U.S. patent application number 16/513765 was filed with the patent office on 2019-11-07 for container with low particulate emission and friction controlled dry sliding surface and methods for producing same.
This patent application is currently assigned to SCHOTT AG. The applicant listed for this patent is SCHOTT AG. Invention is credited to Matthias Bicker, Christian Helbig, Inka Henze, Robert Hormes, Manfred Lohmeyer, Franziska Riethmueller, Joerg Schuhmacher, Marten Walther.
Application Number | 20190336392 16/513765 |
Document ID | / |
Family ID | 50442365 |
Filed Date | 2019-11-07 |
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United States Patent
Application |
20190336392 |
Kind Code |
A1 |
Bicker; Matthias ; et
al. |
November 7, 2019 |
CONTAINER WITH LOW PARTICULATE EMISSION AND FRICTION CONTROLLED DRY
SLIDING SURFACE AND METHODS FOR PRODUCING SAME
Abstract
A container is provided that includes a container body with an
outer surface and an inner surface. The inner surface contains
silicon oxide and the silicon oxide containing inner surface is at
least partially modified with a fluorine containing compound. The
fluorine containing compound is chemically bonded to the silicon
oxide of the container body via at least one Si--O--Si bond.
Inventors: |
Bicker; Matthias; (Mainz,
DE) ; Henze; Inka; (Nieder-Olm, DE) ;
Schuhmacher; Joerg; (Kornwestheim, DE) ;
Riethmueller; Franziska; (Frankfurt am Main, DE) ;
Hormes; Robert; (Godach, CH) ; Helbig; Christian;
(St. Gallen, CH) ; Walther; Marten; (Alfeld,
DE) ; Lohmeyer; Manfred; (Nackenheim, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SCHOTT AG |
Mainz |
|
DE |
|
|
Assignee: |
SCHOTT AG
Mainz
DE
|
Family ID: |
50442365 |
Appl. No.: |
16/513765 |
Filed: |
July 17, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14250494 |
Apr 11, 2014 |
10398626 |
|
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16513765 |
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61847584 |
Jul 18, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
B32B 1/08 20130101; C03C
17/30 20130101; A61M 3/00 20130101; C08G 77/24 20130101; A61J 1/00
20130101; A61J 1/1468 20150501; C09D 183/12 20130101; B32B 1/02
20130101; A61M 1/0009 20130101; C09D 183/08 20130101; A61J 1/05
20130101; B65D 25/14 20130101 |
International
Class: |
A61J 1/14 20060101
A61J001/14; C09D 183/08 20060101 C09D183/08; A61J 1/05 20060101
A61J001/05; B65D 25/14 20060101 B65D025/14; C03C 17/30 20060101
C03C017/30; C09D 183/12 20060101 C09D183/12; A61M 3/00 20060101
A61M003/00; B32B 1/02 20060101 B32B001/02; A61M 1/00 20060101
A61M001/00; A61J 1/00 20060101 A61J001/00; B32B 1/08 20060101
B32B001/08 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 11, 2013 |
DE |
10 2013 103 676.7 |
Claims
1. A method for producing a container of low particulate emission,
comprising the steps of: providing a container body having an outer
surface and an inner surface, the inner surface comprising silicon
oxide; applying a mixture of an organic fluorine compound dissolved
in a solvent to at least a portion of the inner surface; and drying
the fluorine containing compound and crosslinking the fluorine
containing compound with the silicon oxide at the inner surface by
a condensation reaction.
2. The method of claim 1, wherein the fluorine containing compounds
crosslink with each other.
3. The method of claim 1, wherein the organic fluorine compound has
a concentration in a range from 0.01% to 1%.
4. The method of claim 1, wherein the organic fluorine compound has
a concentration in a range from 0.05% to 0.3%.
5. The method of claim 1, wherein the solvent comprises a fluorine
containing solvent comprising at least one compound selected from a
group consisting of Ethoxynonafluorobutane;
Methoxynonafluorobutane; Perfluorohexane; Hydrofluoroether; Solvay
Solexis HAS-110; Fluorinert FC-77; Perfluorosolv PFS-1; and
Perfluorosolv PFS-2.
6. The method of claim 1, wherein the crosslinking comprises
directly exposing the fluorine containing compound to a wet gas
atmosphere.
7. The method of claim 1, wherein the crosslinking comprises
exposing the fluorine containing compound to an acid solution.
8. The method of claim 1, wherein the crosslinking comprises
crosslinking at a temperature above 30.degree. C.
9. The method of claim 1, wherein the crosslinking comprises
crosslinking at a relative humidity in a range from 10% to 95%.
10. The method of claim 1, wherein the crosslinking comprises
crosslinking at a relative humidity in a range from 30% to 70%.
11. The method of claim 1, wherein the crosslinking comprises
crosslinking in air under the effect of atmospheric humidity from
the environment.
12. The method of claim 11, wherein the step of applying the
mixture comprises liquid coating using an ultrasonic atomizer or a
diving nozzle.
13. The method of claim 1, further comprising pretreating, at least
partially, the inner surface, wherein the pretreating comprises at
least one step selected from the group consisting of: thermally
pretreating at a temperature above 350.degree. C.; thermally
pretreating at a temperature above 400.degree. C.; thermally
pretreating at a temperature above 500.degree. C.; washing with a
sterile, low particulate water; wet-chemical pretreating using an
acidic solution; wet-chemical pretreating using an alkaline
solution; cleaning using ultrasound at a frequency in a range from
20 kHz to 2.5 MHz; cleaning using ultrasound at a frequency in a
range from 100 kHz to 2 MHz; drying; drying by blowing in air; and
drying in a continuous furnace.
14. The method of claim 1, further comprising, before applying the
mixture, the step of applying an intermediate layer on at least a
partial area of the inner surface, wherein the intermediate layer
comprises at least one feature or property selected from the group
consisting of: adhesion promotion; silicon oxide; a sol-gel-based
layer; at least one under-stoichiometric compound; at least one
over-stoichiometric oxide compound; doped with further compounds;
mixed oxide; a doped silicon oxide; a silicon oxide doped with an
oxide of elements Al, Mg, P, Ce, Zr, Ti, Ba, Sr, Nb, B, or with
magnesium fluoride.
15. The method of claim 1, further comprising, after crosslinking,
subjecting the inner surface to a posttreatment, at least
partially, wherein the posttreatment comprises at least one step
selected from the group consisting of: drying under ambient
conditions; drying in a furnace; post-cleaning in an ultrasonic
bath; post-cleaning using a solvent; post-cleaning using a fluorine
containing solvent; post-cleaning using the solvent in the mixture;
post-cleaning using water; and post-cleaning using water for
injection.
16. The method of claim 1, wherein the step of applying the mixture
comprises liquid coating using a process selected from the group
consisting of: spray coating; dip coating; strike-off coating;
wipe-on coating; flood coating; and flow coating.
17. The method of claim 1, wherein the step of applying the mixture
comprises: applying the mixture to only a partial surface area of
the inner surface such that at least one unmodified partial surface
remains.
18. The method of claim 17, further comprising bonding a different
material to the at least one unmodified partial surface.
19. The method of claim 17, further comprising applying an adhesive
material to the at least one unmodified partial surface.
20. The method of claim 17, wherein the step of providing the
container body comprises: providing a plastic body made of cyclic
olefin polymer (COP) or cyclic olefin copolymer (COC); and coating
the inner surface with a silicon oxide containing intermediate
layer.
21. The method of claim 20, further comprising applying an adhesion
promoting layer directly coupled to the plastic body before the
step of coating the inner surface with the intermediate layer.
22. The method of claim 1, wherein the fluorine containing compound
is an alkoxysilane compound, the alkoxysilane compound having a
structure as follows: ##STR00003## wherein ORe represents an alkoxy
group, wherein the backbone comprises a fluorine containing entity,
and wherein the linker includes a functional group selected from
the group consisting of at least one of a hydrolyzable group, an
amino group, at least one further silane group, an acrylate, and a
methacrylate group.
23. The method of claim 22, wherein the linker forms bonds between
molecules of the alkoxysilane compound.
24. The method of claim 22, wherein the linker forms crosslinks
between linkers of two or more neighboring fluorine containing
compounds in a condensation reaction.
25. The method of claim 22, wherein the fluorine containing
compound is chemically bonded to the silicon oxide via at least one
Si--O--Si bond.
