 Si peak absorbance . This is an indication of tion , stored at the indicated temperature , and analyzed at a lower cross - link density coating , which is contemplated in several intervals to determine the extraction profile and the any embodiment to be an unfavorable characteristic for pH amount of silicon extracted . An average dissolution rate for protection and long shelf life . protracted storage times was then calculated by extrapolat [0407 ] Sample 2 can be particularly compared to Sample ing the data obtained according to the Protocol for Deter 3 . APH protective coating or layer was deposited according mining Average Dissolution Rate . The results were calcu to the process conditions of sample 2 in Table 9 . The coating lated as described previously and are shown in Table 10 . Of was deposited at a low W /FM . This resulted in a coating that particular note, as shown on Table 10 , were the very long exhibited a low Si — Si sym / asym ratio of 0 .582 , which calculated shelf lives of the filled packages provided with a resulted in a high rate of dissolution of 174 ppb /day and PC 194 pH protective coating or layer: short shelf life of 107 days . The FTIR spectrum of this coating is shown in FIG . 36 , which exhibits a relatively high [0412 ] 21045 days (over 57 years ) based on storage at a asymmetric Si — 0 — Si peak absorbance compared to the pH of 8 , 0 .02 wt. % polysorbate - 80 surfactant, at 23° C .; symmetric Si — 0 Si peak absorbance . This is an indica [0413 ] 38768 days (over 100 years ) based on storage at a tion of a lower cross - link density coating, which is an pH of 8 , 0 .2 wt. % polysorbate -80 surfactant, at 23° C .; US 2019 /0133882 A1 May 9 , 2019 33
[ 04141 8184 days (over 22 years ) based on storage at a pH [0418 ] The 150 Watt data in Table 11 is taken under of 8 , 0 . 02 wt. % polysorbate -80 surfactant, at 40° C . ; and somewhat different conditions than the other data, so it is not [0415 ] 14732 days (over 40 years ) based on storage at a pH of 8 , 0 . 2 wt. % polysorbate - 80 surfactant, at 40° C . directly comparable with the 20 - 100 Watt data discussed [ 0416 ] Referring to Table 10 , the longest calculated shelf above . The FTIR data of samples 6 and 8 of Table 11 was lives corresponded with the use of an RF power level of 150 taken from the upper portion of the vial and the FTIR data Watts and a corresponding high W /FM value. It is believed of samples 7 and 9 of Table 11 was taken from the lower that the use of a higher power level causes higher cross - link portion of the vial. Also , the amount of OMCTS was cut in density of the pH protective coating or layer. half for samples 8 and 9 of Table 11, compared to samples TABLE 10 OMCTS Argon 02 Plasma Total Si Calculated Average Rate Flow Rate Flow Rate Flow Rate Power Duration W /FM (PPb ) (OMCTS ) Shelf- life of Dissolution Sample (sccm ) ( sccm ) ( sccm ) ( W ) ( sec) (kJ / kg ) layer ) (days ) (ppb /day ) Process Parameters Si Dissolution @ pH 8 / 23° C ./ 0 .02 % Tween ? -80 PC194 0 . 5 20 0 . 5 150 20 1223335 73660 21045 3 . 5 018 1 . 0 20 0 . 5 18 15 77157 42982 1330 32 . 3 Process Parameters Si Dissolution @ pH 8 /23° C ./ 0 . 2 % Tween ? -80 PC194 0 . 5 20 0 . 5 150 20 1223335 73660 38768 1 . 9 018 1 . 0 20 0 .5 18 15 77157 42982 665 64 . 6 048 4 80 2 35 20 37507 56520 1074 52 .62 Process Parameters Si Dissolution @ pH 8 /40° C . /0 .02 % Tween ® - 80 PC194 0 . 5 20 0 . 5 150 20 1223335 73660 8184 9 018 1 . 0 20 0 .5 18 15 77157 42982 511 84 Process Parameters Si Dissolution @ pH 8 / 40° C ./ 0 . 2 % Tween ® - 80 PC194 0 . 5 20 0. 5 150 20 1223335 73660147325 018 1 .0 20 0 . 5 18 15 77157 42982 255 168
