U.S. patent application number 13/697048 was filed with the patent office on 2013-08-15 for lubricity vessel coating, coating process and apparatus.
The applicant listed for this patent is Robert Abrams, John Felts, John Ferguson, Tom Fisk, Jonathan Freedman, Robert Pangborn, Peter Sagona. Invention is credited to Robert Abrams, John Felts, John Ferguson, Tom Fisk, Jonathan Freedman, Robert Pangborn, Peter Sagona.
Application Number | 20130209766 13/697048 |
Document ID | / |
Family ID | 44924900 |
Filed Date | 2013-08-15 |
United States Patent
Application |
20130209766 |
Kind Code |
A1 |
Felts; John ; et
al. |
August 15, 2013 |
LUBRICITY VESSEL COATING, COATING PROCESS AND APPARATUS
Abstract
A method for coating a substrate surface by PECVD is provided,
the method comprising generating a plasma from a gaseous reactant
comprising an organosilicon precursor and optionally O.sub.2. The
lubricity, hydrophobicity and/or barrier properties of the coating
are set by setting the ratio of the O.sub.2 to the organo silicon
precursor in the gaseous reactant, and/or by setting the electric
power used for generating the plasma. In particular, a lubricity
coating made by said method is provided. Vessels coated by said
method and the use of such vessels protecting a compound or
composition contained or received in said coated vessel against
mechanical and/or chemical effects of the surface of the uncoated
vessel material are also provided.
Inventors: |
Felts; John; (Alameda,
CA) ; Fisk; Tom; (Green Valley, AZ) ; Abrams;
Robert; (Albany, NY) ; Ferguson; John;
(Auburn, AL) ; Freedman; Jonathan; (Auburn,
AL) ; Pangborn; Robert; (Harbor Springs, MI) ;
Sagona; Peter; (Pottstown, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Felts; John
Fisk; Tom
Abrams; Robert
Ferguson; John
Freedman; Jonathan
Pangborn; Robert
Sagona; Peter |
Alameda
Green Valley
Albany
Auburn
Auburn
Harbor Springs
Pottstown |
CA
AZ
NY
AL
AL
MI
PA |
US
US
US
US
US
US
US |
|
|
Family ID: |
44924900 |
Appl. No.: |
13/697048 |
Filed: |
May 11, 2011 |
PCT Filed: |
May 11, 2011 |
PCT NO: |
PCT/US11/36097 |
371 Date: |
February 18, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12779007 |
May 12, 2010 |
7985188 |
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13697048 |
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PCT/US10/34586 |
May 12, 2010 |
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12779007 |
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61177984 |
May 13, 2009 |
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61222727 |
Jul 2, 2009 |
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61213904 |
Jul 24, 2009 |
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61234505 |
Aug 17, 2009 |
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61261321 |
Nov 14, 2009 |
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61263289 |
Nov 20, 2009 |
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61285813 |
Dec 11, 2009 |
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61298159 |
Jan 25, 2010 |
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61299888 |
Jan 29, 2010 |
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61318197 |
Mar 26, 2010 |
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61333625 |
May 11, 2010 |
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61452526 |
Mar 14, 2011 |
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61413334 |
Nov 12, 2010 |
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61359434 |
Jun 29, 2010 |
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61177984 |
May 13, 2009 |
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61222727 |
Jul 2, 2009 |
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61213904 |
Jul 24, 2009 |
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61234505 |
Aug 17, 2009 |
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61261321 |
Nov 14, 2009 |
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61263289 |
Nov 20, 2009 |
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61285813 |
Dec 11, 2009 |
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61298159 |
Jan 25, 2010 |
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61299888 |
Jan 29, 2010 |
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61318197 |
Mar 26, 2010 |
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61333625 |
May 11, 2010 |
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Current U.S.
Class: |
428/216 ;
206/524.3; 427/578; 427/579; 428/447; 604/230 |
Current CPC
Class: |
B05D 7/02 20130101; B65D
25/14 20130101; C23C 16/50 20130101; C23C 16/505 20130101; C23C
16/045 20130101; G01N 15/082 20130101; Y10T 428/31663 20150401;
C23C 16/52 20130101; C23C 16/54 20130101; C03C 2204/00 20130101;
C23C 16/401 20130101; Y10T 428/24975 20150115; B05D 1/62 20130101;
B05D 5/08 20130101; G01N 2033/0096 20130101; A61M 5/31513 20130101;
C03C 8/00 20130101 |
Class at
Publication: |
428/216 ;
427/578; 427/579; 428/447; 206/524.3; 604/230 |
International
Class: |
C23C 16/50 20060101
C23C016/50; A61M 5/315 20060101 A61M005/315; B65D 25/14 20060101
B65D025/14 |
Foreign Application Data
Date |
Code |
Application Number |
May 12, 2010 |
EP |
10162761.0 |
Claims
1. A method for preparing a lubricity coating on a plastic
substrate, the method comprising: (a) providing a gas comprising an
organosilicon precursor, and optionally O.sub.2, and optionally a
noble gas, in the vicinity of the substrate surface; and (b)
generating a plasma in the gas, thus forming a coating on the
substrate surface by plasma enhanced chemical vapor deposition
(PECVD).
2. The method of claim 1, wherein the organosilicon precursor is a
monocyclic siloxane.
3. The method according to claim 1, wherein O.sub.2 is in a
volume-volume ratio to the organosilicon precursor of from 0:1 to
0.5:1.
4. The method according to claim 1, wherein the noble gas comprises
argon, helium, xenon, neon, or a combination of two or more of
these.
5. The method according to claim 1, wherein the gas comprises from
1 to 6 standard volumes of the organosilicon precursor, from 1 to
100 standard volumes of the noble gas, and from 0.1 to 2 standard
volumes of O.sub.2.
6. The method according to claim 1, wherein both Ar and O.sub.2 are
present.
7. The method according to claim 1: (i) wherein the plasma is
generated with an electric power of from 0.1 to 25 W; and (ii)
wherein the ratio of the electrode power to the plasma volume is
less than 10 W/ml.
8. The method according to claim 1, wherein the resulting coating
has a roughness when determined by AFM and expressed as RMS of from
more than 0 to 25 nm.
9. The method according to claim 1, additionally comprising
preparing a barrier coating on the substrate before the lubricity
coating is applied: (a) providing a gas comprising an organosilicon
precursor and O.sub.2 in the vicinity of the substrate surface; and
(b) generating a plasma from the gas, thus forming a SiO.sub.x
barrier coating on the substrate surface by plasma enhanced
chemical vapor deposition (PECVD).
10. The method according to claim 9 wherein when preparing the
barrier coating: (i) the plasma is generated with electrodes
powered with sufficient power to form a SiO.sub.x barrier coating
on the substrate surface; (ii) the ratio of the electrode power to
the plasma volume is equal or more than 5 W/ml, preferably is from
6 W/ml to 150 W/ml; and (iii) the O.sub.2 is present in a
volume:volume ratio of from 1:1 to 100:1 in relation to the silicon
containing precursor.
11. The method of claim 9, wherein the organosilicon precursor for
the barrier coating is a linear siloxane.
12. The method according to claim 1, wherein the substrate is a
polymer selected from the group consisting of a polycarbonate, an
olefin polymer, a cyclic olefin copolymer and a polyester.
13. The method according to claim 1, wherein the plasma is
generated with electrodes powered at a radio frequency.
14. The method according to claim 1, wherein the resulting
lubricity coating has an atomic ratio Si.sub.wO.sub.xC.sub.y or
Si.sub.wN.sub.xC.sub.y wherein w is 1, x is from about 0.5 to about
2.4, y is from about 0.6 to about 3.
15. (canceled)
16. A plastic substrate coated with a lubricity coating made by:
(a) providing a gas comprising an organosilicon precursor, and
optionally O.sub.2, and optionally a noble gas, in the vicinity of
the substrate surface; and (b) generating a plasma in the gas, thus
forming a coating on the substrate surface by plasma enhanced
chemical vapor deposition (PECVD); wherein the lubricity coating
has a lower frictional resistance than the uncoated surface.
17. The coated substrate according to claim 16, additionally
comprising at least one layer of SiO.sub.x, wherein x is from 1.5
to 2.9, wherein (i) the SiO.sub.x layer is situated between the
lubricity coating and the substrate surface.
18. The coated substrate according to claim 17, wherein the
SiO.sub.x barrier coating has a thickness of from 20 to 30 nm and
the lubricity coating has an average thickness of from 1 to 5000
nm.
19. The coated substrate according to claim 16, wherein the
lubricity coating is more hydrophobic than the uncoated
surface.
20. A vessel having an interior surface coated at least in part
with a lubricity coating made by: (a) providing a gas comprising an
organosilicon precursor, and optionally O.sub.2 and optionally a
noble gas, in the vicinity of the interior surface; and (b)
generating a plasma in the gas, thus forming a coating on the
substrate surface by plasma enhanced chemical vapor deposition
(PECVD); wherein the lubricity coating has a lower frictional
resistance than the uncoated interior surface by at least 25%.
21. The coated vessel according to claim 20 which contains a
medicament.
22. The coated vessel according to claim 20, which is a syringe or
syringe part, in which the interior surface is defined by a syringe
barrel.
23. The coated vessel of claim 22, wherein the plunger initation
force Fi is from 2.5 to 5 lbs and the plunger maintenance force Fm
is from 2.5 to 8 lbs.
24. The coated vessel of claim 22, wherein the lubricity coating
has the atomic ratio Si.sub.wO.sub.xC.sub.y or
Si.sub.wN.sub.xC.sub.y wherein w is 1, x is from about 0.5 to about
2.4, and y is from about 0.6 to about 3.
25. The coated vessel of claim 2, wherein the lubricity coating has
an average thickness of from 10 to 1000 nm.
26. The coated vessel of claim 2, wherein the plastic substrate is
COC, wherein the gas in step (a) comprises
octamethylcyclotetrasiloxane, O.sub.2 and Ar, and wherein the power
for generating the plasma is from 6 W/ml to 0.1 W/ml in relation to
the volume of the syringe lumen.
27. The coated vessel of coated vessel of claim 20, which contains
a medicament.
28-30. (canceled)
Description
[0001] U.S. Provisional Ser. Nos. 61/177,984 filed May 13, 2009;
61/222,727, filed Jul. 2, 2009; 61/213,904, filed Jul. 24, 2009;
61/234,505, filed Aug. 17, 2009; 61/261,321, filed Nov. 14, 2009;
61/263,289, filed Nov. 20, 2009; 61/285,813, filed Dec. 11, 2009;
61/298,159, filed Jan. 25, 2010; 61/299,888, filed Jan. 29, 2010;
61/318,197, filed Mar. 26, 2010; 61/333,625, filed May 11, 2010;
and 61/413,334, filed Nov. 12, 2010; and U.S. Ser. No. 12/779,007,
filed May 12, 2010, are all incorporated here by reference in their
entirety.
[0002] Also incorporated by reference in their entirety are the
following European patent applications: EP10162755.2 filed May 12,
2010; EP10162760.2 filed May 12, 2010; EP10162756.0 filed May 12,
2010; EP10162758.6 filed May 12, 2010; EP10162761.0 filed May 12,
2010; and EP10162757.8 filed May 12, 2010. These European patent
applications describe apparatus, vessels, precursors, coatings and
methods (in particular coating methods and test methods for
examining the coatings) which can generally be used in performing
the present invention, unless stated otherwise herein. They also
describe SiO.sub.x barrier coatings to which reference is made
herein.
FIELD OF THE INVENTION
[0003] The present invention relates to the technical field of
fabrication of coated vessels for storing biologically active
compounds or blood. For example, the invention relates to a vessel
processing system for coating of a vessel, vessel processing system
for coating and inspection of a vessel, to a plasma enhanced
chemical vapour deposition apparatus for coating an interior
surface of a vessel, to a method for coating an interior surface of
a vessel, to a method for coating and inspection of a vessel, to a
method of processing a vessel, to the use of a vessel processing
system, to a computer-readable medium and to a program element.
[0004] A method for coating a substrate surface by PECVD is
provided, the method comprising generating a plasma from a gaseous
reactant comprising an organosilicon precursor and optionally
O.sub.2. A carrier gas may also be present. The lubricity,
hydrophobicity and/or barrier properties of the coating are set by
setting the ratio of the O.sub.2 to the organosilicon precursor and
to the carrier gas in the gaseous reactant, and/or by setting the
electric power used for generating the plasma. In particular, a
lubricity coating made by said method is provided. Vessels coated
by said method and the use of such vessels protecting a compound or
composition contained or received in said coated vessel against
mechanical and/or chemical effects of the surface of the uncoated
vessel material are also provided. Further provided are surfaces
coated with the lubricity coating, and methods for production of
said lubricity coating.
[0005] The present disclosure also relates to improved methods for
processing vessels, for example multiple identical vessels used for
venipuncture and other medical sample collection, pharmaceutical
preparation storage and delivery, and other purposes. Such vessels
are used in large numbers for these purposes, and must be
relatively economical to manufacture and yet highly reliable in
storage and use.
BACKGROUND OF THE INVENTION
[0006] An important consideration when regarding syringes is to
ensure that the plunger can move at a constant speed and with a
constant force when it is pressed into the barrel. For this
purpose, a lubricity layer, either on one or on both of the barrel
and the plunger, is desirable. A similar consideration applies to
vessels which have to be closed by a stopper, and to the stopper
itself, and more generally to any surface which has to provide a
certain lubricity.
[0007] There are additional considerations to be taken into account
when manufacturing a prefilled syringe. Prefilled syringes are
commonly prepared and sold so the syringe does not need to be
filled before use. The syringe can be prefilled with saline
solution, a dye for injection, or a pharmaceutically active
preparation, for some examples.
[0008] Commonly, the prefilled syringe is capped at the distal end,
as with a cap, and is closed at the proximal end by its drawn
plunger. The prefilled syringe can be wrapped in a sterile package
before use. To use the prefilled syringe, the packaging and cap are
removed, optionally a hypodermic needle or another delivery conduit
is attached to the distal end of the barrel, the delivery conduit
or syringe is moved to a use position (such as by inserting the
hypodermic needle into a patient's blood vessel or into apparatus
to be rinsed with the contents of the syringe), and the plunger is
advanced in the barrel to inject the contents of the barrel.
[0009] One important consideration in manufacturing pre-filled
syringes is that the contents of the syringe desirably will have a
substantial shelf life, during which it is important to isolate the
material filling the syringe from the barrel wall containing it, to
avoid leaching material from the barrel into the prefilled contents
or vice versa.
[0010] Since many of these vessels are inexpensive and used in
large quantities, for certain applications it will be useful to
reliably obtain the necessary shelf life without increasing the
manufacturing cost to a prohibitive level. For decades, most
parenteral therapeutics have been delivered to end users in Type I
medical grade borosilicate glass containers such as vials or
pre-filled syringes. The relatively strong, impermeable and inert
surface of borosilicate glass has performed adequately for most
drug products. However, the recent advent of costly, complex and
sensitive biologics as well as such advanced delivery systems as
auto injectors has exposed glass' physical and chemical
shortcomings including possible contamination from metals and
breakage, among other problems. Moreover, glass contains several
components which can leach out during storage and cause damage to
the stored material. In more detail, borosilicate vessels exhibit a
number of drawbacks: [0011] Glass is manufactured from sand
containing a heterogeneous mixture of many elements (silicon,
oxygen, boron, aluminum, sodium, calcium) with trace levels of
other alkali and earth metals. Type I borosilicate glass consists
of approximately 76% SiO.sub.2, 10.5% B.sub.2O.sub.3, 5%
Al.sub.2O.sub.3, 7% Na.sub.2O and 1.5% CaO and often contains trace
metals such as iron, magnesium, zinc, copper and others. The
heterogeneous nature of borosilicate glass creates a non-uniform
surface chemistry at the molecular level. Glass forming processes
used to create glass containers expose some portions of the
containers to temperatures as great as 1200.degree. C. Under such
high temperatures alkali ions migrate to the local surface and form
oxides. The presence of ions extracted from borosilicate glass
devices may be involved in degradation, aggregation and
denaturation of some biologics. Many proteins and other biologics
must be lyophilized (freeze dried), because they are not
sufficiently stable in solution in glass vials or syringes. [0012]
In glass syringes, silicon oil is typically used as a lubricant to
allow the plunger to slide in the barrel. Silicon oil has been
implicated in the precipitation of protein solutions such as
insulin and some other biologics. Additionally, the silicon oil
coating is often non-uniform, resulting in syringe failures in the
market. [0013] Glass vessels are prone to breakage or degradation
during manufacture, filling operations, shipping and use, which
means that glass particulates may enter the drug. The presence of
glass particles has led to many FDA Warning Letters and to product
recalls. [0014] Glass-forming processes do not yield the tight
dimensional tolerances required for some of the newer
auto-injectors and delivery systems.
[0015] As a result, some companies have turned to plastic vessels,
which provide greater dimensional tolerance and less breakage than
glass but lack its impermeability.
[0016] Although plastic is superior to glass with respect to
breakage, dimensional tolerances and surface uniformity, plastic's
use for primary pharmaceutical packaging remains limited due to the
following shortcomings: [0017] Surface characteristics: Plastics
suitable for pre-syringes and vials generally exhibit hydrophobic
surfaces, which often reduce the stability of the biologic drug
contained in the device. [0018] Gas (oxygen) permeability: Plastic
allows small molecule gases to permeate into (or out of) the
device. Plastics' permeability to gases is significantly greater
than that of glass and, in many cases (as with oxygen-sensitive
drugs such as epinephrine), plastics are unacceptable for that
reason. [0019] Water vapor transmission: Plastics allow water
vapors to pass through devices to a greater degree than glass. This
can be detrimental to the shelf life of a solid (lyophilized) drug.
Alternatively, a liquid product may lose water in an arid
environment. [0020] Leachables and extractables: Plastic vessels
contain organic compounds that can leach out or be extracted into
the drug product. These compounds can contaminate the drug and/or
negatively impact the drug's stability.
[0021] Clearly, while plastic and glass vessels each offer certain
advantages in pharmaceutical primary packaging, neither is optimal
for all drugs, biologics or other therapeutics. Thus, there is a
desire for plastic vessels, in particular plastic syringes, with
gas and solute barrier properties which approach the properties of
glass. Moreover, there is a need for plastic syringes with
sufficient lubricity properties and a lubricity coating which is
compatible with the syringe contents.
[0022] A non-exhaustive list of patents of possible relevance
includes U.S. Pat. Nos. 6,068,884 and 4,844,986 and U.S. Published
Applications 20060046006 and 20040267194.
SUMMARY OF THE INVENTION
[0023] The present invention pertains to plastic vessels, in
particular vials and syringes, coated with thin, PECVD coatings
made from organosilicon precursors. These novel devices offer the
superior barrier properties of glass and the dimensional tolerances
and breakage resistance of plastics, yet eliminate the drawbacks of
both materials. With designed modifications to the PECVD process,
the surface chemistry of the coating can be predictably varied. In
particular, a plasma coating (SiOxCyHz) is provided which improves
lubricity ("lubricity coating"), thus eliminating the need for
traditional silicon oil lubricants e.g. in syringes. Further
embodiments of the invention are methods to influence the
hydrophobicity/hydrophilicity of said coatings and the resulting
coated devices.
[0024] A particular embodiment of present invention is a plastic
(in particular, COC) syringe coated with a
Si.sub.wO.sub.xC.sub.yH.sub.z coating providing lubricity to the
syringe interior, thus eliminating the extractables from
traditional silicon oil. The lubricity coating can be on the
syringe barrel, the plunger (or one of its parts, e.g. the side
walls of the piston), or both. Such syringe can also in addition
have a SiO.sub.x barrier coating made by PECVD according to the
present invention. A very particular embodiment is a syringe having
a cyclic olefin copolymer (COC) barrel, a SiO.sub.x barrier layer
on the inner wall of said barrel, and a lubricity layer on said
barrier layer. A SiOx barrier coating typically is 20 to 30 nm
thick.
[0025] The coatings described herein are glass-like, but do not
contain other elements such as boron, sodium, calcium, aluminum and
impurities found in glass.
[0026] The coatings have a surface free of deleterious elements and
impurities found in Type I medical grade borosilicate glass. The
coating is deposited on a plastic substrate from plasma, which
utilizes organosilicons, creating a uniform layer.
[0027] The invention further pertains to a vessel processing system
for coating of a vessel, the system comprising a processing station
arrangement configured for performing the above and/or below
mentioned method steps. Examples of such processing stations
5501-5504 are depicted in FIG. 12-14.
[0028] The invention further pertains to a computer-readable
medium, in which a computer program for coating of a vessel is
stored which, when being executed by a processor of a vessel
processing system, is adapted to instruct the processor to control
the vessel processing system such that it carries out the above
and/or below mentioned method steps.
[0029] The invention further pertains to a program element or
computer program for coating of a vessel, which, when being
executed by a processor of a vessel processing system, is adapted
to instruct the processor to control the vessel processing system
such that it carries out the above and/or below mentioned method
steps.
[0030] The processor may thus be equipped to carry out exemplary
embodiments of the methods of the present invention. The computer
program may be written in any suitable programming language, for
example, C++ and may be stored on the computer-readable medium,
such as a CD-ROM. Also, the computer program may be available from
a network, such as the WorldWideWeb, from which it may be
downloaded into image processing units or processors, or any
suitable computers.
[0031] In the following, coating methods according to the invention
and coated devices according to the invention which are made by
these methods are described. The methods can be carried out on the
equipment (vessel processing system and vessel holder) which is
also described below.
PECVD Coating Method
[0032] The present invention pertains to a method of preparing a
coating by plasma enhanced chemical vapor deposition treatment
(PECVD), and for example a method of coating the interior surface
of a vessel.
[0033] A surface, for example an interior vessel surface, is
provided, as is a reaction mixture comprising an organosilicon
compound gas, optionally an oxidizing gas, optionally a hydrocarbon
gas, and optionally a carrier gas. For preparing a lubricity
coating, a mixture of an organosilicon precursor (e.g. OMCTS),
Oxygen and Argon is preferred.
[0034] The surface is contacted with the reaction mixture. Plasma
is formed in the reaction mixture. The coating is deposited on at
least a portion of the surface, e.g. a portion of the vessel
interior wall.
[0035] The method is carried out as follows.
[0036] A precursor is provided. Preferably, said precursor is an
organosilicon compound (in the following also designated as
"organosilicon precursor"), more preferably an organosilicon
compound selected from the group consisting of a linear siloxane, a
monocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane,
an alkyl trimethoxysilane, an aza analogue of any of these
precursors (i.e. a linear siloxazane, a monocyclic siloxazane, a
polycyclic siloxazane, a polysilsesquioxazane), and a combination
of any two or more of these precursors. The precursor is applied to
a substrate under conditions effective to form a coating by PECVD.
The precursor is thus polymerized, crosslinked, partially or fully
oxidized, or any combination of these.
[0037] In one aspect of the invention, the coating is a lubricity
coating, i.e. it forms a surface having a lower frictional
resistance than the uncoated substrate.
[0038] In another aspect of the invention, the coating is a
passivating coating, for example a hydrophobic coating resulting,
e.g., in a lower precipitation of components of a composition in
contact with the coated surface. Such hydrophobic coating is
characterized by a lower wetting tension than its uncoated
counterpart.
[0039] A lubricity coating of the present invention may also be a
passivating coating and vice versa.
[0040] In a further aspect of the invention, the coating is a
barrier coating, for example an SiO.sub.x coating. Typically, the
barrier is against a gas or liquid, preferably against water vapor,
oxygen and/or air. The barrier may also be used for establishing
and/or maintaining a vacuum inside a vessel coated with the barrier
coating, e.g. inside a blood collection tube.
[0041] The method of the invention may comprise the application of
one or more coatings made by PECVD from the same or different
organosilicon precursors under the same or different reaction
conditions. E.g. s syringe may first be coated with an SiO.sub.x
barrier coating using HMDSO as organosilicon precursor, and
subsequently with a lubricity coating using OMCTS as organosilicon
precursor.
Lubricity Coating
[0042] In its main aspect, the present invention provides a
lubricity coating.
[0043] This coating is advantageously made by the PECVD method and
using the precursors as described above. A preferred precursor for
the lubricating coating is a monocyclic siloxane, for example
octamethylcyclotetrasiloxane (OMCTS).
[0044] For example, the present invention provides a method for
setting the lubricity properties of a coating on a substrate
surface, the method comprising the steps: [0045] (a) providing a
gas comprising an organosilicon precursor and optionally O.sub.2
and optionally a noble gas (e.g. Argon) in the vicinity of the
substrate surface; and [0046] (b) generating a plasma from the gas,
thus forming a coating on the substrate surface by plasma enhanced
chemical vapor deposition (PECVD), wherein the lubricity
characteristics of the coating are set by setting the ratio of the
O.sub.2 to the organosilicon precursor in the gaseous reactant,
and/or by setting the electric power used for generating the
plasma, and/or by setting the ratio of the noble gas to the
organosilicon precursor.
[0047] The resulting coated surface has a lower frictional
resistance than the untreated substrate. For example, when the
coated surface is the inside of a syringe barrel and/or a syringe
plunger, the lubricity coating is effective to provide a breakout
force or plunger sliding force, or both, that is less than the
corresponding force required in the absence of the lubricating
coating.
[0048] The article coated with the lubricity coating may be a
vessel having the lubricating coating on a wall, preferably on the
interior wall, e.g. a syringe barrel, or a vessel part or vessel
cap having said coating on the vessel contacting surface, e.g. a
syringe plunger or a vessel cap.
[0049] The lubricity coating typically has a formula
Si.sub.wO.sub.xC.sub.yH.sub.z. It generally has an atomic ratio
Si.sub.wO.sub.xC.sub.y wherein w is 1, x is from about 0.5 to about
2.4, y is from about 0.6 to about 3, preferably w is 1, x is from
about 0.5 to 1.5, and y is from 0.9 to 2.0, more preferably w is 1,
x is from 0.7 to 1.2 and y is from 0.9 to 2.0. The atomic ratio can
be determined by XPS (X-ray photoelectron spectroscopy). Taking
into account the H atoms, the lubricity coating may thus in one
aspect have the formula Si.sub.wO.sub.xC.sub.yH.sub.z, for example
where w is 1, x is from about 0.5 to about 2.4, y is from about 0.6
to about 3, and z is from about 2 to about 9. Typically, the atomic
ratios are Si 100:O 80-110:C 100-150 in a particular lubricity
coating of present invention. Specifically, the atomic ratio may be
Si 100:O 92-107:C 116-133, and such lubricity coating would hence
contain 36% to 41% carbon normalized to 100% carbon plus oxygen
plus silicon.
Passivating, for Example Hydrophobic Coating
[0050] The passivating coating according to the present invention
is for example a hydrophobic coating.
[0051] A preferred precursor for the passivating, for example the
hydrophobic coating is a linear siloxane, for example
hexamethyldisiloxane (HMDSO).
[0052] A passivating coating according to the present invention
prevents or reduces mechanical and/or chemical effects of the
uncoated surface on a compound or composition contained in the
vessel. For example, precipitation and/or clotting or platelet
activation of a compound or component of a composition in contact
with the surface are prevented or reduced, e.g. blood clotting or
platelet activation or precipitation of insulin, or wetting of the
uncoated surface by an aqueous fluid is prevented.
[0053] A particular aspect of the invention is a surface having a
hydrophobic coating with the formula Si.sub.wO.sub.xC.sub.yH.sub.z.
It generally has an atomic ratio Si.sub.wO.sub.xC.sub.y wherein w
is 1, x is from about 0.5 to about 2.4, y is from about 0.6 to
about 3, preferably w is 1, x is from about 0.5 to 1.5, and y is
from 0.9 to 2.0, more preferably w is 1, x is from 0.7 to 1.2 and y
is from 0.9 to 2.0. The atomic ratio can be determined by XPS
(X-ray photoelectron spectroscopy). Taking into account the H
atoms, the hydrophobic coating may thus in one aspect have the
formula Si.sub.wO.sub.xC.sub.yH.sub.z, for example where w is 1, x
is from about 0.5 to about 2.4, y is from about 0.6 to about 3, and
z is from about 2 to about 9. Typically, the atomic ratios are Si
100:O 80-110:C 100-150 in a particular hydrophobic coating of
present invention. Specifically, the atomic ratio may be Si 100:O
92-107:C 116-133, and such coating would hence contain 36% to 41%
carbon normalized to 100% carbon plus oxygen plus silicon.
[0054] The article coated with the passivating coating may be a
vessel having the coating on a wall, preferably on the interior
wall, e.g. a tube, or a vessel part or vessel cap having said
coating on the vessel contacting surface, e.g. a vessel cap.
Coating of a Vessel
[0055] When a vessel is coated by the above coating method using
PECVD, the coating method comprises several steps. A vessel is
provided having an open end, a closed end, and an interior surface.
At least one gaseous reactant is introduced within the vessel.
Plasma is formed within the vessel under conditions effective to
form a reaction product of the reactant, i.e. a coating, on the
interior surface of the vessel.
[0056] Preferably, the method is performed by seating the open end
of the vessel on a vessel holder as described herein, establishing
a sealed communication between the vessel holder and the interior
of the vessel. In this preferred aspect, the gaseous reactant is
introduced into the vessel through the vessel holder. In a
particularly preferred aspect of the invention, a plasma enhanced
chemical vapor deposition (PECVD) apparatus comprising a vessel
holder, an inner electrode, an outer electrode, and a power supply
is used for the coating method according to the present
invention.
[0057] The vessel holder has a port to receive a vessel in a seated
position for processing. The inner electrode is positioned to be
received within a vessel seated on a vessel holder. The outer
electrode has an interior portion positioned to receive a vessel
seated on the vessel holder. The power supply feeds alternating
current to the inner and/or outer electrodes to form a plasma
within the vessel seated on the vessel holder. Typically, the power
supply feeds alternating current to the outer electrode while the
inner electrode is grounded. In this embodiment, the vessel defines
the plasma reaction chamber.
[0058] In a particular aspect of the invention, the PECVD apparatus
as described in the preceding paragraphs comprises a gas drain, not
necessarily including a source of vacuum, to transfer gas to or
from the interior of a vessel seated on the port to define a closed
chamber.
[0059] In a further particular aspect of the invention, the PECVD
apparatus includes a vessel holder, a first gripper, a seat on the
vessel holder, a reactant supply, a plasma generator, and a vessel
release.
[0060] The vessel holder is configured for seating to the open end
of a vessel. The first gripper is configured for selectively
holding and releasing the closed end of a vessel and, while
gripping the closed end of the vessel, transporting the vessel to
the vicinity of the vessel holder. The vessel holder has a seat
configured for establishing sealed communication between the vessel
holder and the interior space of the first vessel.
[0061] The reactant supply is operatively connected for introducing
at least one gaseous reactant within the first vessel through the
vessel holder. The plasma generator is configured for forming
plasma within the first vessel under conditions effective to form a
reaction product of the reactant on the interior surface of the
first vessel.
[0062] The vessel release is provided for unseating the first
vessel from the vessel holder. A gripper which is the first gripper
or another gripper is configured for axially transporting the first
vessel away from the vessel holder and then releasing the first
vessel.
[0063] In a particular aspect of the invention, the method is for
coating an inner surface of a restricted opening of a vessel, for
example a generally tubular vessel, by PECVD. The vessel includes
an outer surface, an inner surface defining a lumen, a larger
opening having an inner diameter, and a restricted opening that is
defined by an inner surface and has an inner diameter smaller than
the larger opening inner diameter. A processing vessel is provided
having a lumen and a processing vessel opening. The processing
vessel opening is connected with the restricted opening of the
vessel to establish communication between the lumen of the vessel
to be processed and the processing vessel lumen via the restricted
opening. At least a partial vacuum is drawn within the lumen of the
vessel to be processed and the processing vessel lumen. A PECVD
reactant is flowed through the first opening, then through the
lumen of the vessel to be processed, then through the restricted
opening, then into the processing vessel lumen. Plasma is generated
adjacent to the restricted opening under conditions effective to
deposit a coating of a PECVD reaction product on the inner surface
of the restricted opening.
Coated Vessel and Vessel Parts
[0064] The present invention further provides the coating resulting
from the method as described above, a surface coated with said
coating, and a vessel coated with said coating.
[0065] The surface coated with the coating, e.g. the vessel wall or
a part thereof, may be glass or a polymer, preferably a
thermoplastic polymer, more preferably a polymer selected from the
group consisting of a polycarbonate, an olefin polymer, a cyclic
olefin copolymer and a polyester. For example, it is a cyclic
olefin copolymer (COC), a polyethylene terephthalate or a
polypropylene. For syringe barrels, COC is particularly
considered.
[0066] In a particular aspect of the invention, the vessel wall has
an interior polymer layer enclosed by at least one exterior polymer
layer. The polymers may be same or different. E.g., one of the
polymer layers of a cyclic olefin copolymer (COC) resin (e.g.,
defining a water vapor barrier), another polymer layer is a layer
of a polyester resin. Such vessel may be made by a process
including introducing COC and polyester resin layers into an
injection mold through concentric injection nozzles.
[0067] The coated vessel of the invention may be empty, evacuated
or (pre)filled with a compound or composition.
[0068] A particular aspect of the invention is a vessel having a
passivating coating, for example a hydrophobic coating as defined
above.
[0069] A further particular aspect of the invention is a surface
having a lubricity coating as defined above. It may be a vessel
having the lubricity coating on a wall, preferably on the interior
wall, e.g. a syringe barrel, or a vessel part or vessel cap having
said coating on the vessel contacting surface, e.g. a syringe
plunger or a vessel cap.
[0070] A particular aspect of the invention is a syringe including
a plunger, a syringe barrel, and a lubricity coating as defined
above on either one or both of these syringe parts, preferably on
the inside wall of the syringe barrel. The syringe barrel includes
a barrel having an interior surface slidably receiving the plunger.
The lubricity coating may be disposed on the interior surface of
the syringe barrel, or on the plunger surface contacting the
barrel, or on both said surfaces. The lubricity coating is
effective to reduce the breakout force or the plunger sliding force
necessary to move the plunger within the barrel.
[0071] A further particular aspect of the invention is a syringe
barrel coated with the lubricity coating as defined in the
preceding paragraph.
[0072] In a specific aspect of said coated syringe barrel, the
syringe barrel comprises a barrel defining a lumen and having an
interior surface slidably receiving a plunger. The syringe barrel
is advantageously made of thermoplastic material. A lubricity
coating is applied to the barrel interior surface, the plunger, or
both, by plasma-enhanced chemical vapor deposition (PECVD). A
solute retainer is applied over the lubricity coating by surface
treatment, e.g. in an amount effective to reduce a leaching of the
lubricity coating, the thermoplastic material, or both into the
lumen. The lubricity coating and solute retainer are composed, and
present in relative amounts, effective to provide a breakout force,
plunger sliding force, or both that is less than the corresponding
force required in the absence of the lubricity coating and solute
retainer.
[0073] Still another aspect of the invention is a syringe including
a plunger, syringe barrel, and interior and exterior coatings. The
barrel has an interior surface slidably receiving the plunger and
an exterior surface. A lubricity coating is on the interior
surface, and an additional barrier coating of SiO.sub.x, in which x
is from about 1.5 to about 2.9, may be provided on the interior
surface of the barrel. A barrier coating, e.g. of a resin or of a
further SiO.sub.x coating, may additionally be provided on the
exterior surface of the barrel.
[0074] Another aspect of the invention is a syringe including a
plunger, a syringe barrel, and a staked needle (a "staked needle
syringe"). The needle is hollow with a typical size ranging from
18-29 gauge. The syringe barrel has an interior surface slidably
receiving the plunger. The staked needle may be affixed to the
syringe during the injection molding of the syringe or may be
assembled to the formed syringe using an adhesive. A cover is
placed over the staked needle to seal the syringe assembly. The
syringe assembly must be sealed so that a vacuum can be maintained
within the syringe to enable the PECVD coating process. Such
syringes with staked needles are described in U.S. Provisional
Application No. 61/359,434, filed on Jun. 24, 2010.
[0075] Another aspect of the invention is a syringe including a
plunger, a syringe barrel, and a Luer fitting. The syringe barrel
has an interior surface slidably receiving the plunger. The Luer
fitting includes a Luer taper having an internal passage defined by
an internal surface. The Luer fitting is formed as a separate piece
from the syringe barrel and joined to the syringe barrel by a
coupling. The internal passage of the Luer taper has a barrier
coating of SiO.sub.x, in which x is from about 1.5 to about
2.9.
[0076] Another aspect of the invention is a plunger for a syringe,
including a piston and a push rod. The piston has a front face, a
generally cylindrical side face, and a back portion, the side face
being configured to movably seat within a syringe barrel. The
plunger has a lubricity coating according to the present invention
on its side face. The push rod engages the back portion of the
piston and is configured for advancing the piston in a syringe
barrel. The plunger may additionally comprise a SiO.sub.x
coating.
[0077] A further aspect of the invention is a vessel with just one
opening, i.e. a vessel for collecting or storing a compound or
composition. Such vessel is in a specific aspect a tube, e.g. a
sample collecting tube, e.g., a blood collecting tube. Said tube
may be closed with a closure, e.g. a cap or stopper. Such cap or
stopper may comprise a lubricity coating according to the present
invention on its surface which is in contact with the tube, and/or
it may contain a passivating coating according to the present
invention on its surface facing the lumen of the tube. In a
specific aspect, such stopper or a part thereof may be made from an
elastomeric material.
[0078] Such a stopper may be made as follows: The stopper is
located in a substantially evacuated chamber. A reaction mixture is
provided including an organosilicon compound gas, optionally an
oxidizing gas, and optionally a hydrocarbon gas. Plasma is formed
in the reaction mixture, which is contacted with the stopper. A
coating is deposited on at least a portion of the stopper.
[0079] A further aspect of the invention is a vessel having a
barrier coating according to the present invention. The vessel is
generally tubular and may be made of thermoplastic material. The
vessel has a mouth and a lumen bounded at least in part by a wall.
The wall has an inner surface interfacing with the lumen. In a
preferred aspect, an at least essentially continuous barrier
coating made of SiO.sub.x as defined above is applied on the inner
surface of the wall. The barrier coating is effective to maintain
within the vessel at least 90% of its initial vacuum level,
optionally 95% of its initial vacuum level, for a shelf life of at
least 24 months. A closure is provided covering the mouth of the
vessel and isolating the lumen of the vessel from ambient air.
[0080] The PECVD made coatings and PECVD coating methods using an
organosilicon precursor described in this specification are also
useful for coating catheters or cuvettes to form a barrier coating,
a hydrophobic coating, a lubricity coating, or more than one of
these. A cuvette is a small tube of circular or square cross
section, sealed at one end, made of a polymer, glass, or fused
quartz (for UV light) and designed to hold samples for
spectroscopic experiments. The best cuvettes are as clear as
possible, without impurities that might affect a spectroscopic
reading. Like a test tube, a cuvette may be open to the atmosphere
or have a cap to seal it shut. The PECVD-applied coatings of the
present invention can be very thin, transparent, and optically
flat, thus not interfering with optical testing of the cuvette or
its contents.
(Pre)filled Coated Vessel
[0081] A specific aspect of the invention is a coated vessel as
described above which is prefilled or used for being filled with a
compound or composition in its lumen. Said compound or composition
may be
(i) a biologically active compound or composition, preferably a
medicament, more preferably insulin or a composition comprising
insulin; or (ii) a biological fluid, preferably a bodily fluid,
more preferably blood or a blood fraction (e.g. blood cells); or
(iii) a compound or composition for combination with another
compound or composition directly in the vessel, e.g. a compound for
the prevention of blood clotting or platelet activation in a blood
collection tube, like citrate or a citrate containing
composition.
[0082] Generally, the coated vessel of the present invention is
particularly useful for collecting or storing a compound or
composition which is sensitive to mechanical and/or chemical
effects of the surface of the uncoated vessel material, preferably
for preventing or reducing precipitation and/or clotting or
platelet activation of a compound or a component of the composition
in contact with the interior surface of the vessel.
[0083] E.g., a cell preparation tube having a wall provided with a
hydrophobic coating of the present invention and containing an
aqueous sodium citrate reagent is suitable for collecting blood and
preventing or reducing blood coagulation. The aqueous sodium
citrate reagent is disposed in the lumen of the tube in an amount
effective to inhibit coagulation of blood introduced into the
tube.
[0084] A specific aspect of the invention is a vessel for
collecting/receiving blood or a blood containing vessel. The vessel
has a wall; the wall has an inner surface defining a lumen. The
inner surface of the wall has an at least partial hydrophobic
coating of the present invention. The coating can be as thin as
monomolecular thickness or as thick as about 1000 nm (on average or
throughout the coating). The blood collected or stored in the
vessel is preferably viable for return to the vascular system of a
patient disposed within the lumen in contact with the coating. The
coating is effective to reduce the clotting or platelet activation
of blood exposed to the inner surface, compared to the same type of
wall uncoated.
[0085] Another aspect of the invention is an insulin containing
vessel including a wall having an inner surface defining a lumen.
The inner surface has an at least partial hydrophobic coating of
the present invention. The coating can be from monomolecular
thickness to about 1000 nm thick (on average or throughout the
coating) on the inner surface. Insulin or a composition comprising
insulin is disposed within the lumen in contact with the coating.
Optionally, the coating is effective to reduce the formation of a
precipitate from insulin contacting the inner surface, compared to
the same surface absent the coating.
[0086] A particular aspect of the invention is a prefilled syringe,
e.g. a syringe prefilled with a medicament, a diagnostic compound
or composition, or any other biologically of chemically active
compound or composition which is intended to be dispensed using the
syringe.
[0087] The present invention thus provides the following
embodiments with regard to coating methods, coated products and use
of said products:
[0088] 1. A method for preparing a lubricity coating on a plastic
substrate, the method comprising the steps
[0089] (a) providing a gas comprising an organosilicon precursor,
and optionally O.sub.2, and optionally a noble gas, in the vicinity
of the substrate surface; and (b) generating a plasma in the gas,
thus forming a coating on the substrate surface by plasma enhanced
chemical vapor deposition (PECVD).
[0090] 2. The method of (1), wherein the organosilicon precursor is
a monocyclic siloxane, preferably is OMCTS.
[0091] 3. The method according to any one of (1) to (2), wherein
O.sub.2 is present, preferably in a volume-volume ratio to the
organosilicon precursor of from 0:1 to 0.5:1, optionally from
0.01:1 to 0.5:1.
[0092] 4. The method according to any one of (1) to (3), wherein Ar
is present as the noble gas.
[0093] 5. The method according to any of the preceding, wherein the
gas comprises from 1 to 6 standard volumes of the organosilicon
precursor, from 1 to 100 standard volumes of the noble gas, and
from 0.1 to 2 standard volumes of O.sub.2.
[0094] 6. The method according to any one of the preceding, wherein
both Ar and O2 are present.
[0095] 7. The method according to any one of the preceding wherein
the plasma is generated with an electric power of from 0.1 to 25 W,
preferably of from 2 to 4 W; and/or
[0096] (ii) wherein the ratio of the electrode power to the plasma
volume is less than 10 W/ml, preferably from 6 W/ml to 0.1
W/ml.
[0097] 8. The method according to any one of the preceding, wherein
the resulting coating has a roughness when determined by AFM and
expressed as RMS of from more than 0 to 25 nm, preferably from 7 to
20 nm, optionally from 10 to 20 nm, optionally from 13 to 17 nm,
optionally from 13 to 15 nm.