26. The method of claim 1, wherein the fluorine containing compound
is chemically bonded to the silicon oxide via at least one
Si--O--Si bond.
27. A method for producing a container with low particulate
emission, comprising the steps of: providing a container body
having an outer surface and an inner surface, wherein the inner
surface contains silicon oxide; applying a mixture of an organic
fluorine compound dissolved in a solvent to at least a portion of
the inner surface of the container body, wherein the fluorine
containing compound is an alkoxysilane compound, wherein said
alkoxysilane compound has a structure as follows: ##STR00004##
wherein the linker comprises at least one hydrolyzable group,
and/or an amino group, and/or a carboxamide group --OC--NH--,
and/or at least one further silane group, and/or an acrylate or
methacrylate group, and wherein ORe represents an alkoxy group, and
wherein the backbone comprises a fluorine containing entity; drying
the fluorine containing compound and crosslinking the fluorine
containing compound with the silicon oxide at the inner surface of
the container body by a condensation reaction; and crosslinking the
fluorine containing compounds with each other via the linker.
28. The method of claim 27, wherein a fluorine containing solvent
is selected from a group consisting of Ethoxynonafluorobutane,
Methoxynonafluorobutane, Perfluorohexane, Hydrofluoroether, and
combinations thereof.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 14/250,494 filed Apr. 11, 2014, which claims the benefit of
U.S. Provisional Application 61/847,584 filed Jul. 18, 2013 and
claims benefit under 35 USC .sctn. 119(a) of German Application 10
2013 103 676.7 filed Apr. 11, 2013, the entire contents of each of
which are incorporated herein by reference.
BACKGROUND
1. Field of the Invention
[0002] The invention generally relates to containers and more
particularly to containers that are part of a pharmaceutical
packaging or of a medical device or a sterile packaging, such as
syringe, cartridge or cannula systems and pharmaceutical vials.
2. Description of Related Art
[0003] In pharmaceutical packaging, such as syringe, cartridge or
cannula systems and pharmaceutical vials, high demands are placed
on the friction properties of the inner surface of the packaging.
For example, the syringe plunger or the stopper of a vial should
slide over the inner surface of the syringe or vial with the lowest
possible friction. At the same time, as few particles or
particle-forming substances or migratable lubricating oils as
possible should be released from the inner surface of the packaging
into the pharmaceutical contents, i.e. a pharmaceutical drug, in
order to avoid contamination of the contents or an undesirable
interaction of particles with the drug molecules or other
components of the contents. For example, silicone oil-based
particles have been known to be potential triggers of protein
aggregation. Especially protein-based drug formulations may be very
sensitive to contamination and interactions with particles. The
term protein-based drug formulations refers to any liquid solutions
that contain biomolecules, for example aqueous or alcoholic
formulations. The biomolecules contained in the solution may
include peptides, protein fragments, proteins, e.g. in particular
specific species of proteins, such as monoclonal antibodies,
polyclonal antibodies, ligands, receptors, antigens, enzymes, which
have been produced naturally or recombinantly, and derivatives of
these biomolecules.
[0004] Moreover, it is desired that the properties in terms of
friction and particulate emission are maintained during long-term
storage.
[0005] In order to obtain a silicone free syringe, it has already
been proposed to coat the inner surface of the packaging with an
alternative lubricating oil consisting of a fluorinated chemical
compound. For example, U.S. Pat. No. 8,124,207 B2 proposes to apply
lubricating oil including a perfluoropolyether (PFPE) or a
functionalized perfluoropolyether to the surface of a
pharmaceutical article. The surface provided with this lubricating
oil is subjected to a flame plasma or an atmospheric plasma or to
ionizing radiation or to an energy source at atmospheric pressure,
and according to the teachings of this patent document it is in
this way only that the desired sliding properties are obtained.
That means, the desired sliding properties are only achieved by a
very complex process using multi-stage process steps. Furthermore,
what is suggested is not an oil-free solution, rather the silicone
oil is merely replaced by another lubricating oil. Even after
plasma curing, this perfluoropolyether-based lubricating oil
includes free lubricating oil which can migrate into the drug
solution, where it can lead to unwanted side effects. Moreover,
particles might even be formed in conjunction with this method and
the lubricating oil.
[0006] Further, U.S. Pat. No. 6,183,872 B1 and WO 2011/060047 A1
disclose the coating of surfaces with fluorinated chemical
compounds to achieve antireflective and stain-resistant properties.
Possible fields of application mentioned include the coating of
optical elements (lenses, displays, etc.), inter alia.
[0007] In US 2011/0313363 A1 a medical article is described, which
is initially provided with an organopolysiloxane-based layer. A
second layer is applied by plasma-assisted CVD, which includes any
of the following monomer groups: N-vinylpyrrolidone, vinyl acetate,
ethylene oxide, alkyl acrylate, alkyl methacrylate, acrylamide,
acrylic acid, and mixtures thereof. These layers reduce the
breakaway force and the number of particles emitted by only a
factor of about 13.4 as compared to silicone. Also, in US
2011/0313363 A1, the surface of the pharmaceutical packaging is
provided with silicone oils to reduce the frictional force.
However, a drawback thereof is that silicone oil molecules might
migrate from the surface into the active substance solution stored
in the packaging. That is because despite of overcoating the
silicone with a second polymeric layer, silicone oil might be
released from the layer system when subjected to mechanical or
thermal stress, and may migrate into the product.
SUMMARY
[0008] Therefore, an important object of the invention is to
provide a container which exhibits reduced particulate emission
from the inner surface of the container into the contents of the
container as compared to the prior art.
[0009] Another object of the present invention is to provide a
container which besides minimized particulate emission additionally
exhibits improved friction properties at the inner surface and
which can be manufactured cost-efficiently and with low
complexity.
[0010] Another important object of the present invention is to
provide a container in which additional lubricating oils such as
silicone oils can substantially or entirely dispensed with.
[0011] Moreover, a container should be provided, which has a
friction controlled surface of high storage stability, which is
stable in interaction with the drug solution.
[0012] Another object of the present invention is to provide a
container, whose properties in terms of friction and particulate
emission are maintained during long-term storage.
[0013] According to the invention, a container is provided which
comprises a container body with an outer surface and an inner
surface, wherein the inner surface contains silicon oxide and the
silicon oxide containing inner surface is modified with a fluorine
containing compound, at least partially, wherein the fluorine
containing compound is chemically bonded to the silicon oxide of
the container body via at least one Si--O--Si bond. In particular,
the chemical bond may be a chemical covalent bond.
[0014] In a preferred embodiment, the container is part of a
pharmaceutical packaging or a medical device or a sterile packaging
for storing a product, or of a sterile packaging for storing a
pharmaceutical product.
[0015] The fluorine containing compound is an alkoxysilane compound
of the following structure:
##STR00001##
[0016] "ORe" represents an organic radical in form of an alkoxy
group. The entity of the compound which is referred to as
"backbone" contains fluorine.
[0017] The linker or linker entity enables the molecules of the
fluorine containing compounds to form bonds with each other, i.e.
crosslinks. This increases the stability of the compound and
substantially reduces particulate emission from the modified inner
surface of the pharmaceutical packaging according to the
invention.
[0018] According to the invention, the alkoxysilane compound has
one or more of the following features:
a. the alkoxysilane compound contains a perfluoropolyether as the
backbone; b. the backbone comprises at least one (CF.sub.2).sub.3
chain; c. the backbone comprises a plurality of (CF.sub.2).sub.x
entities, and for all (CF.sub.2).sub.x entities x<8 is met; d.
the backbone comprises [(CF.sub.2).sub.xO].sub.n, with
3<n<1000, preferably 4<n<200, more preferably
5<n<100; e. the backbone comprises further branches in form
of linear and/or branched and/or cyclic structures; f. the
alkoxysilane compound comprises at least one CF.sub.3 end group; g.
the linker comprises at least one hydrolyzable group, and/or an
amino group, and/or a carboxamide group --OC--NH--, and/or at least
one further silane group, and/or an acrylate or methacrylate group,
and/or an alkyl group --C.sub.xH.sub.y.
