U.S. patent application number 09/885939 was filed with the patent office on 2002-05-30 for sterilized cyanoacrylate solutions containing thickeners.
This patent application is currently assigned to CLOSURE MEDICAL CORPORATION. Invention is credited to Bobo, John S., Hickey, Timothy, Jonn, Jerry, Stewart, Ubonwan A..
Application Number | 20020065336 09/885939 |
Document ID | / |
Family ID | 23475789 |
Filed Date | 2002-05-30 |
United States Patent
Application |
20020065336 |
Kind Code |
A1 |
Hickey, Timothy ; et
al. |
May 30, 2002 |
Sterilized cyanoacrylate solutions containing thickeners
Abstract
A method of making a sterile adhesive composition includes
placing a mixture of a polymerizable adhesive monomer and a
thickening agent in a container, sealing the container, and
sterilizing the mixture and the container. The method provides
superior viscosity for the monomer composition. An adhesive
composition includes 2-octyl cyanoacrylate and at least one
thickener. The sterile adhesive composition is particularly useful
as a medical adhesive and can comprise 1,1-disubstituted ethylene
monomers, such as .alpha.-cyanoacrylates.
Inventors: |
Hickey, Timothy; (Raleigh,
NC) ; Stewart, Ubonwan A.; (Durham, NC) ;
Jonn, Jerry; (Raleigh, NC) ; Bobo, John S.;
(Raleigh, NC) |
Correspondence
Address: |
OLIFF & BERRIDGE, PLC
P.O. Box 19928
Alexandria
VA
22320
US
|
Assignee: |
CLOSURE MEDICAL CORPORATION
|
Family ID: |
23475789 |
Appl. No.: |
09/885939 |
Filed: |
June 22, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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09885939 |
Jun 22, 2001 |
|
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09374207 |
Aug 12, 1999 |
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Current U.S.
Class: |
522/152 ;
522/173; 522/77; 523/118; 523/503; 526/319 |
Current CPC
Class: |
C08L 35/04 20130101;
A61L 2/081 20130101; A61L 2/12 20130101; A61L 24/06 20130101; A61P
17/02 20180101; A61L 2/087 20130101; A61L 24/06 20130101 |
Class at
Publication: |
522/152 ;
526/319; 523/503; 523/118; 522/77; 522/173 |
International
Class: |
C08J 003/00 |
Claims
What is claimed is:
1. A method of making a sterile adhesive composition comprising:
(a) placing a mixture comprising a polymerizable 1,1-disubstituted
ethylene monomer and a thickening agent in a container, wherein
said thickening agent is soluble in said monomer at room
temperature, (b) sealing said container, and (c) sterilizing the
mixture in the container.
2. The method of claim 1, wherein said monomer is at least one
member selected from the group consisting of n-butyl cyanoacrylate,
2-octyl cyanoacrylate, and ethyl cyanoacrylate.
3. The method of claim 1, wherein said thickening agent is selected
from the group consisting of poly(2-ethylhexyl methacrylate),
poly(2-ethylhexyl acrylate), cellulose acetate butyrate and lactic
acid-caprolactone copolymer.
4. The method of claim 3, wherein said thickening agent is
poly(2-ethylhexyl methacrylate).
5. The method of claim 3, wherein said thickening agent is
poly(2-ethylhexyl acrylate).
6. The method of claim 3, wherein said thickening agent is
cellulose acetate butyrate.
7. The method of claim 3, wherein said thickening agent is lactic
acid-caprolactone copolymer
8. The method of claim 1, wherein said thickening agent is
biodegradable.
9. The method of claim 1, wherein said thickening agent is a lactic
acid-caprolactone copolymer.
10. The method of claim 1, wherein said thickening agent comprises
from about 0.5-25.0% by weight of the composition.
11. The method of claim 1, wherein said thickening agent comprises
from about 1.0-10.0% by weight of the composition.
12. The method of claim 1, wherein said thickening agent comprises
from about 1.0-5.0% by weight of the composition.
13. The method of claim 1, wherein said thickening agent has a
molecular weight of at least 100,000.