[0098] 9. The method according to any one of the preceding,
additionally comprising a step for preparing a barrier coating on
the substrate before the lubricity coating is applied, the
additional step comprising the steps
[0099] (a) providing a gas comprising an organosilicon precursor
and O.sub.2 in the vicinity of the substrate surface; and
[0100] (b) generating a plasma from the gas, thus forming a SiOx
barrier coating on the substrate surface by plasma enhanced
chemical vapor deposition (PECVD).
[0101] 10. The method according to (9) wherein in the step for
preparing a barrier coating
[0102] (i) the plasma is generated with electrodes powered with
sufficient power to form a SiOx barrier coating on the substrate
surface, preferably with electrodes supplied with an electric power
of from 8 to 500 W, preferably from 20 to 400 W, more preferably
from 35 to 350 W, even more preferably of from 44 to 300 W, most
preferably of from 44 to 70 W; and/or
[0103] (ii) the ratio of the electrode power to the plasma volume
is equal or more than 5 W/ml, preferably is from 6 W/ml to 150
W/ml, more preferably is from 7 W/ml to 100 W/ml, most preferably
from 7 W/ml to 20 W/ml; and/or
[0104] (iii) the O.sub.2 is present in a volume:volume ratio of
from 1:1 to 100:1 in relation to the silicon containing precursor,
preferably in a ratio of from 5:1 to 30:1, more preferably in a
ratio of from 10:1 to 20:1, even more preferably in a ratio of
15:1.
[0105] 11. The method of (9) or (10), wherein the organosilicon
precursor for the barrier coating is a linear siloxane, preferably
HMDSO.
[0106] 12. The method according to any one of the preceding,
wherein the substrate is a polymer selected from the group
consisting of a polycarbonate, an olefin polymer, a cyclic olefin
copolymer and a polyester, and preferably is a cyclic olefin
copolymer, a polyethylene terephthalate or a polypropylene, and
more preferably is COC.
[0107] 13. The method according to any one of the preceding,
wherein the plasma is generated with electrodes powered at a
radiofrequency, preferably at 13.56 MHz.
[0108] 14. The method according to any one of the preceding,
wherein the resulting lubricity coating has an atomic ratio SiwOxCy
or SiwNxCy wherein w is 1, x is from about 0.5 to about 2.4, y is
from about 0.6 to about 3.
[0109] 15. A coated substrate coated with a lubricity coating which
is obtainable by the method according to any one of the preceding
and has the characteristics has defined in any one of the
preceding.
[0110] 16. The coated substrate according to (15), wherein the
lubricity coating has a lower frictional resistance than the
uncoated surface, wherein preferably the frictional resistance is
reduced by at least 25%, more preferably by at least 45%, even more
preferably by at least 60% in comparison to the uncoated
surface.
[0111] 17. The coated substrate according to (15) or (16),
additionally comprising at least one layer of SiOx, wherein x is
from 1.5 to 2.9, wherein
[0112] (i) the lubricity coating is situated between the SiOx layer
and the substrate surface or vice versa, or wherein
[0113] (ii) the lubricity coating is situated between two SiOx
layers or vice versa, or wherein
[0114] (iii) the layers of SiOx and the lubricity coating are a
graded composite of SiwOxCyHz to SiOx or vice versa.
[0115] 18. The coated substrate according to (17), wherein the SiOx
barrier coating has a thickness of from 20 to 30 nm and the
lubricity coating has an average thickness of from 1 to 5000 nm,
preferably of from 30 to 1000 nm, more preferably of from 80 to 150
nm.
[0116] 19. The coated substrate according to any one of (15) to
(18), wherein the lubricity coating
[0117] (i) has a lower wetting tension than the uncoated surface,
preferably a wetting tension of from 20 to 72 dyne/cm, more
preferably a wetting tension of from 30 to 60 dynes/cm, more
preferably a wetting tension of from 30 to 40 dynes/cm, preferably
34 dyne/cm; and/or
[0118] (iv) is more hydrophobic than the uncoated surface.
[0119] 20. A vessel coated on at least part of its interior
surface, thus forming a coated substrate according to any one of
(15) to (19), preferably a vessel which is
[0120] (i) a sample collection tube, in particular a blood
collection tube; or
[0121] (ii) a vial; or
[0122] (iii) a syringe or a syringe part, in particular a syringe
barrel or a syringe plunger or a syringe piston; or
[0123] (iv) a pipe; or
[0124] (v) a cuvette.
[0125] 21. The coated vessel according to (20) which contains a
compound or composition in its lumen, preferably a biologically
active compound or composition or a biological fluid, more
preferably (i) citrate or a citrate containing composition, (ii) a
medicament, in particular insulin or an insulin containing
composition, or (iii) blood or blood cells.
[0126] 22. The coated vessel according to (20) or (21), which is a
syringe comprising a barrel having an inner surface, a piston or
plunger having an outer surface engaging the inner surface of the
barrel, wherein at least one of said inner surface and outer
surface is a coated substrate according to any one of (15) to
(19).
[0127] 23. The syringe of (22), wherein the plunger initation force
Fi is from 2.5 to 5 lbs and the plunger maintenance force Fm is
from 2.5 to 8 lbs.
[0128] 24. The syringe of (22) or (23), wherein the lubricity
coating has the atomic ratio SiwOxCy or SiwNxCy wherein w is 1, x
is from about 0.5 to about 2.4, y is from about 0.6 to about 3.
[0129] 25. The syringe of any one of (22) to (24), wherein the
lubricity coating has an average thickness of from 10 to 1000
nm.
[0130] 26. The syringe of any one of (22) to (25), which is in
total or in one or more of its syringe parts made according to the
method according to any one of (1) to (14), wherein the plastic
substrate is COC, wherein the gas in step (a) comprises
octamethylcyclotetrasiloxane, O2 and Ar, and wherein the power for
generating the plasma is from 6 W/ml to 0.1 W/ml in relation to the
volume of the syringe lumen.
[0131] 27. The syringe according to any one of (22) to (26), which
contains a compound or composition in its lumen, preferably a
biologically active compound or composition or a biological fluid,
more preferably (i) citrate or a citrate containing composition,
(ii) a medicament, in particular insulin or an insulin containing
composition, or (iii) blood or blood cells.
[0132] 28. A vessel processing system (20) for coating of a vessel
(80), the system comprising a processing station arrangement (5501,
5502, 5503, 5504, 5505, 5506, 70, 72, 74) configured for performing
the method of one of (1) to (14).
[0133] 29. A computer-readable medium, in which a computer program
for coating of a vessel (80) is stored which, when being executed
by a processor of a vessel processing system (20), is adapted to
instruct the processor to control the vessel processing system such
that it carries out the method of one of (1) to (14).
[0134] 30. A program element for coating of a vessel (80), which,
when being executed by a processor of a vessel processing system
(20), is adapted to instruct the processor to control the vessel
processing system such that it carries out the method of one of (1)
to (14).
[0135] A particular syringe barrel according to present invention
which may form part of a syringe is made according to the method of
(1), wherein the plastic substrate is COC, wherein the gas in step
(a) comprises octamethylcyclotetrasiloxane, O2 and Ar, and wherein
preferably the power for generating the plasma is from 6 W/ml to
0.1 W/ml, in a particular aspect from 0.8 to 1.3 W/ml in relation
to the volume of the syringe lumen.
[0136] An aspect of the invention is a method of applying a coating
to a substrate. The method includes providing a substrate;
providing a vaporizable organosilicon precursor; and applying the
precursor to the substrate by chemical vapor deposition. The
precursor is applied under conditions effective to form a coating.
In a preferred aspect of the invention, a gaseous reactant or
process gas is employed having a standard volume ratio of from 1 to
6 standard volumes of the precursor, from 5 to 100 standard volumes
of a carrier gas, and from 0.1 to 2 standard volumes of an
oxidizing agent.
[0137] Another aspect of the invention is a coating of the type
made by the above process.
[0138] Another aspect of the invention is a vessel including a
lumen defined by a surface defining a substrate. A coating is
present on at least a portion of the substrate. The coating is made
by the previously defined process.
[0139] Still another aspect of the invention is a chemical vapor
deposition apparatus for applying a coating to a substrate. The
chemical vapor deposition apparatus includes a source of an
organosilicon precursor, a source of a carrier gas, and a source of
an oxidizing agent. The chemical vapor deposition apparatus still
further includes one or more conduits for conveying to the
substrate a gaseous reactant or process gas comprising from 1 to 6
standard volumes of the precursor, from 5 to 100 standard volumes
of the carrier gas, and from 0.1 to 2 standard volumes of the
oxidizing agent. The chemical vapor deposition apparatus further
includes a source of microwave or radio frequency energy and an
applicator powered by the source of microwave or radio frequency
energy for generating plasma in the gaseous reactant or process
gas.
[0140] Yet another aspect of the invention is a syringe comprising
a plunger, a barrel, and a coating. The barrel is a vessel and has
an interior surface defining the vessel lumen and receiving the
plunger for sliding. The vessel interior surface is a substrate.
The coating is a lubricity layer or coating on the substrate, the
plunger, or both, applied by chemical vapor deposition, employing
as the gaseous reactant or process gas from 1 to 6 standard volumes
of an organosilicon precursor, from 5 to 100 standard volumes of a
carrier gas, and from 0.1 to 2 standard volumes of an oxidizing
agent.
[0141] Even another aspect of the invention is a plunger for a
syringe, comprising a piston, a coating, and a push rod. The piston
has a front face, a generally cylindrical side face comprising a
substrate, and a back portion. The side face is configured to
movably seat within a syringe barrel. The coating is on the
substrate and is a lubricity layer or coating interfacing with the
side face. The lubricity layer or coating is produced from a
chemical vapor deposition (CVD) process employing the previously
defined gaseous reactant or process gas. The push rod engages the
back portion of the piston and is configured for advancing the
piston in a syringe barrel.
[0142] Another aspect of the invention is a stopper. The stopper
includes a sliding surface defining a substrate and adapted to be
received in an opening to be stopped. The substrate has on it a
lubricity coating made by providing a precursor comprising an
organosilicon compound; and applying the precursor to at least a
portion of the sliding surface by chemical vapor deposition,
employing a gaseous reactant or process gas as defined above.
[0143] Even another aspect of the invention is a medical or
diagnostic kit including a vessel having a coating as defined in
any embodiment above on a substrate as defined in any embodiment
above. Optionally, the kit additionally includes a medicament or
diagnostic agent which is contained in the coated vessel in contact
with the coating; and/or a hypodermic needle, double-ended needle,
or other delivery conduit; and/or an instruction sheet.
[0144] Other aspects of the invention include any one or more of
the following:
[0145] Use of the coating according to any embodiment described
above for coating a surface and thereby preventing or reducing
mechanical and/or chemical effects of the surface on a compound or
composition in contact with the coating;
[0146] Use of the coating according to any described embodiment as
a lubricity layer;
[0147] Use of the coating according to any described embodiment for
protecting a compound or composition contacting the coating against
mechanical and/or chemical effects of the surface of the uncoated
vessel material;
[0148] Use of the coating according to any described embodiment for
preventing or reducing precipitation and/or clotting or platelet
activation of a compound or a component of the composition in
contact with the coating.
[0149] As one option, the compound or a component of the
composition is insulin, and precipitation of the insulin is
prevented or reduced. As another option, the compound or a
component of the composition is blood or a blood fraction, and
blood clotting or platelet activation is prevented or reduced. As
still another option, the coated vessel is a blood collection tube.
Optionally, the blood collection tube can contain an agent for
preventing blood clotting or platelet activation, for example
ethylenediaminetetraacetic acid (EDTA), a sodium salt thereof, or
heparin.
[0150] Additional options for use of the invention include any one
or more of the following:
[0151] Use of a coated substrate according to any described
embodiment for reception and/or storage and/or delivery of a
compound or composition;
[0152] The use of a coated substrate according to any described
embodiment for storing insulin.
[0153] The use of a coated substrate according to any described
embodiment for storing blood. Optionally, the stored blood is
viable for return to the vascular system of a patient.
[0154] Use of a coating according to any described embodiment as
(i) a lubricity layer or coating having a lower frictional
resistance than the uncoated surface; and/or (ii) a hydrophobic
layer or coating that is more hydrophobic than the uncoated
surface.
[0155] Other aspects of the invention will become apparent to a
person of ordinary skill in the art after reviewing the present
disclosure and claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0156] FIG. 1 is a schematic sectional view of a vessel holder in a
coating station according to an embodiment of the disclosure.
[0157] FIG. 2 is a section taken along section lines A-A of FIG.
1.
[0158] FIGS. 3A, 3B, and 3C shows the drawbacks of silicon oil (or
any other oil) as lubricant. Non-uniformity of silicon oil occurs
because it is not covalently bound to the surface and flows. A.)
Silicon oil is pushed off the syringe barrel wall by the plunger
following insertion of the plunger B) Silicon oil is forced out of
the area between the plunger and syringe wall leading to high break
loose forces. C.) Silicon oil flows over time due to gravitational
forces.
[0159] FIG. 4 is an exploded longitudinal sectional view of a
syringe and cap adapted for use as a prefilled syringe.
[0160] FIG. 5 is a perspective view of a blood collection tube
assembly having a closure according to still another embodiment of
the invention.
[0161] FIG. 6 is a fragmentary section of the blood collection tube
and closure assembly of FIG. 5.
[0162] FIG. 7 is an isolated section of an elastomeric insert of
the closure of FIGS. 5 and 6.
[0163] FIG. 8 is a view similar to FIG. 1 of another embodiment for
processing syringe barrels and other vessels.
[0164] FIG. 9 is an enlarged detail view of the processing vessel
of FIG. 8.
[0165] FIG. 10 is an alternative construction for a vessel holder
useful with any embodiment of the invention, for example those of
the other Figures.
[0166] FIG. 11 is a schematic view of an assembly for treating
vessels. The assembly is usable with the apparatus in any of the
preceding figures.
[0167] FIG. 12 shows a schematic representation of an exemplary
vessel processing system.
[0168] FIG. 13 shows a schematic representation of an exemplary
vessel processing system.
[0169] FIG. 14 shows a processing station of an exemplary vessel
processing system.
[0170] FIG. 15 shows a portable vessel holder.
[0171] FIG. 16 shows a SEM image of Example P. The horizontal
edge-to-edge scale is 5 .mu.m.
[0172] FIG. 17 shows a SEM image of Example S. The horizontal
edge-to-edge scale is 5 .mu.m.
[0173] FIG. 18A shows the results of the AFM imaging performed on a
first portion of Example Q. A 10 .mu.m.times.10 .mu.m area was
imaged. A top down view of the area is shown, together with the
topography differences along a first cross section indicated by the
line drawn in the top down view. The vertical depth of the features
was measured using the cross section tool. Results for the
parameters measured, like RMS, Ra and Rmax are indicated in the top
right box.
[0174] FIG. 18B is similar to FIG. 18A, but shows the results of
the AFM imaging performed on Example Q along a second cross section
indicated by the line drawn in the top down view.
[0175] FIG. 18C is similar to FIG. 18A, but shows the results of
the AFM imaging performed on Example Q along a third cross section
indicated by the line drawn in the top down view.
[0176] FIG. 19A is similar to FIG. 18A, but shows the results of
the AFM imaging performed on Example T along a first cross section
indicated by the line drawn in the top down view.
[0177] FIG. 19B is similar to FIG. 19A, but shows the results of
the AFM imaging performed on Example T along a second cross section
indicated by the line drawn in the top down view.
[0178] FIG. 19C is similar to FIG. 19A, but shows the results of
the AFM imaging performed on Example T along a third cross section
indicated by the line drawn in the top down view.
[0179] FIG. 20A is similar to FIG. 18A, but shows the results of
the AFM imaging performed on Example V along a first cross section
indicated by the line drawn in the top down view.
[0180] FIG. 20B is similar to FIG. 20A, but shows the results of
the AFM imaging performed on Example V along a second cross section
indicated by the line drawn in the top down view.
[0181] FIG. 20C is similar to FIG. 20A, but shows the results of
the AFM imaging performed on Example V along a third cross section
indicated by the line drawn in the top down view.
[0182] FIG. 21 shows a TEM image of a lubricity coating according
to the invention coated on a SiO.sub.2 barrier coating, which in
turn is coated on a COC substrate.
[0183] FIG. 22 shows a TEM image of a SiO.sub.2 barrier coating
which is coated on a COC substrate.
[0184] FIG. 23 shows the meniscus made by water in a.) glass tube,
b.) hydrophilic SiO.sub.2 coated COC tube, c.) hydrophobic
Si.sub.wO.sub.xC.sub.yH.sub.z coated COC tube, and d.) uncoated COC
tube. The hydrophilic SiO.sub.2 coated tube and borosilicate glass
tube have a similar meniscus, demonstrating that the hydrophilicity
of the hydrophilic SiO.sub.2 coating is comparable to a glass
surface. The hydrophobic coated tube and the uncoated COC tube each
have a meniscus that is expected from a hydrophobic surface.
[0185] FIG. 24 is a longitudinal section of a syringe with a staked
needle.
[0186] FIG. 25 is a longitudinal section of the dispensing end of
an alternative syringe with a staked needle.
[0187] FIG. 26 is a longitudinal section of an alternative syringe
with a staked needle.
[0188] FIG. 27 is a diagrammatic view showing a flexible diaphragm
71144 to which the needle is attached.
[0189] The following reference characters are used in the drawing
figures:
TABLE-US-00001 20 Vessel processing system 28 Coating station 38
Vessel holder 50 Vessel holder 70 Conveyor 72 Transfer mechanism
(on) 74 Transfer mechanism (off) 80 Vessel 82 Opening 84 Closed end
86 Wall 88 Interior surface 90 Barrier layer 92 Vessel port 94
Vacuum duct 96 Vacuum port 98 Vacuum source 100 O-ring (of 92) 102
O-ring (of 96) 104 Gas inlet port 106 O-ring (of 100) 108 Probe
(counter electrode) 110 Gas delivery port (of 108) 114 Housing (of
50 or 112) 116 Collar 118 Exterior surface (of 80) 144 PECVD gas
source 152 Pressure gauge 160 Electrode 162 Power supply 164
Sidewall (of 160) 166 Sidewall (of 160) 168 Closed end (of 160) 200
Electrode 250 Syringe barrel 252 Syringe 254 Interior surface (of
250) 256 Back end (of 250) 258 Plunger (of 252) 260 Front end (of
250) 262 Cap 264 Interior surface (of 262) 268 Vessel 270 Closure
272 Interior facing surface 274 Lumen 276 Wall-contacting surface
278 Inner surface (of 280) 280 Vessel wall 282 Stopper 284 Shield
286 Lubricity layer 288 Barrier layer 290 Apparatus for coating,
for example, 250 292 Inner surface (of 294) 294 Restricted opening
(of 250) 296 Processing vessel 298 Outer surface (of 250) 300 Lumen
(of 250) 302 Larger opening (of 250) 304 Processing vessel lumen
306 Processing vessel opening 308 Inner electrode 310 Interior
passage (of 308) 312 Proximal end (of 308) 314 Distal end (of 308)
316 Distal opening (of 308) 318 Plasma 332 First fitting (male Luer
taper) 334 Second fitting (female Luer taper) 336 Locking collar
(of 332) 338 First abutment (of 332) 340 Second abutment (of 332)
342 O-ring 344 Dog 408 Inner wall 410 Outer wall 482 Vessel holder
body 484 Upper portion (of 482) 486 Base portion (of 482) 488 Joint
(between 484 and 486) 490 O-ring 492 Annular pocket 494 Radially
extending abutment surface 496 Radially extending wall 498 Screw
500 Screw 502 Vessel port 504 Second O-ring 506 Inner diameter (of
490) 508 Vacuum duct (of 482) 574 Main vacuum valve 576 Vacuum line
578 Manual bypass valve 580 Bypass line 582 Vent valve 584 Main
reactant gas valve 586 Main reactant feed line 588 Organosilicon
liquid reservoir 590 Organosilicon feed line (capillary) 592
Organosilicon shut-off valve 594 Oxygen tank 596 Oxygen feed line
598 Mass flow controller 600 Oxygen shut-off valve 614 Headspace
616 Pressure source 618 Pressure line 620 Capillary connection 5501
First processing station 5502 Second processing station 5503 Third
processing station 5504 Fourth processing station 5505 Processor
5506 User interface 5507 Bus 5701 PECVD apparatus 5702 First
detector 5703 Second detector 5704 Detector 5705 Detector 5706
Detector 5707 Detector 7001 Conveyor exit branch 7002 Conveyor exit
branch 7003 Conveyor exit branch 7004 Conveyor exit branch 7120
Syringe 7122 Needle 7124 Barrel 7126 Cap 7128 Barrier coating 7130
Lubricity coating 7132 Outside surface 7134 Delivery outlet 7136
Base (of 22) 7138 Internal passage 7140 Generally cylindrical
interior surface portion 7142 Generally hemispherical interior
surface portion 7144 Front passage 7146 Lumen 7148 Lumen 7150
Ambient air 7152 Rim 7154 Exterior portion (of 7124) 7156 Opening
7158 Fluid 7160 Material (of 7124) 7164 Non-cylindrical portion (of
7122) 7166 Plunger 7168 Base 7170 Coupling 7172 Flexible lip seal
7174 Detent 7176 Projection 7196 Internal portion (of 7126) 7198
External portion (of 7126) 71106 Rear passage (of barrel) 71110
Tapered nose (of 7120) 71112 Tapered throat (of 7126) 71114 Collar
(of syringe) 71116 Interior thread (of 71114) 71118 Dog (of 26)
71120 Dog (of 26) 71122 Syringe barrel 71124 Syringe cap 71126
(Syringe cap (flexible) 71128 Cap-syringe interface 71130 Syringe
barrel 71134 Delivery outlet 71136 Base (of 22) 71140 Finger grip
71144 Flexible diaphragm
DETAILED DESCRIPTION
[0190] The present invention will now be described more fully,
inter alia with reference to the accompanying drawings, in which
several embodiments are shown. This invention can, however, be
embodied in many different forms and should not be construed as
limited to the embodiments set forth here. Rather, these
embodiments are examples of the invention, which has the full scope
indicated by the language of the claims. Like numbers refer to like
or corresponding elements throughout. The following disclosure
relates to all embodiments unless specifically limited to a certain
embodiment.
DEFINITION SECTION
[0191] In the context of the present invention, the following
definitions and abbreviations are used:
[0192] RF is radio frequency; sccm is standard cubic centimeters
per minute.
[0193] The term "at least" in the context of the present invention
means "equal or more" than the integer following the term. The word
"comprising" does not exclude other elements or steps, and the
indefinite article "a" or "an" does not exclude a plurality unless
indicated otherwise. Whenever a parameter range is indicated, it is
intended to disclose the parameter values given as limits of the
range and all values of the parameter falling within said
range.
[0194] "First" and "second" or similar references to, e.g.,
processing stations or processing devices refer to the minimum
number of processing stations or devices that are present, but do
not necessarily represent the order or total number of processing
stations and devices. These terms do not limit the number of
processing stations or the particular processing carried out at the
respective stations.
[0195] For purposes of the present invention, an "organosilicon
precursor" is a compound having at least one of the linkage:
##STR00001##
which is a tetravalent silicon atom connected to an oxygen or
nitrogen atom and an organic carbon atom (an organic carbon atom
being a carbon atom bonded to at least one hydrogen atom). A
volatile organosilicon precursor, defined as such a precursor that
can be supplied as a vapor in a PECVD apparatus, is an optional
organosilicon precursor. Optionally, the organosilicon precursor is
selected from the group consisting of a linear siloxane, a
monocyclic siloxane, a polycyclic siloxane, a polysilsesquioxane,
an alkyl trimethoxysilane, a linear silazane, a monocyclic
silazane, a polycyclic silazane, a polysilsesquiazane, and a
combination of any two or more of these precursors.
[0196] The feed amounts of PECVD precursors, gaseous reactant or
process gases, and carrier gas are sometimes expressed in "standard
volumes" in the specification and claims. The standard volume of a
charge or other fixed amount of gas is the volume the fixed amount
of the gas would occupy at a standard temperature and pressure
(without regard to the actual temperature and pressure of
delivery). Standard volumes can be measured using different units
of volume, and still be within the scope of the present disclosure
and claims. For example, the same fixed amount of gas could be
expressed as the number of standard cubic centimeters, the number
of standard cubic meters, or the number of standard cubic feet.
Standard volumes can also be defined using different standard
temperatures and pressures, and still be within the scope of the
present disclosure and claims. For example, the standard
temperature might be 0.degree. C. and the standard pressure might
be 760 Torr (as is conventional), or the standard temperature might
be 20.degree. C. and the standard pressure might be 1 Torr. But
whatever standard is used in a given case, when comparing relative
amounts of two or more different gases without specifying
particular parameters, the same units of volume, standard
temperature, and standard pressure are to be used relative to each
gas, unless otherwise indicated.
[0197] The corresponding feed rates of PECVD precursors, gaseous
reactant or process gases, and carrier gas are expressed in
standard volumes per unit of time in the specification. For
example, in the working examples the flow rates are expressed as
standard cubic centimeters per minute, abbreviated as sccm. As with
the other parameters, other units of time can be used, such as
seconds or hours, but consistent parameters are to be used when
comparing the flow rates of two or more gases, unless otherwise
indicated.
[0198] A "vessel" in the context of the present invention can be
any type of vessel with at least one opening and a wall defining an
interior surface. The substrate can be the inside wall of a vessel
having a lumen. Though the invention is not necessarily limited to
vessels of a particular volume, vessels are contemplated in which
the lumen has a void volume of from 0.5 to 50 mL, optionally from 1
to 10 mL, optionally from 0.5 to 5 mL, optionally from 1 to 3 mL.
The substrate surface can be part or all of the inner surface of a
vessel having at least one opening and an inner surface.
[0199] The term "at least" in the context of the present invention
means "equal or more" than the integer following the term. Thus, a
vessel in the context of the present invention has one or more
openings. One or two openings, like the openings of a sample tube
(one opening) or a syringe barrel (two openings) are preferred. If
the vessel has two openings, they can be of same or different size.
If there is more than one opening, one opening can be used for the
gas inlet for a PECVD coating method according to the present
invention, while the other openings are either capped or open. A
vessel according to the present invention can be a sample tube,
e.g. for collecting or storing biological fluids like blood or
urine, a syringe (or a part thereof, for example a syringe barrel)
for storing or delivering a biologically active compound or
composition, e.g. a medicament or pharmaceutical composition, a
vial for storing biological materials or biologically active
compounds or compositions, a pipe, e.g. a catheter for transporting
biological materials or biologically active compounds or
compositions, or a cuvette for holding fluids, e.g. for holding
biological materials or biologically active compounds or
compositions.
[0200] A vessel can be of any shape, a vessel having a
substantially cylindrical wall adjacent to at least one of its open
ends being preferred. Generally, the interior wall of the vessel is
cylindrically shaped, like, e.g. in a sample tube or a syringe
barrel. Sample tubes and syringes or their parts (for example
syringe barrels) are contemplated.
[0201] A "hydrophobic layer" in the context of the present
invention means that the coating lowers the wetting tension of a
surface coated with the coating, compared to the corresponding
uncoated surface. Hydrophobicity is thus a function of both the
uncoated substrate and the coating. The same applies with
appropriate alterations for other contexts wherein the term
"hydrophobic" is used. The term "hydrophilic" means the opposite,
i.e. that the wetting tension is increased compared to reference
sample. The present hydrophobic layers are primarily defined by
their hydrophobicity and the process conditions providing
hydrophobicity, and optionally can have a composition according to
the empirical composition or sum formula
Si.sub.wO.sub.xC.sub.yH.sub.z. It generally has an atomic ratio
Si.sub.wO.sub.xC.sub.y wherein w is 1, x is from about 0.5 to about
2.4, y is from about 0.6 to about 3, preferably w is 1, x is from
about 0.5 to 1.5, and y is from 0.9 to 2.0, more preferably w is 1,
x is from 0.7 to 1.2 and y is from 0.9 to 2.0. The atomic ratio can
be determined by XPS (X-ray photoelectron spectroscopy). Taking
into account the H atoms, the coating may thus in one aspect have
the formula Si.sub.wO.sub.xC.sub.yH.sub.z, for example where w is
1, x is from about 0.5 to about 2.4, y is from about 0.6 to about
3, and z is from about 2 to about 9. Typically, the atomic ratios
are Si 100:O 80-110:C 100-150 in a particular coating of present
invention. Specifically, the atomic ratio may be Si 100:O 92-107:C
116-133, and such coating would hence contain 36% to 41% carbon
normalized to 100% carbon plus oxygen plus silicon.
[0202] These values of w, x, y, and z are applicable to the
empirical composition Si.sub.wO.sub.xC.sub.yH.sub.z throughout this
specification. The values of w, x, y, and z used throughout this
specification should be understood as ratios or an empirical
formula (e.g. for a coating), rather than as a limit on the number
or type of atoms in a molecule. For example,
octamethylcyclotetrasiloxane, which has the molecular composition
Si.sub.4O.sub.4C.sub.8H.sub.24, can be described by the following
empirical formula, arrived at by dividing each of w, x, y, and z in
the molecular formula by 4, the largest common factor:
Si.sub.1O.sub.1C.sub.2H.sub.6. The values of w, x, y, and z are
also not limited to integers. For example, (acyclic)
octamethyltrisiloxane, molecular composition
Si.sub.3O.sub.2C.sub.8H.sub.24, is reducible to
Si.sub.1O.sub.0.67C.sub.2.67H.sub.8.
[0203] "Wetting tension" is a specific measure for the
hydrophobicity or hydrophilicity of a surface. An optional wetting
tension measurement method in the context of the present invention
is ASTM D 2578 or a modification of the method described in ASTM D
2578. This method uses standard wetting tension solutions (called
dyne solutions) to determine the solution that comes nearest to
wetting a plastic film surface for exactly two seconds. This is the
film's wetting tension. The procedure utilized is varied herein
from ASTM D 2578 in that the substrates are not flat plastic films,
but are tubes made according to the Protocol for Forming PET Tube
and (except for controls) coated according to the Protocol for
Coating Tube Interior with Hydrophobic Layer or coating (see
Example 9 of EP2251671 A2).
[0204] A "lubricity layer" according to the present invention is a
coating which has a lower frictional resistance than the uncoated
surface. In other words, it reduces the frictional resistance of
the coated surface in comparison to a reference surface that is
uncoated. The present lubricity layers are primarily defined by
their lower frictional resistance than the uncoated surface and the
process conditions providing lower frictional resistance than the
uncoated surface, and optionally can have a composition according
to the empirical composition Si.sub.wO.sub.xC.sub.yH.sub.z, as
defined herein. It generally has an atomic ratio
Si.sub.wO.sub.xC.sub.y wherein w is 1, x is from about 0.5 to about
2.4, y is from about 0.6 to about 3, preferably w is 1, x is from
about 0.5 to 1.5, and y is from 0.9 to 2.0, more preferably w is 1,
x is from 0.7 to 1.2 and y is from 0.9 to 2.0. The atomic ratio can
be determined by XPS (X-ray photoelectron spectroscopy). Taking
into account the H atoms, the coating may thus in one aspect have
the formula Si.sub.wO.sub.xC.sub.yH.sub.z, for example where w is
1, x is from about 0.5 to about 2.4, y is from about 0.6 to about
3, and z is from about 2 to about 9. Typically, the atomic ratios
are Si 100:O 80-110:C 100-150 in a particular coating of present
invention. Specifically, the atomic ratio may be Si 100:O 92-107:C
116-133, and such coating would hence contain 36% to 41% carbon
normalized to 100% carbon plus oxygen plus silicon.
[0205] "Frictional resistance" can be static frictional resistance
and/or kinetic frictional resistance.
[0206] One of the optional embodiments of the present invention is
a syringe part, e.g. a syringe barrel or plunger, coated with a
lubricity layer. In this contemplated embodiment, the relevant
static frictional resistance in the context of the present
invention is the breakout force as defined herein, and the relevant
kinetic frictional resistance in the context of the present
invention is the plunger sliding force as defined herein. For
example, the plunger sliding force as defined and determined herein
is suitable to determine the presence or absence and the lubricity
characteristics of a lubricity layer or coating in the context of
the present invention whenever the coating is applied to any
syringe or syringe part, for example to the inner wall of a syringe
barrel. The breakout force is of particular relevance for
evaluation of the coating effect on a prefilled syringe, i.e. a
syringe which is filled after coating and can be stored for some
time, e.g. several months or even years, before the plunger is
moved again (has to be "broken out").
[0207] The "plunger sliding force" (synonym to "glide force",
"maintenance force", Fm, also used in this description) in the
context of the present invention is the force required to maintain
movement of a plunger in a syringe barrel, e.g. during aspiration
or dispense. It can advantageously be determined using the ISO
7886-1:1993 test described herein and known in the art. A synonym
for "plunger sliding force" often used in the art is "plunger
force" or "pushing force".
[0208] The "plunger breakout force" (synonym to "breakout force",
"break loose force", "initation force", Fi, also used in this
description) in the context of the present invention is the initial
force required to move the plunger in a syringe, for example in a
prefilled syringe.
[0209] Both "plunger sliding force" and "plunger breakout force"
and methods for their measurement are described in more detail in
subsequent parts of this description. These two forces can be
expressed in N, lbs or kg and all three units are used herein.
These units correlate as follows: 1N=0.102 kg=0.2248 lbs
(pounds).
[0210] Sliding force and breakout force are sometimes used herein
to describe the forces required to advance a stopper or other
closure into a vessel, such as a medical sample tube or a vial, to
seat the stopper in a vessel to close the vessel. Its use is
analogous to use in the context of a syringe and its plunger, and
the measurement of these forces for a vessel and its closure are
contemplated to be analogous to the measurement of these forces for
a syringe, except that at least in most cases no liquid is ejected
from a vessel when advancing the closure to a seated position.
[0211] "Slidably" means that the plunger, closure, or other
removable part is permitted to slide in a syringe barrel or other
vessel.
[0212] In the context of this invention, "substantially rigid"
means that the assembled components (ports, duct, and housing,
explained further below) can be moved as a unit by handling the
housing, without significant displacement of any of the assembled
components respecting the others. Specifically, none of the
components are connected by hoses or the like that allow
substantial relative movement among the parts in normal use. The
provision of a substantially rigid relation of these parts allows
the location of the vessel seated on the vessel holder to be nearly
as well known and precise as the locations of these parts secured
to the housing.
Description Section
[0213] An embodiment of the present invention is a method of
applying a coating such as 90 to a substrate such as the vessel 80
(FIG. 1), the vessel 268 (FIG. 6), the stopper 282 (FIGS. 6-7), or
the syringe 252 (FIG. 4). The method can be used with any disclosed
embodiment. The method includes providing a substrate, for example
any of those mentioned above; providing a vaporizable organosilicon
precursor, for example any of those disclosed in this
specification; and applying the precursor to the substrate by
chemical vapor deposition. The precursor is applied, for example in
the apparatus of FIG. 2, 26, of the EP applications cited in
paragraph [002], or of any other embodiment, under conditions
effective to form a coating.
[0214] A gaseous reactant or process gas can be employed having a
standard volume ratio of, for example when a lubricity coating is
prepared: [0215] from 1 to 6 standard volumes, optionally from 2 to
4 standard volumes, optionally equal to or less than 6 standard
volumes, optionally equal to or less than 2.5 standard volumes,
optionally equal to or less than 1.5 standard volumes, optionally
equal to or less than 1.25 standard volumes of the precursor;
[0216] from 1 to 100 standard volumes, optionally from 5 to 100
standard volumes, optionally from 10 to 70 standard volumes, of a
carrier gas; [0217] from 0.1 to 2 standard volumes, optionally from
0.2 to 1.5 standard volumes, optionally from 0.2 to 1 standard
volumes, optionally from 0.5 to 1.5 standard volumes, optionally
from 0.8 to 1.2 standard volumes of an oxidizing agent.
[0218] Another embodiment is a coating, for example 286 in FIG. 7
or a comparable coating in any embodiment, of the type made by the
above process.
[0219] Another embodiment is a vessel such as the vessel (FIG. 1),
the vessel 268 (FIG. 6), or the syringe 252 (FIG. 4) including a
lumen defined by a surface defining a substrate. A coating is
present on at least a portion of the substrate. The coating is made
by the previously defined process.
[0220] Still another embodiment is a chemical vapor deposition
apparatus such as the apparatus 28 illustrated in FIG. 11 (or any
other illustrated coating apparatus, such as the apparatus
illustrated in FIGS. 1, 2, 8, 10, or 12-15), for applying a coating
to a substrate.
[0221] FIG. 12 shows a vessel processing system 20 according to an
exemplary embodiment of the present invention. The vessel
processing system 20 comprises, inter alia, a first processing
station 5501 and may or may not also comprise a second processing
station 5502. An example for such processing stations is for
example depicted in FIG. 1, reference numeral 28.
[0222] The first vessel processing station 5501 contains a vessel
holder 38 which holds a seated vessel 80. Although FIG. 12 depicts
a blood tube 80, the vessel may also be a syringe body, a vial, a
catheter or, for example, a pipette. The vessel may, for example,
be made of glass or plastic. In case of plastic vessels, the first
processing station may also comprise a mould for moulding the
plastic vessel.
[0223] After the first processing at the first processing station
(which processing may comprise moulding of the vessel, a first
inspection of the vessel for defects, coating of the interior
surface of the vessel and a second inspection of the vessel for
defects, in particular of the interior coating), the vessel holder
38 may be transported together with the vessel 82 to the second
vessel processing station 5502. This transportation is performed by
a conveyor arrangement 70, 72, 74. For example, a gripper or
several grippers may be provided for gripping the vessel holder 38
and/or the vessel 80 in order to move the vessel/holder combination
to the next processing station 5502. Alternatively, only the vessel
may be moved without the holder. However, it may be advantageous to
move the holder together with the vessel in which case the holder
is adapted such that it can be transported by the conveyor
arrangement.
[0224] FIG. 13 shows a vessel processing system 20 according to
another exemplary embodiment of the present invention. Again, two
vessel processing stations 5501, 5502 are provided. Furthermore,
additional vessel processing stations 5503, 5504 may be provided
which are arranged in series and in which the vessel can be
processed, i.e. inspected and/or coated.
[0225] A vessel can be moved from a stock to the left processing
station 5504. Alternatively, the vessel can be moulded in the first
processing station 5504. In any case, a first vessel processing is
performed in the processing station 5504, such as a moulding, an
inspection and/or a coating, which may be followed by a second
inspection. Then, the vessel is moved to the next processing
station 5501 via the conveyor arrangement 70, 72, 74. Typically,
the vessel is moved together with the vessel holder. A second
processing is performed in the second processing station 5501 after
which the vessel and holder are moved to the next processing
station 5502 in which a third processing is performed. The vessel
is then moved (again together with the holder) to the fourth
processing station 5503 for a fourth processing, after which it is
conveyed to a storage.
[0226] Before and after each coating step or moulding step or any
other step which manipulates the vessel an inspection of the whole
vessel, of part of the vessel and in particular of an interior
surface of the vessel may be performed. The result of each
inspection can be transferred to a central processing unit 5505 via
a data bus 5507. Each processing station is connected to the data
bus 5507. The above described program element may run on the
processor 5505, and the processor, which may be adapted in form of
a central control and regulation unit, controls the system and may
also be adapted to process the inspection data, to analyze the data
and to determine whether the last processing step was
successful.
[0227] If it is determined that the last processing step was not
successful, because for example the coating comprises holes or
because the surface of the coating is determined to be regular or
not smooth enough, the vessel does not enter the next processing
station but is either removed from the production process (see
conveyor sections 7001, 7002, 7003, 7004) or conveyed back in order
to become re-processed.
[0228] The processor 5505 may be connected to a user interface 5506
for inputting control or regulation parameters.
[0229] FIG. 14 shows a vessel processing station 5501 according to
an exemplary embodiment of the present invention. The station
comprises a PECVD apparatus 5701 for coating an interior surface of
the vessel. Furthermore, several detectors 5702-5707 may be
provided for vessel inspection. Such detectors may for example be
electrodes for performing electric measurements, optical detectors,
like CCD cameras, gas detectors or pressure detectors.
[0230] FIG. 15 shows a vessel holder 38 according to an exemplary
embodiment of the present invention, together with several
detectors 5702, 5703, 5704 and an electrode with gas inlet port
108, 110.
[0231] The electrode and the detector 5702 may be adapted to be
moved into the interior space of the vessel 80 when the vessel is
seated on the holder 38.
[0232] The optical inspection may be particularly performed during
a coating step, for example with the help of optical detectors
5703, 5704 which are arranged outside the seated vessel 80 or even
with the help of an optical detector 5705 arranged inside the
interior space of the vessel 80.
[0233] The detectors may comprise colour filters such that
different wavelengths can be detected during the coating process.
The processing unit 5505 analyzes the optical data and determines
whether the coating was successful or not to a predetermined level
of certainty. If it is determined that the coating was most
probably unsuccessful, the respective vessel is separated from the
processing system or re-processed.
[0234] Referring now to FIG. 11, the chemical vapor deposition
apparatus includes a source of an organosilicon precursor such as
the reservoir 588, a source of a carrier gas such as 602, and a
source of an oxidizing agent such as 594. The chemical vapor
deposition apparatus still further includes one or more conduits,
such as the conduits 108, 586, 590, 604, and 596, for conveying to
the substrate a gaseous reactant or process gas comprising from 1
to 6 standard volumes of the precursor, from 5 to 100 standard
volumes of the carrier gas, and from 0.1 to 2 standard volumes of
the oxidizing agent. The chemical vapor deposition apparatus
further includes a source 162 of microwave or radio frequency
energy and an applicator or electrode such as 160 powered by the
source of microwave or radio frequency energy for generating plasma
in the gaseous reactant or process gas.
[0235] Yet another embodiment is a syringe such as 252 comprising a
plunger 258, a barrel 250, and a coating on the interior surface
264. The barrel 250 is a vessel and has an interior surface 264
defining the vessel lumen 274 and receiving the plunger 258 for
sliding. The vessel interior surface 264 is a substrate. The
coating is a lubricity layer on the substrate 264, the plunger 258,
or both, applied by chemical vapor deposition, employing as the
gaseous reactant or process gas from 1 to 6 standard volumes of an
organosilicon precursor, from 5 to 100 standard volumes of a
carrier gas, and from 0.1 to 2 standard volumes of an oxidizing
agent. In addition to this lubricity coating, the syringe may
contain one or more other coatings, e.g. a SiO.sub.x barrier
coating as described herein. Said additional coating(s) may be
located under or over the lubricity coating, i.e. nearer to the
coated substrate or nearer to the lumen of the syringe.
[0236] A concern of converting from glass to plastic syringes
centers around the potential for leachable materials from plastics.
With plasma coating technology, the coating, being derived from
non-metal gaseous precursors e.g. HMDSO, will itself contain no
trace metals and function as a barrier to inorganic, metals and
organic solutes, preventing leaching of these species from the
coated substrate into syringe fluids. In addition to leaching
control of plastic syringes, the same plasma coating technology
offers potential to provide a solute barrier to the plunger tip,
typically made of elastomeric plastic compositions containing even
higher levels of leachable organic oligomers and catalysts.
[0237] Moreover, certain syringes prefilled with synthetic and
biological pharmaceutical formulations are very oxygen and moisture
sensitive. A critical factor in the conversion from glass to
plastic syringe barrels will be the improvement of plastic oxygen
and moisture barrier performance. The plasma coating technology is
suitable to provide a SiO.sub.x barrier coating for protection
against oxygen and moisture.