Example 32 6 and 7 . Reducing the oxygen level while maintaining a [0417 ] Another series of experiments similar to those of power level of 150 W raised the symmetric / asymmetric ratio Example 31 are run , showing the effect of progressively still further , as shown by comparing samples 6 and 7 to increasing the RF power level on the FTIR absorbance samples 8 and 9 in Table 11 . spectrum of the pH protective coating or layer. The results [0419 ] It is believed that , other conditions being equal , are tabulated in Table 11 , which in each instance shows a increasing the symmetric / asymmetric ratio increases the symmetric /assymmetric ratio greater than 0 .75 between the shelf life of a vessel filled with a material having a pH maximum amplitude of the Si — o — Si symmetrical stretch exceeding 5 . peak normally located between about 1000 and 1040 cm - 1 , and the maximum amplitude of the Si - 0 — Si assymmetric [0420 ] Table 12 shows the calculated O -Parameters and stretch peak normally located between about 1060 and about N - Parameters (as defined in U . S . Pat. No . 8, 067, 070 ) for the 1100 cm - 1 . Thus , the symmetric /assymmetric ratio is 0 . 79 at experiments summarized in Table 11 . As Table 12 shows, the a power level of 20 W , 1 .21 or 1. 22 at power levels of 40 , O -Parameters ranged from 0 . 134 to 0 .343 , and the N -Pa 60 , or 80 W , and 1 . 26 at 100 Watts under otherwise com rameters ranged from 0 .408 to 0 .623 — all outside the ranges parable conditions. claimed in U . S . Pat. No . 8 , 067 ,070 . TABLE 11 Sym Assym OMCTS Argon 0 Plasma metric Stretch etricStretch Symmetric / Flow Rate Flow Rate Flow Rate Power Duration W / FM Peak at 1000 - Peak at 1060 - Assymetric Samples (sccm ) ( sccm ) (sccm ) ( W ) ( sec ) (kJ / kg ) 1040 cm - 1 1100 cm - 1 Ratio ID Process Parameters FTIR Results 0 .5 20 20 85 , 730 0 . 0793 0 . 1007 0 . 79 0 . 5 40 20 171, 460 0 . 0619 0 . 0507 1 .22 0. 5 60 257 , 190 0 . 1092 0 . 0904 1 . 21 80 342 , 919 0 . 1358 0 . 1116 1 . 22 100 428 , 649 0 . 209 0 . 1658 1 . 26 150 642 ,973 0 . 2312 0 . 1905 1 . 21 un 150 642 , 973 0 . 2324 0 . 1897 1 . 23 0 . 5 150 20 1 ,223 , 335 0 . 1713 0 . 1353 1 . 27 0 . 5 0 .5 150 20 1 ,223 ,335 0 . 1475 0 . 1151 1 . 28 US 2019 /0133882 A1 May 9 , 2019
TABLE 12 OMCTS Argon 02 Plasma Samples Flow Rate Flow Rate Flow Rate Power Duration W /FM O N ID (sccm ) (sccm ) (sccm ) ( W ) ( sec) (kJ / kg ) Parameter Parameter Process Parameters 20 0 .5 20 20 85 ,730 0 . 343 0 . 436 20 0 . 5 40 171, 460 0 . 267 0 .408 20 0 . 5 60 257 , 190 0 . 311 0 . 457 20 0 . 5 80 342 , 919 0 . 270 0 .421 20 0 . 5 100 428 ,649 0 . 177 0 . 406 vauAWN 20 0 . 5 150 642 ,973 0 . 151 0 .453 20 0 . 5 150 642 ,973 0 . 151 0 . 448 20 0 .5 150 1 ,223 , 335 0 . 134 0 .623 0 . 5 20 0 . 5 150 1 ,223 ,335 5 0 . 167 0 .609
Example 33 or layer was applied to some of the syringes according to the [0421 ] The purpose of this example was to evaluate the Protocol for coating COC Syringe Barrel Interior with SiO - recoverability or drainage of a slightly viscous aqueous A pH protective coating or layer was applied to the SiO , solution from glass , COP and coated vials, coated syringes according to the Protocol for Coating COC [ 0422 ] This study evaluated the recovery of a 30 cps Syringe Barrel Interior with OMCTS Lubricity Coating , ( centipoise ) carbohydrate solution in water- for- injection modified as follows. The OMCTS was supplied from a from ( A ) an uncoated COP vial, ( B ) an SiO , + pH protective vaporizer , due to its low volatility . Argon carrier gas was layer coated COP vial prepared according to the above used . The process conditions were set to the following : Protocol for Coating Syringe Barrel Interior with SiO , [ 0427 ] OMCTS3sccm followed by the Protocol for Coating Syringe Barrel Interior [0428 ] Argon gas — 65 sccm with OMCTS PH protective Coating or Layer, and ( C ) a [0429 ] Power — 6 watts glass vial. [ 0430 ] Time - 10 seconds [0423 ] 2 . 0 ml of the carbohydrate solution was pipetted [ 0431 ] The coater was later determined to have a small into 30 vials each of glass, COP and pH protective coated leak while producing the samples identified in the Table , vials . The solution was aspirated from the vials with a 10 ml which resulted in an estimated oxygen flow of 1 . 