14. The method of claim 1, wherein said thickening agent has a
molecular weight of at least 500,000.
15. The method of claim 1, wherein said thickening agent has a
molecular weight of at least 1,000,000.
16. The method of claim 1, wherein said sterilizing is performed by
dry heat, gamma irradiation, electron beam irradiation, or
microwave irradiation.
17. The method of claim 1, wherein said sterilizing is performed by
dry heat.
18. The method of claim 1, wherein said sterilizing is performed by
gamma irradiation.
19. The method of claim 1, wherein said sterilizing is performed by
electron beam irradiation.
20. The method of claim 1, wherein said composition has a viscosity
of about 20-500 centipoise.
21. The method of claim 1, wherein said composition has a viscosity
of about 30-400 centipoise.
22. The method of claim 1, wherein said mixture further comprises
acidic stabilizing agents.
23. The method of claim 1, wherein said mixture further comprises a
plurality of stabilizing agents.
24. The method of claim 1, wherein said mixture further comprises
plasticizing agents.
25. The method of claim 1, wherein said container is made from at
least one material selected from the group consisting of glass,
plastic, and metal.
26. The method of claim 1, wherein said container is made from
plastic.
27. The method of claim 1, wherein said container is made from
glass.
28. The method of claim 1, wherein viscosity of the mixture after
sterilization is greater than the viscosity of the mixture before
sterilization.
29. The method of claim 1, wherein viscosity of the mixture after
sterilization is less than 100% greater than the viscosity before
sterilization.
30. The method of claim 1, wherein said monomer is an
.alpha.-cyanoacrylate.
31. The method of claim 1, wherein said monomer is an
.alpha.-cyanoacrylate of the formula 6wherein R.sup.2 is hydrogen
and R.sup.3 is a group having the formula 7wherein R.sup.7 is
8wherein n is 1-10 and R.sup.8 is an organic moiety.
32. The method of claim 1, wherein said thickening agent comprises
poly(caprolactone+DL-lactide+glycolide).
33. The method of claim 1, wherein said thickening agent is
poly(vinyl acetate).
34. The method of claim 33, wherein said monomer is 2-octyl
cyanoacrylate.
35. An adhesive composition, comprising 2-octyl cyanoacrylate and
at least one thickener selected from the group consisting of
poly(vinyl acetate), poly(2-ethylhexyl methacrylate), and lactic
acid-caprolactone copolymer.
36. The composition of claim 35, wherein said thickener comprises
about 0.5-25.0% by weight of the composition.
37. The composition of claim 35, wherein said thickener comprises
about 1.0-10.0% by weight of the composition.
38. The composition of claim 35, wherein said thickener comprises
about 1.0-5.0% by weight of the composition.
39. The composition of claim 35, further comprising a plasticizer,
a colorant, a radical stabilizer, and an anionic stabilizer.
40. The composition of claim 39, wherein the thickener is
poly(2-ethylhexyl methacrylate).
41. The composition of claim 39, wherein the thickener is lactic
acid-caprolactone copolymer.
42. The composition of claim 39, wherein the plasticizer is acetyl
tributyl citrate.
43. The composition of claim 39, wherein the colorant is
1-hydroxy-4-[4-methylphenylamino]-9,10 anthracenedione.
44. The composition of claim 39, wherein the radical stabilizer is
at least one of hydroquinone and p-methoxyphenol.
45. The composition of claim 39, wherein the anionic stabilizer is
at least one of acetic acid, sulfuric acid and sulfur dioxide.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The invention relates to sterilized monomer and polymer
adhesive and sealant compositions, and to their production for
industrial and medical uses.
[0003] 2. State of the Art
[0004] Monomer and polymer adhesives are used in both industrial
(including household) and medical applications. Included among
these adhesives are the 1,1-disubstituted ethylene monomers and
polymers, such as the .alpha.-cyanoacrylates. Since the discovery
of the adhesive properties of such monomers and polymers, they have
found wide use due to the speed with which they cure, the strength
of the resulting bond formed, and their relative ease of use. These
characteristics have made the .alpha.-cyanoacrylate adhesives the
primary choice for numerous applications such as bonding plastics,
rubbers, glass, metals, wood, and, more recently, biological
tissues.