[0238] Even another embodiment is a plunger 258 for a syringe 252,
comprising a piston or tip, a coating, and a push rod. The piston
or tip has a front face, a generally cylindrical side face that
slides within the barrel 250, comprising a substrate, and a back
portion. The side face is configured to movably seat within a
syringe barrel. The coating is on the substrate and is a lubricity
layer interfacing with the side face. The lubricity layer is
produced from a chemical vapor deposition (CVD) process employing
the previously defined gaseous reactant or process gas. The push
rod engages the back portion of the piston and is configured for
advancing the piston in a syringe barrel.
[0239] Another embodiment is a stopper such as 282 (FIGS. 6-7). The
stopper 282 includes a sliding surface 276 defining a substrate and
adapted to be received in an opening to be stopped. The substrate
has on it a lubricity coating 288 made by providing a precursor
comprising an organosilicon compound and applying the precursor to
at least a portion of the sliding surface by chemical vapor
deposition, employing a gaseous reactant or process gas as defined
above.
[0240] Even another embodiment is a medical or diagnostic kit
including a vessel having a coating as defined in any embodiment
above on a substrate as defined in any embodiment above.
Optionally, the kit additionally includes a medicament or
diagnostic agent which is contained in the coated vessel in contact
with the coating; and/or a hypodermic needle, double-ended needle,
or other delivery conduit; and/or an instruction sheet.
[0241] Other aspects of the invention include any one or more of
the following:
[0242] Use of the coating according to any embodiment described
above for coating a surface and thereby preventing or reducing
mechanical and/or chemical effects of the surface on a compound or
composition in contact with the coating;
[0243] Use of the coating according to any described embodiment as
a lubricity layer;
[0244] Use of the coating according to any described embodiment for
protecting a compound or composition contacting the coating against
mechanical and/or chemical effects of the surface of the uncoated
vessel material;
[0245] Use of the coating according to any described embodiment for
preventing or reducing precipitation and/or clotting or platelet
activation of a compound or a component of the composition in
contact with the coating.
[0246] As one option, the compound or a component of the
composition is insulin, and precipitation of the insulin is
prevented or reduced. As another option, the compound or a
component of the composition is blood or a blood fraction, and
blood clotting or platelet activation is prevented or reduced. As
still another option, the coated vessel is a blood collection tube.
Optionally, the blood collection tube can contain an agent for
preventing blood clotting or platelet activation, for example
ethylenediamineteetraacetic acid (EDTA), a sodium salt thereof, or
heparin.
[0247] Additional options for use of the invention include any one
or more of the following:
[0248] Use of a coated substrate according to any described
embodiment, for example a vessel such as a sample collection tube,
for example a blood collection tube and/or a closed-ended sample
collection tube; a vial; a conduit; a cuvette; or a vessel part,
for example a stopper; or a syringe, or a syringe part, for example
a barrel or piston. for reception and/or storage and/or delivery of
a compound or composition.
[0249] The use of a coated substrate according to any described
embodiment is contemplated for storing insulin.
[0250] The use of a coated substrate according to any described
embodiment is contemplated for storing blood. Optionally, the
stored blood is viable for return to the vascular system of a
patient.
[0251] Use of a coating according to any described embodiment is
contemplated as (i) a lubricity layer having a lower frictional
resistance than the uncoated surface; and/or (ii) a hydrophobic
layer that is more hydrophobic than the uncoated surface.
[0252] Other aspects of the invention include any of the uses
defined above in the summary section.
[0253] The following is a more detailed description of the
invention. It starts with a general description of the lubricity
coating and hydrophobic coating of present invention, then
describes the equipment suitable to prepare the coating of present
invention and subsequently describes the coating embodiments, the
coated vessels, and the methods for their production.
IA. Lubricity Coating
[0254] Devices designed to deliver parenteral drug products have
moveable elastomeric plungers to push the product from the device.
Plungers often are provided with a lubricious surface to ease
movement of the plunger. Free silicon oil is traditionally employed
to create a lubricious surface, but free oil has been implicated in
aggregation and denaturation of proteins.
[0255] Silicon oil, a low molecular weight polydimethylsiloxane
(PDMS), has been the primary traditional means of making glass and
plastic surfaces lubricious and compatible with elastomeric
plungers. It is generally sprayed or wiped on the inside of the
device. These methods deposit a thin liquid layer of silicon oil.
Attempts to permanently adhere the oil on the surface of the device
through a baking process have improved the adhesion but silicon oil
extractables are still found. Non-uniformity of silicon oil on
devices is problematic and can lead to syringe breakage or
misfiring when employed in auto injectors.
[0256] Non-uniformity of silicon oil arises from improper or poor
application of the oil, settling/flow over time under the effects
of gravity, and pressure from plungers. During vacuum placement of
plungers into the device, the plunger will push silicon oil from
the top of the device down to the final resting location of the
plunger, See FIG. 3A. The silicon oil between the ribs of the
plunger and the glass surface of the device will, over time, flow
out of the space between the plunger and syringe wall under the
pressure of the plunger. Additionally it has been found that
silicon oil "settles" or flows under gravity to alter the
distribution of the oil. FIGS. 3A-3C, demonstrates examples of
silicon oil non-uniformity.
[0257] Non uniformity of silicon oil is responsible for a variety
of problems, including localized exposure of drug product to a
large depot of oil, high break loose forces, and unsmooth operation
of the devices due to variable glide forces. Variable glide forces
and high break loose forces are particularly problematic with auto
injectors, since auto injectors are designed to work with a known
and consistent force.
[0258] The lubricity coating of present invention is created from a
plasma that produces a uniform, firmly attached lubricious coating.
It has a superior performance relative to existing lubricity
approaches, comparing wetting tension, plunger force, and
extractables and leachables.
[0259] The lubricity coating of the invention is deposited using a
PECVD process that typically utilizes an organosilicon precursor
(preferably a cyclic organosilicon precursor, in particular
octamethylcyclotetrasiloxane (OMCTS)), oxygen, radiofrequency and
charged electrodes to create the plasma. Without being bound by
theory, it is believed that at the pressures and powers that are
used, the plasma process is driven by electron impact ionization;
that is, the electrons in the process are the driving force behind
the chemistry. The process utilizes radiofrequency to excite
electrons, resulting in lower temperatures than the other standard
method of adding energy to electrons in plasmas, microwaves. The
plasma, containing a mixture of high energy electrons and ions of
the gases, deposits a coating containing silicon and oxygen and
methyl groups attached to the silicon. High energy electrons
activate the substrate surface and bonds reform between the surface
and the silicon/oxygen/methyl species from the OMCTS. A covalently
bound uniform, continuous coating is deposited on the surface.
[0260] Since the coating is deposited from plasma, which uniformly
fills the container it occupies, at a molecular level, a uniform
composition coat is believed to be achieved. The lubricity coating
is essentially comprised of silicon, oxygen and methyl groups. AFM,
FTIR, TOF/SIMS, XPS and scanning electron microscopy confirm the
purity and uniformity.
TABLE-US-00002 TABLE I Lubricity Coating on Syringes Wetting
Tension Standard Package Type (dyne/cm) Deviation Cyclic Olefin
Syringe with CV Holdings 36 0.57 SiOxCyHz Lubricity Coating
Borosilicate Glass Syringe with Silicone Oil 37 0.57 Cyclic Olefin
Container with Triboglide Coating <30 N/A Precision of the
wetting tension measurement is +/-3 dyne/cm
[0261] Table I, above, shows the wetting tension measured a COC
syringe with SiOxCyHz lubricity coating, a borosilicate glass
syringe coated with silicon oil (Dow Corning Medical Grade 360),
and a COC container with Triboglide Coating (another known liquid
lubricant). A wetting tension of 30 dyne/cm is considered very
hydrophobic, a wetting tension of 70 dyne/cm very hydrophilic. All
three surfaces therefore show appreciable hydrophobicity. The
lubricity coating of the invention shows a hydrophobicity similar
to silicon oil, but less than Triboglide.
[0262] The lubricity coating of present invention can also be
applied onto a SiO.sub.x barrier coating. This is shown in FIG. 21,
which contains a TEM picture of a lubricity coating on a SiO.sub.2
layer,
[0263] The determination of an extractables profile for an
exemplary lubricity coating is described in Example Z. The
lubricity coating preferably provides less extractables than a
silicon oil coated glass syringe (Example Z), typically less than
10% of the extractables of the latter. In general, the lubricity
coating extractables amount ranges from 1 to 500 .mu.g/L,
preferably from 5 to 300 .mu.g/L. Typically, it may range from 80
to 300 .mu.g/L, based on the static method of determination.
[0264] Since the lubricity coating is attached to the coated
surface, the coating will remain uniform over time and consistent,
reproducible break loose and glide forces will be maintained.
Exemplary break loose and glide forces are shown in Table II:
TABLE-US-00003 TABLE II Plunger Force Comparison of Lubricity
Coatings Initiation Maintenance Package Type Force (N) Force (N)
Uncoated Cydic Olefin Syringe >15 >15 Cydic Olefin Syringe
with CV Holdings 4.1 3.5 SiOCH Lubricity Coating Cydic Olefin
Syringe with Silicone Oil 8.2 6.3 Cydic Olefin Cotainer with
Triboglide 5.7 2.0 Coating
[0265] The lubricity coating optionally provides a consistent
plunger force that reduces the difference between the break loose
force (Fi) and the glide force (Fm). These two forces are important
performance measures for the effectiveness of a lubricity coating.
For Fi and Fm, it is desired to have a low, but not too low value.
With too low Fi, which means a too low level of resistance (the
extreme being zero), premature/unintended flow may occur, which
might e.g. lead to an unintentional premature or uncontrolled
discharge of the content of a prefilled syringe.
[0266] In order to achieve a sufficient lubricity (e.g. to ensure
that a syringe plunger can be moved in the syringe, but to avoid
uncontrolled movement of the plunger), the following ranges of Fi
and Fm should be advantageously maintained:
Fi: 2.5 to 5 lbs, preferably 2.7 to 4.9 lbs, and in particular 2.9
to 4.7 lbs; Fm: 2.5 to 8.0 lbs, preferably 3.3 to 7.6 lbs, and in
particular 3.3 to 4 lbs. Further advantageous Fi and Fm values can
be found in the Tables of the Examples. From the Examples, it can
also be seen that lower Fi and Fm values can be achieved than the
ranges indicated above. Coatings having such lower values are also
considered to be encompassed by the present invention.
[0267] Table II compares a lubricity coating according to the
invention on a syringe with silicon oil and Triboglide lubricity
coatings. The results demonstrate that the lubricity coating
preferably provides superior consistency between Fi and Fm.
[0268] Break-loose and glide forces are important throughout a
device's shelf life especially in automated devices such as
auto-injectors. Changes in break-loose and/or glide forces can lead
to misfiring of auto injectors.
[0269] The present lubricity coatings can optionally have more than
10-times less silicon extractables compared to a silicon oil coated
syringe. During the PECVD process, the lubricity coating is bonded
to the syringe. This results in dramatically lower extractables.
Through process optimization, the total silicon extractables from
the lubricity coating can be further reduced.
[0270] The lubricity coating according to present invention is
typically prepared by PECVD using an organosilicon precursor and
O2. In a particular embodiment, these two precursors are mixed with
a carrier gas, typically a noble gas, and most typically Argon.
[0271] The organosilicon precursor may be any of the precursors
listed elsewhere in present description. However, cyclic
organosilicon precursors, in particular monocyclic organosilicon
precursors (like the monocyclic precursors listed elsewhere in
present description), and specifically OMCTS, are particularly
suitable to achieve a lubricious coating.
[0272] The presence of O2 and/or of a carrier gas, in particular of
Argon, can increase the lubricity of the resulting coating. The
presence of both O2 and Ar together with the organosilicon
precursor is particularly advantageous. Generally, in order to get
a lubricity coating, O2 is present in an amount (which can, e.g. be
expressed by the flow rate in sccm) which is does not very much
exceed the organosilicon amount and preferably is lower than the
organosilicon amount. In contrast, in order to achieve a barrier
coating, the amount of O2 typically is at least one order of
magnitude higher than the amount of organosilicon precursor. In
particular, the volume ratio (in sccm) of O2 to organosilicon
precursor for a lubricity coating is from 0:1 to 1:1, even
optionally from 0:1 to 0.5:1 or even from 0:1 to 0.1:1. It is
preferred that some O2 is present, optionally in an amount of from
0.01:1 to 0.5:1, even optionally from 0.05:1 to 0.4:1, in
particular from 0.1:1 to 0.2:1 in relation to the organosilicon
precursor. The presence of O2 in a volume of about 5% to about 35%
(v/v in sccm) in relation to the organosilicon precursor, in
particular of about 10% to about 20% and in a ratio as given in the
Examples is specifically suitable to achieve a lubricity
coating.
[0273] In one aspect of the invention, a carrier gas is absent in
the reaction mixture, in another aspect of the invention, it is
present. In a particular aspect of the invention, the carrier gas
is present and it is Argon. When Ar is the carrier gas and it is
present in the reaction mixture, it is typically present in a
volume (in sccm) exceeding the volume of the organosilicon
precursor (and the volume of O2, if present).
[0274] Typically, the plasma in the PECVD process is generated at
RF frequency. The plasma is typically generated with an electric
power of from 0.1 to 25 W, optionally from 1 to 22 W, optionally
from 1 to 10 W, even optionally from 1 to 5 W, optionally from 2 to
4 W, for example of 3 W, optionally from 3 to 17 W, even optionally
from 5 to 14 W, for example 6 or 7.5 W, optionally from 7 to 11 W,
for example of 8 W. The ratio of the electrode power to the plasma
volume can be less than 10 W/ml, optionally is from 5 W/ml to 0.1
W/ml, optionally is from 6 W/ml to 0.1 W/ml, optionally is from 4
W/ml to 0.1 W/ml, optionally from 2 W/ml to 0.2 W/ml. Low power
levels are believed by the inventors to be most advantageous (e.g.
power levels of from 2 to 3.5 W and the power levels given in the
Examples) to prepare a lubricity coating. These power levels are
suitable for applying lubricity coatings to syringes and sample
tubes and vessels of similar geometry having a void volume of 1 to
3 mL in which PECVD plasma is generated. It is contemplated that
for larger or smaller objects the power applied should be increased
or reduced accordingly to scale the process to the size of the
substrate.
[0275] The substrate of the lubricity coating is typically a
surface made of plastic (e.g. the interior surface of a plastic
syringe). Typical plastic substrates are listed elsewhere in
present description. Particularly suitable substrates in the
context of present invention are COC, PET, and polypropylene, with
COC being specifically suitable.
[0276] In one specific aspect of present invention, the substrate
is a plastic which is already coated with a coating, e.g. a SiOx
barrier coating. On said existing coating, the lubricity coating is
applied. Vice versa, the lubricity coating can also be coated with
another coating, e.g. a barrier coating.
[0277] In a very particular aspect of the present invention, the
lubricity is influenced by the roughness of the lubricity coating.
It has surprisingly been found that a rough surface of the coating
is correlated with enhanced lubricity. The roughness of the
lubricity coating is increased with decreasing power (in Watts)
energizing the plasma, and by the presence of O2 in the amounts
described above.
[0278] The vessels (e.g. syringe barrels and/or plungers) coated
with a lubricity coating according to present invention have a
higher lubricity (determined, e.g. by measuring the Fi and/or Fm)
than the uncoated vessels. They also have a higher lubricity than
vessels coated with a SiOx coating as described herein.
[0279] Exemplary reaction conditions for preparing a lubricity
coating according to the present invention in a 3 ml sample size
syringe with a 1/8'' diameter tube (open at the end) are as
follows:
Flow rate ranges: OMCTS: 0.5-5.0 sccm Oxygen: 0.1-5.0 sccm Argon:
1.0-20 sccm Power: 0.1-10 watts Specific Flow rates: OMCTS: 2.0
sccm Oxygen: 0.7 sccm Argon: 7.0 sccm Power: 3.5 watts
[0280] The coating apparatus can advantageously include heated
delivery lines from the exit of the OMCTS reservoir to as close as
possible to the gas inlet into the syringe.
[0281] The lubricity coating is described in more detail under V.C
below.
IB. Hydrophobic Coating
[0282] Silicon, like carbon, is tetravalent, thus preferring to
form four bonds. In glass, silicon bonds to oxygen, which is bonded
to another silicon (siloxane bonds, Si--O--Si), resulting in a
SiO.sub.2 polymer. A network of siloxane bonds form, creating
silica. At the surface of silica, oxygen atoms that are not bonded
to other silicon atoms exist as hydroxyl (OH) groups, known as
silanols. Terminal groups at a glass surface can thus be silanols
with one or more OH groups, or siloxane bonds. Lone silanols are
found in crystalline silica surfaces such as the SiO.sub.x coating
described herein. Both lone and vicinal silanols are found in
amorphous silicas such as traditional glasses. Without being bound
by theory, the chemical nature of the surface chemistry is believed
to be largely determined by the density of silanol groups on it. A
fully hydroxylated glass surface, that has the maximum density of
silanols possible, is quite hydrophilic. A surface on which the
silanols are condensed to form siloxane bonds, (i.e., minimal
density of silanols) has a hydrophobic nature. Using the coating
technologies as described herein, it is possible to control the
density of silanols on the surface of the coating. The chemistry of
the plasma deposition can be controlled to create either a fully
hydroxylated, hydrophilic surface or a minimally hydroxylated,
hydrophobic surface.
[0283] Table III, below, shows the wetting tension of four
different drug container surfaces. A wetting tension of 20 dyne/cm
is considered very hydrophobic, while a wetting tension of 80
dyne/cm is very hydrophilic. The data in Table III shows the
SiO.sub.2 barrier coating is as hydrophilic as traditional glass.
In contrast, the lubricity coating of present invention (designated
as SiOxCyHz Coating in the table) has a hydrophobic nature similar
to that of COC.
TABLE-US-00004 TABLE III Content Contact Surfaces Wetting Tension
Package Type (dyne/cm) Cyclic Olefin Container with SiO.sub.2
Coating >70 Borosilicate Glass Container >70 Cyclic Olefin
Container with SiOxCyHz Coating 46 Uncoated Cyclic Olefin Container
36 Precision of the wetting tension measurement was +/-3
dyne/cm
[0284] "Hydrophobic" in the context of present invention may mean
more hydrophobic than the uncoated substrate (may it be plastic or
another coating). However, as is demonstrated in FIG. 23, it can
also mean that the surface is as hydrophobic as a comparative
hydrophobic surface (like the COC surface in FIG. 23d). Preferably,
"hydrophobic" means a wetting tension of less than 60 dyne/cm, more
preferably less than 50 dyne/cm, in particular a wetting tension of
from 15 dyne/cm to 46 dyne/cm or from 20 dyne/cm to 35 dyne/cm.
[0285] The PECVD conditions for a hydrophobic surface coating are
contemplated to be similar to those for a lubricity coating, and in
fact it is possible that one coating can provide both functions to
a useful degree.
[0286] The difference in conditions to apply a hydrophobic coating
to an SiOx coating is illustrated by comparing a SiOx coating
protocol (US2010/0298738 A1, par. 1000 to 1011) with a hydrophobic
coating protocol (US2010/0298738 A1, par. 1012 to 1023). The
equipment and the precursor (HMDSO) are the same in these two
protocols, but the conditions are different, and generally milder
for the hydrophobic coating, as illustrated by the exemplary
conditions below:
TABLE-US-00005 Parameter SiO.sub.x Protocol Hydrophobic Protocol
O.sub.2 flow rate 90 sccm 60 sccm Pressure within tube 300 mTorr
270 mTorr during gas delivery PECVD RF Power 50 Watts 39 Watts
Power on time 5 sec 7 sec
[0287] An advantageous feature of the hydrophobic coating is that
it optionally can be applied using the same equipment as the SiOx
coating and/or the lubricity coating, so all PECVD coatings can be
applied sequentially in a single process, with minor changes in
conditions.
[0288] The hydrophobic coating can have a lower wetting tension
than the uncoated surface, optionally a wetting tension of from 20
to 72 dyne/cm, optionally from 30 to 60 dyne/cm, optionally from 30
to 50 dyne/cm, 30 to 40 dyne/cm, optionally 34 dyne/cm. One
proposed wetting tension, namely 34 dyne/cm, is similar to that of
a fluid silicone coating on borosilicate glass (30 dynes/cm).
[0289] FIG. 23 shows the effect of a hydrophobic coating according
to present invention and of a hydrophilic coating according to
present invention.
II. Vessel Holders
[0290] II.A. For producing the coating of present invention, a
vessel holder is provided. The portable vessel holders 38, 50, and
482 are provided for holding and conveying a vessel having an
opening while the vessel is processed. The vessel holder includes a
vessel port, a second port, a duct, and a conveyable housing.
[0291] II.A. The vessel port is configured to seat a vessel opening
in a mutually communicating relation. The second port is configured
to receive an outside gas supply or vent. The duct is configured
for passing one or more gases between a vessel opening seated on
the vessel port and the second port. The vessel port, second port,
and duct are attached in substantially rigid relation to the
conveyable housing. Optionally, the portable vessel holder weighs
less than five pounds. An advantage of a lightweight vessel holder
is that it can more readily be transported from one processing
station to another.
[0292] II.A. In certain embodiments of the vessel holder the duct
more specifically is a vacuum duct and the second port more
specifically is a vacuum port. The vacuum duct is configured for
withdrawing a gas via the vessel port from a vessel seated on the
vessel port. The vacuum port is configured for communicating
between the vacuum duct and an outside source of vacuum. The vessel
port, vacuum duct, and vacuum port can be attached in substantially
rigid relation to the conveyable housing.
[0293] II.A. The vessel holders are shown, for example, in FIG. 1.
The vessel holder 50 has a vessel port 82 configured to receive and
seat the opening of a vessel 80. The interior surface of a seated
vessel 80 can be processed via the vessel port 82. The vessel
holder 50 can include a duct, for example a vacuum duct 94, for
withdrawing a gas from a vessel 80 seated on the vessel port 92.
The vessel holder can include a second port, for example a vacuum
port 96 communicating between the vacuum duct 94 and an outside
source of vacuum, such as the vacuum pump 98. The vessel port 92
and vacuum port 96 can have sealing elements, for example O-ring
butt seals, respectively 100 and 102, or side seals between an
inner or outer cylindrical wall of the vessel port 82 and an inner
or outer cylindrical wall of the vessel 80 to receive and form a
seal with the vessel 80 or outside source of vacuum 98 while
allowing communication through the port. Gaskets or other sealing
arrangements can or also be used.
[0294] II.A. The vessel holder such as 50 can be made of any
material, for example thermoplastic material and/or electrically
nonconductive material. Or, the vessel holder such as 50 can be
made partially, or even primarily, of electrically conductive
material and faced with electrically nonconductive material, for
example in the passages defined by the vessel port 92, vacuum duct
94, and vacuum port 96. Examples of suitable materials for the
vessel holder 50 are: a polyacetal, for example Delrin.RTM. acetal
material sold by E.I. du Pont De Nemours and Company, Wilmington
Del.; polytetrafluoroethylene (PTFE), for example Teflon.RTM. PTFE
sold by E.I. du Pont De Nemours and Company, Wilmington Del.;
Ultra-High-Molecular-Weight Polyethylene (UHMWPE); High density
Polyethylene (HDPE); or other materials known in the art or newly
discovered.
[0295] II.A. FIG. 1 also illustrates that the vessel holder, for
example 50, can have a collar 116 for centering the vessel 80 when
it is approaching or seated on the port 92.
[0296] FIG. 10 is an alternative construction for a vessel holder
482 usable, for example, with the embodiments of any other Figure.
The vessel holder 482 comprises an upper portion 484 and a base 486
joined together at a joint 488. A sealing element, for example an
O-ring 490 (the right side of which is cut away to allow the pocket
retaining it to be described) is captured between the upper portion
484 and the base 486 at the joint 488. In the illustrated
embodiment, the O-ring 490 is received in an annular pocket 492 to
locate the O-ring when the upper portion 484 is joined to the base
486.
[0297] II.B. In this embodiment, the O-ring 490 is captured and
bears against a radially extending abutment surface 494 and the
radially extending wall 496 partially defining the pocket 492 when
the upper portion 484 and the base 486 are joined, in this case by
the screws 498 and 500. The O-ring 490 thus seats between the upper
portion 484 and base 486. The O-ring 490 captured between the upper
portion 484 and the base 486 also receives the vessel 80 (removed
in this figure for clarity of illustration of other features) and
forms a first O-ring seal of the vessel port 502 about the vessel
80 opening, analogous to the O-ring seal arrangement about the
vessel back opening.
[0298] II.B. In this embodiment, though not a requirement, the
vessel port 502 has both the first O-ring 490 seal and a second
axially spaced O-ring 504 seal, each having an inner diameter such
as 506 sized to receive the outer diameter (analogous to the
sidewall) of a vessel such as 80 for sealing between the vessel
port 502 and a vessel such as 80. The spacing between the O-rings
490 and 504 provides support for a vessel such as 80 at two axially
spaced points, preventing the vessel such as 80 from being skewed
with respect to the O-rings 490 and 504 or the vessel port 502. In
this embodiment, though not a requirement, the radially extending
abutment surface 494 is located proximal of the O-ring 490 and 506
seals and surrounding the vacuum duct 508.
III. Processing Vessels Seated on Vessel Holders
[0299] III.A. FIG. 1 shows a method for processing a vessel 80. The
method can be carried out as follows.
[0300] III.A. A vessel 80 can be provided having an opening 82 and
a wall 86 defining an interior surface 88. As one embodiment, the
vessel 80 can be formed in and then removed from a mold such as 22.
Optionally within 60 seconds, or within 30 seconds, or within 25
seconds, or within 20 seconds, or within 15 seconds, or within 10
seconds, or within 5 seconds, or within 3 seconds, or within 1
second after removing the vessel from the mold, or as soon as the
vessel 80 can be moved without distorting it during processing
(assuming that it is made at an elevated temperature, from which it
progressively cools), the vessel opening 82 can be seated on the
vessel port 92. Quickly moving the vessel 80 from the mold 22 to
the vessel port 92 reduces the dust or other impurities that can
reach the surface 88 and occlude or prevent adhesion of the barrier
or other type of coating 90. Also, the sooner a vacuum is drawn on
the vessel 80 after it is made, the less chance any particulate
impurities have of adhering to the interior surface 88.
[0301] III.A. A vessel holder such as 50 comprising a vessel port
92 can be provided. The opening 82 of the vessel 80 can be seated
on the vessel port 92. Before, during, or after seating the opening
82 of the vessel 80 on the vessel port 92, the vessel holder such
as 40 can be transported into engagement with one or more of the
bearing surfaces 220-240 to position the vessel holder 40 with
respect to the processing device or station such as 24.
[0302] III.A. The interior surface 88 of the seated vessel 80 can
be then processed via the vessel port 92 at the first processing
station, which can be, as one example, the barrier application or
other type of coating station 28 shown in FIG. 1. The vessel holder
50 and seated vessel 80 are transported from the first processing
station 28 to the second processing station, for example the
processing station 32. The interior surface 88 of the seated vessel
80 can be processed via the vessel port 92 at the second processing
station such as 32.
[0303] III.A. Any of the above methods can include the further step
of removing the vessel 80 from the vessel holder such as 66
following processing the interior surface 88 of the seated vessel
80 at the second processing station or device.
[0304] III.A. Any of the above methods can include the further
step, after the removing step, of providing a second vessel 80
having an opening 82 and a wall 86 defining an interior surface 88.
The opening 82 of the second vessel such as 80 can be seated on the
vessel port 92 of another vessel holder such as 38. The interior
surface of the seated second vessel 80 can be processed via the
vessel port 92 at the first processing station or device such as
24. The vessel holder such as 38 and seated second vessel 80 can be
transported from the first processing station or device 24 to the
second processing station or device such as 26. The seated second
vessel 80 can be processed via the vessel port 92 by the second
processing station or device 26.
IV. PECVD Apparatus for Making Vessels
IV.A. PECVD Apparatus Including Vessel Holder, Internal Electrode,
Vessel As Reaction Chamber
[0305] IV.A. A PECVD apparatus suitable for performing the present
invention includes a vessel holder, an inner electrode, an outer
electrode, and a power supply. A vessel seated on the vessel holder
defines a plasma reaction chamber, which optionally can be a vacuum
chamber. Optionally, a source of vacuum, a reactant gas source, a
gas feed or a combination of two or more of these can be supplied.
Optionally, a gas drain, not necessarily including a source of
vacuum, is provided to transfer gas to or from the interior of a
vessel seated on the port to define a closed chamber.
[0306] IV.A. The PECVD apparatus can be used for
atmospheric-pressure PECVD, in which case the plasma reaction
chamber does not need to function as a vacuum chamber.
[0307] IV.A. In FIG. 1 the vessel holder 50 comprises a gas inlet
port 104 for conveying a gas into a vessel seated on the vessel
port. The gas inlet port 104 has a sliding seal provided by at
least one O-ring 106, or two O-rings in series, or three O-rings in
series, which can seat against a cylindrical probe 108 when the
probe 108 is inserted through the gas inlet port 104. The probe 108
can be a gas inlet conduit that extends to a gas delivery port at
its distal end 110. The distal end 110 of the illustrated
embodiment can be inserted deep into the vessel 80 for providing
one or more PECVD reactants and other gaseous reactant or process
gases.
[0308] IV.A. FIG. 11 shows additional optional details of the
coating station 28 that are usable, for example, with all the
illustrated embodiments. The coating station 28 can also have a
main vacuum valve 574 in its vacuum line 576 leading to the
pressure sensor 152. A manual bypass valve 578 is provided in the
bypass line 580. A vent valve 582 controls flow at the vent
404.
[0309] IV.A. Flow out of the PECVD gas or precursor source 144 is
controlled by a main reactant gas valve 584 regulating flow through
the main reactant feed line 586. One component of the gas source
144 is the organosilicon liquid reservoir 588. The contents of the
reservoir 588 are drawn through the organosilicon capillary line
590, which is provided at a suitable length to provide the desired
flow rate. Flow of organosilicon vapor is controlled by the
organosilicon shut-off valve 592. Pressure is applied to the
headspace 614 of the liquid reservoir 588, for example a pressure
in the range of 0-15 psi (0 to 78 cm. Hg), from a pressure source
616 such as pressurized air connected to the headspace 614 by a
pressure line 618 to establish repeatable organosilicon liquid
delivery that is not dependent on atmospheric pressure (and the
fluctuations therein). The reservoir 588 is sealed and the
capillary connection 620 is at the bottom of the reservoir 588 to
ensure that only neat organosilicon liquid (not the pressurized gas
from the headspace 614) flows through the capillary tube 590. The
organosilicon liquid optionally can be heated above ambient
temperature, if necessary or desirable to cause the organosilicon
liquid to evaporate, forming an organosilicon vapor. Oxygen is
provided from the oxygen tank 594 via an oxygen feed line 596
controlled by a mass flow controller 598 and provided with an
oxygen shut-off valve 600.
[0310] IV.A. Referring especially to FIG. 1, the processing station
28 can include an electrode 160 fed by a radio frequency power
supply 162 for providing an electric field for generating plasma
within the vessel 80 during processing. In this embodiment, the
probe 108 is also electrically conductive and is grounded, thus
providing a counter-electrode within the vessel 80. Alternatively,
in any embodiment the outer electrode 160 can be grounded and the
probe 108 directly connected to the power supply 162.
[0311] IV.A. In the embodiment of FIG. 1 the outer electrode 160
can either be generally cylindrical as illustrated in FIGS. 1 and 2
or a generally U-shaped elongated channel as illustrated in F FIG.
1 (FIG. 2 being an embodiment of the section taken along section
line A-A of FIG. 1). Each illustrated embodiment has one or more
sidewalls, such as 164 and 166, and optionally a top end 168,
disposed about the vessel 80 in close proximity.
[0312] IV.A The electrode 160 shown in FIG. 1 can be shaped like a
"U" channel with its length into the page and the puck or vessel
holder 50 can move through the activated (powered) electrode during
the treatment/coating process. Note that since external and
internal electrodes are used, this apparatus can employ a frequency
between 50 Hz and 1 GHz applied from a power supply 162 to the U
channel electrode 160. The probe 108 can be grounded to complete
the electrical circuit, allowing current to flow through the
low-pressure gas(es) inside of the vessel 80. The current creates
plasma to allow the selective treatment and/or coating of the
interior surface 88 of the device.
[0313] IV.A The electrode in FIG. 1 can also be powered by a pulsed
power supply. Pulsing allows for depletion of reactive gases and
then removal of by-products prior to activation and depletion
(again) of the reactive gases. Pulsed power systems are typically
characterized by their duty cycle which determines the amount of
time that the electric field (and therefore the plasma) is present.
The power-on time is relative to the power-off time. For example a
duty cycle of 10% can correspond to a power on time of 10% of a
cycle where the power was off for 90% of the time. As a specific
example, the power might be on for 0.1 second and off for 1 second.
Pulsed power systems reduce the effective power input for a given
power supply 162, since the off-time results in increased
processing time. When the system is pulsed, the resulting coating
can be very pure (no by products or contaminants). Another result
of pulsed systems is the possibility to achieve atomic layer or
coating deposition (ALD). In this case, the duty cycle can be
adjusted so that the power-on time results in the deposition of a
single layer or coating of a desired material. In this manner, a
single atomic layer or coating is contemplated to be deposited in
each cycle. This approach can result in highly pure and highly
structured coatings (although at the temperatures required for
deposition on polymeric surfaces, temperatures optionally are kept
low (<100.degree. C.) and the low-temperature coatings can be
amorphous).
[0314] IV.A. An alternative coating station employs a microwave
cavity instead of an outer electrode. The energy applied can be a
microwave frequency, for example 2.45 GHz. However, in the context
of present invention, a radiofrequency is preferred.
V.1 Precursors for PECVD Coating
[0315] The precursor for the PECVD coating of the present invention
is broadly defined as an organometallic precursor. An
organometallic precursor is defined in this specification as
comprehending compounds of metal elements from Group III and/or
Group IV of the Periodic Table having organic residues, e.g.
hydrocarbon, aminocarbon or oxycarbon residues. Organometallic
compounds as presently defined include any precursor having organic
moieties bonded to silicon or other Group III/IV metal atoms
directly, or optionally bonded through oxygen or nitrogen atoms.
The relevant elements of Group III of the Periodic Table are Boron,
Aluminum, Gallium, Indium, Thallium, Scandium, Yttrium, and
Lanthanum, Aluminum and Boron being preferred. The relevant
elements of Group IV of the Periodic Table are Silicon, Germanium,
Tin, Lead, Titanium, Zirconium, Hafnium, and Thorium, with Silicon
and Tin being preferred. Other volatile organic compounds can also
be contemplated. However, organosilicon compounds are preferred for
performing present invention.
[0316] An organosilicon precursor is contemplated, where an
"organosilicon precursor" is defined throughout this specification
most broadly as a compound having at least one of the linkages:
##STR00002##
[0317] The first structure immediately above is a tetravalent
silicon atom connected to an oxygen atom and an organic carbon atom
(an organic carbon atom being a carbon atom bonded to at least one
hydrogen atom). The second structure immediately above is a
tetravalent silicon atom connected to an --NH-- linkage and an
organic carbon atom (an organic carbon atom being a carbon atom
bonded to at least one hydrogen atom). Optionally, the
organosilicon precursor is selected from the group consisting of a
linear siloxane, a monocyclic siloxane, a polycyclic siloxane, a
polysilsesquioxane, a linear silazane, a monocyclic silazane, a
polycyclic silazane, a polysilsesquiazane, and a combination of any
two or more of these precursors. Also contemplated as a precursor,
though not within the two formulas immediately above, is an alkyl
trimethoxysilane. If an oxygen-containing precursor (e.g. a
siloxane) is used, a representative predicted empirical composition
resulting from PECVD under conditions forming a hydrophobic or
lubricating coating would be Si.sub.wO.sub.xC.sub.yH.sub.z as
defined in the Definition Section, while a representative predicted
empirical composition resulting from PECVD under conditions forming
a barrier coating would be SiO.sub.x, where x in this formula is
from about 1.5 to about 2.9. If a nitrogen-containing precursor
(e.g. a silazane) is used, the predicted composition would be
Si.sub.w*N.sub.x*C.sub.y*H.sub.z*, i.e. in
Si.sub.wO.sub.xC.sub.yH.sub.z as specified in the Definition
Section, O is replaced by N and the indices are adapted to the
higher valency of N as compared to O (3 instead of 2). The latter
adaptation will generally follow the ratio of w, x, y and z in a
siloxane to the corresponding indices in its aza counterpart. In a
particular aspect of the invention,
Si.sub.w*N.sub.x*C.sub.y*H.sub.z* in which w*, x*, y*, and z* are
defined the same as w, x, y, and z for the siloxane counterparts,
but for an optional deviation in the number of hydrogen atoms.
[0318] One type of precursor starting material having the above
empirical formula is a linear siloxane, for example a material
having the following formula:
##STR00003##
in which each R is independently selected from alkyl, for example
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, vinyl,
alkyne, or others, and n is 1, 2, 3, 4, or greater, optionally two
or greater. Several examples of contemplated linear siloxanes are
[0319] hexamethyldisiloxane (HMDSO), [0320] octamethyltrisiloxane,
[0321] decamethyltetrasiloxane, [0322] dodecamethylpentasiloxane,
or combinations of two or more of these. The analogous silazanes in
which --NH-- is substituted for the oxygen atom in the above
structure are also useful for making analogous coatings. Several
examples of contemplated linear silazanes are
octamethyltrisilazane, decamethyltetrasilazane, or combinations of
two or more of these.
[0323] V.C. Another type of precursor starting material is a
monocyclic siloxane, for example a material having the following
structural formula:
##STR00004##
in which R is defined as for the linear structure and "a" is from 3
to about 10, or the analogous monocyclic silazanes. Several
examples of contemplated hetero-substituted and unsubstituted
monocyclic siloxanes and silazanes include [0324] 1,3,5-tri
methyl-1,3,5-tris(3,3,3-trifluoropropyl)methyl]cyclotrisiloxane
[0325] 2,4,6,8-tetramethyl-2,4,6,8-tetravinylcyclotetrasiloxane,
[0326] pentamethylcyclopentasiloxane, [0327]
pentavinylpentamethylcyclopentasiloxane, [0328]
hexamethylcyclotrisiloxane, [0329] hexaphenylcyclotrisiloxane,
[0330] octamethylcyclotetrasiloxane (OMCTS), [0331]
octaphenylcyclotetrasiloxane, [0332] decamethylcyclopentasiloxane
[0333] dodecamethylcyclohexasiloxane, [0334]
methyl(3,3,3-trifluoropropl)cyclosiloxane, [0335] Cyclic
organosilazanes are also contemplated, such as [0336]
Octamethylcyclotetrasilazane, [0337]
1,3,5,7-tetravinyl-1,3,5,7-tetramethylcyclotetrasilazane
hexamethylcyclotrisilazane, [0338] octamethylcyclotetrasilazane,
[0339] decamethylcyclopentasilazane, [0340]
dodecamethylcyclohexasilazane, or combinations of any two or more
of these.
[0341] V.C. Another type of precursor starting material is a
polycyclic siloxane, for example a material having one of the
following structural formulas:
##STR00005##
in which Y can be oxygen or nitrogen, E is silicon, and Z is a
hydrogen atom or an organic substituent, for example alkyl such as
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, vinyl,
alkyne, or others. When each Y is oxygen, the respective
structures, from left to right, are a silatrane, a silquasilatrane,
and a silproatrane. When Y is nitrogen, the respective structures
are an azasilatrane, an azasilquasiatrane, and an
azasilproatrane.
[0342] V.C. Another type of polycyclic siloxane precursor starting
material is a polysilsesquioxane, with the empirical formula
RSiO.sub.1.5 and the structural formula:
##STR00006##
in which each R is a hydrogen atom or an organic substituent, for
example alkyl such as methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, t-butyl, vinyl, alkyne, or others. Two commercial
materials of this sort are SST-eM01 poly(methylsilsesquioxane), in
which each R is methyl, and SST-3 MH1.1
poly(Methyl-Hydridosilsesquioxane), in which 90% of the R groups
are methyl, 10% are hydrogen atoms. This material is available in a
10% solution in tetrahydrofuran, for example. Combinations of two
or more of these are also contemplated. Other examples of a
contemplated precursor are methylsilatrane, CAS No. 2288-13-3, in
which each Y is oxygen and Z is methyl, methylazasilatrane,
poly(methylsilsesquioxane) (e.g. SST-eM01
poly(methylsilsesquioxane)), in which each R optionally can be
methyl, SST-3 MH1.1 poly(Methyl-Hydridosilsesquioxane) (e.g. SST-3
MH1.1 poly(Methyl-Hydridosilsesquioxane)), in which 90% of the R
groups are methyl and 10% are hydrogen atoms, or a combination of
any two or more of these.
[0343] V.C. The analogous polysilsesquiazanes in which --NH-- is
substituted for the oxygen atom in the above structure are also
useful for making analogous coatings. Examples of contemplated
polysilsesquiazanes are a poly(methylsilsesquiazane), in which each
R is methyl, and a poly(Methyl-Hydridosilsesquiazane, in which 90%
of the R groups are methyl, 10% are hydrogen atoms. Combinations of
two or more of these are also contemplated.
[0344] V.C. One particularly contemplated precursor for the
lubricity layer or coating according to the present invention is a
monocyclic siloxane, for example is
octamethylcyclotetrasiloxane.
[0345] One particularly contemplated precursor for the hydrophobic
layer or coating according to the present invention is a monocyclic
siloxane, for example is octamethylcyclotetrasiloxane. Another
particularly contemplated precursor for the hydrophobic layer or
coating according to the present invention is a linear siloxane,
for example HMDSO.
[0346] One particularly contemplated precursor for the barrier
coating according to the present invention is a linear siloxane,
for example is HMDSO.
[0347] V.C. In any of the coating methods according to the present
invention, the applying step optionally can be carried out by
vaporizing the precursor and providing it in the vicinity of the
substrate. E.g., OMCTS is usually vaporized by heating it to about
50.degree. C. before applying it to the PECVD apparatus.
V.2 General PECVD Method
[0348] In the context of the present invention, the following PECVD
method is generally applied, which contains the following
steps:
[0349] (a) providing a process gas comprising a precursor as
defined herein, optionally an oxidizing gas, optionally a carrier
gas, and optionally a hydrocarbon; and
[0350] (b) generating a plasma from the process gas, thus forming a
coating on the substrate surface by plasma enhanced chemical vapor
deposition (PECVD).
[0351] The plasma coating technology used herein is based on Plasma
Enhanced Chemical Vapor Deposition (PECVD). Methods and apparatus
suitable to perform said PECVD coatings are described in
EP10162755.2 filed May 12, 2010; EP10162760.2 filed May 12, 2010;
EP10162756.0 filed May 12, 2010; EP10162758.6 filed May 12, 2010;
EP10162761.0 filed May 12, 2010; and EP10162757.8 filed May 12,
2010. The PECVD methods and apparatus as described therein are
suitable to perform the present invention and are therefore
incorporated herein by reference.