[0019] To ensure low particulate emission, the silicon oxide
containing inner surface of the container, which is at least
partially modified with a fluorine containing compound has a
surface density of less than 2,000 particles/cm.sup.2 for any
particles of a diameter of .gtoreq.2 .mu.m. Alternatively or
additionally, in contact with an aqueous solution less than 10,000
particles of a diameter of .gtoreq.2 .mu.m per ml solution volume
will be released from the silicon oxide containing inner surface
modified with a fluorine containing compound into the aqueous
solution.
[0020] The container may further comprise an elastomeric stopper
which is frictionally engaged with the inner surface of the
container. In such an embodiment, the container is a syringe or a
pharmaceutical cartridge, for example.
[0021] The modified inner surface of the container has one or more
of the following features:
a. the contact angle to water is greater than 100.degree.,
preferably greater than 105.degree., more preferably greater than
110.degree.; b. the dynamic contact angle is greater than
110.degree. upon immersion and greater than 90.degree. upon
retraction, preferably greater than 115.degree. upon immersion and
greater than 105.degree. upon retraction; c. the roll-off angle is
in a range from 1.degree. to 30.degree., preferably in a range from
5.degree. to 20.degree., as measured for a droplet of 60 .mu.l; d.
the inner surface is oleophobic and/or protein-repellent; e. the
inner surface is oleophobic and hydrophobic.
[0022] In another embodiment, the modified container comprises a
syringe or cartridge system comprising a plastic body made of
cyclic olefin polymer (COP) or cyclic olefin copolymer (COC), and a
glass-like inner coating, for example a silicon oxide containing
intermediate layer to which the fluoroalkoxy silane compound is
chemically bonded, at least partially, by forming an Si--O--Si
bond. In a particular further embodiment, the coating comprises a
further adhesion promoting layer which is directly coupled to the
polymeric substrate of the syringe body.
[0023] Another feature of the container is that the friction
reducing properties of the silicon oxide containing inner surface
modified with a fluorine containing compound are maintained even
after accelerated storage in water or phosphate buffer of pH 7 at
storage conditions of 40.degree. C. and 28 days.
[0024] Further, the container has at least one of the following
material or substrate properties:
a. the container is made of glass of hydrolytic class 1 or 2; b.
the container is made of borosilicate glass; c. the container is a
glass body with low particulate surface of less than 2,000
particles/cm.sup.2 for any boron or tungsten or silicon containing
particles of a diameter of .gtoreq.2 .mu.m; d. the container is
made of cyclic olefin polymer (COP) or cyclic olefin copolymer
(COC); e. the container is a plastic body with a low particulate
surface of less than 2,000 particles/cm.sup.2 for any particles of
diameters .gtoreq.2 .mu.m; and f. the container is a container body
in form of a syringe body, cartridge body, or vial for medical
purposes.
[0025] In another embodiment of the invention, the container
comprises a container body which is modified with a fluorine
containing compound only on a partial surface area S.sub.1, with at
least one of the following features:
a. the container is not modified with a fluorine containing
compound on at least one other partial surface area S.sub.2; b. the
container is not modified with a fluorine containing compound on
two other spatially separated partial surface areas S.sub.2 and
S.sub.3; c. in the area of at least one non-modified partial
surface area the container is bonded to a different material; d. in
the area of at least one non-modified partial surface area an
adhesive material is applied.
[0026] For example, the adhesive material may be an adhesive, e.g.
an adhesive for medical applications, for example an adhesive that
is crosslinkable using electromagnetic radiation.
[0027] The invention also provides a method for producing a
container exhibiting low particulate emission. This method
comprises the steps of: providing a container body having an outer
surface and an inner surface, wherein the inner surface contains
silicon oxide; applying a mixture of an organic fluorine compound
dissolved in a solvent to at least a portion of the inner surface
of the container body; drying the fluorine containing compound and
crosslinking it with the silicon oxide containing inner surface of
the container body by a condensation reaction.
[0028] Another feature of the method is that the fluorine
containing compounds crosslink with each other.
[0029] The concentration of the organic fluorine compound used in
step b) is in a range from 0.01% to 1%, preferably in a range from
0.03% to 0.5%, more preferably in a range from 0.05% to 0.3%.
[0030] In step b) a fluorine containing solvent may be used which
contains at least one of the following compounds:
a. Ethoxynonafluorobutane; b. Methoxynonafluorobutane; c.
Perfluorohexane; d. Hydrofluoroether; e. Solvay Solexis HAS-110; f.
Fluorinert FC-77; g. Perfluorosolv PFS-1; and h. Perfluorosolv
PFS-2.
[0031] The crosslinking may be accomplished under the direct effect
of temperature and/or water, in particular in a wet gas atmosphere,
or under the effect of an aqueous solution, in particular an acid
solution.
[0032] The crosslinking is accomplished at a temperature above
30.degree. C. or at a relative humidity in a range from 10% to 95%,
more preferably in a range from 30% to 70%. For this purpose, the
coated pharmaceutical packaging is placed in a climate cabinet in
which the values of relative humidity and temperature can be
preset.
[0033] Alternatively, it is also possible that crosslinking is
accomplished in air, under the effect of atmospheric humidity from
the environment.
[0034] In the step of providing the container body, the inner
surface of the container may be pretreated, at least partially,
wherein the pretreating is performed by at least one of the steps
of:
a. thermal pretreatment at a temperature above 350.degree. C.,
preferably above 400.degree. C., more preferably above 500.degree.
C.; b. washing with a sterile, low particulate water; c.
wet-chemical pretreatment with an acidic or an alkaline solution;
d. cleaning according to any of the two preceding steps using
ultrasound at a frequency in a range from 20 kHz to 2.5 MHz,
preferably at a frequency in a range from 100 kHz to 2 MHz; e.
drying, preferably by blowing in air, or in a continuous
furnace.
[0035] Between the steps of providing the container body and of
applying a mixture, an intermediate layer may be applied in an
additional step al) upon at least a partial area of the inner
surface of the container body, wherein the intermediate layer
exhibits at least one of the following features:
a. the intermediate layer functions as an adhesion promoting layer;
b. the intermediate layer comprises silicon oxide; c. the
intermediate layer is a sol-gel-based layer; d. the intermediate
layer comprises at least one under-stoichiometric or
over-stoichiometric oxide compound; e. the intermediate layer is
doped with further compounds; f. the intermediate layer comprises a
mixed oxide, preferably a doped silicon oxide, more preferably a
silicon oxide doped with an oxide of elements Al, Mg, P, Ce, Zr,
Ti, Ba, Sr, Nb, B, or with magnesium fluoride.
[0036] To further improve the properties of the coating, the inner
surface of the container may additionally be posttreated after step
c), at least partially, wherein the posttreatment is performed by
at least one of the following steps:
a. drying under ambient conditions or in a furnace; b.
post-cleaning by means of an ultrasonic bath, and/or using a
solvent, and/or using a fluorine-containing solvent, and/or using
the same solvent as in step b), and/or using water, preferably
water for injection (WFI).
[0037] The applying of the mixture may be accomplished by liquid
coating, wherein the liquid coating is performed by any of the
following methods:
a. spray coating; b. dip coating; c. strike-off coating; d. wipe-on
coating; e. flood coating; f. flow coating.
[0038] In the spray coating method, liquid coating is performed
using a two-substance or a single-substance nozzle, preferably a
diving nozzle (i.e. a nozzle which dives into the container during
the spraying operation), or an ultrasonic atomizer.
[0039] The container of the invention is preferably used as a
syringe system with friction controlled surface for storing
pharmaceutical drug solutions, in particular protein-based and
antibody-based pharmaceutical drug formulations.
BRIEF DESCRIPTION OF THE DRAWINGS
[0040] The invention will now be described in more detail with
reference to the accompanying drawings and by way of exemplary
embodiments.