[0005] It is known that monomeric forms of .alpha.-cyanoacrylates
are extremely reactive, polymerizing rapidly in the presence of
even minute amounts of an initiator, including moisture present in
the air or on moist surfaces such as animal tissue. Monomers of
.alpha.-cyanoacrylates are anionically polymerizable or free
radical polymerizable, or polymerizable by zwitterions or ion pairs
to form polymers. Once polymerization has been initiated, the cure
rate can be very rapid.
[0006] Medical applications of 1,1-disubstituted ethylene adhesive
compositions include use as an alternate and an adjunct to surgical
sutures and staples in wound closure as well as for covering and
protecting surface wounds such as lacerations, abrasions, burns,
stomatitis, sores, and other open surface wounds. When an adhesive
is applied to surfaces to be joined, it is usually applied in its
monomeric form, and the resultant polymerization gives rise to the
desired adhesive bond. However, at ordinary temperatures, the
monomeric form runs when applied to surfaces. As a result, the
monomeric adhesive may spread into a wound or along a surface to
areas that do not require an adhesive. Therefore, the monomeric
form must be controlled in order to prevent undue escape of the
adhesive from any given area to which the adhesive is applied.
Additionally, sufficient time must be allowed for the monomeric
material to polymerize and thus to bring about the desired bonding
action. In order to achieve a suitably viscous adhesive, thickening
agents can be added to the monomer compositions.
[0007] For example, U.S. Pat. No. 3,527,841 to Wicker et al.
discloses .alpha.-cyanoacrylate adhesive compositions for both
general and surgical uses containing a viscosity modifier that is
soluble, after heating, in a wide range of the esters of
.alpha.-cyanoacrylic acid. The viscosity modifier is disclosed as
poly(lactic acid). After addition of the poly(lactic acid), the
composition is sterilized at temperatures up to 150.degree. C. Most
of the resulting compositions experienced a decrease in viscosity,
presumably resulting from degradation of the thickener by the
sterilization process.
[0008] U.S. Pat. No. 5,665,817 to Greff et al. discloses alkyl
cyanoacrylate compositions suitable for topical application to
human skin. The compositions may comprise a suitable amount of a
thickening agent to provide a compositional viscosity suitable for
certain applications onto human skin. The thickening agent is added
to provide a viscosity of from about 2 to 50,000 centipoise at
20.degree. C. The thickening agent employed is any biocompatible
material that increases the viscosity of the alkyl cyanoacrylate
composition and includes, by way of example, a partial polymer of
the alkyl cyanoacrylate, polymethylmethacrylate (PMMA), or other
preformed polymers soluble in the alkyl cyanoacrylate. When these
solutions are to be stored in applicators suitable for repeated
intermittent use, the alkyl cyanoacrylate composition is stored at
ambient conditions and is selected to be bacteriostatic. When the
selected composition is bacteriostatic, prolonged storage at
ambient conditions is without regard to the sterility of the
formulation because there is no adverse buildup of bacteria during
storage.
[0009] U.S. Pat. No. 5,328,687 to Leung et al. also discloses
adhesive compositions that may be used for bonding tissue.
Compositions comprising .alpha.-cyanoacrylate monomers are
preferred. The compositions may further contain adjuvant substances
such as thickening agents. Suitable disclosed thickeners include,
for example, polycyanoacrylates, polylactic acid, polyglycolic
acid, lactic-glycolic acid copolymers, polycaprolactone, lactic
acid-caprolactone copolymers, poly-3-hydroxybutyric acid,
polyorthoesters, polyalkyl acrylates, copolymers of alkylacrylate
and vinyl acetate, polyalkyl methacrylates, and copolymers of alkyl
methacrylates and butadiene. Without specific reference to
thickened or unthickened compositions, the '687 patent also
mentions that compositions employed in the invention are
sterilizable by conventional methods such as by autoclave or by
aseptic filtration techniques.