[0352] Without being bound by theory, it is assumed that the
coating is covalently attached to the coated surface (may it be the
plastic substrate surface or the surface of a coating which is
already present on the substrate surface, e.g. a SiO.sub.x barrier
coating) in the PECVD process of the invention. The process uses a
silicon source (e.g. HMDSO or OMCTS), oxygen, radiofrequency (RF)
and charged electrodes to create the plasma. Optionally, a carrier
gas like Argon is present as well. A hydrocarbon gas may also be
present in specific applications. At the pressures and powers that
are used, the plasma process is driven by electron impact
ionization; that is, the electrons in the process are the driving
force of the reaction. The process utilizes RF to excite the
electrons, resulting in lower temperatures than traditional
standard methods of energizing electrons in plasmas, i.e.,
microwaves.
[0353] The plasma, which contains a mixture of high energy
electrons and ions of the gases, deposits a silicon and oxide
containing coating onto the plastic (e.g. COC) surface. Electrons
from the plasma interact at the polymer surface upon initiation of
the plasma reaction, "etching" the surface by breaking C--H bonds
(a similar "etching by breaking bonds" takes place when a coating
is coated again, e.g. when a lubricity coating is applied on a SiOx
barrier coating). Under the right conditions, these sites then are
believed to act as nucleation points where the Si--O--Si backbone
(which is formed from the ionization of the silicon containing
molecule in the gas phase) bonds with the polymer, from which the
coating grows, eventually forming a uniform, continuous coating
over the entire polymer surface. The silicon-carbon (silicon to
methyl groups) bonds in the organosilicon precursor can react with
oxygen, breaking the bond between the methyl group and silicon and
reforming bonds with the plastic surface or other Si--O groups
already on the surface.
[0354] Since the coating is grown from a plasma, which is an
ionized gas, completely filling the container it occupies, a dense,
uniform and conformal coating is achieved at a molecular level. See
FIGS. 21 and 22. The purity of the coating is assured through the
use of pure precursor gases. This process results in a surface with
uniform, controllable energy. Analytical characterization of a
coating with atomic force microscopy (AFM), FTIR, TOF-SIMS, XPS,
electron spectroscopy for chemical analysis (ESCA) and scanning
electron microscopy can confirm the purity and uniformity.
[0355] An exemplary preferred embodiment of the PECVD technology
will be described in the following sections.
[0356] The process utilizes a silicon containing vapor that can be
combined with oxygen at reduced pressures (mTorr range--atmospheric
pressure is 760 Torr) inside a container.
[0357] An electrical field generated at, e.g., 13.56 MHz [radio
frequency range] is then applied between an external electrode and
an internal grounded gas inlet to create a plasma. At the pressures
and powers that are used to coat a container, the plasma process is
driven by electron impact ionization, which means the electrons in
the process are the driving force behind the chemistry.
Specifically, the plasma drives the chemical reaction through
electron impact ionization of the silicon containing material
[e.g., hexamethyldisiloxane (HMDSO) or other reactants like
octamethylcyclotretrasiloxane (OMCTS)] resulting in a silicon
dioxide or Si.sub.wO.sub.xC.sub.yH.sub.z coating deposited onto the
interior surfaces of the container. These coatings are in a typical
embodiment on the order of 20 or more nanometers in thickness.
HMDSO consists of an Si--O--Si backbone with six (6) methyl groups
attached to the silicon atoms. The process breaks the Si--C bonds
and (at the surface of the tube or syringe) reacts with oxygen to
create silicon dioxide. Since the coating is grown on an atomic
basis, dense, conformal coatings with thicknesses of 20-30
nanometers can achieve significant barrier properties. The silicon
oxide acts as a physical barrier to gases, moisture, and small
organic molecules, and is of greater purity than commercial
glasses. OMCTS results in coatings with lubricity or anti-adhesion
properties. Their average thickness is generally higher than the
thickness of the SiO.sub.x barrier coating, e.g. from 30 to 1000 nm
on average. A certain roughness may enhance the lubricious
properties of the lubricity coating, thus its thickness is
advantageously not uniform throughout the coating (see below).
However, a uniform lubricity coating is also considered.
[0358] The technology is unique in several aspects:
[0359] (a) The process utilizes the rigid container as the vacuum
chamber. PECVD conventionally uses a secondary vacuum vessel into
which the part(s) are loaded and coated. Utilizing the container as
a vacuum chamber significantly simplifies the process apparatus and
reduces cycle/processing time, and thus manufacturing cost and
capital. This approach also reduces scale-up issues since scale-up
is as simple as replicating the number of tubes or syringes
required to meet the throughput requirements.
[0360] (b) Radio Frequency excitation of the plasma allows energy
to be imparted to the ionized gas with little heating of the part.
Unlike microwave excitation energies, typically used in PECVD,
which will impart significant energy to water molecules in the part
itself, radio frequency will not preferentially heat the polymeric
tubes or syringes. Controlled heat absorption is critical to
prevent substrate temperature increases approaching plastic glass
transition temperatures, causing loss of dimensional integrity
(collapse under vacuum).
[0361] (c) Single layer gas barrier coating--the new technology can
generate a single layer of silicon dioxide directly on the interior
surface of the part. Most other barrier technologies (thin film)
require at least two layers.
[0362] (d) Combination barrier-lubricity coatings--the new
technology utilizes a combination
SiO.sub.x/Si.sub.wO.sub.xC.sub.yH.sub.z coating to provide multiple
performance attributes (barrier/lubricity). The lubricity coating
can also be coated again with a barrier coating.
[0363] The plasma deposition technology in a preferred aspect
utilizes a simple manufacturing configuration. The system is based
on a "puck," which is used in transportation of tubes and syringes
in and out of the coating station. The device-puck interface is
critical, since once coating/characterization conditions are
established at the pilot scale, there are no scaling issues when
moving to full scale production; one simply increases the number of
pucks through the same process. The puck is manufactured from a
polymeric material (e.g. Delrin.TM.) to provide an electrically
insulated base. The container is mounted into the puck with the
largest opening sealing against an o-ring (mounted in the puck
itself). The o-ring provides the vacuum seal between the part and
the puck so that the ambient air (principally nitrogen and oxygen
with some water vapor) can be removed (pressure reduced) and the
process gases introduced. The puck has several key features in
addition to the o-ring seal. The puck provides a means of
connection to the vacuum pump (which pumps away the atmospheric
gases and the by-products of the silicon dioxide reaction), a means
of accurately aligning the gas inlet in the part, and a means of
providing a vacuum seal between the puck and gas inlet.
[0364] For SiO.sub.2 deposition, HMDSO and oxygen gases are then
admitted into the container through the grounded gas inlet which
extends up into the part. At this point, the puck and container are
moved into the electrode area. The electrode is constructed from a
conductive material (for example copper) and provides a tunnel
through which the part passes. The electrode does not make physical
contact with the container or the puck and is supported
independently. An RF impedance matching network and power supply
are connected directly to the electrode. The power supply provides
energy (at 13.56 MHz) to the impedance matched network. The RF
matching network acts to match the output impedance of the power
supply to the complex (capacitive and inductive) impedance of the
ionized gases. The matching network delivers maximum power delivery
to the ionized gas which ensures deposition of the silicon dioxide
coating.
[0365] Once the container is coated (as the puck moves the
container through the electrode channel--which is stationary), the
gases are stopped and atmospheric air (or pure nitrogen) is allowed
inside the puck/container to bring it back to atmospheric pressure.
At this time, the container can be removed from the puck and moved
to the next processing station.
[0366] The above describes clearly the means of coating a container
having just one opening. Syringes require an additional step before
and after loading onto the puck. Since the syringes have openings
at both ends (one for connection to a needle and the second for
installation of a plunger), the needle end must be sealed prior to
coating. The above process allows reaction gases to be admitted
into the plastic part interior, an electrical current to pass
through the gas inside of the part and a plasma to be established
inside the part. The plasma (an ionized composition of the HMDSO or
OMCTS and oxygen gases) is what drives the chemistry and the
deposition of the plasma coating.
[0367] In the method, the coating characteristics are
advantageously set by one or more of the following conditions: the
plasma properties, the pressure under which the plasma is applied,
the power applied to generate the plasma, the presence and relative
amount of O.sub.2 in the gaseous reactant, the presence and
relative amount of a carrier gas, e.g. of Argon in the gaseous
reactant, the plasma volume, and the organosilicon precursor.
Optionally, the coating characteristics are set by the presence and
relative amount of O.sub.2 in the gaseous reactant, and/or the
presence and relative amount of the carrier gas (e.g. Argon) and/or
the power applied to generate the plasma.
[0368] In all embodiments of the present invention, the plasma is
in an optional aspect a non-hollow-cathode plasma, in particular
when an SiO.sub.x coating is formed. In an alternative optional
aspect, there is a hollow-cathode plasma, in particular when a
lubricity coating is formed.
[0369] In a further preferred aspect, the plasma is generated at
reduced pressure (as compared to the ambient or atmospheric
pressure). Optionally, the reduced pressure is less than 300 mTorr,
optionally less than 200 mTorr, even optionally less than 100
mTorr.
[0370] The PECVD optionally is performed by energizing the gaseous
reactant containing the precursor with electrodes powered at a
frequency at microwave or radio frequency, and optionally at a
radio frequency. The radio frequency preferred to perform an
embodiment of the invention will also be addressed as "RF
frequency". A typical radio frequency range for performing the
present invention is a frequency of from 10 kHz to less than 300
MHz, optionally from 1 to 50 MHz, even optionally from 10 to 15
MHz. A frequency of 13.56 MHz is most preferred, this being a
government sanctioned frequency for conducting PECVD work.
[0371] There are several advantages for using a RF power source
versus a microwave source: Since RF operates a lower power, there
is less heating of the substrate/vessel. Because the focus of the
present invention is putting a plasma coating on plastic
substrates, lower processing temperature are desired to prevent
melting/distortion of the substrate. To prevent substrate
overheating when using microwave PECVD, the microwave PECVD is
applied in short bursts, by pulsing the power. The power pulsing
extends the cycle time for the coating, which is undesired in the
present invention. The higher frequency microwave can also cause
offgassing of volatile substances like residual water, oligomers
and other materials in the plastic substrate. This offgassing can
interfere with the PECVD coating. A major concern with using
microwave for PECVD is delamination of the coating from the
substrate. Delamination occurs because the microwaves change the
surface of the substrate prior to depositing the coating layer. To
mitigate the possibility of delamination, interface coating layers
have been developed for microwave PECVD to achieve good bonding
between the coating and the substrate. No such interface coating
layer or coating is needed with RF PECVD as there is no risk of
delamination. Finally, the lubricity layer or coating and
hydrophobic layer or coating according to the present invention are
advantageously applied using lower power. RF power operates at
lower power and provides more control over the PECVD process than
microwave power. Nonetheless, microwave power, though less
preferred, is usable under suitable process conditions.
[0372] Furthermore, for all PECVD methods described herein, there
is a specific correlation between the power (in Watts) used to
generate the plasma and the volume of the lumen wherein the plasma
is generated. Typically, the lumen is the lumen of a vessel coated
according to the present invention. The RF power should scale with
the volume of the vessel if the same electrode system is employed.
Once the composition of a gaseous reactant, for example the ratio
of the precursor to O.sub.2, and all other parameters of the PECVD
coating method but the power have been set, they will typically not
change when the geometry of a vessel is maintained and only its
volume is varied. In this case, the power will be directly
proportional to the volume. Thus, starting from the power to volume
ratios provided by present description, the power which has to be
applied in order to achieve the same or a similar coating in a
vessel of same geometry, but different size, can easily be found.
The influence of the vessel geometry on the power to be applied is
illustrated by the results of the Examples for tubes in comparison
to the Examples for syringe barrels.
[0373] For any coating of the present invention, the plasma is
generated with electrodes powered with sufficient power to form a
coating on the substrate surface. For a lubricity layer or coating,
or hydrophobic layer or coating (one layer may also be both
lubricant and hydrophobic), in the method according to an
embodiment of the invention the plasma is optionally generated
[0374] (i) with electrodes supplied with an electric power of from
0.1 to 25 W, optionally from 1 to 22 W, optionally from 1 to 10 W,
even optionally from 1 to 5 W, optionally from 2 to 4 W, for
example of 3 W, optionally from 3 to 17 W, even optionally from 5
to 14 W, for example 6 or 7.5 W, optionally from 7 to 11 W, for
example of 8 W.; and/or (ii) wherein the ratio of the electrode
power to the plasma volume is less than 10 W/ml, optionally is from
6 W/ml to 0.1 W/ml, optionally is from 5 W/ml to 0.1 W/ml,
optionally is from 4 W/ml to 0.1 W/ml, optionally is from 3 W/ml to
0.2 W/ml, optionally is from 2 W/ml to 0.2 W/ml.
[0375] Low power levels are believed by the inventors to be most
advantageous (e.g. power levels of from 2 to 3.5 W and the power
levels given in the Examples) to prepare a lubricity coating.
[0376] For a barrier coating or SiO.sub.x coating, the plasma is
optionally generated
[0377] (i) with electrodes supplied with an electric power of from
8 to 500 W, optionally from 20 to 400 W, optionally from 35 to 350
W, even optionally from 44 to 300 W, optionally from 44 to 70 W;
and/or
[0378] (ii) the ratio of the electrode power to the plasma volume
is equal or more than 5 W/ml, optionally is from 6 W/ml to 150
W/ml, optionally is from 7 W/ml to 100 W/ml, optionally from 7 W/ml
to 20 W/ml.
[0379] Low power levels are believed by the inventors to be most
advantageous (e.g. power levels of from 2 to 3.5 W and the power
levels given in the Examples) to prepare a lubricity coating. These
power levels are suitable for applying lubricity coatings to
syringes and sample tubes and vessels of similar geometry having a
void volume of 1 to 3 mL in which PECVD plasma is generated. It is
contemplated that for larger or smaller objects the power applied
should be increased or reduced accordingly to scale the process to
the size of the substrate.
[0380] The vessel geometry can also influence the choice of the gas
inlet used for the PECVD coating. In a particular aspect, a syringe
can be coated with an open tube inlet, and a tube can be coated
with a gas inlet having small holes which is extended into the
tube.
[0381] The power (in Watts) used for PECVD also has an influence on
the coating properties. Typically, an increase of the power will
increase the barrier properties of the coating, and a decrease of
the power will increase the lubricity and hydrophobicity of the
coating. This is demonstrated in several Examples, in particular in
Examples E to V. It is also demonstrated in Examples of EP 2 251
455 A2, to which explicit reference is made herewith.
[0382] A further parameter determining the coating properties is
the ratio of O.sub.2 (or another oxidizing agent) to the precursor
(e.g. organosilicon precursor) in the gaseous reactant used for
generating the plasma. Typically, an increase of the O.sub.2 ratio
in the gaseous reactant will increase the barrier properties of the
coating, and a decrease of the O.sub.2 ratio will increase the
lubricity and hydrophobicity of the coating. If a lubricity layer
or coating is desired, then O.sub.2 is optionally present in a
volume-volume ratio to the gaseous reactant of from 0:1 to 5:1,
optionally from 0:1 to 1:1, even optionally from 0:1 to 0.5:1 or
even from 0:1 to 0.1:1. It is preferred that some O.sub.2 is
present, optionally in an amount of from 0.01:1 to 0.5:1, even
optionally from 0.05:1 to 0.4:1, in particular from 0.1:1 to 0.2:1
in relation to the organosilicon precursor. The presence of O.sub.2
in a volume of about 5% to about 35% (v/v in sccm) in relation to
the organosilicon precursor, in particular of about 10% to about
20% and in a ratio as given in the Examples is specifically
suitable to achieve a lubricity coating.
[0383] If, on the other hand, a barrier or SiO.sub.x coating is
desired, then the O.sub.2 is optionally present in a volume:volume
ratio to the gaseous reactant of from 1:1 to 100:1 in relation to
the silicon containing precursor, optionally in a ratio of from 5:1
to 30:1, optionally in a ratio of from 10:1 to 20:1, even
optionally in a ratio of 15:1.
[0384] V.A. PECVD to Apply SiO.sub.x Barrier Coating, Using Plasma
that is Substantially Free of Hollow Cathode Plasma
[0385] V.A. A specific embodiment encompasses a method of applying
a barrier coating of SiO.sub.x, defined in this specification
(unless otherwise specified in a particular instance) as a coating
containing silicon, oxygen, and optionally other elements, in which
x, the ratio of oxygen to silicon atoms, is from about 1.5 to about
2.9, or 1.5 to about 2.6, or about 2. These alternative definitions
of x apply to any use of the term SiO.sub.x in this specification.
The barrier coating is applied to the interior of a vessel, for
example a sample collection tube, a syringe barrel, or another type
of vessel. The method includes several steps.
[0386] V.A. A vessel wall is provided, as is a reaction mixture
comprising plasma forming gas, i.e. an organosilicon compound gas,
optionally an oxidizing gas, and optionally a hydrocarbon gas.
[0387] V.A. Plasma is formed in the reaction mixture that is
substantially free of hollow cathode plasma. The vessel wall is
contacted with the reaction mixture, and the coating of SiO.sub.x
is deposited on at least a portion of the vessel wall.
[0388] V.A. In certain embodiments, the generation of a uniform
plasma throughout the portion of the vessel to be coated is
contemplated, as it has been found in certain instances to generate
an SiO.sub.x coating providing a better barrier against oxygen.
Uniform plasma means regular plasma that does not include a
substantial amount of hollow cathode plasma (which has a higher
emission intensity than regular plasma and is manifested as a
localized area of higher intensity interrupting the more uniform
intensity of the regular plasma).
[0389] V.A. The hollow cathode effect is generated by a pair of
conductive surfaces opposing each other with the same negative
potential with respect to a common anode. If the spacing is made
(depending on the pressure and gas type) such that the space charge
sheaths overlap, electrons start to oscillate between the
reflecting potentials of the opposite wall sheaths leading to
multiple collisions as the electrons are accelerated by the
potential gradient across the sheath region. The electrons are
confined in the space charge sheath overlap which results in very
high ionization and high ion density plasmas. This phenomenon is
described as the hollow cathode effect. Those skilled in the art
are able to vary the processing conditions, such as the power level
and the feed rates or pressure of the gases, to form uniform plasma
throughout or to form plasma including various degrees of hollow
cathode plasma.
[0390] V.A. The plasma is typically generated using RF energy for
the reasons given above. In an alternate, but less typical method,
microwave energy can be used to generate the plasma in a PECVD
process. The processing conditions can be different, however, as
microwave energy applied to a thermoplastic vessel will excite
(vibrate) water molecules. Since there is a small amount of water
in all plastic materials, the microwaves will heat the plastic. As
the plastic heats, the large driving force created by the vacuum
inside of the device relative to atmospheric pressure outside the
device will pull free or easily desorb materials to the interior
surface 88 where they will either become volatile or will be weakly
bound to the surface. The weakly bound materials will then create
an interface that can hinder subsequent coatings (deposited from
the plasma) from adhering to the plastic interior surface 88 of the
device.
[0391] V.A. As one way to negate this coating hindering effect, a
coating can be deposited at very low power (in the example above 5
to 20 Watts at 2.45 GHz) creating a cap onto which subsequent
coatings can adhere. This results in a two-step coating process
(and two coating layers). In the example above, the initial gas
flows (for the capping layer) can be changed to 2 sccm ("standard
cubic centimeters per minute") HMDSO and 20 sccm oxygen with a
process power of 5 to 20 Watts for approximately 2-10 seconds. Then
the gases can be adjusted to the flows in the example above and the
power level increased to 20-50 Watts so that an SiO.sub.x coating,
in which x in this formula is from about 1.5 to about 2.9,
alternatively from about 1.5 to about 2.6, alternatively about 2,
can be deposited. Note that the capping layer or coating might
provide little to no functionality in certain embodiments, except
to stop materials from migrating to the vessel interior surface 88
during the higher power SiO.sub.x coating deposition. Note also
that migration of easily desorbed materials in the device walls
typically is not an issue at lower frequencies such as most of the
RF range, since the lower frequencies do not excite (vibrate)
molecular species.
[0392] V.A. As another way to negate the coating hindering effect
described above, the vessel 80 can be dried to remove embedded
water before applying microwave energy. Desiccation or drying of
the vessel 80 can be accomplished, for example, by thermally
heating the vessel 80, as by using an electric heater or forced air
heating. Desiccation or drying of the vessel 80 also can be
accomplished by exposing the interior of the vessel 80, or gas
contacting the interior of the vessel 80, to a desiccant. Other
expedients for drying the vessel, such as vacuum drying, can also
be used. These expedients can be carried out in one or more of the
stations or devices illustrated or by a separate station or
device.
[0393] V.A. Additionally, the coating hindering effect described
above can be addressed by selection or processing of the resin from
which the vessels 80 are molded to minimize the water content of
the resin.
V.B. PECVD Coating Restricted Opening of Vessel (Syringe
Capillary)
[0394] V.B. FIGS. 8 and 9 show a method and apparatus generally
indicated at 290 for coating an inner surface 292 of a restricted
opening 294 of a generally tubular vessel 250 to be processed, for
example the restricted front opening 294 of a syringe barrel 250,
by PECVD. The previously described process is modified by
connecting the restricted opening 294 to a processing vessel 296
and optionally making certain other modifications.
[0395] V.B. The generally tubular vessel 250 to be processed
includes an outer surface 298, an inner or interior surface 254
defining a lumen 300, a larger opening 302 having an inner
diameter, and a restricted opening 294 that is defined by an inner
surface 292 and has an inner diameter smaller than the inner
diameter of the larger opening 302.
[0396] V.B. The processing vessel 296 has a lumen 304 and a
processing vessel opening 306, which optionally is the only
opening, although in other embodiments a second opening can be
provided that optionally is closed off during processing. The
processing vessel opening 306 is connected with the restricted
opening 294 of the vessel 250 to be processed to establish
communication between the lumen 300 of the vessel 250 to be
processed and the processing vessel lumen via the restricted
opening 294.
[0397] V.B. At least a partial vacuum is drawn within the lumen 300
of the vessel 250 to be processed and lumen 304 of the processing
vessel 296. A PECVD reactant is flowed from the gas source 144
through the first opening 302, then through the lumen 300 of the
vessel 250 to be processed, then through the restricted opening
294, then into the lumen 304 of the processing vessel 296.
[0398] V.B. The PECVD reactant can be introduced through the larger
opening 302 of the vessel 250 by providing a generally tubular
inner electrode 308 having an interior passage 310, a proximal end
312, a distal end 314, and a distal opening 316, in an alternative
embodiment multiple distal openings can be provided adjacent to the
distal end 314 and communicating with the interior passage 310. The
distal end of the electrode 308 can be placed adjacent to or into
the larger opening 302 of the vessel 250 to be processed. A
reactant gas can be fed through the distal opening 316 of the
electrode 308 into the lumen 300 of the vessel 250 to be processed.
The reactant will flow through the restricted opening 294, then
into the lumen 304, to the extent the PECVD reactant is provided at
a higher pressure than the vacuum initially drawn before
introducing the PECVD reactant.
[0399] V.B. Plasma 318 is generated adjacent to the restricted
opening 294 under conditions effective to deposit a coating of a
PECVD reaction product on the inner surface 292 of the restricted
opening 294. In the embodiment shown in FIG. 8, the plasma is
generated by feeding RF energy to the generally U-shaped outer
electrode 160 and grounding the inner electrode 308. The feed and
ground connections to the electrodes could also be reversed, though
this reversal can introduce complexity if the vessel 250 to be
processed, and thus also the inner electrode 308, are moving
through the U-shaped outer electrode while the plasma is being
generated.
[0400] An aspect of the invention is a syringe including a needle
and a barrel (a "staked needle syringe") as described in U.S. Ser.
No. 61/359,434, filed Jun. 29, 2010. The needle of this aspect of
the invention has an outside surface, a delivery outlet at one end,
a base at the other end, and an internal passage extending from the
base to the delivery outlet. The barrel has a, for example
generally cylindrical, interior surface defining a lumen. The
barrel also has a front passage molded around and in fluid-sealing
contact with the outside surface of the needle.
[0401] The syringe of any "staked needle" embodiment optionally can
further include a cap configured to isolate the delivery outlet of
the needle from ambient air.
[0402] The cap of any "staked needle" embodiment optionally can
further include a lumen having an opening defined by a rim and
sized to receive the delivery outlet, and the rim can be seatable
against an exterior portion of the barrel.
[0403] In the syringe of any "staked needle" embodiment, the barrel
optionally can further include a generally hemispheric interior
surface portion adjacent to its front passage.
[0404] In the syringe of any "staked needle" embodiment, the base
of the needle optionally can be at least substantially flush with
the hemispheric interior surface portion of the barrel.
[0405] The syringe of any "staked needle" embodiment optionally can
further include a PECVD-applied barrier coating on at least the
hemispheric interior surface portion of the barrel.
[0406] In the syringe of any "staked needle" embodiment, the
barrier coating optionally can extend over at least a portion of
the generally cylindrical interior surface portion of the
barrel.
[0407] In the syringe of any "staked needle" embodiment, the
barrier coating optionally can form a barrier between the base of
the needle and the generally cylindrical interior surface portion
of the barrel.
[0408] In the "staked needle" embodiment of FIG. 24, the cap 7126
is held in place on the nose 71110 of the syringe 7120 by a
conventional Luer lock arrangement. The tapered nose 71110 of the
syringe mates with a corresponding tapered throat 71112 of the cap
7126, and the syringe has a collar 71114 with an interior thread
71116 receiving the dogs 71118 and 71120 of the cap 7126 to lock
the tapers 71110 and 71112 together. The cap 7126 can be
substantially rigid.
[0409] Referring now to FIG. 25, a variation on the syringe barrel
71122 and cap 71124 of the "staked needle" embodiment is shown. In
this embodiment, the cap 71124 includes a flexible lip seal 7172 at
its base to form a moisture-tight seal with the syringe barrel
71122.
[0410] Optionally in the "staked needle" embodiments of FIGS. 24
and 25, the caps 7126 and 71124 can withstand vacuum during the
PECVD coating process. The caps 7126 and 71124 can be made of LDPE.
Alternative rigid plastic materials can be used as well, for
example polypropylene. Additional sealing elements can be provided
as well.
[0411] In another option of the "staked needle" embodiment,
illustrated in FIG. 26, the cap 71126 is flexible, and is designed
to seal around the top end of the syringe 7120. A deformable
material--like a rubber or a thermoplastic elastomer (TPE) can be
used for the cap 71126. Preferred TPE materials include
fluoroelastomers, and in particular, medical grade
fluoroelastomers. Examples include VITON.RTM. and TECHNOFLON.RTM..
VITON.RTM. is preferable in some embodiments. An example of a
suitable rubber is EPDM rubber.
[0412] During molding, in certain "staked needle" embodiments
(illustrated for example in FIG. 26) a small amount of the cap
material 71132 will be drawn into the tip or delivery outlet 7134
of the needle 7122 to create a seal. The material 71132 should have
a durometer such as to permit an appropriate amount of material to
be drawn into the needle 7122, and to cause the material drawn into
the needle 7122 to continue to adhere to the cap 71126 when it is
removed, unplugging the needle 7122 for use.
[0413] In other "staked needle" embodiments, the cap material 71132
can block the delivery outlet 7134 of the needle 7122 without being
drawn into the delivery outlet 7134. Suitable material selection to
accomplish the desired purposes is within the capabilities of a
person of ordinary skill in the art.
[0414] An additional seal can be created by coupling an undercut
71134 formed in the syringe barrel and projections 71138 in the
interior of the cap 71126, defining a coupling to retain the cap
71126. Alternative "staked needle" embodiments can include either
one or both of the seals described above.
[0415] Optionally, with reference to FIG. 25, the cap 71124 can
have a base 7168 and a coupling 7170 configured for securing the
cap 7126 in a seated position on the barrel. Alternatively or in
addition, a flexible lip seal 7172 can optionally be provided at
the base 7168 of the cap 71124 for seating against the barrel 71122
when the cap 71124 is secured on the barrel 71122.
[0416] Optionally, referring now to FIG. 26, the delivery outlet
7134 of the needle 7122 can be seated on the cap 71126 when the cap
7126 is secured on the barrel. This expedient is useful for sealing
the delivery outlet 7134 against the ingress or egress of air or
other fluids, when that is desired.
[0417] Optionally, in the "staked needle" embodiment the coupling
7170 can include a detent or groove 7174 on one of the barrel 71122
and the cap 71124 and a projection or rib 7176 on the other of the
barrel 71122 and the cap 71124, the projection 7176 being adapted
to mate with the detent 7174 when the cap 7126 is in its seated
position on the barrel. In one contemplated embodiment, a detent
7174 can be on the barrel and a projection 7176 can be on the cap
7126. In another contemplated embodiment, a detent 7174 can be on
the cap 7126 and a projection 7176 can be an the barrel. In yet
another contemplated embodiment, a first detent 7174 can be on the
barrel and a first projection 7176 mating with the detent 7174 can
be on the cap 7126, while a second detent 7175 can be on the cap
7126 and the mating second projection 7177 can be on the barrel. A
detent 7174 can be molded in the syringe barrel as an undercut by
incorporating side draws such as 7192 and 7194 in the mold.
[0418] The detents 7174 mate with the complementary projections
7176 to assemble (snap) the cap 7126 onto the syringe 7120. In this
respect the cap 7126 is desirably flexible enough to allow
sufficient deformation for a snapping engagement of the detents
7174 and projections 7176.
[0419] The caps in the "staked needle" embodiment such as 7126,
71124, and 71126 can be injection molded or otherwise formed, for
example from thermoplastic material. Several examples of suitable
thermoplastic material are a polyolefin, for example a cyclic
olefin polymer (COP), a cyclic olefin copolymer (COC),
polypropylene, or polyethylene. The cap 7126 can contain or be made
of a thermoplastic elastomer (TPE) or other elastomeric material.
The cap 7126 can also be made of polyethylene terephthalate (PET),
polycarbonate resin, or any other suitable material. Optionally, a
material for the cap 7126 can be selected that can withstand vacuum
and maintain sterility within the syringe 7120.
[0420] V.B. The plasma 318 generated in the vessel 250 during at
least a portion of processing can include hollow cathode plasma
generated inside the restricted opening 294 and/or the processing
vessel lumen 304. The generation of hollow cathode plasma 318 can
contribute to the ability to successfully apply a barrier coating
at the restricted opening 294, although the invention is not
limited according to the accuracy or applicability of this theory
of operation. Thus, in one contemplated mode of operation, the
processing can be carried out partially under conditions generating
a uniform plasma throughout the vessel 250 and the gas inlet, and
partially under conditions generating a hollow cathode plasma, for
example adjacent to the restricted opening 294.
[0421] V.B. The process is desirably operated under such
conditions, as explained here and shown in the drawings, that the
plasma 318 extends substantially throughout the syringe lumen 300
and the restricted opening 294. The plasma 318 also desirably
extends substantially throughout the syringe lumen 300, the
restricted opening 294, and the lumen 304 of the processing vessel
296. This assumes that a uniform coating of the interior 254 of the
vessel 250 is desired. In other embodiments non-uniform plasma can
be desired.
[0422] V.B. It is generally desirable that the plasma 318 have a
substantially uniform color throughout the syringe lumen 300 and
the restricted opening 294 during processing, and optionally a
substantially uniform color substantially throughout the syringe
lumen 300, the restricted opening 294, and the lumen 304 of the
processing vessel 296. The plasma desirably is substantially stable
throughout the syringe lumen 300 and the restricted opening 294,
and optionally also throughout the lumen 304 of the processing
vessel 296.
[0423] V.B. The order of steps in this method is not contemplated
to be critical.
[0424] V.B. In the embodiment of FIGS. 8 and 9, the restricted
opening 294 has a first fitting 332 and the processing vessel
opening 306 has a second fitting 334 adapted to seat to the first
fitting 332 to establish communication between the lumen 304 of the
processing vessel 296 and the lumen 300 of the vessel 250 to be
processed.
[0425] V.B. In the embodiment of FIGS. 8 and 9, the first and
second fittings are male and female Luer lock fittings 332 and 334,
respectively integral with the structure defining the restricted
opening 294 and the processing vessel opening 306. One of the
fittings, in this case the male Luer lock fitting 332, comprises a
locking collar 336 with a threaded inner surface and defining an
axially facing, generally annular first abutment 338 and the other
fitting 334 comprises an axially facing, generally annular second
abutment 340 facing the first abutment 338 when the fittings 332
and 334 are engaged.
[0426] V.B. In the illustrated embodiment a seal, for example an
O-ring 342 can be positioned between the first and second fittings
332 and 334. For example, an annular seal can be engaged between
the first and second abutments 338 and 340. The female Luer fitting
334 also includes dogs 344 that engage the threaded inner surface
of the locking collar 336 to capture the O-ring 342 between the
first and second fittings 332 and 334. Optionally, the
communication established between the lumen 300 of the vessel 250
to be processed and the lumen 304 of the processing vessel 296 via
the restricted opening 294 is at least substantially leak
proof.
[0427] V.B. As a further option, either or both of the Luer lock
fittings 332 and 334 can be made of electrically conductive
material, for example stainless steel. This construction material
forming or adjacent to the restricted opening 294 might contribute
to formation of the plasma in the restricted opening 294.
[0428] V.B. The desirable volume of the lumen 304 of the processing
vessel 296 is contemplated to be a trade-off between a small volume
that will not divert much of the reactant flow away from the
product surfaces desired to be coated and a large volume that will
support a generous reactant gas flow rate through the restricted
opening 294 before filling the lumen 304 sufficiently to reduce
that flow rate to a less desirable value (by reducing the pressure
difference across the restricted opening 294). The contemplated
volume of the lumen 304, in an embodiment, is less than three times
the volume of the lumen 300 of the vessel 250 to be processed, or
less than two times the volume of the lumen 300 of the vessel 250
to be processed, or less than the volume of the lumen 300 of the
vessel 250 to be processed, or less than 50% of the volume of the
lumen 300 of the vessel 250 to be processed, or less than 25% of
the volume of the lumen 300 of the vessel 250 to be processed.
Other effective relationships of the volumes of the respective
lumens are also contemplated.
[0429] V.B. The inventors have found that the uniformity of coating
can be improved in certain embodiments by repositioning the distal
end of the electrode 308 relative to the vessel 250 so it does not
penetrate as far into the lumen 300 of the vessel 250 as the
position of the inner electrode shown in previous Figures. For
example, although in certain embodiments the distal opening 316 can
be positioned adjacent to the restricted opening 294, in other
embodiments the distal opening 316 can be positioned less than 7/8
the distance, optionally less than 3/4 the distance, optionally
less than half the distance to the restricted opening 294 from the
larger opening 302 of the vessel to be processed while feeding the
reactant gas. Or, the distal opening 316 can be positioned less
than 40%, less than 30%, less than 20%, less than 15%, less than
10%, less than 8%, less than 6%, less than 4%, less than 2%, or
less than 1% of the distance to the restricted opening 294 from the
larger opening of the vessel to be processed while feeding the
reactant gas.
[0430] V.B. Or, the distal end of the electrode 308 can be
positioned either slightly inside or outside or flush with the
larger opening 302 of the vessel 250 to be processed while
communicating with, and feeding the reactant gas to, the interior
of the vessel 250. The positioning of the distal opening 316
relative to the vessel 250 to be processed can be optimized for
particular dimensions and other conditions of treatment by testing
it at various positions. One particular position of the electrode
308 contemplated for treating syringe barrels 250 is with the
distal end 314 penetrating about a quarter inch (about 6 mm) into
the vessel lumen 300 above the larger opening 302.
[0431] V.B. The inventors presently contemplate that it is
advantageous to place at least the distal end 314 of the electrode
308 within the vessel 250 so it will function suitably as an
electrode, though that is not necessarily a requirement.
Surprisingly, the plasma 318 generated in the vessel 250 can be
made more uniform, extending through the restricted opening 294
into the processing vessel lumen 304, with less penetration of the
electrode 308 into the lumen 300 than has previously been employed.
With other arrangements, such as processing a closed-ended vessel,
the distal end 314 of the electrode 308 commonly is placed closer
to the closed end of the vessel than to its entrance.
[0432] V.B. Or, the distal end 314 of the electrode 308 can be
positioned at the restricted opening 294 or beyond the restricted
opening 294, for example within the processing vessel lumen 304.
Various expedients can optionally be provided, such as shaping the
processing vessel 296 to improve the gas flow through the
restricted opening 294.
[0433] V.B. In yet another contemplated embodiment, the inner
electrode 308, as in FIG. 8, can be moved during processing, for
example, at first extending into the processing vessel lumen 304,
then being withdrawn progressively proximally as the process
proceeds. This expedient is particularly contemplated if the vessel
250, under the selected processing conditions, is long, and
movement of the inner electrode facilitates more uniform treatment
of the interior surface 254. Using this expedient, the processing
conditions, such as the gas feed rate, the vacuum draw rate, the
electrical energy applied to the outer electrode 160, the rate of
withdrawing the inner electrode 308, or other factors can be varied
as the process proceeds, customizing the process to different parts
of a vessel to be treated.
[0434] V.B. Conveniently, as in the other processes described in
this specification, the larger opening of the generally tubular
vessel 250 to be processed can be placed on a vessel support 320,
as by seating the larger opening 302 of the vessel 250 to be
processed on a port 322 of the vessel support 320. Then the inner
electrode 308 can be positioned within the vessel 250 seated on the
vessel support 320 before drawing at least a partial vacuum within
the lumen 300 of the vessel 250 to be processed.
V.C. Method of Applying a Lubricity Coating; and Lubricity
Coating
[0435] V.C. The main embodiments of present invention are a method
of applying a lubricity layer or coating derived from an
organosilicon precursor, and the resulting coating and coated item.
A "lubricity layer" or any similar term is generally defined as a
coating that reduces the frictional resistance of the coated
surface, relative to the uncoated surface. If the coated object is
a syringe (or syringe part, e.g. syringe barrel) or any other item
generally containing a plunger or movable part in sliding contact
with the coated surface, the frictional resistance has two main
aspects--breakout force and plunger sliding force.
[0436] The plunger sliding force test is a specialized test of the
coefficient of sliding friction of the plunger within a syringe,
accounting for the fact that the normal force associated with a
coefficient of sliding friction as usually measured on a flat
surface is addressed by standardizing the fit between the plunger
or other sliding element and the tube or other vessel within which
it slides. The parallel force associated with a coefficient of
sliding friction as usually measured is comparable to the plunger
sliding force measured as described in this specification. Plunger
sliding force can be measured, for example, as provided in the ISO
7886-1:1993 test.
[0437] The plunger sliding force test can also be adapted to
measure other types of frictional resistance, for example the
friction retaining a stopper within a tube, by suitable variations
on the apparatus and procedure. In one embodiment, the plunger can
be replaced by a closure and the withdrawing force to remove or
insert the closure can be measured as the counterpart of plunger
sliding force.
[0438] Also or instead of the plunger sliding force, the breakout
force can be measured. The breakout force is the force required to
start a stationary plunger moving within a syringe barrel, or the
comparable force required to unseat a seated, stationary closure
and begin its movement. The breakout force is measured by applying
a force to the plunger that starts at zero or a low value and
increases until the plunger begins moving. The breakout force tends
to increase with storage of a syringe, after the prefilled syringe
plunger has pushed away the intervening lubricant or adhered to the
barrel due to decomposition of the lubricant between the plunger
and the barrel. The breakout force is the force needed to overcome
"sticktion," an industry term for the adhesion between the plunger
and barrel that needs to be overcome to break out the plunger and
allow it to begin moving.
[0439] The break loose force (Fi) and the glide force (Fm) are
important performance measures for the effectiveness of a lubricity
coating. For Fi and Fm, it is desired to have a low, but not too
low value. With too low Fi, which means a too low level of
resistance (the extreme being zero), premature/unintended flow may
occur, which might e.g. lead to an unintentional premature or
uncontrolled discharge of the content of a prefilled syringe.
[0440] In order to achieve a sufficient lubricity (e.g. to ensure
that a syringe plunger can be moved in the syringe, but to avoid
uncontrolled movement of the plunger), the following ranges of Fi
and Fm should be advantageously maintained:
Fi: 2.5 to 5 lbs, preferably 2.7 to 4.9 lbs, and in particular 2.9
to 4.7 lbs; Fm: 2.5 to 8.0 lbs, preferably 3.3 to 7.6 lbs, and in
particular 3.3 to 4 lbs.
[0441] Further advantageous Fi and Fm values can be found in the
Tables of the Examples.
[0442] The lubricity coating optionally provides a consistent
plunger force that reduces the difference between the break loose
force (Fi) and the glide force (Fm).
[0443] V.C. Some utilities of coating a vessel in whole or in part
with a lubricity layer, such as selectively at surfaces contacted
in sliding relation to other parts, is to ease the insertion or
removal of a stopper or passage of a sliding element such as a
piston in a syringe or a stopper in a sample tube. The vessel can
be made of glass or a polymer material such as polyester, for
example polyethylene terephthalate (PET), a cyclic olefin copolymer
(COC), an olefin such as polypropylene, or other materials. COC is
particularly suitable for syringes. Applying a lubricity layer or
coating by PECVD can avoid or reduce the need to coat the vessel
wall or closure with a sprayed, dipped, or otherwise applied
organosilicon or other lubricant that commonly is applied in a far
larger quantity than would be deposited by a PECVD process.
[0444] V.C. In any of the above embodiments V.C., a plasma is
formed in the vicinity of the substrate.
[0445] In any of embodiments V.C., the precursor optionally can be
provided in the substantial absence of nitrogen. In any of
embodiments V.C., the precursor optionally can be provided at less
than 1 Torr absolute pressure.
[0446] V.C. In any of embodiments V.C., the precursor optionally
can be provided to the vicinity of a plasma emission.
[0447] V.C. In any of embodiments V.C., the coating optionally can
be applied to the substrate at a thickness of 1 to 5000 nm, or 10
to 1000 nm, or 10 to 500 nm, or 10 to 200 nm, or 20 to 100 nm, or
30 to 1000 nm, or 30 to 500 nm thick. A typical thickness is from
30 to 1000 nm or from 20 to 100 nm, a very typical thickness is
from 80 to 150 nm. These ranges are representing average
thicknesses, as a certain roughness may enhance the lubricious
properties of the lubricity coating. Thus its thickness is
advantageously not uniform throughout the coating (see below).
However, a uniformly thick lubricity coating is also
considered.
[0448] The absolute thickness of the lubricity coating at single
measurement points can be higher or lower than the range limits of
the average thickness, with maximum deviations of preferably
+/-50%, more preferably +/-25% and even more preferably +/-15% from
the average thickness. However, it typically varies within the
thickness ranges given for the average thickness in this
description.
[0449] The thickness of this and other coatings can be measured,
for example, by transmission electron microscopy (TEM). An
exemplary TEM image for a lubricity coating is shown in FIG. 21. An
exemplary TEM image for an SiO.sub.2 barrier coating (described in
more detail elsewhere) is shown in FIG. 22.
[0450] V.C. The TEM can be carried out, for example, as 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 or coating of carbon (50-100 nm thick) and then coated with a
sputtered layer or coating of platinum (50-100 nm thick) using a
K575X Emitech coating system, or the samples can be coated directly
with the protective sputtered Pt layer. The coated samples can be
placed in an FEI FIB200 FIB system. An additional layer or coating
of platinum can be FIB-deposited by injection of an
oregano-metallic gas while rastering the 30 kV gallium ion beam
over the area of interest. The area of interest for each sample can
be chosen to be a location half way down the length of the syringe
barrel. Thin cross sections measuring approximately 15 .mu.m
("micrometers") long, 2 .mu.m wide and 15 .mu.m deep can be
extracted from the die surface using a proprietary in-situ FIB
lift-out technique. The cross sections can be attached to a 200
mesh copper TEM grid using FIB-deposited platinum. One or two
windows in each section, measuring .about.8 .mu.m wide, can be
thinned to electron transparency using the gallium ion beam of the
FEI FIB.