0 sccm . The syringe , through a 23 gauge, 1 . 5 " needle . The vials were samples were produced without introducing oxygen . tipped to one side as the solution was aspirated to maximize [0432 ] The coatings produced according to these working the amount recovered . The same technique and similar examples are contemplated to function as primer coatings or withdrawal time was used for all vials . The vials were layers , and also as protective coatings or layers to increase weighed empty, after placing 2 . 0 ml of the solution to the the shelf life of the vessels , compared to similar vessels vial and at the conclusion of aspirating the solution from the provided with a barrier coating or layer but no pH protective vial. The amount delivered to the vial ( A ) was determined by coating or layer. subtracting the weight of the empty vial from the weight of the vial with the 2 . 0 ml of solution . The weight of solution PECVD Process for Trilayer Coating not recovered ( B ) was determined by subtracting the weight of the empty vial from the weight of the vials after aspirating [ 0433 ] The PECVD trilayer coating described in this the solution from the vial . The percent unrecovered was specification can be applied , for example , as follows for a 1 determined by dividing B by A and multiplying by 100 . to 5 mL vessel . Two specific examples are 1 mL thermo [ 0424 ] It was observed during the aspiration of drug plastic resin syringe and a 5 mL thermoplastic resin drug product that the glass vials remained wetted with the solu vial. Larger or smaller vessels will call for adjustments in tion . The COP vial repelled the liquid and as the solution was parameters that a person of ordinary skill can carry out in aspirated from the vials . This helped with recovery but view of the teaching of this specification . droplets were observed to bead on the sidewalls of the vials [0434 ] The apparatus used is the PECVD apparatus with during the aspiration . The pH protective coated vials also rotating quadrupole magnets as described generally in this repelled the liquid during aspiration but no beading of specification . solution on the sidewalls was observed . [ 0435 ] The general coating parameter ranges, with pre [0425 ] The conclusion was that pH protective coated vials ferred ranges in parentheses , for a trilayer coating for a 1 mL do not wet with aqueous solutions as do glass vials , leading syringe barrel are shown in the PECVD Trilayer Process to superior recovery of drug product relative to glass. PH General Parameters Tables ( 1 mL syringe and 5 mL vial) . protective coated vials were not observed to cause beading of solution on sidewall during aspiration of aqueous prod ucts therefore coated vials performed better than uncoated PECVD Trilaver Process General Parameters Table ( 1 mL syringe ) COP vials in product recovery experiments . Parameter Units Tie Barrier pH Protective Example 34 Power W 40 - 90 140 40 - 90 (60 - 80 ) (60 - 80 ) [ 0426 ] Syringe samples were produced as follows. A COC TMDSO Flow sccm 1 - 10 None 1 - 10 8007 extended barrel syringe was produced according to the ( 3 - 5 ) ( 3 - 5 ) Protocol for Forming COC Syringe Barrel . An SiO , coating US 2019 /0133882 A1 May 9 , 2019 35