[0010] In addition to being viscous, cyanoacrylate compositions for
use in many medical applications should be sterile. Due to the
importance of achieving and maintaining sterility of these
compositions, when an additive, such as a thickening agent, is
added to an .alpha.-cyanoacrylate composition, it should be added
prior to sterilization. A problem arises because some thickeners
require pretreatment prior to addition to the monomer compositions.
U.S. Pat. No. 4,038,345 to O'Sullivan et al. discloses stable
cyanoacrylate adhesive compositions having viscosities greater than
about 200 centipoise. The compositions are prepared by
incorporating, as a thickening agent, a soluble acrylic polymer
having a reduced viscosity of about 5 or greater, and a content of
free radical polymerization initiator less than 1% by weight. These
properties are obtained by subjecting the thickening agent to
temperatures of about 140-180.degree. C. for about 30-180 minutes
prior to incorporating it in the cyanoacrylate. In one aspect, the
'345 patent concerns a process for preparing improved
cyanoacrylates which involves heating a conventional polyacrylate
thickener at a suitable temperature and for a suitable period of
time to reduce its content of free radical polymerization
initiators to below about one percent, and increase its reduced
viscosity to greater than 5; and dissolving a sufficient amount of
the thickener in an ester of 2-cyanoacrylic acid to produce a
cyanoacrylate adhesive composition having a viscosity of at least
about 500 centipoise. The most highly preferred thickening compound
is poly(methylmethacrylate). This thickener is incorporated into
the cyanoacrylate monomer by stirring to form a solution. In
preparing the thickener, it is maintained at an elevated
temperature for a suitable period of time. A satisfactory
temperature range is between about 140.degree. and 180.degree. C.,
and a satisfactory time period is from about 30 to 180 minutes.
[0011] However, regardless of the type and number of additives,
sterilization of .alpha.-cyanoacrylate adhesive compositions is
often difficult to achieve. For example, widely practiced methods
of sterilization, such as dry and moist heat sterilization,
ionizing radiation, exposure to gas, and sterile filtration, are
often not suitable for use with monomeric cyanoacrylate
compositions. Problems arise due to polymerization of the monomer
during the sterilization process. In many cases,
sterilization-induced polymerization is so severe that the
resulting product is unusable.
[0012] Methods currently used to package and sterilize
.alpha.-cyanoacrylate monomer compositions have been developed with
the recognition that, to improve efficiency and productivity, the
packaging and sterilizing steps should be performed in rapid
succession. However, these methods do not provide the desired
viscosity of the adhesive compositions. For example, U.S. Pat. No.
5,530,037 to McDonnell et al. discloses that the composition of a
sterilized adhesive would be very limited because necessary
additives could not be conveniently added and mixed in a controlled
fashion. For example, viscosity modifiers such as
polymethylmethacrylate (PMMA) would require heating in a separate
vessel to achieve dissolution and this step would destroy the
sterility.
[0013] Additionally, the problem exists that some thickeners
decompose in electron beam and dry heat sterilization. One example
of this is poly(2-octylcyanoacrylate), which degrades when exposed
to a 160.degree. C. dry heat sterilization cycle or 20-30 kGy of
electron beam radiation. In order to confirm this, formulations
were prepared using poly(2-octylcyanoacrylate) as a thickening
agent and 2-octylcyanoacetate as the non-polymerizable The data in
Table I confirms that poly(2-octylcyanoacrylate) is unstable under
dry heat and electron beam sterilization methods.
1TABLE I Poly (2-octylcyanoacrylate) (P2OCA) P2OCA Thickened
Formulations Viscosity (cps) 160.degree. C. Run Dry % 20 % 30 % #
Control Heat Change kGy Change kGy Change 1 117 31 -73.2 37 -68.3
31 -73.5 2 138 62 -55.2 46 -67.0 37 -73.2 3 133 48 -64.2 36 -73.0
32 -73.9 4 139 63 -54.7 43 -69.1 37 -73.4 5 139 64 -53.9 40 -71.2
35 -74.8 6 143 57 -60.1 45 -68.3 38 -73.4 7 142 70 -50.4 40 -71.6
33 -76.8 8 142 67 -53.1 44 -68.8 38 -73.2
[0014] Viscosity is used as a measure of stability since a stable
formulation should have a viscosity change of zero after
sterilization. If the viscosity decreases, this indicates
degradation of the thickener (here,
poly(2-octylcyanoacrylate)).