[0451] V.C. Cross-sectional image analysis of the prepared samples
can be performed utilizing either a Transmission Electron
Microscope (TEM), or a Scanning Transmission Electron Microscope
(STEM), or both. All imaging data can be recorded digitally. For
STEM imaging, the grid with the thinned foils can be transferred to
a Hitachi HD2300 dedicated STEM. Scanning transmitted electron
images can be acquired at appropriate magnifications in atomic
number contrast mode (ZC) and transmitted electron mode (TE). The
following instrument settings can be used.
TABLE-US-00006 Scanning Transmission Electron 1. Instrument
Microscope Manufacturer/Model Hitachi HD2300 Accelerating Voltage
200 kV Objective Aperture #2 Condenser Lens 1 Setting 1.672
Condenser Lens 2 Setting 1.747 Approximate Objective Lens Setting
5.86 ZC Mode Projector Lens 1.149 TE Mode Projector Lens 0.7 Image
Acquisition Pixel Resolution 1280 .times. 960 Acquisition Time 20
sec.(x4)
[0452] V.C. For TEM analysis the sample grids can be transferred to
a Hitachi HF2000 transmission electron microscope. Transmitted
electron images can be acquired at appropriate magnifications. The
relevant instrument settings used during image acquisition can be
those given below.
TABLE-US-00007 Transmission Electron Instrument Microscope
Manufacturer/Model Hitachi HF2000 Accelerating Voltage 200 kV
Condenser Lens 1 0.78 Condenser Lens 2 0 Objective Lens 6.34
Condenser Lens Aperture #1 Objective Lens Aperture for imaging #3
Selective Area Aperture for SAD N/A
[0453] V.C. In any of embodiments V.C., the substrate can comprise
glass or a polymer, for example a polycarbonate polymer, an olefin
polymer, a cyclic olefin copolymer, a polypropylene polymer, a
polyester polymer, a polyethylene terephthalate polymer or a
combination of any two or more of these.
[0454] V.C. In any of embodiments V.C., the PECVD optionally can be
performed by energizing the gaseous reactant containing the
precursor with electrodes powered at a RF frequency as defined
above, for example a frequency from 10 kHz to less than 300 MHz,
optionally from 1 to 50 MHz, even optionally from 10 to 15 MHz,
optionally a frequency of 13.56 MHz.
[0455] V.C. In any of embodiments V.C., the plasma can be generated
by energizing the gaseous reactant comprising the precursor with
electrodes supplied with electric power sufficient to form a
lubricity layer. Optionally, the plasma is generated by energizing
the gaseous reactant containing the precursor with electrodes
supplied with an electric power of from 0.1 to 25 W, optionally
from 1 to 22 W, optionally from 1 to 10 W, even optionally from 1
to 5 W, optionally from 2 to 4 W, for example of 3 W, optionally
from 3 to 17 W, even optionally from 5 to 14 W, for example 6 or
7.5 W, optionally from 7 to 11 W, for example of 8 W. The ratio of
the electrode power to the plasma volume can be less than 10 W/ml,
optionally is from 6 W/ml to 0.1 W/ml, optionally is from 5 W/ml to
0.1 W/ml, optionally is from 4 W/ml to 0.1 W/ml, optionally is from
2 W/ml to 0.2 W/ml. Low power levels are believed by the inventors
to be most advantageous (e.g. power levels of from 2 to 3.5 W and
the power levels given in the Examples) to prepare a lubricity
coating. These power levels are suitable for applying lubricity
coatings to syringes and sample tubes and vessels of similar
geometry having a void volume of 1 to 3 mL in which PECVD plasma is
generated. It is contemplated that for larger or smaller objects
the power applied should be increased or reduced accordingly to
scale the process to the size of the substrate.
[0456] V.C. In any of embodiments V.C., one preferred combination
of process gases includes octamethylcyclotetrasiloxane (OMCTS) or
another cyclic siloxane as the precursor, in the presence of oxygen
as the oxidizing gas and argon as the carrier gas. Without being
bound to the accuracy of this theory, the inventors believe this
particular combination is effective for the following reasons.
[0457] V.C. It is believed that the OMCTS or other cyclic siloxane
molecule provides several advantages over other siloxane materials.
First, its ring structure results in a less dense coating (as
compared to coatings prepared from HMDSO). The molecule also allows
selective ionization so that the final structure and chemical
composition of the coating can be directly controlled through the
application of the plasma power. Other organosilicon molecules are
readily ionized (fractured) so that it is more difficult to retain
the original structure of the molecule.
[0458] V.C. Since the addition of Argon gas improves the lubricity
performance (see the working examples below), it is believed that
additional ionization of the molecule in the presence of Argon
contributes to providing lubricity. The Si--O--Si bonds of the
molecule have a high bond energy followed by the Si--C, with the
C--H bonds being the weakest. Lubricity appears to be achieved when
a portion of the C--H bonds are broken. This allows the connecting
(cross-linking) of the structure as it grows. Addition of oxygen
(with the Argon) is understood to enhance this process. A small
amount of oxygen can also provide C--O bonding to which other
molecules can bond. The combination of breaking C--H bonds and
adding oxygen all at low pressure and power leads to a chemical
structure that is solid while providing lubricity.
[0459] In a specific embodiment of the present invention, the
lubricity can also be influenced by the roughness of the lubricity
coating which results from the PECVD process using the precursors
and conditions described herein. It has now surprisingly been found
in the context of present invention by performing scanning electron
microscopy (SEM) and atomic force microscopy (AFM), that a rough,
non-continuous OMCTS plasma coating offers lower plunger force (Fi,
Fm) than a smooth, continuous OMCTS plasma coating. This is
demonstrated by Examples O to V.
[0460] While not bound by theory, the inventors assume that this
particular effect could be, in part, based on one or both of the
following mechanistic effects:
[0461] (a) lower surface contact of the plunger with the lubricity
coating (e.g. the circular rigid plunger surface contacting only
the peaks of a rough coating), either initially and/or throughout
the plunger movement, resulting in overall lower contact and thus
friction. (b) Upon plunger movement, the plunger causes the initial
non-uniform, rough coating to be spread and smoothed into the
uncoated "valleys".
[0462] The roughness of the lubricity coating is increased with
decreasing power (in Watts) energizing the plasma, and by the
presence of O2 in the amounts described above. The roughness can be
expressed as "RMS roughness" or "RMS" determined by AFM. RMS is the
standard deviation of the difference between the highest and lowest
points in an AFM image (the difference is designated as "Z"). It is
calculated according to the formula:
Rq={.SIGMA.(Z1-Zavg).sub.2/N}-2
where Zavg is the average Z value within the image; Z1 is the
current value of Z; and N is the number of points in the image.
[0463] The RMS range in this specific embodiment is typically from
7 to 20 nm, preferably from 12 to 20 nm. A lower RMS can, however,
still lead to satisfying lubricity properties.
[0464] V.C. One contemplated product optionally can be a syringe
having a barrel treated by the method of any one or more of
embodiments V.C. Said syringe can either have just a lubricity
coating according to present invention, or it can have the
lubricity coating and one or more other coatings in addition, e.g.
a SiO.sub.x barrier coating under or over the lubricity
coating.
V.D. Liquid-Applied Coatings
[0465] V.D. An example of a suitable barrier or other type of
coating, usable in conjunction with the PECVD-applied coatings or
other PECVD treatment as disclosed here, can be a liquid barrier,
lubricant, surface energy tailoring, or other type of coating 90
applied to the interior surface of a vessel, either directly or
with one or more intervening PECVD-applied coatings described in
this specification, for example SiO.sub.x, a lubricity layer or
coating according to present invention, or both.
[0466] V.D. Suitable liquid barriers or other types of coatings 90
also optionally can be applied, for example, by applying a liquid
monomer or other polymerizable or curable material to the interior
surface of the vessel 80 and curing, polymerizing, or crosslinking
the liquid monomer to form a solid polymer. Suitable liquid barrier
or other types of coatings 90 can also be provided by applying a
solvent-dispersed polymer to the surface 88 and removing the
solvent.
[0467] V.D. Either of the above methods can include as a step
forming a coating 90 on the interior 88 of a vessel 80 via the
vessel port 92 at a processing station or device 28. One example is
applying a liquid coating, for example of a curable monomer,
prepolymer, or polymer dispersion, to the interior surface 88 of a
vessel 80 and curing it to form a film that physically isolates the
contents of the vessel 80 from its interior surface 88. The prior
art describes polymer coating technology as suitable for coating
plastic blood collection tubes. For example, the acrylic and
polyvinylidene chloride (PVdC) coating materials and coating
methods described in U.S. Pat. No. 6,165,566, which is hereby
incorporated by reference, optionally can be used.
[0468] V.D. Either of the above methods can also or include as a
step forming a coating on the exterior outer wall of a vessel 80.
The coating optionally can be a barrier coating, optionally an
oxygen barrier coating, or optionally a water barrier coating. One
example of a suitable coating is polyvinylidene chloride, which
functions both as a water barrier and an oxygen barrier.
Optionally, the barrier coating can be applied as a water-based
coating. The coating optionally can be applied by dipping the
vessel in it, spraying it on the vessel, or other expedients. A
vessel having an exterior barrier coating as described above is
also contemplated.
VII. Pecvd Treated Vessels
[0469] VII. Vessels are contemplated having a barrier coating 90
(shown in FIG. 1, for example), which can be an SiO.sub.x coating
applied to a thickness of at least 2 nm, or at least 4 nm, or at
least 7 nm, or at least 10 nm, or at least 20 nm, or at least 30
nm, or at least 40 nm, or at least 50 nm, or at least 100 nm, or at
least 150 nm, or at least 200 nm, or at least 300 nm, or at least
400 nm, or at least 500 nm, or at least 600 nm, or at least 700 nm,
or at least 800 nm, or at least 900 nm. The coating can be up to
1000 nm, or at most 900 nm, or at most 800 nm, or at most 700 nm,
or at most 600 nm, or at most 500 nm, or at most 400 nm, or at most
300 nm, or at most 200 nm, or at most 100 nm, or at most 90 nm, or
at most 80 nm, or at most 70 nm, or at most 60 nm, or at most 50
nm, or at most 40 nm, or at most 30 nm, or at most 20 nm, or at
most 10 nm, or at most 5 nm thick. Specific thickness ranges
composed of any one of the minimum thicknesses expressed above,
plus any equal or greater one of the maximum thicknesses expressed
above, are expressly contemplated. The thickness of the SiO.sub.x
or other coating can be measured, for example, by transmission
electron microscopy (TEM), and its composition can be measured by
X-ray photoelectron spectroscopy (XPS).
[0470] VII. It is contemplated that the choice of the material to
be barred from permeating the coating and the nature of the
SiO.sub.x coating applied can affect its barrier efficacy. For
example, two examples of material commonly intended to be barred
are oxygen and water/water vapor. Materials commonly are a better
barrier to one than to the other. This is believed to be so at
least in part because oxygen is transmitted through the coating by
a different mechanism than water is transmitted.
[0471] VII. Oxygen transmission is affected by the physical
features of the coating, such as its thickness, the presence of
cracks, and other physical details of the coating. Water
transmission, on the other hand, is believed to commonly be
affected by chemical factors, i.e. the material of which the
coating is made, more than physical factors. The inventors also
believe that at least one of these chemical factors is a
substantial concentration of OH moieties in the coating, which
leads to a higher transmission rate of water through the barrier.
An SiO.sub.x coating often contains OH moieties, and thus a
physically sound coating containing a high proportion of OH
moieties is a better barrier to oxygen than to water. A physically
sound carbon-based barrier, such as amorphous carbon or
diamond-like carbon (DLC) commonly is a better barrier to water
than is a SiO.sub.x coating because the carbon-based barrier more
commonly has a lower concentration of OH moieties.
[0472] VII. Other factors lead to a preference for an SiO.sub.x
coating, however, such as its oxygen barrier efficacy and its close
chemical resemblance to glass and quartz. Glass and quartz (when
used as the base material of a vessel) are two materials long known
to present a very high barrier to oxygen and water transmission as
well as substantial inertness to many materials commonly carried in
vessels. Thus, it is commonly desirable to optimize the water
barrier properties such as the water vapor transmission rate (WVTR)
of an SiO.sub.x coating, rather than choosing a different or
additional type of coating to serve as a water transmission
barrier.
[0473] VII. Several ways contemplated to improve the WVTR of an
SiO.sub.x coating are as follow.
[0474] VII. The concentration ratio of organic moieties (carbon and
hydrogen compounds) to OH moieties in the deposited coating can be
increased. This can be done, for example, by increasing the
proportion of oxygen in the feed gases (as by increasing the oxygen
feed rate or by lowering the feed rate of one or more other
constituents). The lowered incidence of OH moieties is believed to
result from increasing the degree of reaction of the oxygen feed
with the hydrogen in the silicone source to yield more volatile
water in the PECVD exhaust and a lower concentration of OH moieties
trapped or incorporated in the coating.
[0475] VII. Higher energy can be applied in the PECVD process,
either by raising the plasma generation power level, by applying
the power for a longer period, or both. An increase in the applied
energy must be employed with care when used to coat a plastic tube
or other device, as it also has a tendency to distort the vessel
being treated, to the extent the tube absorbs the plasma generation
power. This is why RF power is contemplated in the context of
present application. Distortion of the medical devices can be
reduced or eliminated by employing the energy in a series of two or
more pulses separated by cooling time, by cooling the vessels while
applying energy, by applying the coating in a shorter time
(commonly thus making it thinner), by selecting a frequency of the
applied coating that is absorbed minimally by the base material
selected for being coated, and/or by applying more than one
coating, with time in between the respective energy application
steps. For example, high power pulsing can be used with a duty
cycle of 1 millisecond on, 99 milliseconds off, while continuing to
feed the gaseous reactant or process gas. The gaseous reactant or
process gas is then the coolant, as it keeps flowing between
pulses. Another alternative is to reconfigure the power applicator,
as by adding magnets to confine the plasma increase the effective
power application (the power that actually results in incremental
coating, as opposed to waste power that results in heating or
unwanted coating). This expedient results in the application of
more coating-formation energy per total Watt-hour of energy
applied. See for example U.S. Pat. No. 5,904,952.
[0476] VII. An oxygen post-treatment of the coating can be applied
to remove OH moieties from the previously-deposited coating. This
treatment is also contemplated to remove residual volatile
organosilicon compounds or silicones or oxidize the coating to form
additional SiO.sub.x.
[0477] VII. The plastic base material tube can be preheated.
[0478] VII. A different volatile source of silicon, such as
hexamethyldisilazane (HMDZ), can be used as part or all of the
silicone feed. It is contemplated that changing the feed gas to
HMDZ will address the problem because this compound has no oxygen
moieties in it, as supplied. It is contemplated that one source of
OH moieties in the HMDSO-sourced coating is hydrogenation of at
least some of the oxygen atoms present in unreacted HMDSO.
[0479] VII. A composite coating can be used, such as a carbon-based
coating combined with SiOx. This can be done, for example, by
changing the reaction conditions or by adding a substituted or
unsubstituted hydrocarbon, such as an alkane, alkene, or alkyne, to
the feed gas as well as an organosilicon-based compound. See for
example U.S. Pat. No. 5,904,952, which states in relevant part:
"For example, inclusion of a lower hydrocarbon such as propylene
provides carbon moieties and improves most properties of the
deposited films (except for light transmission), and bonding
analysis indicates the film to be silicon dioxide in nature. Use of
methane, methanol, or acetylene, however, produces films that are
silicone in nature. The inclusion of a minor amount of gaseous
nitrogen to the gas stream provides nitrogen moieties in the
deposited films and increases the deposition rate, improves the
transmission and reflection optical properties on glass, and varies
the index of refraction in response to varied amounts of N2. The
addition of nitrous oxide to the gas stream increases the
deposition rate and improves the optical properties, but tends to
decrease the film hardness." Suitable hydrocarbons include methane,
ethane, ethylene, propane, acetylene, or a combination of two or
more of these.
[0480] VII. A diamond-like carbon (DLC) coating can be formed as
the primary or sole coating deposited. This can be done, for
example, by changing the reaction conditions or by feeding methane,
hydrogen, and helium to a PECVD process. These reaction feeds have
no oxygen, so no OH moieties can be formed. For one example, an
SiO.sub.x coating can be applied on the interior of a tube or
syringe barrel and an outer DLC coating can be applied on the
exterior surface of a tube or syringe barrel. Or, the SiO.sub.x and
DLC coatings can both be applied as a single layer or coating or
plural layers of an interior tube or syringe barrel coating.
[0481] VII. Referring to FIG. 1, the barrier or other type of
coating 90 reduces the transmission of atmospheric gases into the
vessel 80 through its interior surface 88. Or, the barrier or other
type of coating 90 reduces the contact of the contents of the
vessel 80 with the interior surface 88. The barrier or other type
of coating can comprise, for example, SiO.sub.x, amorphous (for
example, diamond-like) carbon, or a combination of these.
[0482] VII. Any coating described herein can be used for coating a
surface, for example a plastic surface. It can further be used as a
barrier layer, for example as a barrier against a gas or liquid,
optionally against water vapor, oxygen and/or air. It can also be
used for preventing or reducing mechanical and/or chemical effects
which the coated surface would have on a compound or composition if
the surface were uncoated. For example, it can prevent or reduce
the precipitation of a compound or composition, for example insulin
precipitation or blood clotting or platelet activation.
VII.A. Coated Vessels
[0483] The coatings described herein can be applied to a variety of
vessels made from plastic or glass, most prominently to plastic
tubes and syringes. A process is contemplated for applying a
lubricity layer or coating on a substrate, for example the interior
of the barrel of a syringe, comprising applying one of the
described precursors on or in the vicinity of a substrate at a
thickness of 1 to 5000 nm, or 10 to 1000 nm, or to 500 nm, or 10 to
200 nm, or 20 to 100 nm, or 30 to 1000 nm, or 30 to 500 nm thick,
or 30 to 1000 nm, or 20 to 100 nm, or 80 to 150 nm, and
crosslinking or polymerizing (or both) the coating, optionally in a
PECVD process, to provide a lubricated surface. The coating applied
by this process is also contemplated to be new.
[0484] A coating of Si.sub.wO.sub.xC.sub.yH.sub.z as defined in the
Definition Section can have utility as a hydrophobic layer.
Coatings of this kind are contemplated to be hydrophobic,
independent of whether they function as lubricity layers. A coating
or treatment is defined as "hydrophobic" if it lowers the wetting
tension of a surface, compared to the corresponding uncoated or
untreated surface. Hydrophobicity is thus a function of both the
untreated substrate and the treatment.
[0485] The degree of hydrophobicity of a coating can be varied by
varying its composition, properties, or deposition method. For
example, a coating of SiOx having little or no hydrocarbon content
is more hydrophilic than a coating of Si.sub.wO.sub.xC.sub.yH.sub.z
as defined in the Definition Section. Generally speaking, the
higher the C--H.sub.x (e.g. CH, CH.sub.2, or CH.sub.3) moiety
content of the coating, either by weight, volume, or molarity,
relative to its silicon content, the more hydrophobic the
coating.
[0486] A hydrophobic layer or coating can be very thin, having a
thickness of at least 4 nm, or at least 7 nm, or at least 10 nm, or
at least 20 nm, or at least 30 nm, or at least 40 nm, or at least
50 nm, or at least 100 nm, or at least 150 nm, or at least 200 nm,
or at least 300 nm, or at least 400 nm, or at least 500 nm, or at
least 600 nm, or at least 700 nm, or at least 800 nm, or at least
900 nm. The coating can be up to 1000 nm, or at most 900 nm, or at
most 800 nm, or at most 700 nm, or at most 600 nm, or at most 500
nm, or at most 400 nm, or at most 300 nm, or at most 200 nm, or at
most 100 nm, or at most 90 nm, or at most 80 nm, or at most 70 nm,
or at most 60 nm, or at most 50 nm, or at most 40 nm, or at most 30
nm, or at most 20 nm, or at most 10 nm, or at most 5 nm thick.
Specific thickness ranges composed of any one of the minimum
thicknesses expressed above, plus any equal or greater one of the
maximum thicknesses expressed above, are expressly
contemplated.
[0487] One utility for such a hydrophobic layer or coating is to
isolate a thermoplastic tube wall, made for example of polyethylene
terephthalate (PET), from blood collected within the tube. The
hydrophobic layer or coating can be applied on top of a hydrophilic
SiO.sub.x coating on the internal surface of the tube. The
SiO.sub.x coating increases the barrier properties of the
thermoplastic tube and the hydrophobic layer or coating changes the
surface energy of blood contact surface with the tube wall. The
hydrophobic layer or coating can be made by providing a precursor
selected from those identified in this specification. For example,
the hydrophobic layer or coating precursor can comprise
hexamethyldisiloxane (HMDSO) or octamethylcyclotetrasiloxane
(OMCTS).
[0488] Another use for a hydrophobic layer or coating is to prepare
a glass cell preparation tube. The tube has a wall defining a
lumen, a hydrophobic layer or coating in the internal surface of
the glass wall, and contains a citrate reagent. The hydrophobic
layer or coating can be made by providing a precursor selected from
those identified elsewhere in this specification. For another
example, the hydrophobic layer or coating precursor can comprise
hexamethyldisiloxane (HMDSO) or octamethylcyclotetrasiloxane
(OMCTS). Another source material for hydrophobic layers is an alkyl
trimethoxysilane of the formula:
R--Si(OCH.sub.3).sub.3
in which R is a hydrogen atom or an organic substituent, for
example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,
vinyl, alkyne, epoxide, or others. Combinations of two or more of
these are also contemplated.
[0489] Combinations of acid or base catalysis and heating, using an
alkyl rimethoxysilane precursor as described above, can condense
the precursor (removing ROH by-products) to form crosslinked
polymers, which can optionally be further crosslinked via an
alternative method. One specific example is by Shimojima et. al. J.
Mater. Chem., 2007, 17, 658-663.
[0490] A lubricity layer can be applied as a subsequent coating
after applying an SiO.sub.x barrier coating to the interior surface
88 of the vessel 80 to provide a lubricity layer, particularly if
the lubricity layer or coating is a liquid organosiloxane compound
at the end of the coating process.
[0491] Optionally, after the lubricity layer or coating is applied,
it can be post-cured after the PECVD process. Radiation curing
approaches, including UV-initiated (free radial or cationic),
electron-beam (E-beam), and thermal as described in Development Of
Novel Cycloaliphatic Siloxanes For Thermal And UV-Curable
Applications (Ruby Chakraborty Dissertation, can 2008) be
utilized.
[0492] Another approach for providing a lubricity layer or coating
is to use a silicone demolding agent when injection-molding the
thermoplastic vessel to be lubricated. For example, it is
contemplated that any of the demolding agents and latent monomers
causing in-situ thermal lubricity layer or coating formation during
the molding process can be used. Or, the aforementioned monomers
can be doped into traditional demolding agents to accomplish the
same result.
[0493] A lubricity layer, is particularly contemplated for the
internal surface of a syringe barrel as further described below. A
lubricated internal surface of a syringe barrel can reduce the
plunger sliding force needed to advance a plunger in the barrel
during operation of a syringe, or the breakout force to start a
plunger moving after the prefilled syringe plunger has pushed away
the intervening lubricant or adhered to the barrel, for example due
to decomposition of the lubricant between the plunger and the
barrel. As explained elsewhere in this specification, a lubricity
layer or coating also can be applied to the interior surface 88 of
the vessel 80 to improve adhesion of a subsequent coating of
SiO.sub.x.
[0494] Thus, the coating 90 can comprise a layer or coating of
SiO.sub.x and a lubricity layer or coating and/or hydrophobic
layer, characterized as defined in the Definition Section. The
lubricity layer or coating and/or hydrophobic layer or coating of
Si.sub.wO.sub.xC.sub.yH.sub.z can be deposited between the layer or
coating of SiO.sub.x and the interior surface of the vessel. Or,
the layer or coating of SiO.sub.x can be deposited between the
lubricity layer or coating and/or hydrophobic layer or coating and
the interior surface of the vessel. Or, three or more layers,
either alternating or graduated between these two coating
compositions: (1) a layer or coating of SiO.sub.x and (2) the
lubricity layer or coating and/or hydrophobic layer; can also be
used. The layer or coating of SiO.sub.x can be deposited adjacent
to the lubricity layer or coating and/or hydrophobic layer or
coating or remotely, with at least one intervening layer or coating
of another material. The layer or coating of SiO.sub.x can be
deposited adjacent to the interior surface of the vessel. Or, the
lubricity layer or coating and/or hydrophobic layer or coating can
be deposited adjacent to the interior surface of the vessel.
[0495] Another expedient contemplated here, for adjacent layers of
SiO.sub.x and a lubricity layer or coating and/or hydrophobic
layer, is a graded composite of Si.sub.wO.sub.xC.sub.yH.sub.z, as
defined in the Definition Section. A graded composite can be
separate layers of a lubricity layer or coating and/or hydrophobic
layer or coating and SiO.sub.x with a transition or interface of
intermediate composition between them, or separate layers of a
lubricity layer or coating and/or hydrophobic layer or coating and
SiO.sub.x with an intermediate distinct layer or coating of
intermediate composition between them, or a single layer or coating
that changes continuously or in steps from a composition of a
lubricity layer or coating and/or hydrophobic layer or coating to a
composition more like SiO.sub.x, going through the coating in a
normal direction.
[0496] The grade in the graded composite can go in either
direction. For example, the a lubricity layer or coating and/or
hydrophobic layer or coating can be applied directly to the
substrate and graduate to a composition further from the surface of
SiO.sub.x. Or, the composition of SiO.sub.x can be applied directly
to the substrate and graduate to a composition further from the
surface of a lubricity layer or coating and/or hydrophobic layer. A
graduated coating is particularly contemplated if a coating of one
composition is better for adhering to the substrate than the other,
in which case the better-adhering composition can, for example, be
applied directly to the substrate. It is contemplated that the more
distant portions of the graded coating can be less compatible with
the substrate than the adjacent portions of the graded coating,
since at any point the coating is changing gradually in properties,
so adjacent portions at nearly the same depth of the coating have
nearly identical composition, and more widely physically separated
portions at substantially different depths can have more diverse
properties. It is also contemplated that a coating portion that
forms a better barrier against transfer of material to or from the
substrate can be directly against the substrate, to prevent the
more remote coating portion that forms a poorer barrier from being
contaminated with the material intended to be barred or impeded by
the barrier.
[0497] The coating, instead of being graded, optionally can have
sharp transitions between one layer or coating and the next,
without a substantial gradient of composition. Such coatings can be
made, for example, by providing the gases to produce a layer or
coating as a steady state flow in a non-plasma state, then
energizing the system with a brief plasma discharge to form a
coating on the substrate. If a subsequent coating is to be applied,
the gases for the previous coating are cleared out and the gases
for the next coating are applied in a steady-state fashion before
energizing the plasma and again forming a distinct layer or coating
on the surface of the substrate or its outermost previous coating,
with little if any gradual transition at the interface.
VII.A.1.a. Exemplary Vessels
[0498] VII.A.1.a. Referring to FIG. 1, more details of the vessel
such as 80 are shown. The illustrated vessel 80 can be generally
tubular, having an opening 82 at one end of the vessel, opposed by
a closed end 84. The vessel 80 also has a wall 86 defining an
interior surface 88. One example of the vessel 80 is a medical
sample tube, such as an evacuated blood collection tube, as
commonly is used by a phlebotomist for receiving a venipuncture
sample of a patient's blood for use in a medical laboratory.
[0499] VII.A.1.a. The vessel 80 can be made, for example, of
thermoplastic material. Some examples of suitable thermoplastic
material are polyethylene terephthalate or a polyolefin such as
polypropylene or a cyclic polyolefin copolymer.
[0500] VII.A.1.a. The vessel 80 can be made by any suitable method,
such as by injection molding, by blow molding, by machining, by
fabrication from tubing stock, or by other suitable means. PECVD
can be used to form a coating on the internal surface of
SiO.sub.x.
[0501] VII.A.1.a. If intended for use as an evacuated blood
collection tube, the vessel 80 desirably can be strong enough to
withstand a substantially total internal vacuum substantially
without deformation when exposed to an external pressure of 760
Torr or atmospheric pressure and other coating processing
conditions. This property can be provided, in a thermoplastic
vessel 80, by providing a vessel 80 made of suitable materials
having suitable dimensions and a glass transition temperature
higher than the processing temperature of the coating process, for
example a cylindrical wall 86 having sufficient wall thickness for
its diameter and material.
[0502] VII.A.1.a. Medical vessels or containers like sample
collection tubes and syringes are relatively small and are
injection molded with relatively thick walls, which renders them
able to be evacuated without being crushed by the ambient
atmospheric pressure. They are thus stronger than carbonated soft
drink bottles or other larger or thinner-walled plastic containers.
Since sample collection tubes designed for use as evacuated vessels
typically are constructed to withstand a full vacuum during
storage, they can be used as vacuum chambers.
[0503] VII.A.1.a. Such adaptation of the vessels to be their own
vacuum chambers might eliminate the need to place the vessels into
a vacuum chamber for PECVD treatment, which typically is carried
out at very low pressure. The use of a vessel as its own vacuum
chamber can result in faster processing time (since loading and
unloading of the parts from a separate vacuum chamber is not
necessary) and can lead to simplified equipment configurations.
Furthermore, a vessel holder is contemplated, for certain
embodiments, that will hold the device (for alignment to gas tubes
and other apparatus), seal the device (so that the vacuum can be
created by attaching the vessel holder to a vacuum pump) and move
the device between molding and subsequent processing steps.
[0504] VII.A.1.a. A vessel 80 used as an evacuated blood collection
tube should be able to withstand external atmospheric pressure,
while internally evacuated to a reduced pressure useful for the
intended application, without a substantial volume of air or other
atmospheric gas leaking into the tube (as by bypassing the closure)
or permeating through the wall 86 during its shelf life. If the
as-molded vessel 80 cannot meet this requirement, it can be
processed by coating the interior surface 88 with a barrier or
other type of coating 90. It is desirable to treat and/or coat the
interior surfaces of these devices (such as sample collection tubes
and syringe barrels) to impart various properties that will offer
advantages over existing polymeric devices and/or to mimic existing
glass products. It is also desirable to measure various properties
of the devices before and/or after treatment or coating.
[0505] Further exemplary vessels are the syringes described
herein.
VII.A.1.b. Vessel Having Wall Coated With Hydrophobic Coating
[0506] VII.A.1.b. Another embodiment is a vessel having a wall
provided with a hydrophobic layer or coating on its inside surface
and containing an aqueous sodium citrate reagent. The hydrophobic
layer or coating can be also be applied on top of a hydrophilic
SiO.sub.x coating on the internal surface of the vessel. The
SiO.sub.x coating increases the barrier properties of the plastic
vessel and the hydrophobic layer or coating changes the surface
energy of the contact surface of the composition or compound inside
the vessel with the vessel wall.
[0507] VII.A.1.b. The wall is made of thermoplastic material having
an internal surface defining a lumen.
[0508] VII.A.1.b. A vessel according to the embodiment VII.A.1.b
can have a first layer or coating of SiO.sub.x on the internal
surface of the tube, applied as explained in this specification, to
function as an oxygen barrier and extend the shelf life of an
evacuated blood collection tube made of thermoplastic material. A
second layer or coating of a hydrophobic layer, characterized as
defined in the Definition Section, can then be applied over the
barrier layer or coating on the internal surface of the vessel to
provide a hydrophobic surface. In a blood collection tube or
syringe, the coating optionally is effective to reduce the platelet
activation of blood plasma treated with a sodium citrate additive
and exposed to the inner surface, compared to the same type of wall
uncoated.
[0509] VII.A.1.b. PECVD is used to form a hydrophobic layer or
coating on the internal surface. Unlike conventional citrate blood
collection tubes, a blood collection tube having a hydrophobic
layer as defined herein does not require a coating of baked on
silicone on the vessel wall, as is conventionally applied to make
the surface of the tube hydrophobic.
[0510] VII.A.1.b. Both layers can be applied using the same
precursor, for example HMDSO or OMCTS, and different PECVD reaction
conditions.
[0511] VII.A.1.b. When preparing a blood collection tube or
syringe, a sodium citrate anticoagulation reagent may then be
placed within the tube and it is evacuated and sealed with a
closure to produce an evacuated blood collection tube. The
components and formulation of the reagent are known to those
skilled in the art. The aqueous sodium citrate reagent is disposed
in the lumen of the tube in an amount effective to inhibit
coagulation of blood introduced into the tube.
[0512] VII.A.1.c. SiO.sub.x Barrier Coated Double Wall Plastic
Vessel--COC, PET, SiO.sub.x Layers
[0513] VII.A.1.c. Another embodiment is a vessel having a wall at
least partially enclosing a lumen. The wall has an interior polymer
layer or coating enclosed by an exterior polymer layer. One of the
polymer layers is a layer or coating at least 0.1 mm thick of a
cyclic olefin copolymer (COC) resin defining a water vapor barrier.
Another of the polymer layers is a layer or coating at least 0.1 mm
thick of a polyester resin.
[0514] VII.A.1.c. The wall includes an oxygen barrier layer or
coating of SiO.sub.x having a thickness of from about 10 to about
500 angstroms.
[0515] VII.A.1.c. In an embodiment, the vessel 80 can be a
double-walled vessel having an inner wall 408 and an outer wall
410, respectively made of the same or different materials. One
particular embodiment of this type can be made with one wall molded
from a cyclic olefin copolymer (COC) and the other wall molded from
a polyester such as polyethylene terephthalate (PET), with an
SiO.sub.x coating as previously described on the interior surface
412. As needed, a tie coating or layer or coating can be inserted
between the inner and outer walls to promote adhesion between them.
An advantage of this wall construction is that walls having
different properties can be combined to form a composite having the
respective properties of each wall.
[0516] VII.A.1.c. As one example, the inner wall 408 can be made of
PET coated on the interior surface 412 with an SiO.sub.x barrier
layer, and the outer wall 410 can be made of COC. PET coated with
SiO.sub.x, as shown elsewhere in this specification, is an
excellent oxygen barrier, while COC is an excellent barrier for
water vapor, providing a low water vapor transition rate (WVTR).
This composite vessel can have superior barrier properties for both
oxygen and water vapor. This construction is contemplated, for
example, for an evacuated medical sample collection tube that
contains an aqueous reagent as manufactured, and has a substantial
shelf life, so it should have a barrier preventing transfer of
water vapor outward or transfer of oxygen or other gases inward
through its composite wall during its shelf life.
[0517] VII.A.1.c. As another example, the inner wall 408 can be
made of COC coated on the interior surface 412 with an SiO.sub.x
barrier layer, and the outer wall 410 can be made of PET. This
construction is contemplated, for example, for a prefilled syringe
that contains an aqueous sterile fluid as manufactured. The
SiO.sub.x barrier will prevent oxygen from entering the syringe
through its wall. The COC inner wall will prevent ingress or egress
of other materials such as water, thus preventing the water in the
aqueous sterile fluid from leaching materials from the wall
material into the syringe. The COC inner wall is also contemplated
to prevent water derived from the aqueous sterile fluid from
passing out of the syringe (thus undesirably concentrating the
aqueous sterile fluid), and will prevent non-sterile water or other
fluids outside the syringe from entering through the syringe wall
and causing the contents to become non-sterile. The COC inner wall
is also contemplated to be useful for decreasing the breaking force
or friction of the plunger against the inner wall of a syringe.
[0518] VII.A.1.d. Method of Making Double Wall Plastic Vessel--COC,
PET, SiO.sub.x Layers
[0519] VII.A.1.d. Another embodiment is a method of making a vessel
having a wall having an interior polymer layer or coating enclosed
by an exterior polymer layer, one layer or coating made of COC and
the other made of polyester. The vessel is made by a process
including introducing COC and polyester resin layers into an
injection mold through concentric injection nozzles.
[0520] VII.A.1.d. An optional additional step is applying an
amorphous carbon coating to the vessel by PECVD, as an inside
coating, an outside coating, or as an interlayer or coating coating
located between the layers.
[0521] VII.A.1.d. An optional additional step is applying an
SiO.sub.x barrier layer or coating to the inside of the vessel
wall, where SiO.sub.x is defined as before. Another optional
additional step is post-treating the SiO.sub.x layer or coating
with a gaseous reactant or process gas consisting essentially of
oxygen and essentially free of a volatile silicon compound.
[0522] VII.A.1.d. Optionally, the SiO.sub.x coating can be formed
at least partially from a silazane feed gas.
[0523] VII.A.1.d. The vessel 80 can be made from the inside out,
for one example, by injection molding the inner wall in a first
mold cavity, then removing the core and molded inner wall from the
first mold cavity to a second, larger mold cavity, then injection
molding the outer wall against the inner wall in the second mold
cavity. Optionally, a tie layer or coating can be provided to the
exterior surface of the molded inner wall before over-molding the
outer wall onto the tie layer.
[0524] VII.A.1.d. Or, the vessel 80 can be made from the outside
in, for one example, by inserting a first core in the mold cavity,
injection molding the outer wall in the mold cavity, then removing
the first core from the molded first wall and inserting a second,
smaller core, then injection molding the inner wall against the
outer wall still residing in the mold cavity. Optionally, a tie
layer or coating can be provided to the interior surface of the
molded outer wall before over-molding the inner wall onto the tie
layer.
[0525] VII.A.1.d. Or, the vessel 80 can be made in a two shot mold.
This can be done, for one example, by injection molding material
for the inner wall from an inner nozzle and the material for the
outer wall from a concentric outer nozzle. Optionally, a tie layer
or coating can be provided from a third, concentric nozzle disposed
between the inner and outer nozzles. The nozzles can feed the
respective wall materials simultaneously. One useful expedient is
to begin feeding the outer wall material through the outer nozzle
slightly before feeding the inner wall material through the inner
nozzle. If there is an intermediate concentric nozzle, the order of
flow can begin with the outer nozzle and continue in sequence from
the intermediate nozzle and then from the inner nozzle. Or, the
order of beginning feeding can start from the inside nozzle and
work outward, in reverse order compared to the preceding
description.
VII.A.1.e. Vessel or Coating Made Of Glass
[0526] VII.A.1.e. Another embodiment is a vessel including a
vessel, a barrier coating, and a closure. The vessel is generally
tubular and made of thermoplastic material. The vessel has a mouth
and a lumen bounded at least in part by a wall having an inner
surface interfacing with the lumen. There is an at least
essentially continuous barrier coating made of glass on the inner
surface of the wall. A closure covers the mouth and isolates the
lumen of the vessel from ambient air.
[0527] VII.A.1.e. The vessel 80 can also be made, for example of
glass of any type used in medical or laboratory applications, such
as soda-lime glass, borosilicate glass, or other glass
formulations. Other vessels having any shape or size, made of any
material, are also contemplated for use in the system 20. One
function of coating a glass vessel can be to reduce the ingress of
ions in the glass, either intentionally or as impurities, for
example sodium, calcium, or others, from the glass to the contents
of the vessel, such as a reagent or blood in an evacuated blood
collection tube. Another function of coating a glass vessel in
whole or in part, such as selectively at surfaces contacted in
sliding relation to other parts, is to provide lubricity to the
coating, for example to ease the insertion or removal of a stopper
or passage of a sliding element such as a piston in a syringe.
Still another reason to coat a glass vessel is to prevent a reagent
or intended sample for the vessel, such as blood, from sticking to
the wall of the vessel or an increase in the rate of coagulation of
the blood in contact with the wall of the vessel.
[0528] VII.A.1.e.i. A related embodiment is a vessel as described
in the previous paragraph, in which the barrier coating is made of
soda lime glass, borosilicate glass, or another type of glass.
VII.A.2. Stoppers
[0529] VII.A.2. FIGS. 5-7 illustrate a vessel 268, which can be an
evacuated blood collection tube, having a closure 270 to isolate
the lumen 274 from the ambient environment. The closure 270
comprises a interior-facing surface 272 exposed to the lumen 274 of
the vessel 268 and a wall-contacting surface 276 that is in contact
with the inner surface 278 of the vessel wall 280. In the
illustrated embodiment the closure 270 is an assembly of a stopper
282 and a shield 284.
VII.A.2.a. Method of Applying Lubricity layer or coating to Stopper
In Vacuum Chamber
[0530] VII.A.2.a. Another embodiment is a method of applying a
coating on an elastomeric stopper such as 282. The stopper 282,
separate from the vessel 268, is placed in a substantially
evacuated chamber. A reaction mixture is provided including plasma
forming gas, i.e. an organosilicon compound gas, optionally an
oxidizing gas, and optionally a hydrocarbon gas. Plasma is formed
in the reaction mixture, which is contacted with the stopper. A
lubricity and/or hydrophobic layer, characterized as defined in the
Definition Section, is deposited on at least a portion of the
stopper.
[0531] VII.A.2.a. In the illustrated embodiment, the
wall-contacting surface 276 of the closure 270 is coated with a
lubricity layer or coating 286.
[0532] VII.A.2.a. In some embodiments, the lubricity and/or
hydrophobic layer, characterized as defined in the Definition
Section, is effective to reduce the transmission of one or more
constituents of the stopper, such as a metal ion constituent of the
stopper, or of the vessel wall, into the vessel lumen. Certain
elastomeric compositions of the type useful for fabricating a
stopper 282 contain trace amounts of one or more metal ions. These
ions sometimes should not be able to migrate into the lumen 274 or
come in substantial quantities into contact with the vessel
contents, particularly if the sample vessel 268 is to be used to
collect a sample for trace metal analysis. It is contemplated for
example that coatings containing relatively little organic content,
i.e. where y and z of Si.sub.wO.sub.xC.sub.yH.sub.z as defined in
the Definition Section are low or zero, are particularly useful as
a metal ion barrier in this application. Regarding silica as a
metal ion barrier see, for example, Anupama Mallikarjunan, Jasbir
Juneja, Guangrong Yang, Shyam P. Murarka, and Toh-Ming Lu, The
Effect of Interfacial Chemistry on Metal Ion Penetration into
Polymeric Films, Mat. Res. Soc. Symp. Proc., Vol. 734, pp. B9.60.1
to B9.60.6 (Materials Research Society, 2003); U.S. Pat. Nos.
5,578,103 and 6,200,658, and European Appl. EP0697378 A2, which are
all incorporated here by reference. It is contemplated, however,
that some organic content can be useful to provide a more elastic
coating and to adhere the coating to the elastomeric surface of the
stopper 282.
[0533] VII.A.2.a. In some embodiments, the lubricity and/or
hydrophobic layer, characterized as defined in the Definition
Section, can be a composite of material having first and second
layers, in which the first or inner layer or coating 288 interfaces
with the elastomeric stopper 282 and is effective to reduce the
transmission of one or more constituents of the stopper 282 into
the vessel lumen. The second layer or coating 286 can interface
with the inner wall 280 of the vessel and is effective as a
lubricity layer or coating to reduce friction between the stopper
282 and the inner wall 280 of the vessel when the stopper 282 is
seated on or in the vessel 268. Such composites are described in
connection with syringe coatings elsewhere in this
specification.