[0041] FIG. 1 shows values of static and sliding friction for a
glass syringe coated according to the invention;
[0042] FIG. 2 shows values of the contact angle to water for a
glass syringe coated according to the invention;
[0043] FIG. 3 shows the breakaway force at the inner surface for a
glass syringe coated according to the invention as a function of
storage time and storage medium;
[0044] FIG. 4 shows the sliding friction force at the inner surface
of a glass syringe coated according to the invention as a function
of storage time and storage medium;
[0045] FIG. 5a shows particle concentration for a glass syringe
coated according to the invention in comparison to a siliconized
glass syringe and an uncoated glass syringe;
[0046] FIG. 5b shows an enlarged detail of FIG. 5a;
[0047] FIG. 6 shows the contact angle to water for a glass syringe
coated according to the invention with and without thermal
pretreatment;
[0048] FIG. 7 shows the sliding friction for a glass syringe coated
according to the invention with and without thermal
pretreatment;
[0049] FIG. 8 is a Pareto analysis of a statistical experimental
design for target parameter "contact angle to water" after storage
with water for 28 days at 40.degree. C.;
[0050] FIG. 9 is a Pareto analysis of a statistical experimental
design for target parameter "contact angle to water" after storage
with a phosphate buffer for 28 days at 40.degree. C.;
[0051] FIG. 10 is a Pareto analysis of a statistical experimental
design for target parameter "sliding friction" after storage with
water for 28 days at 40.degree. C.;
[0052] FIG. 11 is a Pareto analysis of a statistical experimental
design for target parameter "sliding friction" after storage with a
phosphate buffer for 28 days at 40.degree. C.;
[0053] FIG. 12 shows the sliding friction force for glass syringes
coated according to the invention as a function of the coating
method;
[0054] FIG. 13 shows the breakaway force for glass syringes coated
according to the invention as a function of the coating method;
and
[0055] FIG. 14 shows a force-distance chart of glass syringes
coated with DC2634.
DETAILED DESCRIPTION
[0056] According to the invention a container is provided which in
particular is a syringe system or cartridge system for storing
and/or administering medical drugs in liquid form, or a
pharmaceutical vial for storing such drugs. Such a container
comprises a glass body having an outer surface and an inner
surface, and the latter has an at least partially modified surface.
The glass body comprises glass of hydrolytic class I or II.
[0057] Alternatively, the container may comprise a plastic body
preferably based on cyclic olefin polymer (COP) or cyclic olefin
copolymer (COC), which has an at least partially modified
glass-like coating on its inner surface.
[0058] Further, the container comprises an elastomeric stopper
which is frictionally engaged with the inner surface of the
container. Moreover, the container may comprise a closure, such as
an elastomeric tip cap.
[0059] The glass or glass-like surface has a content of silicon
oxide of more than 50%, preferably of more than 60%, and more
preferably of more than 65%.
[0060] The at least partial modification of the surface is
accomplished using a fluorine containing compound which is
chemically bonded to the silicon oxide containing inner surface via
Si--O--Si bonds, at least partially. The fluorine containing
compound applied to the surface is a monopodal fluorine containing
alkoxysilane compound. Chemical bonding to the glass is effected by
a condensation reaction.
[0061] An advantage of chemically binding the alkoxysilane compound
as compared to a substance that is only spray-deposited, such as
for example a spray-deposited perfluorinated polyether (PFPE) oil,
is increased stability of the coating and enhanced connection to
the substrate.
[0062] The alkoxysilane compound has the following basic
structure:
##STR00002##
[0063] The abbreviation "ORe" designates an alkoxy group.
[0064] The alkoxysilane compound has at least one of the following
features.
[0065] Because of the chemical bonding of the alkoxysilane to the
surface, the backbone of the alkoxysilane compound is aligned
towards the surface, with the result that the backbone remains
movable thereby improving the friction properties of the
surface.
[0066] The backbone contains fluorine. In particular, this backbone
may include perfluoropolyether.
[0067] Additionally, the fluorine containing backbone comprises at
least one (CF.sub.2).sub.3 chain, and optionally a plurality of
(CF.sub.2).sub.x entities, for all of which x<8 applies.
[0068] Also, the fluorine containing backbone may comprise
[(CF.sub.2).sub.xO].sub.n, with 3<n<1000, preferably with
4<n<200, more preferably with 5<n<100.
[0069] The backbone may additionally include further branches.
Moreover, it may include CF.sub.3 groups as further branches,
and/or linear, branched, and/or cyclic structures.
[0070] The backbone may be saturated or unsaturated.
[0071] The alkoxysilane compound may include at least one CF.sub.3
end group.
[0072] Preferably, the alkoxysilane compound comprises a
methoxysilane, so that the compound exhibits higher chemical
reactivity when compared to an ethoxysilane, for example.
[0073] Between the backbone and the alkoxy silane group, a linker
may be provided. The task of this linker is to crosslink two or
more neighboring alkoxysilane containing molecules with each other,
to thereby increase the stability of the coating applied to the
surface.
[0074] The linker includes at least one of the following
compounds:
a. a hydrolyzable group; b. an amino group; c. a carboxamide group
--OC--NH--; d. at least one further siloxane group; e. at least one
further silane group; f. an acrylate or methacrylate group; or g.
an alkyl group --C.sub.xH.sub.y.
[0075] An essential feature of the container or pharmaceutical
packaging according to the invention is reduced contamination of
the contents of the packaging due to minimized migration into and
minimized interaction of components of the modified inner surface
with the medical drugs. To avoid such contamination of the medical
drugs, the modified inner surface is substantially free of fluid or
mobile lubricating oils, at least until just before filling of the
syringe or vial or before placing the stopper, so that it forms a
dry sliding surface. The modified inner surface has not more than 5
kg/cm.sup.2, preferably not more than 0.5 .mu.g/cm.sup.2, more
preferably 0.005 .mu.g/cm.sup.2 mass of lubricating oil, normalized
to 1 cm.sup.2 of modified inner surface area.
[0076] Furthermore, the modified inner surface is substantially
free of polyorganosiloxane compounds, such as silicone oils. This
means that the surface does not include any polyorganosiloxane
compounds, such as polydimethylsiloxane compounds (PDMS). The
latter is defined by a maximum of 5 .mu.g/cm.sup.2, preferably a
maximum of 0.5 .mu.g/cm.sup.2, more preferably 0.005 .mu.g/cm.sup.2
mass of such compounds, normalized to 1 cm.sup.2 of modified inner
surface area.
[0077] In a first refinement, the container body is completely free
of polyorganosiloxane compounds on its entire inner surface. In a
second refinement, the container is completely free of
polyorganosiloxane compounds on those inner surface areas, which
are in direct contact with the product during storage.
[0078] In a third refinement, the container body is completely free
of polyorganosiloxane compounds on both its inner and outer
surfaces. In a fourth refinement, the entire container body is
completely free of polyorganosiloxane compounds. In a fifth
refinement, the entire container is completely free of
polyorganosiloxane compounds.
[0079] The absence of silicone oils on the modified surface
moreover reduces protein aggregation when compared to siliconized
syringe bodies. A further advantage that may arise is reduced
protein adsorption.
[0080] Furthermore, the alkoxysilane compound applied to the inner
surface of the container or pharmaceutical packaging according to
the invention is immobilized, at least substantially immobilized,
and in particular is not able to migrate. This is defined by
specifying that not more than 1%, preferably not more than 0.1%,
more preferably not more than 0.01%, and most preferably a maximum
of 10 ppm of the alkoxysilane compound is able to migrate from the
surface into a solvent or into an aqueous solution. Further, when
in contact with an aqueous solution having a volume V, not more
than 1000 ppb, preferably not more than 500 ppb, and most
preferably not more than 50 ppb of metal ions or metal oxide ions
or metal containing particles, e.g. tungsten containing ions, will
be released from the modified surface.
[0081] From particles formed during the manufacturing of glass,
such as silicon oxide particles or borate or metal containing
particles, not more than 10,000 particles per ml will be released
from the modified surface, those particles having a diameter of
.gtoreq.2 .mu.m.
[0082] In summary, from a measurement that has been performed using
a HYAC-Roco particle tester, the following distribution of the
number of particles migrated into an aqueous solution resulted as a
function of particle diameter:
a. less than 10,000 particles of a diameter of .gtoreq.2 .mu.m; b.
less than 3,000 particles of a diameter of .gtoreq.5 .mu.m; c. less
than 100 particles of a diameter of .gtoreq.10 .mu.m; d. less than
10 particles of a diameter of .gtoreq.25 .mu.m; and e. less than 5
particles of a diameter of .gtoreq.50 .mu.m.
[0083] Preferably, the following distribution of the number of
particles migrated into an aqueous solution results:
a. less than 1,000 particles of a diameter of .gtoreq.2 .mu.m; b.
less than 300 particles of a diameter of .gtoreq.5 .mu.m; c. less
than 50 particles of a diameter of .gtoreq.10 .mu.m; d. less than 8
particles of a diameter of .gtoreq.25 .mu.m; and e. less than 3
particles of a diameter of .gtoreq.50 .mu.m.