[0015] Many other thickeners are also subject to decomposition
under sterilization conditions. Such instability is particularly
common in compositions in which the adhesive monomers are
stabilized by the presence of acids, because those acids frequently
destabilize the thickening polymers also present in the
composition. For example, lactic acid-caprolactone copolymers in a
stabilized 2-octylcyanoacrylate monomer composition tend to
decompose when such a composition is subjected to dry heat
sterilization conditions, causing the thickener to lose thickening
effect. Such acid stabilizers are, however, present in many
cyanoacrylate adhesive compositions.
[0016] In addition, aseptic filtration is a known method for
sterilizing cyanoacrylate compositions before they are placed into
a container. However, aseptic filtration is very difficult with
high viscosity compositions, and involves prohibitively expensive
technology.
[0017] Thus, a need exists for improved monomer cyanoacrylate
adhesive compositions, especially for medical uses, having a
greater viscosity without sacrificing the performance of the
adhesive. The need further exists for a sterilized monomeric
adhesive composition that does not require pre-treatment of the
thickener prior to its addition to the monomeric adhesive.
Additionally, the need exists for a sterilized monomeric adhesive
in which the thickener has not decomposed during sterilization.
SUMMARY OF THE INVENTION
[0018] The present invention provides a method of making a
thickened sterile monomeric adhesive composition. Production of the
composition includes placing a mixture of a polymerizable
1,1-disubstituted ethylene monomer and a thickening agent in a
container, sealing the container and sterilizing the container and
the mixture. The thickening agent is soluble in the monomer at room
temperature. The compositions produced, packaged and sterilized
according to the present invention have greater viscosity, and
extended utility, as compared to adhesive compositions of the prior
art.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0019] According to the invention, a sterile viscous monomeric
adhesive composition is manufactured by adding a thickening agent
to a composition comprising a monomer adhesive prior to
sterilization.
[0020] The thickening agents may be selected from among known
thickeners, including, but not limited to, poly(2-ethylhexyl
methacrylate), poly(2-ethylhexyl acrylate) and cellulose acetate
butyrate. Suitable thickeners include, for example,
polycyanoacrylates, polyoxalates, lactic-glycolic acid copolymers,
polycaprolactone, lactic acid-caprolactone copolymers,
poly(caporolactone+DL-lactide+glycolide), polyorthoesters,
polyalkyl acrylates, copolymers of alkylacrylate and vinyl acetate,
polyalkyl methacrylates, and copolymers of alkyl methacrylates and
butadiene. Examples of alkyl methacrylates and acrylates are
poly(butylmethacrylate) and poly(butylacrylate), also copolymers of
various acrylate and methacrylate monomers, such as
poly(butylmethacrylate-co-methylmethacrylate). Biodegradable
polymer thickeners are preferred for some uses such as some
surgical uses. Preferably, the thickening agent is soluble in a
monomer composition at room temperature (i.e., 20-25.degree. C.) so
that it may be added to the monomer composition without excessive
heating of the monomer composition and remain uniformly combined in
the composition.
[0021] The amount of thickening agent that is added to the monomer
composition depends upon the molecular weight of the thickening
agent. The thickening agent preferably comprises from about
0.5-25.0% by weight of the adhesive composition. In preferred
embodiments, the thickening agent comprises from about 1.0-10.0%,
more preferably 1.0-5.0%, of the adhesive composition. In
embodiments, the thickening agent has a high molecular weight,
preferably at least 100,000, or at least 500,000 or at least
1,000,000. The thickening agent is selected such that it is
compatible with the monomer (i.e., does not adversely affect
polymerization, bond strength, core properties, or shelf-life). The
amount of thickening agent to be used can be determined by one of
ordinary skill in the art using known techniques without undue
experimentation.