[0534] VII.A.2.a. Or, the first and second layers 288 and 286 are
defined by a coating of graduated properties, in which the values
of y and z defined in the Definition Section are greater in the
first layer or coating than in the second layer.
[0535] VII.A.2.a. The lubricity and/or hydrophobic layer or coating
can be applied, for example, by PECVD substantially as previously
described. The lubricity and/or hydrophobic layer or coating can
be, for example, between 0.5 and 5000 nm (5 to 50,000 Angstroms)
thick, or between 1 and 5000 nm thick, or between 5 and 5000 nm
thick, or between 10 and 5000 nm thick, or between 20 and 5000 nm
thick, or between 50 and 5000 nm thick, or between 100 and 5000 nm
thick, or between 200 and 5000 nm thick, or between 500 and 5000 nm
thick, or between 1000 and 5000 nm thick, or between 2000 and 5000
nm thick, or between 3000 and 5000 nm thick, or between 4000 and
10,000 nm thick.
[0536] VII.A.2.a. Certain advantages are contemplated for plasma
coated lubricity layers, versus the much thicker (one micron or
greater) conventional spray applied silicone lubricants. Plasma
coatings have a much lower migratory potential to move into blood
versus sprayed or micron-coated silicones, both because the amount
of plasma coated material is much less and because it can be more
intimately applied to the coated surface and better bonded in
place.
[0537] VII.A.2.a. Nanocoatings, as applied by PECVD, are
contemplated to offer lower resistance to sliding of an adjacent
surface or flow of an adjacent fluid than micron coatings, as the
plasma coating tends to provide a smoother surface.
[0538] VII.A.2.a. Still another embodiment is a method of applying
a coating of a lubricity and/or hydrophobic layer or coating on an
elastomeric stopper. The stopper can be used, for example, to close
the vessel previously described. The method includes several parts.
A stopper is placed in a substantially evacuated chamber. A
reaction mixture is provided comprising plasma forming gas, i.e. an
organosilicon compound gas, optionally an oxidizing gas, and
optionally a hydrocarbon gas. Plasma is formed in the reaction
mixture. The stopper is contacted with the reaction mixture,
depositing the coating of a lubricity and/or hydrophobic layer or
coating on at least a portion of the stopper.
[0539] VII.A.2.a. In practicing this method, to obtain higher
values of y and z as defined in the Definition Section, it is
contemplated that the reaction mixture can comprise a hydrocarbon
gas, as further described above and below. Optionally, the reaction
mixture can contain oxygen, if lower values of y and z or higher
values of x are contemplated. Or, particularly to reduce oxidation
and increase the values of y and z, the reaction mixture can be
essentially free of an oxidizing gas.
[0540] VII.A.2.a. In practicing this method to coat certain
embodiments of the stopper such as the stopper 282, it is
contemplated to be unnecessary to project the reaction mixture into
the concavities of the stopper. For example, the wall-contacting
and interior facing surfaces 276 and 272 of the stopper 282 are
essentially convex, and thus readily treated by a batch process in
which a multiplicity of stoppers such as 282 can be located and
treated in a single substantially evacuated reaction chamber. It is
further contemplated that in some embodiments the coatings 286 and
288 do not need to present as formidable a barrier to oxygen or
water as the barrier coating on the interior surface 280 of the
vessel 268, as the material of the stopper 282 can serve this
function to a large degree.
[0541] VII.A.2.a. Many variations of the stopper and the stopper
coating process are contemplated. The stopper 282 can be contacted
with the plasma. Or, the plasma can be formed upstream of the
stopper 282, producing plasma product, and the plasma product can
be contacted with the stopper 282. The plasma can be formed by
exciting the reaction mixture with electromagnetic energy and/or
microwave energy.
[0542] VII.A.2.a. Variations of the reaction mixture are
contemplated. The plasma forming gas can include an inert gas, also
referred to herein as a carrier gas. The inert gas can be, for
example, argon, helium, xenon, neon, krypton, or any mixture of two
or more of these. In particular, the inert gas can be neon, argon
or helium. The organosilicon compound gas can be, or include,
HMDSO, OMCTS, any of the other organosilicon compounds mentioned in
this disclosure, or a combination of two or more of these. The
oxidizing gas can be oxygen or the other gases mentioned in this
disclosure, or a combination of two or more of these. The
hydrocarbon gas can be, for example, methane, methanol, ethane,
ethylene, ethanol, propane, propylene, propanol, acetylene, or a
combination of two or more of these.
VII.A.2.b. Applying by PECVD a Coating of Group III or IV Element
and Carbon on a Stopper
[0543] VII.A.2.b. Another embodiment is a method of applying a
coating of a composition including carbon and one or more elements
of Groups III or IV on an elastomeric stopper. To carry out the
method, a stopper is located in a deposition chamber.
[0544] VII.A.2.b. A reaction mixture is provided in the deposition
chamber, including a plasma forming gas with a gaseous source of a
Group III element, a Group IV element, or a combination of two or
more of these. The reaction mixture optionally contains an
oxidizing gas and optionally contains a gaseous compound having one
or more C--H bonds. Plasma is formed in the reaction mixture, and
the stopper is contacted with the reaction mixture. A coating of a
Group III element or compound, a Group IV element or compound, or a
combination of two or more of these is deposited on at least a
portion of the stopper.
VII.A.3. Stoppered Plastic Vessel Having Barrier Coating Effective
To Provide 95% Vacuum Retention for 24 Months
[0545] VII.A.3. Another embodiment is a vessel including a vessel,
a barrier coating, and a closure. The vessel is generally tubular
and made of thermoplastic material. The vessel has a mouth and a
lumen bounded at least in part by a wall. The wall has an inner
surface interfacing with the lumen. An at least essentially
continuous barrier coating is applied on the inner surface of the
wall. The barrier coating is effective to provide a substantial
shelf life. A closure is provided covering the mouth of the vessel
and isolating the lumen of the vessel from ambient air.
[0546] VII.A.3. Referring to FIGS. 5-7, a vessel 268 such as an
evacuated blood collection tube or other vessel is shown.
[0547] VII.A.3. The vessel is, in this embodiment, a generally
tubular vessel having an at least essentially continuous barrier
coating and a closure. The vessel is made of thermoplastic material
having a mouth and a lumen bounded at least in part by a wall
having an inner surface interfacing with the lumen. The barrier
coating is deposited on the inner surface of the wall, and is
effective to maintain at least 95%, or at least 90%, of the initial
vacuum level of the vessel for a shelf life of at least 24 months,
optionally at least 30 months, optionally at least 36 months. The
closure covers the mouth of the vessel and isolates the lumen of
the vessel from ambient air.
[0548] VII.A.3. The closure, for example the closure 270
illustrated in the Figures or another type of closure, is provided
to maintain a partial vacuum and/or to contain a sample and limit
or prevent its exposure to oxygen or contaminants. FIGS. 5-7 are
based on figures found in U.S. Pat. No. 6,602,206, but the present
discovery is not limited to that or any other particular type of
closure.
[0549] VII.A.3. The closure 270 comprises a interior-facing surface
272 exposed to the lumen 274 of the vessel 268 and a
wall-contacting surface 276 that is in contact with the inner
surface 278 of the vessel wall 280. In the illustrated embodiment
the closure 270 is an assembly of a stopper 282 and a shield
284.
[0550] VII.A.3. In the illustrated embodiment, the stopper 282
defines the wall-contacting surface 276 and the inner surface 278,
while the shield is largely or entirely outside the stoppered
vessel 268, retains and provides a grip for the stopper 282, and
shields a person removing the closure 270 from being exposed to any
contents expelled from the vessel 268, such as due to a pressure
difference inside and outside of the vessel 268 when the vessel 268
is opened and air rushes in or out to equalize the pressure
difference.
[0551] VII.A.3. It is further contemplated that the coatings on the
vessel wall 280 and the wall contacting surface 276 of the stopper
can be coordinated. The stopper can be coated with a lubricity
silicone layer, and the vessel wall 280, made for example of PET or
glass, can be coated with a harder SiO.sub.x layer, or with an
underlying SiO.sub.x layer or coating and a lubricity overcoat.
VII.B. Syringes
[0552] VII.B. The foregoing description has largely addressed
applying a barrier coating to a tube with one permanently closed
end, such as a blood collection tube or, more generally, a specimen
receiving tube 80. The apparatus is not limited to such a
device.
[0553] VII.B. Another example of a suitable vessel, shown in FIG.
20, is a syringe barrel 250 for a medical syringe 252. Such
syringes 252 are sometimes supplied prefilled with saline solution,
a pharmaceutical preparation, or the like for use in medical
techniques. Pre-filled syringes 252 are also contemplated to
benefit from an SiO.sub.x barrier or other type of coating on the
interior surface 254 to keep the contents of the prefilled syringe
252 out of contact with the plastic of the syringe, for example of
the syringe barrel 250 during storage. The barrier or other type of
coating can be used to avoid leaching components of the plastic
into the contents of the barrel through the interior surface
254.
[0554] VII.B. A syringe barrel 250 as molded commonly can be open
at both the back end 256, to receive a plunger 258, and at the
front end 260, to receive a hypodermic needle, a nozzle, or tubing
for dispensing the contents of the syringe 252 or for receiving
material into the syringe 252. But the front end 260 can optionally
be capped and the plunger 258 optionally can be fitted in place
before the prefilled syringe 252 is used, closing the barrel 250 at
both ends. A cap 262 can be installed either for the purpose of
processing the syringe barrel 250 or assembled syringe, or to
remain in place during storage of the prefilled syringe 252, up to
the time the cap 262 is removed and (optionally) a hypodermic
needle or other delivery conduit is fitted on the front end 260 to
prepare the syringe 252 for use.
[0555] Another example of a suitable vessel, shown in FIGS. 24-26,
is a syringe including a plunger, a syringe barrel, and a staked
needle (a "staked needle syringe"). The needle is hollow with a
typical size ranging from 18-29 gauge. The syringe barrel has an
interior surface slidably receiving the plunger. The staked needle
may be affixed to the syringe during the injection molding of the
syringe or may be assembled to the formed syringe using an
adhesive. A cover is placed over the staked needle to seal the
syringe assembly. The syringe assembly must be sealed so that a
vacuum can be maintained within the syringe to enable the PECVD
coating process.
[0556] The needle of the staked needle syringe has an outside
surface, a delivery outlet at one end, a base at the other end, and
an internal passage extending from the base to the delivery outlet.
The barrel has a, for example generally cylindrical, interior
surface defining a lumen. The barrel also has a front passage
molded around and in fluid-sealing contact with the outside surface
of the needle.
[0557] The syringe of any "staked needle" embodiment optionally can
further include a cap configured to isolate the delivery outlet of
the needle from ambient air.
[0558] The cap of any "staked needle" embodiment optionally can
further include a lumen having an opening defined by a rim and
sized to receive the delivery outlet, and the rim can be seatable
against an exterior portion of the barrel.
[0559] In the syringe of any "staked needle" embodiment, the barrel
optionally can further include a generally hemispheric interior
surface portion adjacent to its front passage.
[0560] In the syringe of any "staked needle" embodiment, the base
of the needle optionally can be at least substantially flush with
the hemispheric interior surface portion of the barrel.
[0561] The syringe of any "staked needle" embodiment optionally can
further include a PECVD-applied barrier coating on at least the
hemispheric interior surface portion of the barrel.
[0562] In the syringe of any "staked needle" embodiment, the
barrier coating optionally can extend over at least a portion of
the generally cylindrical interior surface portion of the
barrel.
[0563] In the syringe of any "staked needle" embodiment, the
barrier coating optionally can form a barrier between the base of
the needle and the generally cylindrical interior surface portion
of the barrel.
[0564] In the "staked needle" embodiment of FIG. 24, the cap 7126
is held in place on the nose 71110 of the syringe 7120 by a
conventional Luer lock arrangement. The tapered nose 71110 of the
syringe mates with a corresponding tapered throat 71112 of the cap
7126, and the syringe has a collar 71114 with an interior thread
71116 receiving the dogs 71118 and 71120 of the cap 7126 to lock
the tapers 71110 and 71112 together. The cap 7126 can be
substantially rigid.
[0565] Referring now to FIG. 25, a variation on the syringe barrel
71122 and cap 71124 of the "staked needle" embodiment is shown. In
this embodiment, the cap 71124 includes a flexible lip seal 7172 at
its base to form a moisture-tight seal with the syringe barrel
71122.
[0566] Optionally in the "staked needle" embodiments of FIGS. 24
and 25, the caps 7126 and 71124 can withstand vacuum during the
PECVD coating process. The caps 7126 and 71124 can be made of LDPE.
Alternative rigid plastic materials can be used as well, for
example polypropylene. Additional sealing elements can be provided
as well.
[0567] In another option of the "staked needle" embodiment,
illustrated in FIG. 26, the cap 71126 is flexible, and is designed
to seal around the top end of the syringe 7120. A deformable
material--like a rubber or a thermoplastic elastomer (TPE) can be
used for the cap 71126. Preferred TPE materials include
fluoroelastomers, and in particular, medical grade
fluoroelastomers. Examples include VITON.RTM. and TECHNOFLON.RTM..
VITON.RTM. is preferable in some embodiments. An example of a
suitable rubber is EPDM rubber.
[0568] During molding, in certain "staked needle" embodiments
(illustrated for example in FIG. 26) a small amount of the cap
material 71132 will be drawn into the tip or delivery outlet 7134
of the needle 7122 to create a seal. The material 71132 should have
a durometer such as to permit an appropriate amount of material to
be drawn into the needle 7122, and to cause the material drawn into
the needle 7122 to continue to adhere to the cap 71126 when it is
removed, unplugging the needle 7122 for use.
[0569] In other "staked needle" embodiments, the cap material 71132
can block the delivery outlet 7134 of the needle 7122 without being
drawn into the delivery outlet 7134. Suitable material selection to
accomplish the desired purposes is within the capabilities of a
person of ordinary skill in the art.
[0570] An additional seal can be created by coupling an undercut
71134 formed in the syringe barrel and projections 71138 in the
interior of the cap 71126, defining a coupling to retain the cap
71126. Alternative "staked needle" embodiments can include either
one or both of the seals described above.
[0571] Optionally, with reference to FIG. 25, the cap 71124 can
have a base 7168 and a coupling 7170 configured for securing the
cap 7126 in a seated position on the barrel. Alternatively or in
addition, a flexible lip seal 7172 can optionally be provided at
the base 7168 of the cap 71124 for seating against the barrel 71122
when the cap 71124 is secured on the barrel 71122.
[0572] Optionally, referring now to FIG. 26, the delivery outlet
7134 of the needle 7122 can be seated on the cap 71126 when the cap
7126 is secured on the barrel. This expedient is useful for sealing
the delivery outlet 7134 against the ingress or egress of air or
other fluids, when that is desired.
[0573] Optionally, in the "staked needle" embodiment the coupling
7170 can include a detent or groove 7174 on one of the barrel 71122
and the cap 71124 and a projection or rib 76 on the other of the
barrel 71122 and the cap 71124, the projection 7176 being adapted
to mate with the detent 7174 when the cap 7126 is in its seated
position on the barrel. In one contemplated embodiment, a detent
7174 can be on the barrel and a projection 7176 can be on the cap
7126. In another contemplated embodiment, a detent 7174 can be on
the cap 7126 and a projection 7176 can be on the barrel. In yet
another contemplated embodiment, a first detent 7174 can be on the
barrel and a first projection 7176 mating with the detent 7174 can
be on the cap 7126, while a second detent 7175 can be on the cap
7126 and the mating second projection 7177 can be on the barrel. A
detent 7174 can be molded in the syringe barrel as an undercut by
incorporating side draws such as 7192 and 7194 in the mold. The
detents 7174 mate with the complementary projections 7176 to
assemble (snap) the cap 7126 onto the syringe 7120. In this respect
the cap 7126 is desirably flexible enough to allow sufficient
deformation for a snapping engagement of the detents 7174 and
projections 7176.
[0574] The caps in the "staked needle" embodiment such as 7126,
71124, and 71126 can be injection molded or otherwise formed, for
example from thermoplastic material. Several examples of suitable
thermoplastic material are a polyolefin, for example a cyclic
olefin polymer (COP), a cyclic olefin copolymer (COC),
polypropylene, or polyethylene. The cap 7126 can contain or be made
of a thermoplastic elastomer (TPE) or other elastomeric material.
The cap 7126 can also be made of polyethylene terephthalate (PET),
polycarbonate resin, or any other suitable material. Optionally, a
material for the cap 7126 can be selected that can withstand vacuum
and maintain sterility within the syringe 7120.
[0575] Typically, when the syringe barrel is coated, the PECVD
coating methods described herein are performed such that the coated
substrate surface is part or all of the inner surface of the
barrel, the gas for the PECVD reaction fills the interior lumen of
the barrel, and the plasma is generated within part or all of the
interior lumen of the barrel.
VII.B.1.a. Syringe Having Barrel Coated With Lubricity Layer
[0576] VII.B.1.a. A syringe having a lubricity layer of the type
can be made by the following process.
[0577] VII.B.1.a. A precursor is provided as defined above.
[0578] VII.B.1.a. The precursor is applied to a substrate under
conditions effective to form a coating. The coating is polymerized
or crosslinked, or both, to form a lubricated surface having a
lower plunger sliding force or breakout force than the untreated
substrate.
[0579] VII.B.1.a. Respecting any of the Embodiments VII and
sub-parts, optionally the applying step is carried out by
vaporizing the precursor and providing it in the vicinity of the
substrate.
[0580] VII.B.1.a. A plasma, is formed in the vicinity of the
substrate. Optionally, the precursor is provided in the substantial
absence of nitrogen. Optionally, the precursor is provided at less
than 1 Torr absolute pressure. Optionally, the precursor is
provided to the vicinity of a plasma emission. Optionally, the
precursor its reaction product is applied to the substrate at an
average thickness of 1 to 5000 nm, or 10 to 1000 nm, or to 500 nm,
or 10 to 200 nm, or 20 to 100 nm, or 30 to 1000 nm, or 30 to 500
nm, or to 1000 nm, or 20 to 100 nm, or 80 to 150 nm thick.
Optionally, the substrate comprises glass. Optionally, the
substrate comprises a polymer, optionally a polycarbonate polymer,
optionally an olefin polymer, optionally a cyclic olefin copolymer,
optionally a polypropylene polymer, optionally a polyester polymer,
optionally a polyethylene terephthalate polymer. COC is
particularly considered for syringes and syringe barrels.
[0581] VII.B.1.a. Optionally, the plasma is generated by energizing
the gaseous reactant containing the precursor with electrodes
powered, for example, at a RF frequency as defined above, for
example a frequency of from 10 kHz to less than 300 MHz, optionally
from 1 to 50 MHz, even optionally from 10 to 15 MHz, optionally a
frequency of 13.56 MHz.
[0582] VII.B.1.a. Optionally, the plasma is generated by energizing
the gaseous reactant containing the precursor with electrodes
supplied with an electric power of from 0.1 to 25 W, optionally
from 1 to 22 W, optionally from 3 to 17 W, even optionally from 5
to 14 W, optionally from 7 to 11 W, optionally 8 W. The ratio of
the electrode power to the plasma volume can be less than 10 W/ml,
optionally is from 6 W/ml to 0.1 W/ml, optionally is from 5 W/ml to
0.1 W/ml, optionally is from 4 W/ml to 0.1 W/ml, optionally is from
2 W/ml to 0.2 W/ml. Low power levels are believed by the inventors
to be most advantageous (e.g. power levels of from 2 to 3.5 W and
the power levels given in the Examples) to prepare a lubricity
coating. These power levels are suitable for applying lubricity
layers to syringes and sample tubes and vessels of similar geometry
having a void volume of 1 to 3 mL in which PECVD plasma is
generated. It is contemplated that for larger or smaller objects
the power applied should be increased or reduced accordingly to
scale the process to the size of the substrate.
[0583] VII.B.1.a. Another embodiment is a lubricity coating of the
present invention on the inner wall of a syringe barrel. The
coating is produced from a PECVD process using the following
materials and conditions. A cyclic precursor is optionally
employed, selected from a monocyclic siloxane, a polycyclic
siloxane, or a combination of two or more of these, as defined
elsewhere in this specification for lubricity layers. One example
of a suitable cyclic precursor comprises
octamethylcyclotetrasiloxane (OMCTS), optionally mixed with other
precursor materials in any proportion. Optionally, the cyclic
precursor consists essentially of octamethycyclotetrasiloxane
(OMCTS), meaning that other precursors can be present in amounts
which do not change the basic and novel properties of the resulting
lubricity layer, i.e. its reduction of the plunger sliding force or
breakout force of the coated surface.
[0584] VII.B.1.a. A sufficient plasma generation power input, for
example any power level successfully used in one or more working
examples of this specification or described in the specification,
is provided to induce coating formation.
[0585] VII.B.1.a. The materials and conditions employed are
effective to reduce the syringe plunger sliding force or breakout
force moving through the syringe barrel at least 25 percent,
alternatively at least 45 percent, alternatively at least 60
percent, alternatively greater than 60 percent, relative to an
uncoated syringe barrel. Ranges of plunger sliding force or
breakout force reduction of from 20 to 95 percent, alternatively
from 30 to 80 percent, alternatively from 40 to 75 percent,
alternatively from 60 to 70 percent, are contemplated.
[0586] VII.B.1.a. Another embodiment is a vessel having a
hydrophobic layer, characterized as defined in the Definition
Section, on the inside wall. The coating is made as explained for
the lubricant coating of similar composition, but under conditions
effective to form a hydrophobic surface having a higher contact
angle than the untreated substrate.
[0587] VII.B.1.a. Respecting any of the Embodiments VII.A.1.a.ii,
optionally the substrate comprises glass or a polymer. The glass
optionally is borosilicate glass. The polymer is optionally a
polycarbonate polymer, optionally an olefin polymer, optionally a
cyclic olefin copolymer, optionally a polypropylene polymer,
optionally a polyester polymer, optionally a polyethylene
terephthalate polymer.
[0588] VII.B.1.a. Another embodiment is a syringe including a
plunger, a syringe barrel, and a lubricity layer. The syringe
barrel includes an interior surface receiving the plunger for
sliding. The lubricity layer or coating is disposed on part or all
of the interior surface of the syringe barrel. The lubricity layer
or coating optionally can be less than 1000 nm thick and effective
to reduce the breakout force or the plunger sliding force necessary
to move the plunger within the barrel. Reducing the plunger sliding
force is alternatively expressed as reducing the coefficient of
sliding friction of the plunger within the barrel or reducing the
plunger force; these terms are regarded as having the same meaning
in this specification.
[0589] VII.B.1.a. The syringe 544 comprises a plunger 546 and a
syringe barrel 548. The syringe barrel 548 has an interior surface
552 receiving the plunger for sliding 546. The interior surface 552
of the syringe barrel 548 further comprises a lubricity layer or
coating 554. The lubricity layer or coating is less than 1000 nm
thick, optionally less than 500 nm thick, optionally less than 200
nm thick, optionally less than 100 nm thick, optionally less than
50 nm thick, and is effective to reduce the breakout force
necessary to overcome adhesion of the plunger after storage or the
plunger sliding force necessary to move the plunger within the
barrel after it has broken away. The lubricity layer or coating is
characterized by having a plunger sliding force or breakout force
lower than that of the uncoated surface.
[0590] VII.B.1.a. Any of the above precursors of any type can be
used alone or in combinations of two or more of them to provide a
lubricity layer.
[0591] VII.B.1.a. In addition to utilizing vacuum processes, low
temperature atmospheric (non-vacuum) plasma processes can also be
utilized to induce molecular ionization and deposition through
precursor monomer vapor delivery optionally in a non-oxidizing
atmosphere such as helium or argon. Separately, thermal CVD can be
considered via flash thermolysis deposition.
[0592] VII.B.1.a. The approaches above are similar to vacuum PECVD
in that the surface coating and crosslinking mechanisms can occur
simultaneously.
[0593] VII.B.1.a. Yet another expedient contemplated for any
coating or coatings described here is a coating that is not
uniformly applied over the entire interior 88 of a vessel. For
example, a different or additional coating can be applied
selectively to the cylindrical portion of the vessel interior,
compared to the hemispherical portion of the vessel interior at its
closed end 84, or vice versa. This expedient is particularly
contemplated for a syringe barrel or a sample collection tube as
described below, in which a lubricity layer or coating might be
provided on part or all of the cylindrical portion of the barrel,
where the plunger or piston or closure slides, and not
elsewhere.
[0594] VII.B.1.a. Optionally, the precursor can be provided in the
presence, substantial absence, or absence of nitrogen. In one
contemplated embodiment, the precursor alone is delivered to the
substrate and subjected to PECVD to apply and cure the coating.
[0595] VII.B.1.a. Optionally, the precursor can be provided at less
than 1 Torr absolute pressure.
[0596] VII.B.1.a. Optionally, the precursor can be provided to the
vicinity of a plasma emission.
[0597] VII.B.1.a. In any of the above embodiments, the substrate
can comprise glass, or a polymer, for example one or more of a
polycarbonate polymer, an olefin polymer (for example a cyclic
olefin copolymer or a polypropylene polymer), or a polyester
polymer (for example, a polyethylene terephthalate polymer).
[0598] VII.B.1.a. In any of the above embodiments, the plasma is
generated by energizing the gaseous reactant containing the
precursor with electrodes powered at a RF frequency as defined in
this description.
[0599] VII.B.1.a. In any of the above embodiments, the plasma is
generated by energizing the gaseous reactant containing the
precursor with electrodes supplied with sufficient electric power
to generate a lubricity layer. Optionally, the plasma is generated
by energizing the gaseous reactant containing the precursor with
electrodes supplied with an electric power of from 0.1 to 25 W,
optionally from 1 to 22 W, optionally from 3 to 17 W, even
optionally from 5 to 14 W, optionally from 7 to 11 W, optionally 8
W. The ratio of the electrode power to the plasma volume can be
less than 10 W/ml, optionally is from 6 W/ml to 0.1 W/ml,
optionally is from 5 W/ml to 0.1 W/ml, optionally is from 4 W/ml to
0.1 W/ml, optionally from 2 W/ml to 0.2 W/ml. Low power levels are
believed by the inventors to be most advantageous (e.g. power
levels of from 2 to 3.5 W and the power levels given in the
Examples) to prepare a lubricity coating. These power levels are
suitable for applying lubricity layers to syringes and sample tubes
and vessels of similar geometry having a void volume of 1 to 3 mL
in which PECVD plasma is generated. It is contemplated that for
larger or smaller objects the power applied should be increased or
reduced accordingly to scale the process to the size of the
substrate.
[0600] VII.B.1.a. The coating can be cured, as by polymerizing or
crosslinking the coating, or both, to form a lubricated surface
having a lower plunger sliding force or breakout force than the
untreated substrate. Curing can occur during the application
process such as PECVD, or can be carried out or at least completed
by separate processing.
[0601] VII.B.1.a. Although plasma deposition has been used herein
to demonstrate the coating characteristics, alternate deposition
methods can be used as long as the chemical composition of the
starting material is preserved as much as possible while still
depositing a solid film that is adhered to the base substrate.
[0602] VII.B.1.a. For example, the coating material can be applied
onto the syringe barrel (from the liquid state) by spraying the
coating or dipping the substrate into the coating, where the
coating is either the neat precursor a solvent-diluted precursor
(allowing the mechanical deposition of a thinner coating). The
coating optionally can be crosslinked using thermal energy, UV
energy, electron beam energy, plasma energy, or any combination of
these.
[0603] VII.B.1.a. Application of a silicone precursor as described
above onto a surface followed by a separate curing step is also
contemplated. The conditions of application and curing can be
analogous to those used for the atmospheric plasma curing of
pre-coated polyfluoroalkyl ethers, a process practiced under the
trademark TriboGlide.RTM.. More details of this process can be
found at http://www.triboglide.com/process.htm.
[0604] VII.B.1.a. In such a process, the area of the part to be
coated can optionally be pre-treated with an atmospheric plasma.
This pretreatment cleans and activates the surface so that it is
receptive to the lubricant that is sprayed in the next step.
[0605] VII.B.1.a. The lubrication fluid, in this case one of the
above precursors or a polymerized precursor, is then sprayed on to
the surface to be treated. For example, IVEK precision dispensing
technology can be used to accurately atomize the fluid and create a
uniform coating.
[0606] VII.B.1.a. The coating is then bonded or crosslinked to the
part, again using an atmospheric plasma field. This both
immobilizes the coating and improves the lubricant's
performance.
[0607] VII.B.1.a. Optionally, the atmospheric plasma can be
generated from ambient air in the vessel, in which case no gas feed
and no vacuum drawing equipment is needed. Optionally, however, the
vessel is at least substantially closed while plasma is generated,
to minimize the power requirement and prevent contact of the plasma
with surfaces or materials outside the vessel.
[0608] VII.B.1.a.i. Lubricity layer: SiO.sub.x Barrier, Lubricity
Layer, Surface Treatment
Surface Treatment
[0609] VII.B.1.a.i. Another embodiment is a syringe comprising a
barrel defining a lumen and having an interior surface slidably
receiving a plunger, i.e. receiving a plunger for sliding contact
to the interior surface.
[0610] VII.B.1.a.i. The syringe barrel is made of thermoplastic
base material.
[0611] VII.B.1.a.i. Optionally, the interior surface of the barrel
is coated with an SiO.sub.x barrier layer or coating as described
elsewhere in this specification.
[0612] VII.B.1.a.i. A lubricity layer or coating is applied to part
or all the barrel interior surface, the plunger, or both, or to the
previously applied SiO.sub.x barrier layer. The lubricity layer or
coating can be provided, applied, and cured as set out in
embodiment VII.B.1.a or elsewhere in this specification.
[0613] VII.B.1.a.i. For example, the lubricity layer or coating can
be applied, in any embodiment, by PECVD. The lubricity layer or
coating is deposited from an organosilicon precursor, and is less
than 1000 nm thick.
[0614] VII.B.1.a.i. A surface treatment is carried out on the
lubricity layer or coating in an amount effective to reduce the
leaching or extractables of the lubricity layer, the thermoplastic
base material, or both. The treated surface can thus act as a
solute retainer. This surface treatment can result in a skin
coating, e.g. a skin coating which is at least 1 nm thick and less
than 100 nm thick, or less than 50 nm thick, or less than 40 nm
thick, or less than 30 nm thick, or less than 20 nm thick, or less
than 10 nm thick, or less than 5 nm thick, or less than 3 nm thick,
or less than 2 nm thick, or less than 1 nm thick, or less than 0.5
nm thick.
[0615] VII.B.1.a.i. As used herein, "leaching" refers to material
transferred out of a substrate, such as a vessel wall, into the
contents of a vessel, for example a syringe. Commonly, leachables
are measured by storing the vessel filled with intended contents,
then analyzing the contents to determine what material leached from
the vessel wall into the intended contents. "Extraction" refers to
material removed from a substrate by introducing a solvent or
dispersion medium other than the intended contents of the vessel,
to determine what material can be removed from the substrate into
the extraction medium under the conditions of the test.
[0616] VII.B.1.a.i. The surface treatment resulting in a solute
retainer optionally can be a SiO.sub.x layer or coating as
previously defined in this specification or a hydrophobic layer,
characterized as defined in the Definition Section. In one
embodiment, the surface treatment can be applied by PECVD deposit
of SiO.sub.x or a hydrophobic layer. Optionally, the surface
treatment can be applied using higher power or stronger oxidation
conditions than used for creating the lubricity layer, or both,
thus providing a harder, thinner, continuous solute retainer 539.
Surface treatment can be less than 100 nm deep, optionally less
than 50 nm deep, optionally less than 40 nm deep, optionally less
than 30 nm deep, optionally less than 20 nm deep, optionally less
than 10 nm deep, optionally less than 5 nm deep, optionally less
than 3 nm deep, optionally less than 1 nm deep, optionally less
than 0.5 nm deep, optionally between 0.1 and 50 nm deep in the
lubricity layer.
[0617] VII.B.1.a.i. The solute retainer is contemplated to provide
low solute leaching performance to the underlying lubricity and
other layers, including the substrate, as required. This retainer
would only need to be a solute retainer to large solute molecules
and oligomers (for example siloxane monomers such as HMDSO, OMCTS,
their fragments and mobile oligomers derived from lubricants, for
example a "leachables retainer") and not a gas
(O.sub.2/N.sub.2/CO.sub.2/water vapor) barrier layer. A solute
retainer can, however, also be a gas barrier (e.g. the SiOx coating
according to present invention. One can create a good leachable
retainer without gas barrier performance, either by vacuum or
atmospheric-based PECVD processes. It is desirable that the
"leachables barrier" will be sufficiently thin that, upon syringe
plunger movement, the plunger will readily penetrate the "solute
retainer" exposing the sliding plunger nipple to the lubricity
layer or coating immediately below to form a lubricated surface
having a lower plunger sliding force or breakout force than the
untreated substrate.
[0618] VII.B.1.a.i. In another embodiment, the surface treatment
can be performed by oxidizing the surface of a previously applied
lubricity layer, as by exposing the surface to oxygen in a plasma
environment. The plasma environment described in this specification
for forming SiO.sub.x coatings can be used. Or, atmospheric plasma
conditions can be employed in an oxygen-rich environment.
[0619] VII.B.1.a.i. The lubricity layer or coating and solute
retainer, however formed, optionally can be cured at the same time.
In another embodiment, the lubricity layer or coating can be at
least partially cured, optionally fully cured, after which the
surface treatment can be provided, applied, and the solute retainer
can be cured.
[0620] VII.B.1.a.i. The lubricity layer or coating and solute
retainer are composed, and present in relative amounts, effective
to provide a breakout force, plunger sliding force, or both that is
less than the corresponding force required in the absence of the
lubricity layer or coating and surface treatment. In other words,
the thickness and composition of the solute retainer are such as to
reduce the leaching of material from the lubricity layer or coating
into the contents of the syringe, while allowing the underlying
lubricity layer or coating to lubricate the plunger. It is
contemplated that the solute retainer will break away easily and be
thin enough that the lubricity layer or coating will still function
to lubricate the plunger when it is moved.
[0621] VII.B.1.a.i. In one contemplated embodiment, the lubricity
and surface treatments can be applied on the barrel interior
surface. In another contemplated embodiment, the lubricity and
surface treatments can be applied on the plunger. In still another
contemplated embodiment, the lubricity and surface treatments can
be applied both on the barrel interior surface and on the plunger.
In any of these embodiments, the optional SiO.sub.x barrier layer
or coating on the interior of the syringe barrel can either be
present or absent.
[0622] VII.B.1.a.i. One embodiment contemplated is a plural-layer,
e.g. a 3-layer, configuration applied to the inside surface of a
syringe barrel. Layer or coating 1 can be an SiO.sub.x gas barrier
made by PECVD of HMDSO, OMCTS, or both, in an oxidizing atmosphere.
Such an atmosphere can be provided, for example, by feeding HMDSO
and oxygen gas to a PECVD coating apparatus as described in this
specification. Layer or coating 2 can be a lubricity layer or
coating using OMCTS applied in a non-oxidizing atmosphere. Such a
non-oxidizing atmosphere can be provided, for example, by feeding
OMCTS to a PECVD coating apparatus as described in this
specification, optionally in the substantial or complete absence of
oxygen. A subsequent solute retainer can be formed by a treatment
forming a thin skin layer or coating of SiO.sub.x or a hydrophobic
layer or coating as a solute retainer using higher power and oxygen
using OMCTS and/or HMDSO.
[0623] VII.B.1.a.i. Certain of these plural-layer or coating
coatings are contemplated to have one or more of the following
optional advantages, at least to some degree. They can address the
reported difficulty of handling silicone, since the solute retainer
can confine the interior silicone and prevent if from migrating
into the contents of the syringe or elsewhere, resulting in fewer
silicone particles in the deliverable contents of the syringe and
less opportunity for interaction between the lubricity layer or
coating and the contents of the syringe. They can also address the
issue of migration of the lubricity layer or coating away from the
point of lubrication, improving the lubricity of the interface
between the syringe barrel and the plunger. For example, the
break-free force can be reduced and the drag on the moving plunger
can be reduced, or optionally both.
[0624] VII.B.1.a.i. It is contemplated that when the solute
retainer is broken, the solute retainer will continue to adhere to
the lubricity layer or coating and the syringe barrel, which can
inhibit any particles from being entrained in the deliverable
contents of the syringe.
[0625] VII.B.1.a.i. Certain of these coatings will also provide
manufacturing advantages, particularly if the barrier coating,
lubricity layer or coating and surface treatment are applied in the
same apparatus, for example the illustrated PECVD apparatus.
Optionally, the SiO.sub.x barrier coating, lubricity layer, and
surface treatment can all be applied in one PECVD apparatus, thus
greatly reducing the amount of handling necessary.
[0626] Further advantages can be obtained by forming the barrier
coating, lubricity layer, and solute retainer using the same
precursors and varying the process. For example, an SiO.sub.x gas
barrier layer or coating can be applied using an OMCTS precursor
under high power/high O.sub.2 conditions, followed by applying a
lubricity layer or coating applied using an OMCTS precursor under
low power and/or in the substantial or complete absence of oxygen,
finishing with a surface treatment using an OMCTS precursor under
intermediate power and oxygen.
VII.B.2. Plungers
[0627] VII.B.2.a. With Barrier Coated Piston Front Face
[0628] VII.B.2.a. Another embodiment is a plunger for a syringe,
including a piston and a push rod. The piston has a front face, a
generally cylindrical side face, and a back portion, the side face
being configured to movably seat within a syringe barrel. The front
face has a barrier coating. The push rod engages the back portion
and is configured for advancing the piston in a syringe barrel.
VII.B.2.b. With Lubricity Layer or Coating Interfacing With Side
Face
[0629] VII.B.2.b. Yet another embodiment is a plunger for a
syringe, including a piston, a lubricity layer, and a push rod. The
piston has a front face, a generally cylindrical side face, and a
back portion. The side face is configured to movably seat within a
syringe barrel. The lubricity layer or coating interfaces with the
side face. The push rod engages the back portion of the piston and
is configured for advancing the piston in a syringe barrel.
VII.B.3.a Two Piece Syringe and Luer Fitting
[0630] VII.B.3.a Another embodiment is a syringe including a
plunger, a syringe barrel, and a Luer fitting. The syringe includes
a barrel having an interior surface receiving the plunger for
sliding. The Luer fitting includes a Luer taper having an internal
passage defined by an internal surface. The Luer fitting is formed
as a separate piece from the syringe barrel and joined to the
syringe barrel by a coupling. The internal passage of the Luer
taper optionally has a barrier coating of SiO.sub.x.
VII.B.3.b Staked Needle Syringe
[0631] VII.B.3.b Another embodiment is a syringe including a
plunger, a syringe barrel, and a staked needle (a "staked needle
syringe"). The needle is hollow with a typical size ranging from
18-29 gauge. The syringe barrel has an interior surface slidably
receiving the plunger. The staked needle may be affixed to the
syringe during the injection molding of the syringe or may be
assembled to the formed syringe using an adhesive. A cover is
placed over the staked needle to seal the syringe assembly. The
syringe assembly must be sealed so that a vacuum can be maintained
within the syringe to enable the PECVD coating process.
VII.B.4. Lubricity layer or coating In general VII.B.4.a. Product
By Process and Lubricity
[0632] VII.B.4.a. Still another embodiment is a lubricity layer.
This coating can be of the type made by the process for preparing a
lubricity coating as described herein.
[0633] VII.B.4.a. Any of the precursors for lubricity coatings
mentioned elsewhere in this specification can be used, alone or in
combination. The precursor is applied to a substrate under
conditions effective to form a coating. The coating is polymerized
or crosslinked, or both, to form a lubricated surface having a
lower plunger sliding force or breakout force than the untreated
substrate.
[0634] VII.B.4.a. Another embodiment is a method of applying a
lubricity layer. An organosilicon precursor is applied to a
substrate under conditions effective to form a coating. The coating
is polymerized or crosslinked, or both, to form a lubricated
surface having a lower plunger sliding force or breakout force than
the untreated substrate.
VII.B.4.b. Product by Process and Analytical Properties
[0635] VII.B.4.b. Even another aspect of the invention is a
lubricity layer or coating deposited by PECVD from a feed gas
comprising an organometallic precursor, optionally an organosilicon
precursor, optionally a linear siloxane, a linear silazane, a
monocyclic siloxane, a monocyclic silazane, a polycyclic siloxane,
a polycyclic silazane, or any combination of two or more of these.
The coating can have a density between 1.25 and 1.65 g/cm.sup.3
optionally between 1.35 and 1.55 g/cm.sup.3, optionally between 1.4
and 1.5 g/cm.sup.3, optionally between 1.44 and 1.48 g/cm.sup.3 as
determined by X-ray reflectivity (XRR).
[0636] VII.B.4.b. Still another aspect of the invention is a
lubricity layer or coating deposited by PECVD from a feed gas
comprising an organometallic precursor, optionally an organosilicon
precursor, optionally a linear siloxane, a linear silazane, a
monocyclic siloxane, a monocyclic silazane, a polycyclic siloxane,
a polycyclic silazane, or any combination of two or more of these.
The coating has as an outgas component one or more oligomers
containing repeating -(Me).sub.2SiO-- moieties, as determined by
gas chromatography/mass spectrometry. Optionally, the coating meets
the limitations of any of embodiments VII.B.4.a. Optionally, the
coating outgas component as determined by gas chromatography/mass
spectrometry is substantially free of trimethylsilanol.
[0637] VII.B.4.b. Optionally, the coating outgas component can be
at least 10 ng/test of oligomers containing repeating
-(Me).sub.2SiO-- moieties, as determined by gas chromatography/mass
spectrometry using the following test conditions: [0638] GC Column:
30 m.times.0.25 mm DB-5MS (J&W Scientific), 0.25 .mu.m film
thickness [0639] Flow rate: 1.0 ml/min, constant flow mode [0640]
Detector: Mass Selective Detector (MSD) [0641] Injection Mode:
Split injection (10:1 split ratio) [0642] Outgassing Conditions:
11/2'' (37 mm) Chamber, purge for three hour at 85.degree. C., flow
60 ml/min [0643] Oven temperature: 40.degree. C. (5 min.) to
300.degree. C. at 10.degree. C./min.; hold for 5 min. at
300.degree. C.
[0644] VII.B.4.b. Optionally, the outgas component can include at
least 20 ng/test of oligomers containing repeating -(Me).sub.2SiO--
moieties.
[0645] VII.B.4.b. Optionally, the feed gas comprises a monocyclic
siloxane, a monocyclic silazane, a polycyclic siloxane, a
polycyclic silazane, or any combination of two or more of these,
for example a monocyclic siloxane, a monocyclic silazane, or any
combination of two or more of these, for example
octamethylcyclotetrasiloxane.
[0646] VII.B.4.b. The lubricity layer or coating of any embodiment
can have an average thickness measured by transmission electron
microscopy (TEM) of from 1 to 5000 nm, or 10 to 1000 nm, or 10 to
200 nm, or 20 to 100 nm, or 30 to 1000 nm, or 30 to 500 nm thick.
Preferred ranges are from 30 to 1000 nm and from 20 to 100 nm, and
a particularly preferred range is from 80 to 150 nm. The absolute
thickness of the coating at single measurement points can be higher
or lower than the range limits of the average thickness. However,
it typically varies within the thickness ranges given for the
average thickness.