[0084] Based on 1 ml of aqueous solution, the following
distribution was measured:
a. less than 300 particles/ml of a diameter of .gtoreq.2 .mu.m; b.
less than 70 particles/ml of a diameter of .gtoreq.5 .mu.m; c. less
than 30 particles/ml of a diameter of .gtoreq.10 .mu.m; d. less
than 5 particles/ml of a diameter of .gtoreq.25 .mu.m; and e. less
than 2 particles/ml of a diameter of .gtoreq.50.
[0085] The friction properties of the modified surface will now be
characterized by a comparison to the static and sliding friction
forces resulting at a non-modified surface.
[0086] When compared to a non-modified surface, static and sliding
friction is reduced by 1 N, preferably by 5 N. The variance of
static and sliding friction is reduced by at least 0.5 N,
preferably by at least 1 N.
[0087] In the unfilled state, i.e. dry, the modified surface
exhibits a static friction below 20 N, preferably below 15 N, and
more preferably below 15 N. Sliding friction is less than 10 N,
preferably less than 8 N, and most preferably less than 4 N. The
variance of static and sliding friction is less than .+-.4 N,
preferably less than .+-.2 N, and more preferably less than .+-.1
N. These figures are also valid during the setting process of the
stopper after filling.
[0088] In the "wet" state, i.e. when filled with water, the
modified surface exhibits a static friction below 20 N, preferably
below 15 N, and more preferably below 10 N. Sliding friction is
less than 6 N, preferably less than 4 N, and more preferably less
than 3 N. The variance of static and sliding friction is less than
.+-.2 N, preferably less than .+-.1 N, and more preferably less
than .+-.0.5 N. These figures are also valid during injection of
the medical drug.
[0089] The specified values of resulting frictional forces were
preferably measured using a FluroTec stopper Westar RU, B2-40, at a
stroke speed of the plunger stopper of 100 mm/min, preferably with
an Instron measuring system. The needles preferably used for this
purpose were needles of size 27 G.times.1/2'' or size 29
G.times.1/2''.
[0090] Another potential source of contamination of the medical
drug is that the stopper of the packaging is frictionally engaged
with the modified inner surface, and therefore, when the stopper is
moved along the surface, particles are released from the surface
and migrate into and thereby contaminate the medical drugs.
[0091] The modified surface is distinguished by the feature that
after one or more strokes of the elastomeric stopper frictionally
engaged with the inner surface, not more than 2,000 particles per
cm.sup.2 surface area are released from the modified surface, those
particles having a diameter of .gtoreq.2 .mu.m. This feature is
preferably measured using a scanning electron microscope.
[0092] If another friction partner is provided between the modified
inner surface and the elastomeric stopper, for example an aqueous
solution or a buffering solution, not more than 2,000 particles per
cm.sup.2 surface area are released from the modified surface, those
particles having a diameter of .gtoreq.2 .mu.m. This feature is
preferably measured using a scanning electron microscope.
[0093] The thickness of the organic fluorine layer is in a range
from 0.1 nm to 40 nm, preferably in a range from 0.5 nm to 10 nm,
and more preferably in a range up to not more than 10 nm for a
monolayer.
[0094] Another parameter of interaction between the surface
modified according to the invention and water is the contact angle
to water. For the coating of the invention, this angle is greater
than 100.degree., preferably greater than 105.degree., and more
preferably greater than 110.degree..
[0095] The dynamic contact angle of the layer surface is
.gtoreq.110.degree. upon immersion (advancing angle), preferably
.gtoreq. 115.degree., and is .gtoreq.115.degree. upon retraction
(receding angle), preferably .gtoreq.105.degree..
[0096] For a droplet of 60 .mu.l volume, the roll-off angle of the
layer is in a range from 1.degree. to 30.degree., preferably in a
range from 5.degree. to 20.degree..
[0097] The glass body of the syringe comprises a cannula. When the
inner surface of the cannula is not coated, adhesion of a needle
glued to or staked in the cannula is increased. This is measured by
a needle pull-off test in which the needle pull-off force is
greater than 10 N, preferably greater than 22 N.
[0098] Since the outer surface of the container or pharmaceutical
packaging is not coated, this increases the sticking strength of an
adhesive label applied to the outer surface.
[0099] The invention also provides a method for producing a
container that exhibits low particulate emission.
[0100] In a first step, a container body is provided having an
outer surface and an inner surface. The inner surface contains
silicon oxide.
[0101] Coating according to the invention is accomplished by
applying a mixture of an organic fluorine compound dissolved in a
solvent on at least a portion of the inner surface of the container
body. The solvent used for this purpose contains fluorine and does
not have a detrimental effect on ozone (zero ozone depletion
potential).
[0102] The solvent or the diluted solution of the solvent and the
organic fluorine compound have a boiling point in a range from
30.degree. C. to 200.degree. C., preferably in a range from
40.degree. C. to 95.degree. C., and more preferably in a range from
50.degree. C. to 80.degree. C.
[0103] The concentration of the organic fluorine compound in the
solvent is in a range from 0.01% to 1%, preferably in a range from
0.03% to 0.5%, and more preferably in a range from 0.05% to
0.3%.
[0104] The solvent used for the method of the invention includes at
least one of the following compounds:
a. Ethoxynonafluorobutane (3M Novec HFE7200,
C.sub.4F.sub.9OC.sub.2H.sub.5); b. Methoxynonafluorobutane
(HFE-7100, C.sub.4F.sub.9OCH.sub.3 consisting of the two isomers
(CF.sub.3).sub.2CFCF.sub.2OCH.sub.3 and
CF.sub.3CF.sub.2CF.sub.2CF.sub.2OCH.sub.3; [0105] c.
Perfluorohexane; [0106] d. Hydrofluoroether; [0107] e. Solvay
Solexis HAS-110; [0108] f. Fluorinert FC-77; [0109] g.
Perfluorosolv PFS-1; or h. Perfluorosolv PFS-2.
[0110] In a further step, drying of the fluorine containing
compound and crosslinking with the silicon oxide containing inner
surface of the container body is accomplished by a condensation
reaction.
[0111] Crosslinking of the layer is accomplished in a wet gas
atmosphere or under direct exposure to water, to an aqueous
solution, or in particular by being exposed to an acidic
solution.
[0112] Relative humidity during the crosslinking of the layer is in
a range from 10% to 95%, preferably in a range from 30% to 70%.
[0113] It is also possible to accomplish crosslinking of the layer
by exposure to the atmospheric humidity from the environment.
[0114] During drying, in a temperature range between room
temperature and 250.degree. C., at least two volatile compounds
will evaporate from of the layer.
[0115] Furthermore, crosslinking of the layer may be accomplished
during a simultaneous sterilization process, e.g. ETO
sterilization.
[0116] In one embodiment, the solution applied to the inner surface
of the container or pharmaceutical packaging includes further
additives or crosslinking agents, for example crosslinking agents
which can be enabled by UV light or by heat.
[0117] In a further embodiment of the method, the glass or the
glass-like surface of the container or pharmaceutical packaging may
be pretreated prior to the actual coating. In this way, bound water
or organic compounds may be removed from the glass surface.
[0118] For the pretreatment at least one of the methods described
below is employed.
[0119] The glass is thermally pretreated at a temperature above
350.degree. C., preferably above 400.degree. C., and more
preferably above 500.degree. C.
[0120] The surface may be washed with sterile low particulate
water.
[0121] The surface may be subjected to a wet-chemical pretreatment
using an acidic or alkaline solution.
[0122] Additionally, the two latter pretreatment methods may be
performed in an ultrasonic bath. The ultrasound employed has a
frequency in a range from 20 kHz to 2.5 MHz, preferably in a range
from 100 kHz to 2 MHz.
[0123] Following the pretreatment by any of the methods described
above, drying of the surface is effected, preferably by blown-in
air, or in a continuous furnace.
[0124] It could be demonstrated that such a pretreatment
significantly increases the storage stability of the coating, which
will be explained in more detail below, in conjunction with the
description of exemplary embodiments.
[0125] The pretreatment of the glass or glass-like surface leads to
a removal of the water skin and of organic substances on the
surface, wherein the contact angle to water prior to coating is
less than 50.degree., preferably less than 20.degree..