[0022] In embodiments, the sterilized adhesive composition has a
viscosity of about 20-500 centipoise, preferably 30-400 centipoise,
as measured with a Brookfield Viscometer at 25.degree. C.
Additionally, the viscosity of the composition should be maintained
or increased by a controlled and acceptable amount after
sterilization.
[0023] According to embodiments of the present invention, the
stability, and thus the shelf-life, of some monomeric adhesive
compositions can be further enhanced and extended through careful
regulation of the packaging (i.e., dispensing into a container) and
sterilizing procedures. In preferred embodiments, there is
substantially no initiation of polymerization of monomeric liquid
adhesive compositions that affects the utility of the monomer or
monomers caused by the sterilization process. In particular, a
polymerizable 1,1-disubstituted monomer and a thickening agent are
dispensed into a container. The container is sealed and subjected
to sterilization.
[0024] The monomeric composition may be packaged in any type of
suitable container fabricated from materials including, but not
limited to, glass, plastic, metal packages, and film-formed
packages. Suitable containers are those into which the compositions
can be dispensed and sterilized without unacceptable damage to, or
degradation of, the container or the components of the monomer
composition. Glass is especially preferred when sterilization is
achieved with dry heat because of the lack of stability of many
plastics at the temperatures used for dry heat sterilization
(typically at least 160.degree. C.). Examples of types of
containers include, but are not limited to, ampoules, vials,
syringes, pipettes, and the like. In a preferred embodiment, the
container comprises a sealable container.
[0025] In embodiments, monomer compositions according to the
invention are sterilized. The sterilization can be accomplished by
techniques known to the skilled artisan, and is preferably
accomplished by methods including, but not limited to, chemical,
physical, and irradiation methods. Examples of chemical methods
include, but are not limited to, exposure to ethylene oxide or
hydrogen peroxide vapor. Examples of physical methods include, but
are not limited to, sterilization by heat (dry or moist). Examples
of irradiation methods include, but are not limited to, gamma
irradiation, electron beam irradiation, and microwave irradiation.
Preferred methods are dry and moist heat sterilization and electron
beam sterilization. In embodiments where a composition is to be
used for medical applications, the sterilized composition must show
low levels of toxicity to living tissue during its useable
life.
[0026] The sterilization conditions and thickeners should be
selected in light of each other, and preferably also in light of
other components of the composition. For example, in a highly acid
stabilized composition, a less acid-unstable thickener and/or less
degrading sterilization conditions would be preferable.
Biodegradable polymer thickeners such as lactic acid-caprolactone
copolymers, for example, better survive electron beam sterilization
rather than dry heat sterilization in acid stabilized cyanoacrylate
compositions. Where a biodegradable thickener is not required, on
the other hand, a more acid-stable thickener such as
poly(2-ethylhexyl) methacrylate may be used with, for example, dry
heat sterilization. Thus, by taking into account the selection of
the thickener and the selection of the sterilization conditions,
along with the nature of the underlying composition, one of
ordinary skill in the art can readily select appropriate parameters
by routine experimentation to allow sterilization of a thickened
adhesive composition in a container.
[0027] The monomer composition, in embodiments, is preferably a
monomeric (including prepolymeric) adhesive composition. The
monomer composition may further include one or more polymerizable
monomers. In embodiments, at least one of the one or more monomers
is a 1,1-disubstituted ethylene monomer, e.g., an
.alpha.-cyanoacrylate. Preferred monomer compositions of the
present invention, and polymers formed therefrom, are useful as
tissue adhesives, sealants for preventing bleeding or for covering
open wounds, and in other biomedical applications. They find uses
in, for example, apposing surgically incised or traumatically
lacerated tissues; retarding blood flow from wounds; drug delivery;
dressing burns; dressing skin or other superficial or surface
wounds (such as abrasions, chaffed or raw skin, and/or stomatitis);
and aiding repair and regrowth of living tissue. Other preferred
monomer compositions of the present invention, and polymers formed
therefrom, are useful in industrial and home applications, for
example in bonding rubbers, plastics, wood, composites, fabrics,
and other natural and synthetic materials.