-continued -continued PECVD Trilayer Process General Parameters Table ( 1 mL syringe ) PECVD Trilayer Process Specific Parameters Table (5 mL vial) Parameter Units Tie Barrier pH Protective Parameter Units Adhesion Barrier Protection HMDSO Flow sccm None 1 . 56 None Deposition Time seconds 2 . 5 10 10 O2 Flow sccm 0 . 5 - 5 20 0 . 5 - 5 Tube Pressure Torr 0 . 85 1 . 29 0 . 85 ( 1 . 5 - 2 . 5 ) ( 1 . 5 - 2 . 5 ) Argon Flow sccm 40 - 120 O 40 - 120 (70 - 90 ) ( 70 - 90 ) [ 0437 ] The O - parameter and N - parameter values for the Ramp Time seconds None None None pH protective coating or layer applied to the 1 mL syringe Deposition Time seconds 0 . 1 - 10 20 0 . 1 - 40 as described above are 0 .34 and 0 .55 , respectively . ( 1 - 3 ) (15 - 25 ) [0438 ] The O - parameter and N -parameter values for the Tube Pressure Torr 0 .01 - 10 0 . 59 0 .01 - 10 pH protective coating or layer applied to the 5 mL vial are (0 . 1 - 1 . 5 ) ( 0 . 1 - 1 . 5 ) 0 . 24 and 0 .63 , respectively . Example 36 PECVD Trilayer Process General Parameters Table ( 5 mL vial) [0439 ] Referring to FIG . 18 and Table , Example 36 , the thickness uniformity at four different points along the length Parameter Units Adhesion Barrier Protection of a 1 mL syringe with a staked needle (present during Power 40 - 90 140 40 - 90 PECVD deposition ) and the indicated trilayer coating ( avg. (60 - 80 ) ( 60 - 80 ) thicknesses: 38 nm adhesion or tie coating or layer ; 55 nm TMDSO Flow sccm 1 - 10 None 1 - 10 barrier coating or layer, 273 nm pH protective coating or ( 3 - 5 ) ( 3 - 5 ) HMDSO Flow sccm None 1 . 56 None layer ) is shown . The table shows individual layer thick O2 Flow sccm 0 . 5 - 5 20 0 . 5 - 5 nesses at the four marked points, showing adequate thick ( 1 . 5 - 2 . 5 ) ( 1 . 5 - 2 . 5 ) ness of each layer at each point along the high profile syringe Argon Flow sccm 40 - 120 40 - 120 barrel. ( 70 - 90 ) (70 - 90 ) Ramp Time seconds None None None Deposition Time seconds 0 . 1 - 10 20 0 . 1 - 40 TABLE ( 1 - 3 ) ( 15 - 25 ) Tube Pressure Torr 0 .01 - 10 0 . 59 0 .01 - 10 Example 36 ( 0 . 1 - 1 . 5 ) ( 0 . 1 - 1. 5 ) Syringe Location Adhesion Barrier Protection 46 N 343 in 273 Anm 493 Example 35 42 287 [0436 ] Examples of specific coating parameters that have been used for a 1 mL syringe and 5 mL vial are shown in the [0440 ] Referring to FIG . 19 , the plot maps the coating PECVD Trilayer Process Specific Parameters Tables ( 1 mL thickness over the portion of the cylindrical inner surface of syringe and 5 mL vial) : the barrel shown in FIG . 18 , as though unrolled to form a rectangle . The overall range of thickness of the trilayer coating is 572 plus or minus 89 nm . PECVD Trilayer Process Specific Parameters Table ( 1 mL syringe ) [0441 ] FIG . 20 is a photomicrograph showing a cross section of the trilayer coating on a COP syringe substrate at Parameter Units Tie Barrier Protection the point 2 shown in FIG . 18 . Power W 70 140 70 [0442 ] A syringe having a coating similar to the trilayer TMDSO Flow sccm 4 . None coating of FIGS . 18 - 20 is tested for shelf life , using the HMDSO Flow sccm None 1 . 56 None silicon dissolution and extrapolation method described in O , Flow sccm 2 20 2 Argon Flow sccm 80 80 this specification , compared to syringes having a bilayer Ramp Time seconds None None None coating (similar to the trilayer coating except lacking the tie Deposition Time seconds 2 .5 20 10 coating or layer ) and a monolayer coating which is just the Tube Pressure Torr 1 0 591. pH protective coating or layer directly applied to the ther moplastic barrel of the syringe , with no barrier layer. The test solution was a 0 . 2 % Tween , pH 8 phosphate buffer . The extrapolated shelf lives of the monolayer and trilayer coat PECVD Trilayer Process Specific Parameters Table ( 5 mL vial) ings were similar and very long on the order of 14 years . The shelf life of the syringes having a bilayer coating were Parameter Units Adhesion Barrier Protection much lower - less than two years. In other words, the Power presence of a barrier layer under the pH protective layer TMDSO Flow sccm shortened the shelf life of the coating substantially, but the HMDSO Flow sccm 0 , Flow sccm shelf life was restored by providing a tie coating or layer Argon Flow sccm under the barrier layer, sandwiching the barrier coating or Ramp Time seconds layer with respective SiO , C , , layers . The barrier layer is necessary to establish a gas barrier, so