[0126] In a further step of the inventive method, once the
container has been provided, an intermediate layer is applied to
the surface to enhance stability of the coating.
[0127] This intermediate layer may serve as an adhesion promoting
layer. It may include silicon oxide. It is also possible that the
intermediate layer is a sol-gel-based layer. Additionally or
alternatively, the intermediate layer may include at least one
under-stoichiometric or over-stoichiometric oxide compound.
Moreover, this intermediate layer may be doped with further
compounds.
[0128] In one preferred embodiment, the intermediate layer
comprises a mixed oxide, preferably a doped silicon oxide. In a
preferred embodiment, the silicon oxide is doped with an oxide of
the following elements: aluminum, magnesium, phosphorus, cerium,
zirconium, titanium, barium, strontium, niobium, boron. The silicon
oxide may also be doped with magnesium fluoride.
[0129] In another embodiment of the inventive method, the coating
is posttreated in a final step by post-cleaning the layer after it
has been dried under ambient conditions or in a furnace.
[0130] This post-cleaning may be performed in an ultrasonic bath.
In this case a solvent may be used which may include fluorine. The
solvent may be the same as that used for the coating. It is also
possible to use water, e.g. water for injection (WFI), for the
post-cleaning.
[0131] The actual deposition of the layer is accomplished by liquid
coating. Techniques of liquid coating that may be employed include
spray coating, dip coating, strike-off coating, wipe-on coating,
flood coating, or flow coating.
[0132] In one preferred embodiment, spray coating is performed
using a two-substance or a single-substance nozzle, e.g. an
ultrasonic atomizer.
[0133] A homogeneous and local coating in the interior of a syringe
is in particular achieved by using a diving nozzle.
[0134] The spray volume used for spray coating ranges from 0.1
.mu.l to 500 .mu.l, preferably from 3 .mu.l to 150 .mu.l, and more
preferably from 20 .mu.l to 100 .mu.l.
[0135] When using a two-substance nozzle, the employed spray
pressure ranges from 0.1 bar to 5 bar, preferably from 0.2 bar to
2.5 bar, and more preferably from 0.5 bar to 1.5 bar. The gas flow,
when using a two-substance nozzle, is from 0.1 to 50 l/min,
preferably from 0.5 to 20 l/min, and more preferably from 2 to 5
l/min.
[0136] The spray rate in the spraying process for applying the
coating is from 0.01 .mu.l/s to 100 .mu.l/s, preferably from 25
.mu.l/s to 100 .mu.l/s. With the latter spray rate a spraying time
from 0.5 s to 4 s will result.
[0137] Given the very short spraying time, high productivity is
achieved in the production process according to the invention.
[0138] If a diving nozzle is employed, it will have an aperture
diameter in a range from 0.1 mm to 1 mm.
[0139] The diving depth of the nozzle is in a range from 10% to
95%, preferably in a range from 30% to 90%, and more preferably in
a range from 45% to 85% with respect to the height of the syringe
or cartridge cylinder or to the height of the vial cylinder or of
the ampoule.
[0140] The spray nozzle may be introduced into the interior of the
pharmaceutical packaging to be coated either vertically from above
or from below, or horizontally.
[0141] For spray-coating a solution is used which has a kinematic
viscosity, as measured at room temperature and atmospheric
pressure, in a range from 0.01 to 10,000 centistokes, preferably in
a range from 0.03 to 100 centistokes, more preferably in a range
from 0.05 to 20 centistokes, and most preferably in a range from
0.1 to 2 centistokes.
[0142] In another embodiment of the method according to the
invention, a staked needle syringe (i.e. a syringe with a glued-in
needle) is coated by applying the coating only when the needle has
already been introduced into the cannula. It has been found that
with this approach, the glue bond of the needle and in particular
the pull-off force of the needle are not adversely affected by
spray-coating with the solution.
[0143] An syringe system coated according to the invention is used
for storing pharmaceutical drug solutions, especially protein-based
pharmaceutical drug formulations. By virtue of the inventive
coating, protein adsorption, protein aggregation, and protein
denaturation are reduced as compared to a conventional silicone
containing syringe. This is especially true in the case that the
pharmaceutical drug includes biomolecules that are intolerant or
unstable to silicone oil.
[0144] According to the invention, the container described above
may be used for storing a medical solution. In particular the
container with modified glass surface may be used for storing
solutions that include protein-based active substances and/or
surfactants, such as polysorbate, e.g. Tween20 or Tween80, or
Pluronics, and/or buffered or unbuffered drug solutions, and/or
formulations with acidic or neutral or alkaline pH, and/or
solutions of a formulation including sugar or sugar alcohol.
Furthermore, the invention also comprises the use for storing drug
solutions for example in pre-filled syringes or cartridges, e.g. in
auto-injectors, or medical devices, which include medical drug
solutions with the following ingredients: aqueous or alcoholic
formulations, biomolecules, such as peptides, protein fragments,
proteins, such as specific monoclonal antibodies, polyclonal
antibodies, ligands, receptors, antigens, enzymes, which have been
produced naturally or recombinantly, and derivatives of such
biomolecules. Specific drug proteins include antibodies (e.g.
Remicade and ReoPro from Centocor; Herceptin from Genentech;
Mylotarg from Wyeth; Synagis from MedImmune), enzymes (e.g.
Pulmozyme from Genentech; Cerezyme from Genzyme), recombinant
hormones (e.g. Protropin from Genentech; Novolin from ZymoGenetics;
Humulin from Lilly), recombinant interferons (e.g. Actimmune from
InterMune Pharmaceutical; Avonex from Biogenldec; Betaseron from
Chiron; Infergen from Amgen; Intron A from Schering-Plough; Roferon
from Hoffman-La Roche), recombinant blood factors (e.g. TNKase from
Genentech; Retavase from Centocor; ReFacto from Genetics Institute;
Kogenate from Bayer), and recombinant erythropoietin (e.g. Epogen
from Amgen; Procrit from J&J), and furthermore also
recombinantly manufactured fusion proteins (e.g. Orencia/Abatacept
from BMS), and vaccines (e.g. Engerix-B from GSK; Recombivax HB
from Merck & Co.). Further, this layer may also be used for
other biomolecular applications, e.g. nucleic acids,
polynucleotides, such as DNA, RNA, pDNA, oligonucleotides,
protein/nucleic acid complexes, and for iron-sucrose-containing
formulation constituents, such as iron-sucrose complexes, and
furthermore proteins with an amino-terminal .gamma.-carboxyglutamic
acid (Gla) domain with 9 to 12 Gla residues, such as a vitamin
K-dependent coagulation zymogen protein or an activated form
thereof, from the group comprising prothrombin, Factor VII, Factor
IX, Factor X, and protein C, e.g. a recombinant human factor VII
(Novo Nordisk).
[0145] Below, some embodiments of the container or pharmaceutical
packaging of the invention will be described.
[0146] In a first embodiment, the pharmaceutical packaging of the
invention is a glass syringe made of borosilicate glass. Such a
glass is, for example, commercially available from the Applicant as
pharmaceutical glass tubing under the trade name FIOLAX. The
syringe is of the 1 ml long size and has a staked needle of the 27
G.times.1/2'' type.
[0147] The glass syringe is first cleaned with water for injection
(WFI) and is then cleaned for 10 minutes in an ultrasonic bath
using solvent HFE7200. For the subsequent coating of the inner
surface of the syringe, one of the commercially available coatings
Daikin AES4-E, Daikin DSX ("OPTOOL"), or Dow Corning 2634 is used.
Each of these three coatings comprises a perfluoropolyether silane.
By means of solvent HFE7200 the employed perfluoropolyether silane
is diluted to a concentration of 0.1% and is stirred with a
magnetic stirrer.
[0148] The interior of the glass syringe is flooded with the
diluted solution. After a contact time of 3 minutes, excess coating
solution is removed from the syringe. Then the syringe is dried in
air, so that the solvent evaporates. In a next step, the coatings
on the inner surfaces of the syringes are cured in a climate
cabinet at a temperature of 50.degree. C. and relative humidity of
50% for one hour. Finally, the syringes including the post-cured
coating are post-cleaned in an ultrasonic bath using HFE7200.