[0647] VII.B.4.b. Another aspect of the invention is a lubricity
layer or coating deposited by PECVD from a feed gas comprising a
monocyclic siloxane, a monocyclic silazane, a polycyclic siloxane,
a polycyclic silazane, or any combination of two or more of these.
The coating has an atomic concentration of carbon, normalized to
100% of carbon, oxygen, and silicon, as determined by X-ray
photoelectron spectroscopy (XPS), greater than the atomic
concentration of carbon in the atomic formula for the feed gas.
Optionally, the coating meets the limitations of embodiments
VII.B.4.a or VII.B.4.b.A.
[0648] VII.B.4.b. Optionally, the atomic concentration of carbon
increases by from 1 to 80 atomic percent (as calculated and based
on the XPS conditions in Example 15 of EP 2 251 455), alternatively
from 10 to 70 atomic percent, alternatively from 20 to 60 atomic
percent, alternatively from 30 to 50 atomic percent, alternatively
from 35 to 45 atomic percent, alternatively from 37 to 41 atomic
percent in relation to the atomic concentration of carbon in the
organosilicon precursor when a lubricity coating is made.
[0649] VII.B.4.b. An additional aspect of the invention is a
lubricity layer or coating deposited by PECVD from a feed gas
comprising a monocyclic siloxane, a monocyclic silazane, a
polycyclic siloxane, a polycyclic silazane, or any combination of
two or more of these. The coating has an atomic concentration of
silicon, normalized to 100% of carbon, oxygen, and silicon, as
determined by X-ray photoelectron spectroscopy (XPS), less than the
atomic concentration of silicon in the atomic formula for the feed
gas. See Example 15 of EP 2 251 455.
[0650] VII.B.4.b. Optionally, the atomic concentration of silicon
decreases by from 1 to 80 atomic percent (as calculated and based
on the XPS conditions in Example 15 of EP 2251 455), alternatively
from 10 to 70 atomic percent, alternatively from 20 to 60 atomic
percent, alternatively from 30 to 55 atomic percent, alternatively
from 40 to 50 atomic percent, alternatively from 42 to 46 atomic
percent.
[0651] VII.B.4.b. Lubricity layers having combinations of any two
or more properties recited in Section VII.B.4 are also expressly
contemplated.
VII.C. Vessels Generally
[0652] VII.C. A coated vessel or container as described herein
and/or prepared according to a method described herein can be used
for reception and/or storage and/or delivery of a compound or
composition. The compound or composition can be sensitive, for
example air-sensitive, oxygen-sensitive, sensitive to humidity
and/or sensitive to mechanical influences. It can be a biologically
active compound or composition, for example a medicament like
insulin or a composition comprising insulin. In another aspect, it
can be a biological fluid, optionally a bodily fluid, for example
blood or a blood fraction. In certain aspects of the present
invention, the compound or composition is a product to be
administrated to a subject in need thereof, for example a product
to be injected, like blood (as in transfusion of blood from a donor
to a recipient or reintroduction of blood from a patient back to
the patient) or insulin.
[0653] VII.C. A coated vessel or container as described herein
and/or prepared according to a method described herein can further
be used for protecting a compound or composition contained in its
interior space against mechanical and/or chemical effects of the
surface of the uncoated vessel material. For example, it can be
used for preventing or reducing precipitation and/or clotting or
platelet activation of the compound or a component of the
composition, for example insulin precipitation or blood clotting or
platelet activation.
[0654] VII.C. It can further be used for protecting a compound or
composition contained in its interior against the environment
outside of the vessel, for example by preventing or reducing the
entry of one or more compounds from the environment surrounding the
vessel into the interior space of the vessel. Such environmental
compound can be a gas or liquid, for example an atmospheric gas or
liquid containing oxygen, air, and/or water vapor.
[0655] VII.C. A coated vessel as described herein can also be
evacuated and stored in an evacuated state. For example, the
coating allows better maintenance of the vacuum in comparison to a
corresponding uncoated vessel. In one aspect of this embodiment,
the coated vessel is a blood collection tube. The tube can also
contain an agent for preventing blood clotting or platelet
activation, for example EDTA or heparin.
[0656] VII.C. Any of the above-described embodiments can be made,
for example, by providing as the vessel a length of tubing from
about 1 cm to about 200 cm, optionally from about 1 cm to about 150
cm, optionally from about 1 cm to about 120 cm, optionally from
about 1 cm to about 100 cm, optionally from about 1 cm to about 80
cm, optionally from about 1 cm to about 60 cm, optionally from
about 1 cm to about 40 cm, optionally from about 1 cm to about 30
cm long, and processing it with a probe electrode as described
below. Particularly for the longer lengths in the above ranges, it
is contemplated that relative motion between the probe and the
vessel can be useful during coating formation. This can be done,
for example, by moving the vessel with respect to the probe or
moving the probe with respect to the vessel.
[0657] VII.C. In these embodiments, it is contemplated that the
coating can be thinner or less complete than can be preferred for a
barrier coating, as the vessel in some embodiments will not require
the high barrier integrity of an evacuated blood collection
tube.
[0658] VII.C. As an optional feature of any of the foregoing
embodiments the vessel has a central axis.
[0659] VII.C. As an optional feature of any of the foregoing
embodiments the vessel wall is sufficiently flexible to be flexed
at least once at 20.degree. C., without breaking the wall, over a
range from at least substantially straight to a bending radius at
the central axis of not more than 100 times as great as the outer
diameter of the vessel.
[0660] VII.C. As an optional feature of any of the foregoing
embodiments the bending radius at the central axis is not more than
90 times as great as, or not more than 80 times as great as, or not
more than 70 times as great as, or not more than 60 times as great
as, or not more than 50 times as great as, or not more than 40
times as great as, or not more than 30 times as great as, or not
more than 20 times as great as, or not more than 10 times as great
as, or not more than 9 times as great as, or not more than 8 times
as great as, or not more than 7 times as great as, or not more than
6 times as great as, or not more than 5 times as great as, or not
more than 4 times as great as, or not more than 3 times as great
as, or not more than 2 times as great as, or not more than, the
outer diameter of the vessel.
[0661] VII.C. As an optional feature of any of the foregoing
embodiments the vessel wall can be a fluid-contacting surface made
of flexible material.
[0662] VII.C. As an optional feature of any of the foregoing
embodiments the vessel lumen can be the fluid flow passage of a
pump.
[0663] VII.C. As an optional feature of any of the foregoing
embodiments the vessel can be a blood bag adapted to maintain blood
in good condition for medical use.
[0664] VII.C., VII.D. As an optional feature of any of the
foregoing embodiments the polymeric material can be a silicone
elastomer or a thermoplastic polyurethane, as two examples, or any
material suitable for contact with blood, or with insulin.
[0665] VII.C., VII.D. In an optional embodiment, the vessel has an
inner diameter of at least 2 mm, or at least 4 mm.
[0666] VII.C. As an optional feature of any of the foregoing
embodiments the vessel is a tube.
[0667] VII.C. As an optional feature of any of the foregoing
embodiments the lumen has at least two open ends.
VII.C.1. Vessel Containing Viable Blood, Having a Coating Deposited
from an Organosilicon Precursor
[0668] VII.C.1. Even another embodiment is a blood containing
vessel. Several non-limiting examples of such a vessel are a blood
transfusion bag, a blood sample collection vessel in which a sample
has been collected, the tubing of a heart-lung machine, a
flexible-walled blood collection bag, or tubing used to collect a
patient's blood during surgery and reintroduce the blood into the
patient's vasculature. If the vessel includes a pump for pumping
blood, a particularly suitable pump is a centrifugal pump or a
peristaltic pump. The vessel has a wall; the wall has an inner
surface defining a lumen. The inner surface of the wall has an at
least partial coating of a hydrophobic layer, characterized as
defined in the Definition Section. The coating can be as thin as
monomolecular thickness or as thick as about 1000 nm. The vessel
contains blood viable for return to the vascular system of a
patient disposed within the lumen in contact with the hydrophobic
layer.
[0669] VII.C.1. An embodiment is a blood containing vessel
including a wall and having an inner surface defining a lumen. The
inner surface has an at least partial coating of a hydrophobic
layer. The coating can also comprise or consist essentially of
SiO.sub.x, where x is as defined in this specification. The
thickness of the coating is within the range from monomolecular
thickness to about 1000 nm thick on the inner surface. The vessel
contains blood viable for return to the vascular system of a
patient disposed within the lumen in contact with the hydrophobic
layer or coating.
VII.C.2. Coating Deposited from an Organosilicon Precursor Reduces
Clotting or platelet activation of Blood in the Vessel
[0670] VII.C.2. Another embodiment is a vessel having a wall. The
wall has an inner surface defining a lumen and has an at least
partial coating of a hydrophobic layer, where optionally w, x, y,
and z are as previously defined in the Definition Section. The
thickness of the coating is from monomolecular thickness to about
1000 nm thick on the inner surface. The coating is effective to
reduce the clotting or platelet activation of blood exposed to the
inner surface, compared to the same type of wall uncoated with a
hydrophobic layer.
[0671] VII.C.2. It is contemplated that the incorporation of a
hydrophobic layer or coating will reduce the adhesion or clot
forming tendency of the blood, as compared to its properties in
contact with an unmodified polymeric or SiO.sub.x surface. This
property is contemplated to reduce or potentially eliminate the
need for treating the blood with heparin, as by reducing the
necessary blood concentration of heparin in a patient undergoing
surgery of a type requiring blood to be removed from the patient
and then returned to the patient, as when using a heart-lung
machine during cardiac surgery. It is contemplated that this will
reduce the complications of surgery involving the passage of blood
through such a vessel, by reducing the bleeding complications
resulting from the use of heparin.
[0672] VII.C.2. Another embodiment is a vessel including a wall and
having an inner surface defining a lumen. The inner surface has an
at least partial coating of a hydrophobic layer, the thickness of
the coating being from monomolecular thickness to about 1000 nm
thick on the inner surface, the coating being effective to reduce
the clotting or platelet activation of blood exposed to the inner
surface.
[0673] VII.C.3. Vessel Containing Viable Blood, Having a Coating of
Group III or IV Element
[0674] VII.C.3. Another embodiment is a blood containing vessel
having a wall having an inner surface defining a lumen. The inner
surface has an at least partial coating of a composition comprising
one or more elements of Group III, one or more elements of Group
IV, or a combination of two or more of these. The thickness of the
coating is between monomolecular thickness and about 1000 nm thick,
inclusive, on the inner surface. The vessel contains blood viable
for return to the vascular system of a patient disposed within the
lumen in contact with the hydrophobic layer.
VII.C.4. Coating of Group III or IV Element Reduces Clotting or
Platelet Activation of Blood in the Vessel
[0675] VII.C.4. Optionally, in the vessel of the preceding
paragraph, the coating of the Group III or IV Element is effective
to reduce the clotting or platelet activation of blood exposed to
the inner surface of the vessel wall.
VII.D. Pharmaceutical Delivery Vessels
[0676] VII.D. A coated vessel or container as described herein can
be used for preventing or reducing the escape of a compound or
composition contained in the vessel into the environment
surrounding the vessel.
[0677] Further uses of the coating and vessel as described herein,
which are apparent from any part of the description and claims, are
also contemplated.
VII.D.1. Vessel Containing Insulin, Having a Coating Deposited from
an Organosilicon Precursor
[0678] VII.D.1. Another embodiment is an insulin containing vessel
including a wall having an inner surface defining a lumen. The
inner surface has an at least partial coating of a hydrophobic
layer, characterized as defined in the Definition Section. The
coating can be from monomolecular thickness to about 1000 nm thick
on the inner surface. Insulin is disposed within the lumen in
contact with the Si.sub.wO.sub.xC.sub.yH.sub.z coating.
[0679] VII.D.1. Still another embodiment is an insulin containing
vessel including a wall and having an inner surface defining a
lumen. The inner surface has an at least partial coating of a
hydrophobic layer, characterized as defined in the Definition
Section, the thickness of the coating being from monomolecular
thickness to about 1000 nm thick on the inner surface. Insulin, for
example pharmaceutical insulin FDA approved for human use, is
disposed within the lumen in contact with the hydrophobic
layer.
[0680] VII.D.1. It is contemplated that the incorporation of a
hydrophobic layer, characterized as defined in the Definition
Section, will reduce the adhesion or precipitation forming tendency
of the insulin in a delivery tube of an insulin pump, as compared
to its properties in contact with an unmodified polymeric surface.
This property is contemplated to reduce or potentially eliminate
the need for filtering the insulin passing through the delivery
tube to remove a solid precipitate.
VII.D.2. Coating Deposited from an Organosilicon Precursor Reduces
Precipitation of Insulin in the Vessel
[0681] VII.D.2. Optionally, in the vessel of the preceding
paragraph, the coating of a hydrophobic layer or coating is
effective to reduce the formation of a precipitate from insulin
contacting the inner surface, compared to the same surface absent
the hydrophobic layer.
[0682] VII.D.2. Even another embodiment is a vessel again
comprising a wall and having an inner surface defining a lumen. The
inner surface includes an at least partial coating of a hydrophobic
layer. The thickness of the coating is in the range from
monomolecular thickness to about 1000 nm thick on the inner
surface. The coating is effective to reduce the formation of a
precipitate from insulin contacting the inner surface.
VII.D.3. Vessel Containing Insulin, Having a Coating of Group III
or IV Element
[0683] VII.D.3. Another embodiment is an insulin containing vessel
including a wall having an inner surface defining a lumen. The
inner surface has an at least partial coating of a composition
comprising carbon, one or more elements of Group III, one or more
elements of Group IV, or a combination of two or more of these. The
coating can be from monomolecular thickness to about 1000 nm thick
on the inner surface. Insulin is disposed within the lumen in
contact with the coating.
VII.D.4. Coating of Group III or IV Element Reduces Precipitation
of Insulin in the Vessel
[0684] VII.D.4. Optionally, in the vessel of the preceding
paragraph, the coating of a composition comprising carbon, one or
more elements of Group III, one or more elements of Group IV, or a
combination of two or more of these, is effective to reduce the
formation of a precipitate from insulin contacting the inner
surface, compared to the same surface absent the coating.
Common Conditions for all Embodiments
[0685] In any embodiment contemplated here, many common conditions
can be used, for example any of the following, in any combination.
Alternatively, any different conditions described elsewhere in this
specification or claims can be employed.
I. Substrate of any Embodiment
I.A. Vessel of any Embodiment
[0686] The vessel can be a sample collection tube, for example a
blood collection tube, or a syringe, or a syringe part, for example
a barrel or piston or plunger; a vial; a conduit; or a cuvette. The
substrate can be a closed-ended tube, for example a medical sample
collection tube. The substrate can be the inside wall of a vessel
having a lumen, the lumen having a void volume of from 0.5 to 50
mL, optionally from 1 to 10 mL, optionally from 0.5 to 5 mL,
optionally from 1 to 3 mL. The substrate surface can be part or all
of the inner surface of a vessel having at least one opening and an
inner surface, and wherein the gaseous reactant fills the interior
lumen of the vessel and the plasma can be generated in part or all
of the interior lumen of the vessel.
I.B. Syringe and parts
[0687] The substrate can be a syringe barrel. The syringe barrel
can have a plunger sliding surface and the coating can be disposed
on at least a portion of the plunger sliding surface. The coating
can be a lubricity layer. The lubricity layer or coating can be on
the barrel interior surface. The lubricity layer or coating can be
on the plunger. In a particular aspect, the substrate is a staked
needle syringe or part of a staked needle syringe.
I.C. Vessel to Receive Stopper
[0688] The substrate can be a stopper receiving surface in the
mouth of a vessel. The substrate can be a generally conical or
cylindrical inner surface of an opening of a vessel adapted to
receive a stopper.
I.D. Stopper
[0689] The substrate can be a sliding surface of a stopper. The
substrates can be coated by providing a multiplicity of the
stoppers located in a single substantially evacuated vessel. The
chemical vapor deposition can be plasma-enhanced chemical vapor
deposition and the stopper can be contacted with the plasma. The
chemical vapor deposition can be plasma-enhanced chemical vapor
deposition. The plasma can be formed upstream of the stopper,
producing plasma product, and the plasma product can be contacted
with the stopper.
[0690] A closure can define a substrate coated with a coating,
optionally a stopper coated with a lubricity layer. The substrate
can be a closure seated in a vessel defining a lumen and a surface
of the closure facing the lumen can be coated with the coating.
[0691] The coating can be effective to reduce the transmission of a
metal ion constituent of the stopper into the lumen of the
vessel.
I.E. The Substrate of any Embodiment
[0692] The substrate can be a vessel wall. A portion of the vessel
wall in contact with a wall-contacting surface of a closure can be
coated with the coating. The coating can be a composite of material
having first and second layers. The first layer or coating can
interface with the elastomeric stopper. The first layer of the
coating can be effective to reduce the transmission of one or more
constituents of the stopper into the vessel lumen. The second layer
or coating can interface with the inner wall of the vessel. The
second layer can be effective to reduce friction between the
stopper and the inner wall of the vessel when the stopper can be
seated on the vessel.
[0693] Alternatively, the first and second layers of any embodiment
can be defined by a coating of graduated properties containing
carbon and hydrogen, in which the proportions of carbon and
hydrogen are greater in the first layer or coating than in the
second layer.
[0694] The coating of any embodiment can be applied by plasma
enhanced chemical vapor deposition.
[0695] The substrate of any embodiment can comprise glass,
alternatively a polymer, alternatively a polycarbonate polymer,
alternatively an olefin polymer, alternatively a cyclic olefin
copolymer, alternatively a polypropylene polymer, alternatively a
polyester polymer, alternatively a polyethylene terephthalate
polymer, alternatively a polyethylene naphthalate polymer,
alternatively a combination, composite or blend of any two or more
of the above materials.
II. Gaseous Reactant or Process Gas Limitations of any
Embodiment
II.A Deposition Conditions of any Embodiment
[0696] The plasma for PECVD, if used, can be generated at reduced
pressure and the reduced pressure can be less than 300 mTorr,
optionally less than 200 mTorr, even optionally less than 100
mTorr. The physical and chemical properties of the coating can be
set by setting the ratio of O.sub.2 to the organosilicon precursor
in the gaseous reactant, and/or by setting the electric power used
for generating the plasma.
II.B. Relative Proportions of Gases of any Embodiment
[0697] The process gas can contain this ratio of gases for
preparing a lubricity coating: [0698] from 1 to 6 standard volumes
of the precursor; [0699] from 1 to 100 standard volumes of a
carrier gas, [0700] from 0.1 to 2 standard volumes of an oxidizing
agent.
[0701] alternatively this ratio: [0702] from 2 to 4 standard
volumes, of the precursor; [0703] from 1 to 100 standard volumes of
a carrier gas, [0704] from 0.1 to 2 standard volumes [0705] of an
oxidizing agent.
[0706] alternatively this ratio: [0707] from 1 to 6 standard
volumes of the precursor; [0708] from 3 to 70 standard volumes, of
a carrier gas, [0709] from 0.1 to 2 standard volumes of an
oxidizing agent.
[0710] alternatively this ratio: [0711] from 2 to 4 standard
volumes, of the precursor; [0712] from 3 to 70 standard volumes of
a carrier gas, [0713] from 0.1 to 2 standard volumes of an
oxidizing agent.
[0714] alternatively this ratio: [0715] from 1 to 6 standard
volumes of the precursor; [0716] from 1 to 100 standard volumes of
a carrier gas, [0717] from 0.2 to 1.5 standard volumes of an
oxidizing agent.
[0718] alternatively this ratio: [0719] from 2 to 4 standard
volumes, of the precursor; [0720] from 1 to 100 standard volumes of
a carrier gas, [0721] from 0.2 to 1.5 standard volumes of an
oxidizing agent.
[0722] alternatively this ratio: [0723] from 1 to 6 standard
volumes of the precursor; [0724] from 3 to 70 standard volumes of a
carrier gas, [0725] from 0.2 to 1.5 standard volumes of an
oxidizing agent.
[0726] alternatively this ratio: [0727] from 2 to 4 standard
volumes of the precursor; [0728] from 3 to 70 standard volumes of a
carrier gas, [0729] from 0.2 to 1.5 standard volumes of an
oxidizing agent.
[0730] alternatively this ratio: [0731] from 1 to 6 standard
volumes of the precursor; [0732] from 1 to 100 standard volumes of
a carrier gas, [0733] from 0.2 to 1 standard volumes of an
oxidizing agent.
[0734] alternatively this ratio: [0735] from 2 to 4 standard
volumes of the precursor; [0736] from 1 to 100 standard volumes of
a carrier gas, [0737] from 0.2 to 1 standard volumes of an
oxidizing agent.
[0738] alternatively this ratio: [0739] from 1 to 6 standard
volumes of the precursor; [0740] from 3 to 70 standard volumes of a
carrier gas, [0741] from 0.2 to 1 standard volumes of an oxidizing
agent.
[0742] alternatively this ratio: [0743] d 2 to 4 standard volumes,
of the precursor; [0744] from 3 to 70 standard volumes of a carrier
gas, [0745] from 0.2 to 1 standard volumes of an oxidizing
agent.
[0746] alternatively this ratio: [0747] from 1 to 6 standard
volumes of the precursor; [0748] from 5 to 100 standard volumes of
a carrier gas, [0749] from 0.1 to 2 standard volumes of an
oxidizing agent.
[0750] alternatively this ratio: [0751] from 2 to 4 standard
volumes, of the precursor; [0752] from 5 to 100 standard volumes of
a carrier gas, [0753] from 0.1 to 2 standard volumes [0754] of an
oxidizing agent.
[0755] alternatively this ratio: [0756] from 1 to 6 standard
volumes of the precursor; [0757] from 10 to 70 standard volumes, of
a carrier gas, [0758] from 0.1 to 2 standard volumes of an
oxidizing agent.
[0759] alternatively this ratio: [0760] from 2 to 4 standard
volumes, of the precursor; [0761] from 10 to 70 standard volumes of
a carrier gas, [0762] from 0.1 to 2 standard volumes of an
oxidizing agent.
[0763] alternatively this ratio: [0764] from 1 to 6 standard
volumes of the precursor; [0765] from 5 to 100 standard volumes of
a carrier gas, [0766] from 0.5 to 1.5 standard volumes of an
oxidizing agent.
[0767] alternatively this ratio: [0768] from 2 to 4 standard
volumes, of the precursor; [0769] from 5 to 100 standard volumes of
a carrier gas, [0770] from 0.5 to 1.5 standard volumes of an
oxidizing agent.
[0771] alternatively this ratio: [0772] from 1 to 6 standard
volumes of the precursor; [0773] from 10 to 70 standard volumes, of
a carrier gas, [0774] from 0.5 to 1.5 standard volumes of an
oxidizing agent.
[0775] alternatively this ratio: [0776] from 2 to 4 standard
volumes of the precursor; [0777] from 10 to 70 standard volumes of
a carrier gas, [0778] from 0.5 to 1.5 standard volumes of an
oxidizing agent.
[0779] alternatively this ratio: [0780] from 1 to 6 standard
volumes of the precursor; [0781] from 5 to 100 standard volumes of
a carrier gas, [0782] from 0.8 to 1.2 standard volumes of an
oxidizing agent.
[0783] alternatively this ratio: [0784] from 2 to 4 standard
volumes of the precursor; [0785] from 5 to 100 standard volumes of
a carrier gas, [0786] from 0.8 to 1.2 standard volumes of an
oxidizing agent.
[0787] alternatively this ratio: [0788] from 1 to 6 standard
volumes of the precursor; [0789] from 10 to 70 standard volumes of
a carrier gas, [0790] from 0.8 to 1.2 standard volumes of an
oxidizing agent.
[0791] alternatively this ratio: [0792] 2 to 4 standard volumes, of
the precursor; [0793] from 10 to 70 standard volumes of a carrier
gas, [0794] from 0.8 to 1.2 standard volumes of an oxidizing
agent.
II.C. Precursor of any Embodiment
[0795] The organosilicon precursor has been described elsewhere in
this description.
[0796] The organosilicon compound can in certain aspects,
particularly when a lubricity coating is formed, comprise
octamethylcyclotetrasiloxane (OMCTS). The organosilicon compound
for any embodiment of said certain aspects can consist essentially
of octamethycyclotetrasiloxane (OMCTS). The organosilicon compound
can in certain aspects, particularly when a barrier coating is
formed, be or comprise hexamethyldisiloxane.
[0797] The reaction gas can also include a hydrocarbon. The
hydrocarbon can comprise methane, ethane, ethylene, propane,
acetylene, or a combination of two or more of these.
[0798] The organosilicon precursor can be delivered at a rate of
equal to or less than 6 sccm, optionally equal to or less than 2.5
sccm, optionally equal to or less than 1.5 sccm, optionally equal
to or less than 1.25 sccm. Larger vessels or other changes in
conditions or scale may require more or less of the precursor. The
precursor can be provided at less than 1 Torr absolute
pressure.
II.D. Carrier Gas of any Embodiment
[0799] The carrier gas can comprise or consist of an inert gas, for
example argon, helium, xenon, neon, another gas that is inert to
the other constituents of the process gas under the deposition
conditions, or any combination of two or more of these.
II.E. Oxidizing Gas of any Embodiment
[0800] The oxidizing gas can comprise or consist of oxygen (O.sub.2
and/or O.sub.3 (commonly known as ozone)), nitrous oxide, or any
other gas that oxidizes the precursor during PECVD at the
conditions employed. The oxidizing gas comprises about 1 standard
volume of oxygen. The gaseous reactant or process gas can be at
least substantially free of nitrogen.
III. Plasma of any Embodiment
[0801] The plasma of any PECVD embodiment can be formed in the
vicinity of the substrate. The plasma can in certain cases,
especially when preparing an SiOx coating, be a non-hollow-cathode
plasma. In other certain cases, especially when preparing a
lubricity coating, a non-hollow-cathode plasma is not desired. The
plasma can be formed from the gaseous reactant at reduced pressure.
Sufficient plasma generation power input can be provided to induce
coating formation on the substrate.
IV. RF Power of any Embodiment
[0802] The precursor can be contacted with a plasma made by
energizing the vicinity of the precursor with electrodes powered at
a frequency of 10 kHz to 2.45 GHz, alternatively from about 13 to
about 14 MHz.
[0803] The precursor can be contacted with a plasma made by
energizing the vicinity of the precursor with electrodes powered at
radio frequency, optionally at a frequency of from 10 kHz to less
than 300 MHz, optionally from 1 to 50 MHz, even optionally from 10
to 15 MHz, optionally at 13.56 MHz.
[0804] The precursor can be contacted with a plasma made by
energizing the vicinity of the precursor with electrodes supplied
with electric power at from 0.1 to 25 W, optionally from 1 to 22 W,
optionally from 1 to 10 W, even optionally from 1 to 5 W,
optionally from 2 to 4 W, for example of 3 W, optionally from 3 to
17 W, even optionally from 5 to 14 W, for example 6 or 7.5 W,
optionally from 7 to 11 W, for example of 8 W.
[0805] The precursor can be contacted with a plasma made by
energizing the vicinity of the precursor with electrodes supplied
with electric power density at less than 10 W/ml of plasma volume,
alternatively from 6 W/ml to 0.1 W/ml of plasma volume,
alternatively from 5 W/ml to 0.1 W/ml of plasma volume,
alternatively from 4 W/ml to 0.1 W/ml of plasma volume,
alternatively from 2 W/ml to 0.2 W/ml of plasma volume.
[0806] The plasma can be formed by exciting the reaction mixture
with electromagnetic energy, alternatively microwave energy.
V. Other Process Options of any Embodiment
[0807] The applying step for applying a coating to the substrate
can be carried out by vaporizing the precursor and providing it in
the vicinity of the substrate.
[0808] The chemical vapor deposition employed can be PECVD and the
deposition time can be from 1 to 30 sec, alternatively from 2 to 10
sec, alternatively from 3 to 9 sec. The purposes for optionally
limiting deposition time can be to avoid overheating the substrate,
to increase the rate of production, and to reduce the use of
process gas and its constituents. The purposes for optionally
extending deposition time can be to provide a thicker coating for
particular deposition conditions.
VI. Coating Properties of any Embodiment
VI.A. Lubricity Properties of any Embodiment
[0809] The vessels (e.g. syringe barrels and/or plungers) coated
with a lubricity coating according to present invention have a
higher lubricity (determined, e.g. by measuring the Fi and/or Fm)
than the uncoated vessels. They also have a higher lubricity than
vessels coated with a SiO.sub.x coating as described herein. An
embodiment can be carried out under conditions effective to form a
lubricated surface of the substrate having a lower sliding force or
breakout force (or optionally both) than the untreated substrate.
Optionally, the materials and conditions can be effective to reduce
the sliding force or breakout force at least at least 25 percent,
alternatively at least 45 percent, alternatively at least 60
percent, alternatively more than 60 percent relative to an uncoated
syringe barrel. Expressed otherwise, the coating can have a lower
frictional resistance than the uncoated surface, wherein optionally
the frictional resistance can be reduced by at least 25%,
optionally by at least 45%, even optionally by at least 60% in
comparison to the uncoated surface.
[0810] The break loose force (Fi) and the glide force (Fm) are
important performance measures for the effectiveness of a lubricity
coating. For Fi and Fm, it is desired to have a low, but not too
low value. With too low Fi, which means a too low level of
resistance (the extreme being zero), premature/unintended flow may
occur, which might e.g. lead to an unintentional premature or
uncontrolled discharge of the content of a prefilled syringe.
[0811] In order to achieve a sufficient lubricity (e.g. to ensure
that a syringe plunger can be moved in the syringe, but to avoid
uncontrolled movement of the plunger), the following ranges of Fi
and Fm should be advantageously maintained:
Fi: 2.5 to 5 lbs, preferably 2.7 to 4.9 lbs, and in particular 2.9
to 4.7 lbs; Fm: 2.5 to 8.0 lbs, preferably 3.3 to 7.6 lbs, and in
particular 3.3 to 4 lbs.
[0812] Further advantageous Fi and Fm values can be found in the
Tables of the Examples.
[0813] The lubricity coating optionally provides a consistent
plunger force that reduces the difference between the break loose
force (Fi) and the glide force (Fm).
VI.B. Hydrophobicity Properties of any Embodiment
[0814] An embodiment can be carried out under conditions effective
to form a hydrophobic layer or coating on the substrate.
Optionally, the hydrophobic characteristics of the coating can be
set by setting the ratio of the O.sub.2 to the organosilicon
precursor in the gaseous reactant, and/or by setting the electric
power used for generating the plasma. Optionally, the coating can
have a lower wetting tension than the uncoated surface, optionally
a wetting tension of from 20 to 72 dyne/cm, optionally from 30 to
60 dynes/cm, optionally from 30 to 40 dynes/cm, optionally 34
dyne/cm. Optionally, the coating can be more hydrophobic than the
uncoated surface.
VI.C. Thickness of any Embodiment
[0815] Optionally, the coating can have a thickness determined by
transmission electron microscopy (TEM), of any amount stated in
this disclosure.
[0816] For the lubricity coatings described herein, the indicated
thickness ranges are representing average thickness, as a certain
roughness may enhance the lubricious properties of the lubricity
coating. Thus the thickness of the lubricity coating is
advantageously not uniform throughout the coating (see above).
However, a uniformly thick lubricity coating is also considered.
The absolute thickness of the lubricity coating at single
measurement points can be higher or lower than the range limits of
the average thickness, with maximum deviations of preferably
+/-50%, more preferably +/-25% and even more preferably +/-15% from
the average thickness. However, it typically varies within the
thickness ranges given for the average thickness in this
description.
VI.D. Composition of any Embodiment
[0817] Optionally, the lubricity coating can be composed of
Si.sub.wO.sub.xC.sub.yH.sub.z or SiwNxCyHz. It generally has an
atomic ratio Si.sub.wO.sub.xC.sub.y wherein w is 1, x is from about
0.5 to about 2.4, y is from about 0.6 to about 3, preferably w is
1, x is from about 0.5 to 1.5, and y is from 0.9 to 2.0, more
preferably w is 1, x is from 0.7 to 1.2 and y is from 0.9 to 2.0.
The atomic ratio can be determined by XPS (X-ray photoelectron
spectroscopy). Taking into account the H atoms, the coating may
thus in one aspect have the formula Si.sub.wO.sub.xC.sub.yH.sub.z,
for example where w is 1, x is from about 0.5 to about 2.4, y is
from about 0.6 to about 3, and z is from about 2 to about 9.
Typically, the atomic ratios are Si 100:O 80-110:C 100-150 in a
particular coating of present invention. Specifically, the atomic
ratio may be Si 100:O 92-107:C 116-133, and such coating would
hence contain 36% to 41% carbon normalized to 100% carbon plus
oxygen plus silicon. Alternatively, w can be 1, x can be from about
0.5 to 1.5 y can be from about 2 to about 3, and z can be from 6 to
about 9. Alternatively, the coating can have atomic concentrations
normalized to 100% carbon, oxygen, and silicon, as determined by
X-ray photoelectron spectroscopy (XPS) of less than 50% carbon and
more than 25% silicon. Alternatively, the atomic concentrations are
from 25 to 45% carbon, 25 to 65% silicon, and 10 to 35% oxygen.
Alternatively, the atomic concentrations are from 30 to 40% carbon,
32 to 52% silicon, and 20 to 27% oxygen. Alternatively, the atomic
concentrations are from 33 to 37% carbon, 37 to 47% silicon, and 22
to 26% oxygen.
[0818] Optionally, the atomic concentration of carbon, normalized
to 100% of carbon, oxygen, and silicon, as determined by X-ray
photoelectron spectroscopy (XPS), can be greater than the atomic
concentration of carbon in the atomic formula for the organosilicon
precursor. For example, embodiments are contemplated in which the
atomic concentration of carbon increases by from 1 to 80 atomic
percent, alternatively from 10 to 70 atomic percent, alternatively
from 20 to 60 atomic percent, alternatively from 30 to 50 atomic
percent, alternatively from 35 to 45 atomic percent, alternatively
from 37 to 41 atomic percent.
[0819] Optionally, the atomic ratio of carbon to oxygen in the
coating can be increased in comparison to the organosilicon
precursor, and/or the atomic ratio of oxygen to silicon can be
decreased in comparison to the organosilicon precursor.
[0820] Optionally, the coating can have an atomic concentration of
silicon, normalized to 100% of carbon, oxygen, and silicon, as
determined by X-ray photoelectron spectroscopy (XPS), less than the
atomic concentration of silicon in the atomic formula for the feed
gas. For example, embodiments are contemplated in which the atomic
concentration of silicon decreases by from 1 to 80 atomic percent,
alternatively by from 10 to 70 atomic percent, alternatively by
from 20 to 60 atomic percent, alternatively by from 30 to 55 atomic
percent, alternatively by from 40 to 50 atomic percent,
alternatively by from 42 to 46 atomic percent.
[0821] As another option, a coating is contemplated that can be
characterized by a sum formula wherein the atomic ratio C:0 can be
increased and/or the atomic ratio Si:O can be decreased in
comparison to the sum formula of the organosilicon precursor.
VI.E. Outgassing Species of any Embodiment
[0822] The lubricity coating can have as an outgas component one or
more oligomers containing repeating -(Me).sub.2SiO-- moieties, as
determined by gas chromatography/mass spectrometry. The coating
outgas component can be determined by gas chromatography/mass
spectrometry. For example, the coating outgas component can have at
least 10 ng/test of oligomers containing repeating -(Me).sub.2SiO--
moieties, alternatively at least 20 ng/test of oligomers containing
repeating -(Me).sub.2SiO-- moieties, as determined using the
following test conditions: [0823] GC Column: 30 m.times.0.25 mm
DB-5MS (J&W Scientific), 0.25 .mu.m film thickness [0824] Flow
rate 1.0 ml/min, constant flow mode [0825] Detector: Mass Selective
Detector (MSD) [0826] Injection Mode: Split injection (10:1 split
ratio) [0827] Outgassing Conditions: 11/2'' (37 mm) Chamber, purge
for three hour at 85.degree. C., flow 60 ml/min [0828] Oven
temperature: 40.degree. C. (5 min.) to 300.degree. C. @10'C/min.;
hold for 5 min. at 300.degree. C.
[0829] Optionally, the lubricity coating can have an outgas
component at least substantially free of trimethylsilanol.
VI.E. Other Coating Properties of any Embodiment
[0830] The coating can have a density between 1.25 and 1.65
g/cm.sup.3, alternatively between 1.35 and 1.55 g/cm.sup.3,
alternatively between 1.4 and 1.5 g/cm.sup.3, alternatively between
1.4 and 1.5 g/cm.sup.3, alternatively between 1.44 and 1.48
g/cm.sup.3, as determined by X-ray reflectivity (XRR). Optionally,
the organosilicon compound can be octamethylcyclotetrasiloxane and
the coating can have a density which can be higher than the density
of a coating made from HMDSO as the organosilicon compound under
the same PECVD reaction conditions.
[0831] The coating optionally can prevent or reduce the
precipitation of a compound or component of a composition in
contact with the coating, in particular can prevent or reduce
insulin precipitation or blood clotting, in comparison to the
uncoated surface and/or to a barrier coated surface using HMDSO as
precursor.
[0832] The substrate can be a vessel, for protecting a compound or
composition contained or received in the coated vessel against
mechanical and/or chemical effects of the surface of the uncoated
substrate.
[0833] The substrate can be a vessel, for preventing or reducing
precipitation and/or clotting of a compound or a component of the
composition in contact with the interior surface of the vessel. The
compound or composition can be a biologically active compound or
composition, for example a medicament, for example the compound or
composition can comprise insulin, wherein insulin precipitation can
be reduced or prevented. Alternatively, the compound or composition
can be a biological fluid, for example a bodily fluid, for example
blood or a blood fraction wherein blood clotting can be reduced or
prevented.
VII. Plus Sio.sub.x Coating, Optional for any Embodiment
[0834] The coating on a substrate, for example a vessel wall, as
well as comprising a lubricity coating, additionally can comprise
at least one layer or coating of SiOx, wherein x can be from 1.5 to
2.9, adjacent to the coating on the substrate, alternatively
between the coating and the substrate, alternatively on the
opposite side of the coating as the substrate. Optionally, the
layers of SiOx and the coating can either form a sharp interface or
a graded composite of Si.sub.wO.sub.xC.sub.yH.sub.z to SiO.sub.x or
vice versa. The substrate coated with a lubricity coating can
further comprise a surface treatment of the coating in an amount
effective to reduce the leaching of the coating, the substrate, or
both. For example, the coating and surface treatment can be
composed and present in relative amounts effective to provide a
breakout force, sliding force, or both less than the corresponding
force required in the absence of the coating and surface treatment.
Optionally, the surface treatment can be less than 100 nm deep,
alternatively less than 50 nm deep, alternatively less than 40 nm
deep, alternatively less than 30 nm deep, alternatively less than
20 nm deep, alternatively less than 10 nm deep, alternatively less
than 5 nm deep, alternatively less than 3 nm deep, alternatively
less than 1 nm deep, alternatively less than 0.5 nm deep in the
lubricity layer. As another contemplated option, the surface
treatment can be between 0.1 and 50 nm deep in the lubricity
layer.
[0835] The optional surface treatment can comprise SiO.sub.x, in
which x can be from about 1.5 to about 2.9. Optionally, at least a
second layer or coating of SiOx, wherein x can be from 1.5 to 2.9,
can be applied between the coating and the substrate surface.
[0836] Embodiments are contemplated in which the substrate is a
vessel having an interior surface defining a lumen and an exterior
surface. The lubricity coating can be on the interior surface of
the vessel, and the vessel can contain at least one further layer
or coating on its exterior surface of SiO.sub.x, wherein x can be
from 1.5 to 2.9. Alternatively, the further layer or coating on the
exterior surface can comprise polyvinylidene chloride (PVDC). The
further layer or coating on the exterior surface optionally can be
a barrier coating.
VIII. Product Made of Vessel Plus Contents, Optional for any
Embodiment
[0837] In any embodiment, the substrate can be a vessel having an
interior surface defining a lumen and an exterior surface, the
coating can be on the interior surface of the vessel, and the
vessel can contain a compound or composition in its lumen, e.g.
citrate or a citrate containing composition, or e.g. insulin or an
insulin containing composition. A prefilled syringe is especially
considered which contains injectable or other liquid drugs like
insulin.
EXAMPLES
[0838] The following Examples are in part already disclosed in EP 2
251 455. In order to avoid unnecessary repetition, not all of the
Examples in EP 2 251 455 A2 are repeated here, but explicit
reference is herewith made to them.
Basic Protocols for Forming and Coating Syringe Barrels
[0839] The vessels tested in the subsequent working examples were
formed and coated according to the following exemplary protocols,
except as otherwise indicated in individual examples. Particular
parameter values given in the following basic protocols, e.g. the
electric power and gaseous reactant or process gas flow, are
typical values. Whenever parameter values were changed in
comparison to these typical values, this will be indicated in the
subsequent working examples. The same applies to the type and
composition of the gaseous reactant or process gas.
Protocol for Coating Tube Interior with SiO.sub.x
[0840] The apparatus as shown in FIG. 1 with the sealing mechanism
of FIG. 10, which is a specific contemplated embodiment, was used.
The vessel holder 50 was made from Delrin.RTM. acetal resin,
available from E.I. du Pont de Nemours and Co., Wilmington Del.,
USA, with an outside diameter of 1.75 inches (44 mm) and a height
of 1.75 inches (44 mm). The vessel holder 50 was housed in a
Delrin.RTM. structure that allowed the device to move in and out of
the electrode (160).
[0841] The electrode 160 was made from copper with a Delrin.RTM.
shield. The Delrin.RTM. shield was conformal around the outside of
the copper electrode 160. The electrode 160 measured approximately
3 inches (76 mm) high (inside) and was approximately 0.75 inches
(19 mm) wide.
[0842] The tube used as the vessel 80 was inserted into the vessel
holder 50 base sealing with Viton.RTM. O-rings 490, 504 (Viton.RTM.
is a trademark of DuPont Performance Elastomers LLC, Wilmington
Del., USA) around the exterior of the tube (FIG. 10). The tube 80
was carefully moved into the sealing position over the extended
(stationary) 1/8-inch (3-mm) diameter brass probe or counter
electrode 108 and pushed against a copper plasma screen.
[0843] The copper plasma screen 610 was a perforated copper foil
material (K&S Engineering, Chicago Ill., USA, Part #LXMUW5
copper mesh) cut to fit the outside diameter of the tube, and was
held in place by a radially extending abutment surface 494 that
acted as a stop for the tube insertion (see FIG. 10). Two pieces of
the copper mesh were fit snugly around the brass probe or counter
electrode 108, insuring good electrical contact.
[0844] The brass probe or counter electrode 108 extended
approximately 70 mm into the interior of the tube and had an array
of #80 wire (diameter=0.0135 inch or 0.343 mm). The brass probe or
counter electrode 108 extended through a Swagelok.RTM. fitting
(available from Swagelok Co., Solon Ohio, USA) located at the
bottom of the vessel holder 50, extending through the vessel holder
50 base structure. The brass probe or counter electrode 108 was
grounded to the casing of the RF matching network.
[0845] The gas delivery port 110 was 12 holes in the probe or
counter electrode 108 along the length of the tube (three on each
of four sides oriented 90 degrees from each other) and two holes in
the aluminum cap that plugged the end of the gas delivery port 110.