[0028] Monomers that may be used in this invention are readily
polymerizable, e.g. anionically polymerizable or free radical
polymerizable, or polymerizable by zwitterions or ion pairs to form
polymers. Such monomers include those that form polymers, that may,
but do not need to, biodegrade. Such monomers are disclosed in, for
example, U.S. Pat. No. 5,328,687 to Leung, et al., which is hereby
incorporated in its entirety by reference herein.
[0029] Useful 1,1-disubstituted ethylene monomers include, but are
not limited to, monomers of the formula:
[0030] (I) HRC.dbd.CXY
[0031] wherein X and Y are each strong electron withdrawing groups,
and R is H, --CH.dbd.CH.sub.2 or, provided that X and Y are both
cyano groups, a C.sub.1-C.sub.4 alkyl group.
[0032] Examples of monomers within the scope of formula (I) include
.alpha.-cyanoacrylates, vinylidene cyanides, C.sub.1-C.sub.4 alkyl
homologues of vinylidene cyanides, dialkyl methylene malonates,
acylacrylonitriles, vinyl sulfinates and vinyl sulfonates of the
formula CH.sub.2.dbd.CX'Y' wherein X' is --SO.sub.2R' or
--SO.sub.3R' and Y' is --CN, --COOR', --COCH.sub.3, --SO.sub.2R' or
--SO.sub.3R', and R' is H or hydrocarbyl.
[0033] Preferred monomers of formula (I) for use in this invention
are .alpha.-cyanoacrylates. These monomers are known in the art and
have the formula 1
[0034] wherein R.sup.2 is hydrogen and R.sup.3 is a hydrocarbyl or
substituted hydrocarbyl group; a group having the formula
--R.sup.4--O--R.sup.5--O--R.sup.6, wherein R.sup.4 is a
1,2-alkylene group having 2-4 carbon atoms, R.sup.5 is an alkylene
group having 2-4 carbon atoms, and R.sup.6 is an alkyl group having
1-6 carbon atoms; or a group having the formula 2
[0035] wherein R.sup.7 is 3
[0036] wherein n is 1-10, preferably 1-5 carbon atoms and R.sup.8
is an organic moiety.
[0037] Examples of suitable hydrocarbyl and substituted hydrocarbyl
groups include straight chain or branched chain alkyl groups having
1-16 carbon atoms; straight chain or branched chain
C.sub.1-C.sub.16 alkyl groups substituted with an acyloxy group, a
haloalkyl group, an alkoxy group, a halogen atom, a cyano group, or
a haloalkyl group; straight chain or branched chain alkenyl groups
having 2 to 16 carbon atoms; straight chain or branched chain
alkynyl groups having 2 to 12 carbon atoms; cycloalkyl groups;
aralkyl groups; alkylaryl groups; and aryl groups.
[0038] The organic moiety R.sup.8 may be substituted or
unsubstituted and may be straight chain, branched or cyclic,
saturated, unsaturated or aromatic. Examples of such organic
moieties include C.sub.1-C.sub.8 alkyl moieties, C.sub.2-C.sub.8
alkenyl moieties, C.sub.2-C.sub.8 alkynyl moieties,
C.sub.3-C.sub.12 cycloaliphatic moieties, aryl moieties such as
phenyl and substituted phenyl and aralkyl moieties such as benzyl,
methylbenzyl, and phenylethyl. Other organic moieties include
substituted hydrocarbon moieties, such as halo (e.g., chloro-,
fluoro- and bromo-substituted hydrocarbons) and oxy-substituted
hydrocarbon (e.g., alkoxy substituted hydrocarbons) moieties.
Preferred organic radicals are alkyl, alkenyl, and alkynyl moieties
having from 1 to about 8 carbon atoms, and halo-substituted
derivatives thereof. Particularly preferred are alkyl moieties of 4
to 6 carbon atoms.