[0149] FIG. 1 shows measured values of the breakaway force and
gliding friction force, that were determined using a Flurotec
Westar RU B2-40 stopper, both for unfilled syringes ("dry") and for
syringes filled with water ("wet"), with a speed of 100 mm/min. A
glass syringe with uncoated inner surface serves as a reference.
The measurements were performed for each of the coatings mentioned
above. The measurements indicate a significant reduction of the
values of static and sliding friction. Also, the variance of these
values is significantly reduced. For example, in the case of
unfilled syringes, sliding friction was reduced to less than
one-fifth of the reference value.
[0150] FIG. 2 shows measurements of the contact angle to water. In
case of glass syringes with the inner surface coated, the contact
angle to water is in a range from 115.degree. to 120.degree. for
all of the three coatings, while it is only about 25.degree. for
the uncoated reference sample.
[0151] For the coatings Daikin DSX ("OPTOOL") and Dow Corning 2634,
it was examined to what extent the friction values change as a
function of storage period and storage medium of the syringes. For
this purpose, a first number of the coated syringes and uncoated
reference syringes was filled with water, and a second number with
phosphate buffer of pH 7, and stored at a temperature of 40.degree.
C. in an accelerated test.
[0152] FIG. 3 shows the breakaway force of the samples as a
function of storage time at a temperature of 40.degree. C. and
storage medium. For each of the two storage media, namely water and
a phosphate buffer solution of pH 7 (PBS, pH 7), the breakaway
force was measured before storage, after a storage period of 7
days, and after a storage period of 28 days. As can be seen from
FIG. 3, a sustained reduction of the breakaway force of the filled
syringes is achieved with the inventive coating.
[0153] FIG. 4 shows the sliding friction of the samples as a
function of storage time and storage medium. The sliding friction
was measured before storage with water, and for each of the two
storage media (water and phosphate buffer) the sliding friction was
measured in an accelerated test at a temperature of 40.degree. C.
after a storage period of 7 days and after a storage period of 28
days.
[0154] The measurements reveal a significant enhancement of storage
stability of the syringe samples coated at the inner surface, both
for water and for a phosphate buffer, when compared to an uncoated
sample. FIG. 3 and FIG. 4 show that the low values of static and
sliding friction of the coated syringe samples remain largely
stable even over a long-term storage period.
[0155] In further measurements series, the glass syringes coated
according to the invention with perfluoropolyether silane (Daikin
DSX) were compared with glass syringes that were siliconized by
spray-coating after a conventional manufacturing process with
WFI.
[0156] FIG. 5a shows the number of particles in an aqueous solution
for siliconized glass syringes and glass syringes coated with
perfluoropolyether silane according to the invention. Uncoated
syringes serve as a reference. FIG. 5a shows the entire measured
distribution of particle sizes of the three syringes. FIG. 5b is an
enlarged detail of FIG. 5a to make visible even the extremely low
measured values of the syringe coated according to the
invention.
[0157] The illustrated measurement results show that by coating the
glass syringes with perfluoropolyether silane, a significant
reduction of the invisible particles that are released into an
aqueous solution is achieved, when compared to a siliconized
syringe and an uncoated syringe. In particular, by virtue of the
coating particulate emission of small invisible particles with
diameters of 2 .mu.m and 5 .mu.m is reduced by more than a factor
of 50.
[0158] Thus, the glass syringes coated according to the invention
represent a significant improvement in terms of particulate
emission over conventional siliconized syringes.
[0159] In a second exemplary embodiment, the pharmaceutical
packaging according to the invention is again a glass syringe made
of borosilicate glass. The syringe is of the 1 ml long size and has
a staked needle of the 27 G.times.1/2'' type.
[0160] In a subsequent step, the syringes are thermally pretreated
at 550.degree. C. for 30 minutes, preferably under air.
[0161] For the subsequent coating of the inner surface of the
syringe, the commercially available perfluoropolyether silane
Daikin DSX ("OPTOOL") is used.
[0162] By means of solvent HFE7200, the employed perfluoropolyether
silane is diluted to a concentration of 0.1% and is stirred with a
magnetic stirrer.
[0163] The interior of the glass syringe is flooded with the
diluted solution. After a contact time of 3 minutes, excess coating
solution is removed from the syringe. Then, the syringe is dried in
air, so that the solvent evaporates.
[0164] In a next step, the coatings on the inner surfaces of the
syringes are cured in a climate cabinet at temperatures from
20.degree. C. to 70.degree. C. and a relative humidity from 30% to
90% for 0.5 to 72 hours, as a posttreatment.
[0165] Then, the syringes with the posttreated coating are
post-cleaned in an ultrasonic bath using HFE7200.
[0166] With a statistical experimental design, a screening
experimental design was performed using the parameters thermal
pretreatment and the three posttreatment parameters temperature,
relative humidity, and duration of posttreatment.
[0167] Summary of Parameters Variations of Samples 1-9 and 10-18 of
FIG. 6 and FIG. 7:
TABLE-US-00001 sample # T (.degree. C.) rel. humidity (%) t (h) 1
45 60 36.3 2 20 90 0.5 3 20 30 72 4 70 90 0.5 5 70 30 72 6 20 90 72
7 70 30 0.5 8 70 90 72 9 20 30 0.5 10 20 30 0.5 11 70 30 0.5 12 70
30 72 13 20 90 0.5 14 20 90 72 15 70 90 0.5 16 20 30 72 17 70 90 72
18 45 60 36.3
[0168] From the thermally pretreated and from the not thermally
pretreated syringes, a first number of the samples was filled with
water, and a second number with a phosphate buffer solution of pH 7
(PBS, pH 7), and stored in an accelerated test at a temperature of
60.degree. C.
[0169] FIG. 6 shows results of measurements on these samples of the
contact angle to water. The storage period was 28 days in each
case.
[0170] Furthermore, sliding friction values of the pretreated and
not pretreated glass syringes were measured and compared. The
results of these measurements are shown in FIG. 7. Sliding friction
was measured using a FluroTec Westar RU B2-40 stopper. The syringes
were filled with water and phosphate buffer solution of pH 7,
respectively, and stored as in the example of FIG. 6. The
measurements were performed with a speed of 100 mm/min.
[0171] As can be seen from the measured values of FIG. 7, a thermal
pretreatment of the glass syringes prior to being coated with a
perfluoropolyether silane leads to a significant increase in the
contact angle to water, even after storage in water or in a
phosphate buffer. That means, the coatings on thermally pretreated
glass syringes exhibit a much better storage stability when
compared to similar coatings on glass syringes that had not been
thermally pretreated.
[0172] Moreover, a thermal pretreatment of the glass syringes prior
to being coated with a perfluoropolyether silane results in a
significant reduction of the sliding friction values when compared
to not thermally pretreated glass syringes, even after storage in
water or phosphate buffer. This proves the enhanced stability of
the coatings on thermally pretreated glass syringes. From the
measured values shown in FIG. 7 it can be concluded that among the
thermally pretreated glass syringes parameter variations 16 and 17
represent an optimum, since in these two cases sliding friction
only slightly increases after having been stored.
[0173] These conclusions as to a substantial stability improvement
of the coating are proved by the Pareto analyses of the statistical
experimental design shown in FIGS. 8 and 9.
[0174] FIG. 8 shows the results of a Pareto analysis of the
statistical experimental design for target parameter "contact angle
to water" after a storage period of 28 days when filling the glass
syringes with water at 60.degree. C.
[0175] FIG. 9 shows the results of a Pareto analysis of the
statistical experimental design for target parameter "contact angle
to water" after a storage period of 28 days when filling the glass
syringes with a phosphate buffer of pH 7 at 60.degree. C.
[0176] FIGS. 8 and 9 show that a thermal pretreatment of the glass
syringes prior to being coated statistically significantly
increases the contact angle to water measured after a storage
period of 28 days with water or with a phosphate buffer at
60.degree. C. when compared to glass syringes that were not
thermally pretreated. FIGS. 8 and 9 furthermore show that the
parameter "thermal pretreatment" is the stronger influencing factor
when compared to posttreatment parameters temperature, relative
humidity and duration of posttreatment.
[0177] FIG. 10 shows the results of a Pareto analysis of the
statistical experimental design for target parameter "sliding
friction" after a storage period of 28 days when filling the glass
syringes with water at 60.degree. C.