The gas delivery port 110 was connected to a stainless steel
assembly comprised of Swagelok.RTM. fittings incorporating a manual
ball valve for venting, a thermocouple pressure gauge and a bypass
valve connected to the vacuum pumping line. In addition, the gas
system was connected to the gas delivery port 110 allowing the
gaseous reactant or process gases, oxygen and hexamethyldisiloxane
(HMDSO) to be flowed through the gas delivery port 110 (under
process pressures) into the interior of the tube.
[0846] The gas system was comprised of a Aalborg.RTM. GFC17 mass
flow meter (Part # EW-32661-34, Cole-Parmer Instrument Co.,
Barrington Ill. USA) for controllably flowing oxygen at 90 sccm (or
at the specific flow reported for a particular example) into the
process and a polyether ether ketone ("PEEK") capillary (outside
diameter, "OD" 1/16-inch (1.5-mm.), inside diameter, "ID" 0.004
inch (0.1 mm)) of length 49.5 inches (1.26 m). The PEEK capillary
end was inserted into liquid hexamethyldisiloxane ("HMDSO," Alfa
Aesar.RTM. Part Number L16970, NMR Grade, available from Johnson
Matthey PLC, London). The liquid HMDSO was pulled through the
capillary due to the lower pressure in the tube during processing.
The HMDSO was then vaporized into a vapor at the exit of the
capillary as it entered the low pressure region.
[0847] To ensure no condensation of the liquid HMDSO past this
point, the gas stream (including the oxygen) was diverted to the
pumping line when it was not flowing into the interior of the tube
for processing via a Swagelok.RTM. 3-way valve. Once the tube was
installed, the vacuum pump valve was opened to the vessel holder 50
and the interior of the tube.
[0848] An Alcatel rotary vane vacuum pump and blower comprised the
vacuum pump system. The pumping system allowed the interior of the
tube to be reduced to pressure(s) of less than 200 mTorr while the
gaseous reactant or process gases were flowing at the indicated
rates.
[0849] Once the base vacuum level was achieved, the vessel holder
50 assembly was moved into the electrode 160 assembly. The gas
stream (oxygen and HMDSO vapor) was flowed into the brass gas
delivery port 110 (by adjusting the 3-way valve from the pumping
line to the gas delivery port 110). Pressure inside the tube was
approximately 300 mTorr as measured by a capacitance manometer
(MKS) installed on the pumping line near the valve that controlled
the vacuum. In addition to the tube pressure, the pressure inside
the gas delivery port 110 and gas system was also measured with the
thermocouple vacuum gauge that was connected to the gas system.
This pressure was typically less than 8 Torr.
[0850] Once the gas was flowing to the interior of the tube, the RF
power supply was turned on to its fixed power level. A ENI ACG-6
600 Watt RF power supply was used (at 13.56 MHz) at a fixed power
level of approximately 50 Watts. The output power was calibrated in
this and all following Protocols and Examples using a Bird
Corporation Model 43 RF Watt meter connected to the RF output of
the power supply during operation of the coating apparatus. The
following relationship was found between the dial setting on the
power supply and the output power: RF Power Out=55.times.Dial
Setting. In the priority applications to the present application, a
factor 100 was used, which was incorrect. The RF power supply was
connected to a COMDEL CPMX1000 auto match which matched the complex
impedance of the plasma (to be created in the tube) to the 50 ohm
output impedance of the ENI ACG-6 RF power supply. The forward
power was 50 Watts (or the specific amount reported for a
particular example) and the reflected power was 0 Watts so that the
applied power was delivered to the interior of the tube. The RF
power supply was controlled by a laboratory timer and the power on
time set to 5 seconds (or the specific time period reported for a
particular example). Upon initiation of the RF power, a uniform
plasma was established inside the interior of the tube. The plasma
was maintained for the entire 5 seconds until the RF power was
terminated by the timer. The plasma produced a silicon oxide
coating of approximately 20 nm thickness (or the specific thickness
reported in a particular example) on the interior of the tube
surface.
[0851] After coating, the gas flow was diverted back to the vacuum
line and the vacuum valve was closed. The vent valve was then
opened, returning the interior of the tube to atmospheric pressure
(approximately 760 Torr). The tube was then carefully removed from
the vessel holder 50 assembly (after moving the vessel holder 50
assembly out of the electrode 160 assembly).
Protocol for Forming COC Syringe Barrel
[0852] Syringe barrels for an extended barrel syringe ("COC syringe
barrels"), CV Holdings Part 11447, can be used, each having a 2.8
mL overall volume (excluding the Luer fitting) and a nominal 1 mL
delivery volume or plunger displacement, Luer adapter type, were
injection molded from Topas.RTM. 8007-04 cyclic olefin copolymer
(COC) resin, available from Hoechst AG, Frankfurt am Main, Germany,
having these dimensions: about 51 mm overall length, 8.6 mm inner
syringe barrel diameter and 1.27 mm wall thickness at the
cylindrical portion, with an integral 9.5 millimeter length needle
capillary Luer adapter molded on one end and two finger flanges
molded near the other end.
Protocol for Coating COC Syringe Barrel Interior with SiO.sub.x
[0853] An injection molded COC syringe barrel can be interior
coated with SiOx. The apparatus as shown in FIG. 1 was modified to
hold a COC syringe barrel with butt sealing at the base of the COC
syringe barrel. Additionally a cap was fabricated out of a
stainless steel Luer fitting and a polypropylene cap that sealed
the end of the COC syringe barrel (illustrated in FIG. 8), allowing
the interior of the COC syringe barrel to be evacuated.
[0854] The vessel holder 50 can be made from Delrin.RTM. with an
outside diameter of 1.75 inches (44 mm) and a height of 1.75 inches
(44 mm). The vessel holder 50 can be housed in a Delrin.RTM.
structure that allowed the device to move in and out of the
electrode 160.
[0855] The electrode 160 can be made from copper with a Delrin.RTM.
shield. The Delrin.RTM. shield can be conformal around the outside
of the copper electrode 160. The electrode 160 can be approximately
3 inches (76 mm) high (inside) and approximately 0.75 inches (19
mm) wide. The COC syringe barrel can be inserted into the vessel
holder 50, base sealing with an Viton.RTM. O-rings.
[0856] The COC syringe barrel can be carefully moved into the
sealing position over the extended (stationary) 1/8-inch (3-mm.)
diameter brass probe or counter electrode 108 and pushed against a
copper plasma screen. The copper plasma screen can be a perforated
copper foil material (K&S Engineering Part #LXMUW5 Copper mesh)
cut to fit the outside diameter of the COC syringe barrel and can
be held in place by a abutment surface 494 that acted as a stop for
the COC syringe barrel insertion. Two pieces of the copper mesh
were fit snugly around the brass probe or counter electrode 108
insuring good electrical contact.
[0857] The probe or counter electrode 108 extended approximately 20
mm into the interior of the COC syringe barrel and can be open at
its end. The brass probe or counter electrode 108 extended through
a Swagelok.RTM. fitting located at the bottom of the vessel holder
50, extending through the vessel holder 50 base structure. The
brass probe or counter electrode 108 can be grounded to the casing
of the RF matching network.
[0858] The gas delivery port 110 can be connected to a stainless
steel assembly comprised of Swagelok.RTM. fittings incorporating a
manual ball valve for venting, a thermocouple pressure gauge and a
bypass valve connected to the vacuum pumping line. In addition, the
gas system can be connected to the gas delivery port 110 allowing
the gaseous reactant or process gases, oxygen and
hexamethyldisiloxane (HMDSO) to be flowed through the gas delivery
port 110 (under process pressures) into the interior of the COC
syringe barrel.
[0859] The gas system can be comprised of a Aalborg.RTM. GFC17 mass
flow meter (Cole Parmer Part # EW-32661-34) for controllably
flowing oxygen at 90 sccm (or at the specific flow reported for a
particular example) into the process and a PEEK capillary (OD
1/16-inch (3-mm) ID 0.004 inches (0.1 mm)) of length 49.5 inches
(1.26 m) or other length as indicated in a particular example. The
PEEK capillary end can be inserted into liquid hexamethyldisiloxane
(Alfa Aesar.RTM. Part Number L16970, NMR Grade). The liquid HMDSO
can be pulled through the capillary due to the lower pressure in
the COC syringe barrel during processing. The HMDSO can be then
vaporized into a vapor at the exit of the capillary as it entered
the low pressure region.
[0860] To ensure no condensation of the liquid HMDSO past this
point, the gas stream (including the oxygen) can be diverted to the
pumping line when it was not flowing into the interior of the COC
syringe barrel for processing via a Swagelok.RTM. 3-way valve.
[0861] Once the COC syringe barrel was installed, the vacuum pump
valve can be opened to the vessel holder 50 and the interior of the
COC syringe barrel. An Alcatel rotary vane vacuum pump and blower
comprised the vacuum pump system. The pumping system allowed the
interior of the COC syringe barrel to be reduced to pressure(s) of
less than 150 mTorr while the gaseous reactant or process gases
were flowing at the indicated rates. A lower pumping pressure can
be achievable with the COC syringe barrel, as opposed to the tube,
because the COC syringe barrel has a much smaller internal
volume.
[0862] After the base vacuum level was achieved, the vessel holder
50 assembly was moved into the electrode 160 assembly. The gas
stream (oxygen and HMDSO vapor) was flowed into the brass gas
delivery port 110 (by adjusting the 3-way valve from the pumping
line to the gas delivery port 110). The pressure inside the COC
syringe barrel is approximately 200 mTorr as measured by a
capacitance manometer (MKS) installed on the pumping line near the
valve that controlled the vacuum. In addition to the COC syringe
barrel pressure, the pressure inside the gas delivery port 110 and
gas system is also measured with the thermocouple vacuum gauge that
is connected to the gas system. This pressure is typically less
than 8 Torr.
[0863] When the gas is flowing to the interior of the COC syringe
barrel, the RF power supply is turned on to its fixed power level.
A ENI ACG-6 600 Watt RF power supply is used (at 13.56 MHz) at a
fixed power level of approximately 30 Watts. The RF power supply is
connected to a COMDEL CPMX1000 auto match that matched the complex
impedance of the plasma (to be created in the COC syringe barrel)
to the 50 ohm output impedance of the ENI ACG-6 RF power supply.
The forward power is 30 Watts (or whatever value is reported in a
working example) and the reflected power is 0 Watts so that the
power is delivered to the interior of the COC syringe barrel. The
RF power supply is controlled by a laboratory timer and the power
on time set to 5 seconds (or the specific time period reported for
a particular example).
[0864] Upon initiation of the RF power, a uniform plasma is
established inside the interior of the COC syringe barrel. The
plasma is maintained for the entire 5 seconds (or other coating
time indicated in a specific example) until the RF power is
terminated by the timer. The plasma produced a silicon oxide
coating of approximately 20 nm thickness (or the thickness reported
in a specific example) on the interior of the COC syringe barrel
surface.
[0865] After coating, the gas flow is diverted back to the vacuum
line and the vacuum valve is closed. The vent valve is then opened,
returning the interior of the COC syringe barrel to atmospheric
pressure (approximately 760 Torr). The COC syringe barrel is then
carefully removed from the vessel holder 50 assembly (after moving
the vessel holder 50 assembly out of the electrode 160
assembly).
[0866] Protocol for Coating COC Syringe Barrel Interior with OMCTS
Lubricity Layer or Coating
[0867] COC syringe barrels as previously identified were interior
coated with a lubricity layer. The apparatus as shown in FIG. 1 is
modified to hold a COC syringe barrel with butt sealing at the base
of the COC syringe barrel. Additionally a cap is fabricated out of
a stainless steel Luer fitting and a polypropylene cap that sealed
the end of the COC syringe barrel (illustrated in FIG. 8). The
installation of a Buna-N O-ring onto the Luer fitting allowed a
vacuum tight seal, allowing the interior of the COC syringe barrel
to be evacuated.
[0868] The vessel holder 50 is made from Delrin.RTM. with an
outside diameter of 1.75 inches (44 mm) and a height of 1.75 inches
(44 mm). The vessel holder 50 is housed in a Delrin.RTM. structure
that allowed the device to move in and out of the electrode
160.
[0869] The electrode 160 is made from copper with a Delrin.RTM.
shield. The Delrin.RTM. shield is conformal around the outside of
the copper electrode 160. The electrode 160 measured approximately
3 inches (76 mm) high (inside) and is approximately 0.75 inches (19
mm) wide. The COC syringe barrel is inserted into the vessel holder
50, base sealing with Viton.RTM. O-rings around the bottom of the
finger flanges and lip of the COC syringe barrel.
[0870] The COC syringe barrel is carefully moved into the sealing
position over the extended (stationary) 1/8-inch (3-mm.) diameter
brass probe or counter electrode 108 and pushed against a copper
plasma screen. The copper plasma screen is a perforated copper foil
material (K&S Engineering Part #LXMUW5 Copper mesh) cut to fit
the outside diameter of the COC syringe barrel and is held in place
by a abutment surface 494 that acted as a stop for the COC syringe
barrel insertion. Two pieces of the copper mesh were fit snugly
around the brass probe or counter electrode 108 insuring good
electrical contact.
[0871] The probe or counter electrode 108 extended approximately 20
mm (unless otherwise indicated) into the interior of the COC
syringe barrel and is open at its end. The brass probe or counter
electrode 108 extended through a Swagelok.RTM. fitting located at
the bottom of the vessel holder 50, extending through the vessel
holder 50 base structure. The brass probe or counter electrode 108
is grounded to the casing of the RF matching network.
[0872] The gas delivery port 110 is connected to a stainless steel
assembly comprised of Swagelok.RTM. fittings incorporating a manual
ball valve for venting, a thermocouple pressure gauge and a bypass
valve connected to the vacuum pumping line. In addition, the gas
system is connected to the gas delivery port 110 allowing the
gaseous reactant or process gas, octamethylcyclotetrasiloxane
(OMCTS) (or the specific gaseous reactant or process gas reported
for a particular example) to be flowed through the gas delivery
port 110 (under process pressures) into the interior of the COC
syringe barrel.
[0873] The gas system is comprised of a commercially available
Horiba VC1310/SEF8240 OMCTS 10SC 4CR heated mass flow vaporization
system that heated the OMCTS to about 100.degree. C. The Horiba
system is connected to liquid octamethylcyclotetrasiloxane (Alfa
Aesar.RTM. Part Number A12540, 98%) through a 1/8-inch (3-mm)
outside diameter PFA tube with an inside diameter of 1/16 in (1.5
mm). The OMCTS flow rate is set to 1.25 sccm (or the specific
organosilicon precursor flow reported for a particular example). To
ensure no condensation of the vaporized OMCTS flow past this point,
the gas stream is diverted to the pumping line when it is not
flowing into the interior of the COC syringe barrel for processing
via a Swagelok.RTM. 3-way valve.
[0874] Once the COC syringe barrel is installed, the vacuum pump
valve is opened to the vessel holder 50 and the interior of the COC
syringe barrel. An Alcatel rotary vane vacuum pump and blower
comprise--the vacuum pump system. The pumping system allows the
interior of the COC syringe barrel to be reduced to pressure(s) of
less than 100 mTorr while the gaseous reactant or process gases is
flowing at the indicated rates. A lower pressure can be obtained in
this instance, compared to the tube and previous COC syringe barrel
examples, because the overall gaseous reactant or process gas flow
rate is lower in this instance.
[0875] Once the base vacuum level is achieved, the vessel holder 50
assembly is moved into the electrode 160 assembly. The gas stream
(OMCTS vapor) is flowed into the brass gas delivery port 110 (by
adjusting the 3-way valve from the pumping line to the gas delivery
port 110). Pressure inside the COC syringe barrel is approximately
140 mTorr as measured by a capacitance manometer (MKS) installed on
the pumping line near the valve that controlled the vacuum. In
addition to the COC syringe barrel pressure, the pressure inside
the gas delivery port 110 and gas system is also measured with the
thermocouple vacuum gauge that is connected to the gas system. This
pressure is typically less than 6 Torr.
[0876] Once the gas is flowing to the interior of the COC syringe
barrel, the RF power supply is turned on to its fixed power level.
A ENI ACG-6 600 Watt RF power supply is used (at 13.56 MHz) at a
fixed power level of approximately 6 Watts (or other power level
indicated in a specific example). The RF power supply is connected
to a COMDEL CPMX1000 auto match which matched the complex impedance
of the plasma (to be created in the COC syringe barrel) to the 50
ohm output impedance of the ENI ACG-6 RF power supply. The forward
power is 6 Watts and the reflected power is 0 Watts so that 6 Watts
of power (or a different power level delivered in a given example)
is delivered to the interior of the COC syringe barrel. The RF
power supply is controlled by a laboratory timer and the power on
time set to 10 seconds (or a different time stated in a given
example).
[0877] Upon initiation of the RF power, a uniform plasma is
established inside the interior of the COC syringe barrel. The
plasma is maintained for the entire coating time, until the RF
power is terminated by the timer. The plasma produced a lubricity
layer or coating on the interior of the COC syringe barrel
surface.
[0878] After coating, the gas flow is diverted back to the vacuum
line and the vacuum valve is closed. The vent valve is then opened,
returning the interior of the COC syringe barrel to atmospheric
pressure (approximately 760 Torr). The COC syringe barrel is then
carefully removed from the vessel holder 50 assembly (after moving
the vessel holder 50 assembly out of the electrode 160
assembly).
Protocol for Coating COC Syringe Barrel Interior with HMDSO
Coating
[0879] The Protocol for Coating COC Syringe Barrel Interior with
OMCTS Lubricity layer or coating is also used for applying an HMDSO
coating, except substituting HMDSO for OMCTS.
Protocol for Lubricity Testing
[0880] VII.B.1.a. The following materials is used in this test:
[0881] Commercial (BD Hypak.RTM. PRTC) glass prefillable syringes
with Luer-lok.RTM. tip) (ca 1 mL) [0882] COC syringe barrels made
according to the Protocol for Forming COC Syringe barrel; [0883]
Commercial plastic syringe plungers with elastomeric tips taken
from Becton Dickinson Product No. 306507 (obtained as saline
prefilled syringes); [0884] Normal saline solution (taken from the
Becton-Dickinson Product No. 306507 prefilled syringes); [0885]
Dillon Test Stand with an Advanced Force Gauge (Model AFG-50N)
[0886] Syringe holder and drain jig (fabricated to fit the Dillon
Test Stand)
[0887] VII.B.1.a. The following procedure is used in this test.
[0888] VII.B.1.a. The jig is installed on the Dillon Test Stand.
The platform probe movement is adjusted to 6 in/min (2.5 mm/sec)
and upper and lower stop locations were set. The stop locations
were verified using an empty syringe and barrel. The commercial
saline-filled syringes were labeled, the plungers were removed, and
the saline solution is drained via the open ends of the syringe
barrels for re-use. Extra plungers were obtained in the same manner
for use with the COC and glass barrels.
[0889] VII.B.1.a. Syringe plungers were inserted into the COC
syringe barrels so that the second horizontal molding point of each
plunger is even with the syringe barrel lip (about 10 mm from the
tip end). Using another syringe and needle assembly, the test
syringes were filled via the capillary end with 2-3 milliliters of
saline solution, with the capillary end uppermost. The sides of the
syringe were tapped to remove any large air bubbles at the
plunger/fluid interface and along the walls, and any air bubbles
were carefully pushed out of the syringe while maintaining the
plunger in its vertical orientation.
[0890] VII.B.1.a. Each filled syringe barrel/plunger assembly is
installed into the syringe jig. The test is initiated by pressing
the down switch on the test stand to advance the moving metal
hammer toward the plunger. When the moving metal hammer is within 5
mm of contacting the top of the plunger, the data button on the
Dillon module is repeatedly tapped to record the force at the time
of each data button depression, from before initial contact with
the syringe plunger until the plunger is stopped by contact with
the front wall of the syringe barrel.
[0891] VII.B.1.a. All benchmark and coated syringe barrels were run
with five replicates (using a new plunger and barrel for each
replicate).
[0892] VII.B.1.a. COC syringe barrels made according to the
Protocol for Forming COC Syringe barrel were coated with an OMCTS
lubricity layer or coating according to the Protocol for Coating
COC Syringe Barrel Interior with OMCTS Lubricity layer, except at a
power of 7.5 Watts, assembled and filled with saline, and tested as
described above in this Example for lubricity layers. The
polypropylene chamber used per the Protocol for Coating COC Syringe
Barrel Interior with OMCTS Lubricity layer or coating allowed the
OMCTS vapor (and oxygen, if added) to flow through the syringe
barrel and through the syringe capillary into the polypropylene
chamber (although a lubricity layer or coating can not be needed in
the capillary section of the syringe in this instance). Different
coating conditions were tested. All of the depositions were
completed on COC syringe barrels from the same production
batch.
[0893] VII.B.1.a. The samples were created by coating COC syringe
barrels according to the Protocol for Coating COC Syringe Barrel
Interior with OMCTS Lubricity layer. An alternative embodiment of
the technology herein, would apply the lubricity layer or coating
over another thin film coating, such as SiO.sub.x, for example
applied according to the Protocol for Coating COC Syringe barrel
Interior with SiO.sub.x.
[0894] Instead of the Dillon Test Stand and drain jig, a Genesis
Packaging Plunger Force Tester (Model SFT-01 Syringe Force Tester,
manufactured by Genesis Machinery, Lionville, Pa.) can also be used
following the manufacturer's instructions for measuring Fi and Fm.
The parameters that are used on the Genesis tester are:
[0895] Start: 10 mm
[0896] Speed: 100 mm/min
[0897] Range: 20
[0898] Units: Newtons
WORKING EXAMPLES
[0899] in addition to the Working Examples presented in EP 2 251
455 A2 which are also understood as Working Examples for the
present invention.
Examples A-D
[0900] Syringe samples were produced as follows. A COC 8007
extended barrel syringe was produced according to the Protocol for
Forming COC Syringe Barrel. An SiOx coating was applied to some of
the syringes according to the Protocol for Coating COC Syringe
Barrel Interior with SiOx. A lubricity coating was applied to the
SiOx coated syringes according to the Protocol for Coating COC
Syringe Barrel Interior with OMCTS Lubricity layer, modified as
follows. The OMCTS was supplied from a vaporizer, due to its low
volatility. Argon carrier gas was used. The process conditions were
set to the following: [0901] OMCTS--3 sccm [0902] Argon gas--65
sccm [0903] Power--6 watts [0904] Time--10 seconds
[0905] The coater was later determined to have a small leak while
producing the L2 samples identified in the Table, which resulted in
an estimated oxygen flow of 1.0 sccm. The L3 samples were produced
without introducing oxygen.
[0906] Several syringes were then tested for lubricity using a
Genesis Packaging Plunger Force Tester (Model SFT-01 Syringe Force
Tester, manufactured by Genesis Machinery, Lionville, Pa.)
according to the Protocol for Lubricity Testing. Both the
initiation force and maintenance forces (in Newtons) were noted
relative to an uncoated sample, and are reported in Table 1.
[0907] Syringes coated with silicon oil were included as a
reference since this is the current industry standard.
Examples E-H
[0908] Syringe samples were produced as follows. A COC 8007
extended barrel syringe was produced according to the Protocol for
Forming COC Syringe Barrel. An SiOx coating was applied to the
syringe barrels according to the Protocol for Coating COC Syringe
Barrel Interior with SiOx. A lubricity coating was applied to the
SiOx coated syringes according to the Protocol for Coating COC
Syringe Barrel Interior with OMCTS Lubricity layer, modified as
follows. The OMCTS was supplied from a vaporizer, due to its low
volatility. Argon carrier gas and oxygen were used where noted in
Table 2. The process conditions were set to the following, or as
indicated in Table 2: [0909] OMCTS--3 sccm (when used) [0910] Argon
gas--7.8 sccm (when used) [0911] Oxygen 0.38 sccm (when used)
[0912] Power--3 watts [0913] Power on time--10 seconds
[0914] Syringes E and F prepared under these conditions, Syringes G
prepared under these conditions except without a lubricity coating,
and Syringes H (a commercial syringe coated with silicon oil) were
then tested for lubricity using a Genesis Packaging Plunger Force
Tester according to the Protocol for Lubricity Testing. Both the
initiation force and maintenance forces (in Newtons) were noted
relative to an uncoated sample, and are reported in Table 2.
Syringes coated with silicon oil were included as a reference since
this is the current industry standard.
[0915] The lubricity results are shown in Table 2 (Initiation Force
and Maintenance Force), illustrating under these test conditions as
well that the lubricity coating on Syringes E and F markedly
improved their lubricity compared to Syringes G which lacked any
lubricity coating. The lubricity coating on Syringes E and F also
markedly improved their lubricity compared to Syringes H which
contained the standard lubricity coating in the industry.
[0916] Syringes E, F, and G were also tested to determine total
extractable silicon levels (representing extraction of the
organosilicon-based PECVD coatings) using an Inductively Coupled
Plasma-Mass Spectrometry (ICP-MS) analysis.
[0917] The silicon was extracted using saline water digestion. The
tip of each syringe plunger was covered with PTFE tape to prevent
extracting material from the elastomeric tip material, then
inserted into the syringe barrel base. The syringe barrel was
filled with two milliliters of 0.9% aqueous saline solution via a
hypodermic needle inserted through the Luer tip of the syringe.
This is an appropriate test for extractables because many prefilled
syringes are used to contain and deliver saline solution. The Luer
tip was plugged with a piece of PTFE beading of appropriate
diameter. The syringe was set into a PTFE test stand with the Luer
tip facing up and placed in an oven at 50.degree. C. for 72
hours.
[0918] Then, either a static or a dynamic mode was used 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 fluid in the syringe was decanted into
a vessel. According to the dynamic mode indicated in Table 2, the
Luer tip seal was removed and the plunger was depressed to push
fluid through the syringe barrel and expel the contents into a
vessel. In either case, the fluid obtained from each syringe barrel
was brought to a volume of 50 ml using 18.2M.OMEGA.*cm deionized
water and further diluted 2.times. to minimize sodium background
during analysis. The CVH barrels contained two milliliters and the
commercial barrels contained 2.32 milliliters.
[0919] Next, the fluid recovered from each syringe was tested for
extractable silicon using Inductively Coupled Plasma-Mass
Spectrometry (ICP-MS) Analysis. The instrument: used was a Perkin
Elmer Elan DRC II equipped with a Cetac ASX-520 autosampler. The
following ICP-MS conditions were employed: [0920] Nebulizer: Quartz
Meinhardt [0921] Spray Chamber: Cyclonic [0922] RF (radio
frequency) power: 1550 Watts [0923] Argon (Ar) Flow: 15.0 L/min
[0924] Auxiliary Ar Flow: 1.2 L/min [0925] Nebulizer Gas Flow: 0.88
L/min [0926] Integration time: 80 sec [0927] Scanning mode: Peak
hopping [0928] RPq (The RPq is a rejection parameter) for Cerium as
CeO (m/z 156): <2%
[0929] Aliquots from aqueous dilutions obtained from Syringes E, F,
and G were injected and analyzed for Si in concentration units of
micrograms per liter. The results of this test are shown in Table
2. While the results are not quantitative, they do indicate that
extractables from the lubricity coating are not clearly higher than
the extractables for the SiOx barrier layer only. Also, the static
mode produced far less extractables than the dynamic mode, which
was expected.
Examples I-K
[0930] Syringe samples I, J, and K, employing three different
lubricity coatings, were produced in the same manner as for
Examples E-H except as follows or as indicated in Table 3: [0931]
OMCTS--2.5 sccm [0932] Argon gas--7.6 sccm (when used) [0933]
Oxygen 0.38 sccm (when used) [0934] Power--3 watts [0935] Power on
time--10 seconds
[0936] Syringe I had a three-component coating employing OMCTS,
oxygen, and carrier gas. Syringe J had a two component coating
employing OMCTS and oxygen, but no carrier gas. Syringe K had a
one-component coating (OMCTS only). Syringes I, J, and K were then
tested for lubricity as described for Examples E-H.
[0937] The lubricity results are shown in Table 3 (Initiation Force
and Maintenance Force). Syringe I with a three-component coating
employing OMCTS, oxygen, and carrier gas provided the best
lubricity results for both initiation force and maintenance force.
Syringe J omitting the carrier gas yielded intermediate results.
Syringe K had a one-component coating (OMCTS only), and provided
the lowest lubricity. This example shows that the addition of both
a carrier gas and oxygen to the process gas improved lubricity
under the tested conditions.
Examples L-N
[0938] Examples I-K using an OMCTS precursor gas were repeated in
Examples L-N, except that HMDSO was used as the precursor in
Examples L-N. The results are shown in Table 3. The results show
that for the tested three-component, two-component, and
one-component lubricity coatings, the OMCTS coatings provided lower
resistance, thus better lubricity, than the HMDSO coatings,
demonstrating the value of OMCTS as the precursor gas for lubricity
coatings.
Examples O-V, W, X, Y
[0939] In these examples the surface roughness of the lubricity
coatings was correlated with lubricity performance.
[0940] OMCTS coatings were applied with previously described
equipment with the indicated specific process conditions (Table 5)
onto one milliliter COC 6013 molded syringe barrels. Plunger force
measurements (F.sub.i, F.sub.m) (Table 5) were performed with
previously described equipment under the same protocols. Scanning
electron spectroscopy (SEM) photomicrographs (Table 5, FIGS. 16 to
20) and atomic force microscopy (AFM) Root Mean Square (RMS) and
other roughness determinations (Tables 5 and 6) were made using the
procedures indicated below. Average RMS values are taken from three
different RMS readings on the surface. The plunger force tests, AFM
and SEM tests reported in table 5 were performed on different
samples due to the nature of the individual tests which prohibited
a performance of all tests on one sample.
[0941] Comparison of Fi/Fm to SEM photomicrograph to AFM Average
RMS values clearly indicates that lower plunger forces are realized
with non-continuous, rougher OMCTS plasma-coated surfaces (cf.
Samples O to Q vs. R to V; FIG. 18-20).
[0942] Further testing was carried out on sister samples Examples
W, X, and Y, respectively made under conditions similar to Example
Q, T, and V, to show the F.sub.i and F.sub.m values corresponding
to the AFM roughness data. Example W which has a higher surface
roughness (compare Example Q in FIG. 18, Table 5) has much lower
F.sub.i and F.sub.m friction values (Table 6) than Example X
(compare Example T in FIG. 19) D or Y. The F.sub.m test shown in
Table 6 was interrupted before reaching the measured value of
F.sub.m for Examples X and Y because the F.sub.m value was too
high.
SEM Procedure
[0943] SEM Sample Preparation: Each syringe sample was cut in half
along its length (to expose the interior surface). The top of the
syringe (Luer end) was cut off to make the sample smaller.
[0944] The sample was mounted onto the sample holder with
conductive graphite adhesive, then put into a Denton Desk IV SEM
Sample Preparation System, and a thin (approximately 50 .ANG.)
thick gold coating was sputtered onto the interior surface of the
syringe. The gold coating is required to eliminate charging of the
surface during measurement.
[0945] The sample was removed from the sputter system and mounted
onto the sample stage of a Jeol JSM 6390 SEM (Scanning Electron
Microscope). The sample was pumped down to at least
1.times.10.sup.-6 Torr in the sample compartment. Once the sample
reached the required vacuum level, the slit valve was opened and
the sample was moved into the analysis station.
[0946] The sample was imaged at a coarse resolution first, then
higher magnification images were accumulated. The SEM images
provided in the Figures are 5 .mu.m edge-to-edge (horizontal and
vertical).
AFM (Atomic Force Microscopy) Procedure.
[0947] AFM images were collected using a NanoScope III Dimension
3000 machine (Digital Instruments, Santa Barbara, Calif., USA). The
instrument was calibrated against a NIST traceable standard. Etched
silicon scanning probe microscopy (SPM) tips were used. Image
processing procedures involving auto-flattening, plane fitting or
convolution were employed. One 10 .mu.m.times.10 .mu.m area was
imaged. Roughness analyses were performed and were expressed in:
(1) Root-Mean-Square Roughness, RMS; (2) Mean Roughness, Ra; and
(3) Maximum Height (Peak-to-Valley), Rmax, all measured in nm (see
Table 5 and FIGS. 18 to 20). For the roughness analyses, each
sample was imaged over the 10 .mu.m.times.10 .mu.m area, followed
by three cross sections selected by the analyst to cut through
features in the 10 .mu.m.times.10 .mu.m images. The vertical depth
of the features was measures using the cross section tool. For each
cross section, a Root-Mean-Square Roughness (RMS) in nanmeters was
reported. These RMS values along with the average of the three
cross sections for each sample are listed in Table 5.
[0948] Additional analysis of the 10 .mu.m.times.10 .mu.m images
represented by FIGS. 18 to 20 (Examples Q, T and V) was carried
out. For this analysis three cross sections were extracted from
each image. The locations of the cross sections were selected by
the analyst to cut through features in the images. The vertical
depth of the features was measured using the cross section
tool.
[0949] The Digital Instruments Nanoscope III AFM/STM acquires and
stores 3-dimensional representations of surfaces in a digital
format. These surfaces can be analyzed in a variety of ways.
[0950] The Nanoscope III software can perform a roughness analysis
of any AFM or S.TM. image. The product of this analysis is a single
color page reproducing the selected image in top view. To the upper
right of the image is the "Image Statistics" box, which lists the
calculated characteristics of the whole image minus any areas
excluded by a stopband (a box with an X through it). Similar
additional statistics can be calculated for a selected portion of
the image and these are listed in the "Box Statistics" in the lower
right portion of the page. What follows is a description and
explanation of these statistics.
[0951] Image Statistics:
[0952] Z Range (R.sub.p): The difference between the highest and
lowest points in the image. The value is not corrected for tilt in
the plane of the image; therefore, plane fitting or flattening the
data will change the value.
[0953] Mean: The average of all of the Z values in the imaged area.
This value is not corrected for the tilt in the plane of the image;
therefore, plane fitting or flattening the data will change this
value.
[0954] RMS (R.sub.q): This is the standard deviation of the Z
values (or RMS roughness) in the image. It is calculated according
to the formula:
R.sub.q={.SIGMA.(Z.sub.1-Z.sub.avg)2/N}
[0955] where Zavg is the average Z value within the image; Z1 is
the current value of Z; and N is the number of points in the image.
This value is not corrected for tilt in the plane of the image;
therefore, plane fitting or flattening the data will change this
value.
[0956] Mean roughness (R.sub.a): This is the mean value of the
surface relative to the Center Plane and is calculated using the
formula:
R.sub.a=[1/(L.sub.xL.sub.y)].intg..sub.o.sup.Ly.intg..sub.o.sup.Lx{f(x,y-
)}dxdy
where f(x,y) is the surface relative to the Center plane, and
L.sub.x and L.sub.y are the dimensions of the surface.
[0957] Max height (R.sub.max): This is the difference in height
between the highest and lowest points of the surface relative to
the Mean Plane.
[0958] Surface area: (Optical calculation): This is the area of the
3-dimensional surface of the imaged area. It is calculated by
taking the sum of the areas of the triangles formed by 3 adjacent
data points throughout the image.
[0959] Surface area diff: (Optional calculation) This is the amount
that the Surface area is in excess of the imaged area. It is
expressed as a percentage and is calculated according to the
formula:
Surface area diff=100[(Surface area/S.sub.12)-1]
[0960] where S.sub.1 is the length (and width) of the scanned area
minus any areas excluded by stopbands.
[0961] Center Plane: A flat plane that is parallel to the Mean
Plane. The volumes enclosed by the image surface above and below
the center plane are equal.
[0962] Mean Plane: The image data has a minimum variance about this
flat plane. It results from a first order least squares fit on the
Z data.
Summary of Lubricity Measurements
[0963] Table 8 shows a summary of the above OMCTS coatings and
their Fi and Fm values. It has to be understood that the initial
lubricity coating work (C-K; roughness not known) was to identify
the lowest possible plunger force attainable. From subsequent
market input, it was determined that the lowest achievable plunger
force was not necessarily most desirable, for reasons explained in
the generic description (e.g. premature release). Thus, the PECVD
reaction parameters were varied to obtain a plunger force of
practical market use.
Example Z
Lubricity Coating Extractables
[0964] Total silicon extractables were measured using ICP-MS
analysis. The syringes were evaluated in both static and dynamic
situations. The following describes the test procedure: [0965]
Syringe filled with 2 ml of 0.9% saline solution [0966] Syringe
placed in a stand--stored at 50.degree. C. for 72 hours. [0967]
After 72 hours saline solution test for total silicon [0968] Total
silicon measure before and after saline solution expelled through
syringe.
[0969] The extractable Silicon Levels from a silicon oil coated
glass syringe and a Lubricity coated and SiO.sub.2 coated COC
syringe are shown in Table 7. Precision of the ICP-MS total silicon
measurement is +/-3%.
TABLE-US-00008 TABLE 1 PLUNGER SLIDING FORCE MEASUREMENTS OF OMCTS-
BASED PLASMA COATINGS MADE WITH CARRIER GAS Lubricity Lubricity
Lubricity Lubricity Carrier Layer or Coating OMCTS O2 Gas (Ar)
Coating Initiation Maintenance Coating coating Time Flow Rate Flow
Rate Flow Rate Power Force, F.sub.i Force, F.sub.m Example Type
Monomer (sec) (sccm) (sccm) (sccm) (Watts) (N, Kg.) (N, Kg.) A
Uncoated n/a n/a n/a n/a n/a n/a >11 N >11 N (Control) COC
>1.1 Kg. >1.1 Kg. B Silicon oil n/a n/a n/a n/a n/a n/a 8.2 N
6.3 N (Industry on COC 0.84 Kg. 0.64 Kg. Standard) C L3 OMCTS 10
sec 3 0 65 6 4.6 N 4.6 N (without Lubricity layer 0.47 Kg. 0.47 Kg.
Oxygen) or coating over SiO.sub.x on COC D L2 OMCTS 10 sec 3 1 65 6
4.8 N 3.5 N (with Lubricity layer 0.49 Kg. 0.36 Kg. Oxygen) or
coating over SiO.sub.x on COC
TABLE-US-00009 TABLE 2 OMCTS Lubricity Coatings (E and F) OMCTS
O.sub.2 Ar Initiation Maintenance ICPMS ICPMS Example (sccm) (sccm)
(sccm) Force, Fi (N) Force, Fm (N) (.mu.g./liter) Mode E 3.0 0.38
7.8 4.8 3.5 <5 static F 3.0 0.38 7.8 5.4 4.3 38 dynamic G (SiOx
only) n/a n/a n/a 13 11 <5 static H (silicon oil) n/a n/a n/a
8.2 6.3
TABLE-US-00010 TABLE 3 OMCTS Lubricity Coatings OMCTS O.sub.2 Ar
Initiation Maintenance Example (sccm) (sccm) (sccm) Force, Fi (N)
Force, Fm (N) I 2.5 0.38 7.6 5.1 4.4 J 2.5 0.38 -- 7.1 6.2 K 2.5 --
-- 8.2 7.2
TABLE-US-00011 TABLE 4 HMDSO Coatings HMDSO O.sub.2 Ar Initiation
Maintenance Example (sccm) (sccm) (sccm) Force, Fi (N) Force, Fm
(N) L 2.5 0.38 7.6 9 8.4 M 2.5 0.38 -- >11 >11 N 2.5 -- --
>11 >11
TABLE-US-00012 TABLE 5 SEM Dep. Micrograph OMCTS Ar/O.sub.2 Power
Time Plunger Force (5 micronAF AFM RMS Example (sccm) (sccm)
(Watts) (sec) Fi (lbs, Kg) Fm (lbs, Kg) Vertical) (nanometers) O
Baseline 2.0 10/0.38 3.5 10 4.66, 2.11 3.47, 1.57 OMCTS (ave) (ave)
P Lubricity FIG. 16 Q 19.6, 9.9, 9.4 (Average = 13.0) FIGS.
18A,18B, 18C R High Power 2.0 10/0.38 4.5 10 4.9, 2.2 7.6, 3.4 S
OMCTS FIG. 17 12.5, 8.4, 6.1 T Lubricity (Average = 6.3) FIG. 19A,
20B, 20C U No O.sub.2 2.0 10/0 3.4 10 4.9, 2.2 9.7, 4.4 OMCTS
(stopped) V Lubricity 1.9, 2.6, 3.0 (Average = 2.3) FIG. 20A, 20B,
20C
TABLE-US-00013 TABLE 6 Dep. Siloxane Power Time F.sub.i (lb.,
F.sub.m (lb., SiO.sub.x/Lub Coater Mode Feed Ar/O.sub.2 (W) (Sec.)
Kg.) Kg.) Example W SiO.sub.x: Auto-Tube Auto HMDSO 0 sccm Ar, 37 7
~ ~ SiOx/Baseline 52.5 in, 90 sccm O.sub.2 133.4 cm. OMCTS Lub
Lubricity: Auto-S same OMCTS, 10 sccm Ar 3.4 10 2.9, 1.3 3.3, 1.5
2.0 sccm 0.38 sccm O.sub.2 Example X SiO.sub.x: same same same same
37 7 ~ ~ SiOx/High Pwr OMCTS Lubricity: same same same same 4.5 10
5, 2.3 9.5, 4.3 Lub stopped Example Y SiOx: Auto-Tube same same 0
sccm Ar, 37 7 ~ ~ SiOx/No O.sub.2 90 sccm O.sub.2 OMCTS Lub
Lubricity: Auto-S same same 10 sccm Ar 3.4 10 5.6, 9.5,4.3 0 sccm
O.sub.2 stopped
TABLE-US-00014 TABLE 7 Silicon Extractables Comparison of Lubricity
Coatings Package Type Static (ug/L) Dynamic (ug/L) Cyclic Olefin
Syringe with CV 70 81 Holdings SiOCH Lubricity Coating Borocilicate
Glass Syringe with 825 835 silicone oil
TABLE-US-00015 TABLE 8 Summary Table of OMCTS coatings from Tables
1, 2, 3 and 5 OMCTS O.sub.2 Ar Dep Time Example (sccm) (sccm)
(sccm) Power (Watt) (sec) F.sub.i(lbs) F.sub.m(lbs) C 3.0 0.00 65 6
10 1.0 1.0 D 3.0 1.00 65 6 10 1.1 0.8 E 3.0 0.38 7.8 6 10 0.8 1.1 F
3.0 0.38 7.8 6 10 1.2 1.0 I 2.5 0.38 7.6 6 10 1.1 1.0 J 2.5 0.38
0.0 6 10 1.6 1.4 K 2.5 0.00 0.0 6 10 1.8 1.6 O 2.0 0.38 10 3.5 10
4,6 3.5 R 2.0 0.38 10 4.5 10 4.9 7.6 U 2.0 0.00 10 3.4 10 4.9
9.7(stop) W 2.0 0.38 10 3.4 10 2.9 3.3 X 2.0 0.38 10 4.5 10 5.0
9.5(stop) Y 2.0 0.00 10 3.4 10 5.6 9.5(stop)
[0970] While the invention has been illustrated and described in
detail in the drawings and foregoing description, such illustration
and description are to be considered illustrative or exemplary and
not restrictive; the invention is not limited to the disclosed
embodiments. Other variations to the disclosed embodiments can be
understood and effected by those skilled in the art and practising
the claimed invention, from a study of the drawings, the
disclosure, and the appended claims. In the claims, the word
"comprising" does not exclude other elements or steps, and the
indefinite article "a" or "an" does not exclude a plurality. The
mere fact that certain measures are recited in mutually different
dependent claims does not indicate that a combination of these
measures cannot be used to advantage. Any reference signs in the
claims should not be construed as limiting the scope.
* * * * *
References