the monolayer coating US 2019 /0133882 A1 May 9 , 2019 36 would not be expected to provide adequate gas barrier the stain penetrated . The trilayer coating, however, protected properties by itself . Thus, only the trilayer coating had the the entire vial against penetration of the stain , and the combination of gas barrier properties and a long shelf life , illustrated vial remains clear after treatment. This is believed even while in contact with a solution that would attack an to be the result of sandwiching the barrier coating or layer exposed barrier coating or layer. between two layers of SiO _ C , which both protects the barrier layer against direct etching and against undercutting Example 37 and removal of flakes of the barrier layer . 1 - 13 . ( canceled ) [ 0443 ] FIGS. 21 and 22 show a trilayer coating distribu 14 . A vessel comprising: tion for the 5 mL vial, which is much shorter in relation to a thermoplastic wall having an interior surface enclosing its inner diameter and thus easier to coat uniformly , showing at least a portion of a lumen ; very little variation in coating thickness , with the great a tie coating or layer comprising SiO CH , or SiN _CH , majority of the surface coated between 150 and 250 nm in which x is from 0 . 5 to 2 . 4 as measured by X - ray thickness of the trilayer, with only a small proportion of the photoelectron spectroscopy ( XPS ) , y is from 0 . 6 to 3 as container coated with between 50 and 250 nm of the trilayer. measured by XPS , and z is from 2 to 9 as measured by Example 38 Rutherford backscattering spectrometry (RBS ) , the tie coating or layer having an outer surface facing the [ 0444 ] FIG . 23 shows the breakdown of coating thickness interior surface of the thermoplastic wall and the tie ( nm ) by vial location . The Vial Coating Distribution Table coating or layer having an interior surface ; shows the uniformity of coating. a barrier coating or layer of SiOr, in which x is from 1 . 5 to 2 . 9 as measured by XPS , the barrier coating or layer positioned between the interior surface of the tie coat Vial Coating Distribution Table ing or layer and the lumen ; and Vial Location Adhesion Barrier Protection Total Trilayer, nm a pH protective coating or layer of SiO C , H ,, in which x is from 0 . 5 to 2 . 4 as measured by XPS , y is from 0 .6 to 77 119 3 as measured by XPS , and z is from 2 to 9 as measured ? 58 93 115 177 by RBS , positioned between the barrier coating or layer ? 158 242 and the lumen , in which an FTIR absorbance spectrum 161 249 of the pH protective coating or layer has a ratio greater 45AwNN 148 226 153 than 0 . 9 between : OvaAWNA ??? 29 213 wwwWNPA 10 218 282 the maximum amplitude of the Si — Si symmetrical 155 241 stretch peak between 1000 and 1040 cm - , and 10 29 150 210 the maximum amplitude of the Si — 0 — Si asymmetric Average 36 139 205 stretch peak between 1060 and 1100 cm - l ; in which the silicon dissolution rate by a 50 mM potassium phosphate buffer diluted in water for injection , adjusted to Example 39 pH 8 with concentrated nitric acid , and containing 0 . 2 wt. % [0445 ] FIG . 24 is a visual test result showing the integrity polysorbate - 80 surfactant, from the vessel is less than 170 of the trilayer vial coating described above . The three 5 mL ppb /day . cyclic olefin polymer (COC ) vials of FIGS. 24 and 24A were 15 . The vessel of claim 14 , in which at least one of the tie respectively : coating or layer, the barrier coating or layer, or the pH [0446 ] uncoated ( left vial) , protective coating or layer is applied by plasma enhanced [0447 ] coated with the bilayer coating described in this chemical vapor deposition (PECVD ). specification ( a barrier coating or layer plus a pH 16 . The vessel of claim 14 , which is a syringe barrel , a protective coating or layer — the second and third com vial, a cartridge or a blister package . ponents of the trilayer coating ) (center vial) ; and 17 . The vessel of claim 14 , in which at least a portion of [0448 ] coated with the trilayer coating as described the thermoplastic wall comprises: above (right vial) . a polyolefin , [ 04491. The three vials were each exposed to 1 N potas a polyvinylalcohol sium hydroxide for four hours , then exposed for 24 hours to a polymethacrylate ether a ruthenium oxide (Ru04 ) stain that darkens any exposed a polyacrylic acid part of the thermoplastic vial unprotected by the coatings . a polyamide The high pH potassium hydroxide exposure erodes any a polyimide exposed part of the barrier coating or layer at a substantial a polysulfone rate , greatly reduced , however by an intact pH protective a polylactic acid coating or layer. In particular , the high pH exposure opens a cyclic olefin polymer or copolymer up any pinholes in the coating system . As FIG . # 24 shows , a polyester or the uncoated vial is completely black , showing the absence a combination of a polyolefin and a polyester of any effective coating . The bilayer coating was mostly 18 . The vessel of claim 14 , in which , for at least one of the intact under the treatment conditions , but on microscopic pH protective coating or layer or the tie coating or layer , x inspection has many pinholes ( illustrated by FIG . 24A ) is from 1 to 2 as measured by XPS , y is from 0 . 6 to 1 . 5 as where the ruthenium stain reached the thermoplastic sub measured by XPS , and z is from 2 to 5 as measured by RBS . strate through the coating . The overall appearance of the 19 . The vessel of claim 14 , in which the pH protective bilayer coating clearly shows visible “ soiled ” areas where coating or layer is from about 10 to about 1000 nm thick . US 2019 /0133882 A1 May 9 , 2019 37
20 . The vessel of claim 14 , in which the rate of erosion of 24 . The vessel of claim 14 , in which the tie coating or the pH protective coating or layer, if directly contacted by a layer has an average thickness from 5 to 200 nm . fluid contained in the lumen having a pH greater than 5 , is less than 20 % of the rate of erosion of the barrier coating or 25 . The vessel of claim 14, which is a prefilled syringe layer , if directly contacted by the same fluid under the same having a syringe barrel coated on its interior wall with the tie conditions . coating or layer , barrier coating or layer, and pH protective 21 . The vessel of claim 14 , having a shelf life , while coating or layer, further having a plunger seated in the barrel directly contacted by a fluid contained in the lumen having and containing a pharmaceutical composition having a pH a pH greater than 5 , of at least two years , based on storage greater than 5 contained in the lumen , the prefilled syringe of the vessel containing the fluid at 20° C . having a shelf life of at least six months. 22 . The vessel of claim 14 , in which a fluid contained in the lumen having a pH greater than 5 removes the pH 26 . A process for making a vessel according to claim 14 , protective coating or layer at a rate of 1 nm or less of pH the process comprising the steps : protective coating or layer thickness per 88 hours of contact forming a tie coating or layer; with the fluid . 23 . The vessel of claim 14 , wherein the pH protective forming a barrier coating or layer ; and coating or layer shows an O - Parameter measured with forming a pH protective coating or layer positioned attenuated total reflection (ATR ) of less than 0 . 4 , measured between the barrier coating or layer and the lumen , as: the pH protective coating or layer and tie coating or layer together being effective to keep the barrier coating or layer Intensity at 1253 cm - 1 at least substantially undissolved as a result of attack by a 0 - Parameter = fluid contained in the lumen having a pH greater than 5 for Maximum intensity in the range from 1000 to 1100 cm - 1 . a period of at least six months.