[0178] FIG. 11 shows the results of a Pareto analysis of the
statistical experimental design for target parameter "sliding
friction" after a storage period of 28 days when filling the glass
syringes with a phosphate buffer of pH 7 at 60.degree. C.
[0179] FIGS. 10 and 11 show that due to the thermal pretreatment of
the glass syringes prior to being coated, the sliding friction
after storage with water or with a phosphate buffer is
statistically significantly lower than without thermal
pretreatment. FIGS. 10 and 11 furthermore show that the parameter
"thermal pretreatment" is the stronger influencing factor when
compared to posttreatment parameters temperature, relative humidity
and duration of posttreatment.
[0180] In a third exemplary embodiment, the pharmaceutical
packaging of the invention is again a glass syringe made of
borosilicate glass, e.g. of FIOLAX. Again, it is of the 1 ml long
size with staked needle (27 G.times.1/2''). First, the syringe is
cleaned with WFI.
[0181] For the coating according to the invention, the
perfluoropolyether silane Daikin DSX ("OPTOOL") is diluted to a
concentration of 0.1% using solvent HFE7200, and is stirred with a
magnetic stirrer.
[0182] Then, a two-substance nozzle (5 mm.times.90 mm, orifice
diameter 0.25 mm) is introduced into the glass syringe from above,
as a diving nozzle, over a travel distance of 40 mm. The inner
surface of the glass syringe is spray-coated with the diluted
solution in a dynamic spraying process. During this process, the
spraying nozzle is retracted from the syringe body over the travel
distance of 40 mm with a travel speed of 20 mm/s. The spraying
volume is 50 .mu.l. The spraying pressure is 0.5 bar, the gas flow
is 2.8 l/min.
[0183] In a next step, the coating on the syringe is cured in a
climate cabinet for a period of one hour, at a temperature of
50.degree. C. and a relative humidity of 50%.
[0184] For the syringes coated in this manner, values of static and
sliding friction were measured. For this purpose, a number of the
syringes was filled with water and another number was filled with a
phosphate buffer of pH 7 and stored in an accelerated test at a
temperature of 40.degree. C., for a period of 28 days. The values
of static and sliding friction were measured using a FluroTec
Westar RU B2-40 stopper.
[0185] FIG. 12 shows the values of static and sliding friction for
unfilled ("dry") and filled ("wet") syringes. A comparison was made
between syringes in which the coating was applied by a spray
coating method and syringes in which the coating was applied by a
dip coating method according the first exemplary embodiment. Again,
an uncoated syringe served as a reference.
[0186] FIG. 13 shows the breakaway force for syringes of the same
type as in FIG. 12.
[0187] FIGS. 12 and 13 show that the coated syringes exhibit
significantly lower values of sliding friction force and breakaway
force as compared to uncoated syringes. A significant dependency of
this reduction of friction forces on the type of coating method,
spray coating or dip coating, could not be determined. The extent
of reduction is similar for both methods.
[0188] In a fourth exemplary embodiment, the glass syringes are
coated using a two-substance nozzle, like in the third exemplary
embodiment described above. However, in this case a
perfluoropolyether silane containing mixture of type DC2634 was
used.
[0189] FIG. 14 shows the force-distance curve of glass syringes
coated using DC2634. The measured values of static and sliding
friction are very low, in a range around 4 N, at a speed of 100
mm/min.
[0190] In a fifth exemplary embodiment, the pharmaceutical
packaging of the invention is a pharmaceutical vial. It is first
cleaned using WFI and then coated by a process as follows.
[0191] As a perfluoropolyether silane, Daikin DSX ("OPTOOL") is
diluted to a concentration of 0.1% using solvent HFE7200, and is
stirred with a magnetic stirrer. The interior of the vial is
flooded with the diluted solution.
[0192] After a contact time of three minutes, excessive coating
solution is removed from the vial. Subsequently the vials are dried
in air, so that the solvent evaporates. In a next step, the
coatings on the inner surface of the vials are cured in a climate
cabinet for a duration of one hour, at a temperature of 50.degree.
C. and a relative humidity of 50%. Then, the vials with the
post-cured coating are post-cleaned in an ultrasonic bath using
HFE7200.
[0193] The pharmaceutical vials coated in this manner according to
the invention had protein-repelling layers with a contact angle in
a range from 115.degree. to 125.degree..
[0194] In a sixth exemplary embodiment, the pharmaceutical
packaging according to the invention is again a pharmaceutical
vials. It is first cleaned using WFI and then coated by a process
as follows.
[0195] As a perfluoropolyether silane, Daikin DSX ("OPTOOL") is
diluted to a concentration of 0.1% using solvent HFE7200, and is
stirred with a magnetic stirrer.
[0196] The vial is immersed in the diluted solution and is thereby
coated on its outer surface. After a holding time of three minutes,
the vial is retracted from the solution and then dried in air, so
that the solvent evaporates.
[0197] In a next step, the vials are cured in a climate cabinet for
a duration of one hour, at a temperature of 50.degree. C. and a
relative humidity of 50%. Then, the vials with the post-cured
coating are post-cleaned in an ultrasonic bath using HFE7200.
[0198] Measurements showed that the vials coated according to the
invention exhibited significantly reduced particulate emission,
friction-reducing properties, and a contact angle in a range from
115.degree. to 120.degree..
[0199] In a seventh exemplary embodiment, the pharmaceutical
packaging according to the invention is again a pharmaceutical
vial. It is first cleaned using WFI and then coated by a process as
follows.
[0200] As a perfluoropolyether silane, Daikin DSX ("OPTOOL") is
diluted to a concentration of 0.1% using solvent HFE7200, and is
stirred with a magnetic stirrer.
[0201] A diving nozzle (5 mm.times.90 mm, orifice diameter 0.25 mm)
is introduced into the vial. The inner surface of the vial is
spray-coated with the diluted solution, while the spraying nozzle
is retracted from the vial body. In a next step, the coating on the
vial is cured in a climate cabinet for a duration of one hour, at a
temperature of 50.degree. C. and a relative humidity of 50%.
[0202] A result of the inventive coating for the pharmaceutical
vials are protein-repellent layers with a contact angle in a range
from 115.degree. to 125.degree..
[0203] In an eighth exemplary embodiment, the pharmaceutical
packaging is a plastic syringe of cyclic olefin copolymer (COC) of
size 50 ml. This plastic syringe has a glass-like, i.e. silicon
oxide containing, coating on its inner surface. The syringe is
first cleaned using WFI, and is then coated by the method as
follows.
[0204] As the perfluoropolyether silane, Daikin DSX ("OPTOOL") is
diluted to a concentration of 0.1% using solvent HFE7200, and is
stirred with a magnetic stirrer.
[0205] The interior of the syringe is flooded with the diluted
solution. After a contact time of three minutes, the syringe is
removed from the solution and is then dried in air, so that the
solvent evaporates.
[0206] In a next step, the coatings on the syringes are cured in a
climate cabinet for a duration of one hour, at a temperature of
50.degree. C. and a relative humidity of 50%. Then, the syringes
with the post-cured coating are post-cleaned in an ultrasonic bath
using HFE7200.
[0207] Measurements showed that the syringes coated according to
the invention exhibited significantly reduced particulate emission,
improved values of static and sliding friction, and a contact angle
in a range from 115.degree. to 120.degree..
[0208] In a ninth exemplary embodiment, the coatings were prepared
similarly to the previous exemplary embodiments, however,
pre-cleaning of the glass substrate with a solvent was dispensed
with. In this case similarly good results were achieved, so that
the manufacturing process may be significantly simplified.
[0209] In a tenth exemplary embodiment, the coatings were prepared
similarly to the previous exemplary embodiments, however,
post-cleaning of the coatings with a solvent was dispensed with. In
this case similarly good results were achieved, so that the
manufacturing process may be significantly simplified.
[0210] In an eleventh exemplary embodiment, the coatings were
prepared similarly to the previous exemplary embodiments, however,
pre-cleaning of the substrates and post-cleaning of the coated
substrates were dispensed with. In this case similarly good results
were achieved, so that the manufacturing process may be
significantly simplified.
[0211] In a twelfth exemplary embodiment, the coatings were
prepared similarly to the previous exemplary embodiments, however,
post-curing and a wet climate were dispensed with. In this case
similarly good results were achieved, so that the manufacturing
process may be significantly simplified.
* * * * *