[0039] In the cyanoacrylate monomer of formula (II), R.sup.3 is
preferably an alkyl group having 1-10 carbon atoms or a group
having the formula --AOR.sup.9, wherein A is a divalent straight or
branched chain alkylene or oxyalkylene moiety having 2-8 carbon
atoms, and R.sup.9 is a straight or branched alkyl moiety having
1-8 carbon atoms.
[0040] Examples of groups represented by the formula --AOR.sup.9
include 1-methoxy-2-propyl, 2-butoxy ethyl, isopropoxy ethyl,
2-methoxy ethyl, and 2-ethoxy ethyl.
[0041] The .alpha.-cyanoacrylates of formula (II) can be prepared
according to methods known in the art. U.S. Pat. Nos. 2,721,858 and
3,254,111, each of which is hereby incorporated in its entirety by
reference, disclose methods for preparing .alpha.-cyanoacrylates.
For example, the .alpha.-cyanoacrylates can be prepared by reacting
an alkyl cyanoacetate with formaldehyde in a non-aqueous organic
solvent and in the presence of a basic catalyst, followed by
pyrolysis of the anhydrous intermediate polymer in the presence of
a polymerization inhibitor. The .alpha.-cyanoacrylate monomers
prepared with low moisture content and essentially free of
impurities are preferred for biomedical use.
[0042] The .alpha.-cyanoacrylates of formula (II) wherein R.sup.3
is a group having the formula R.sup.4--O--R.sup.5--O--R.sup.6 can
be prepared according to the method disclosed in U.S. Pat. No.
4,364,876 to Kimura et al., which is hereby incorporated in its
entirety by reference. In the Kimura et al. method, the
.alpha.-cyanoacrylates are prepared by producing a cyanoacetate by
esterifying cyanoacetic acid with an alcohol or by transesterifying
an alkyl cyanoacetate and an alcohol; condensing the cyanoacetate
and formaldehyde or para-formaldehyde in the presence of a catalyst
at a molar ratio of 0.5-1.5:1, preferably 0.8-1.2:1, to obtain a
condensate; depolymerizing the condensation reaction mixture either
directly or after removal of the condensation catalyst to yield
crude cyanoacrylate; and distilling the crude cyanoacrylate to form
a high purity cyanoacrylate.
[0043] The .alpha.-cyanoacrylates of formula (II) wherein R.sup.3
is a group having the formula 4
[0044] can be prepared according to the procedure described in U.S.
Pat. No. 3,995,641 to Kronenthal et al., which is hereby
incorporated in its entirety by reference. In the Kronenthal et al.
method, such .alpha.-cyanoacrylate monomers are prepared by
reacting an alkyl ester of an .alpha.-cyanoacrylic acid with a
cyclic 1,3-diene to form a Diels-Alder adduct which is then
subjected to alkaline hydrolysis followed by acidification to form
the corresponding .alpha.-cyanoacrylic acid adduct. The
.alpha.-cyanoacrylic acid adduct is preferably esterified by an
alkyl bromoacetate to yield the corresponding carbalkoxymethyl
.alpha.-cyanoacrylate adduct. Alternatively, the
.alpha.-cyanoacrylic acid adduct may be converted to the
.alpha.-cyanoacrylyl halide adduct by reaction with thionyl
chloride. The .alpha.-cyanoacrylyl halide adduct is then reacted
with an alkyl hydroxyacetate or a methyl substituted alkyl
hydroxyacetate to yield the corresponding carbalkoxymethyl
.alpha.-cyanoacrylate adduct or carbalkoxy alkyl
.alpha.-cyanoacrylate adduct, respectively. The cyclic 1,3-diene
blocking group is finally removed and the carbalkoxy methyl
.alpha.-cyanoacrylate adduct or the carbalkoxy alkyl
.alpha.-cyanoacrylate adduct is converted into the corresponding
carbalkoxy alkyl .alpha.-cyanoacrylate by heating the adduct in the
presence of a slight deficit of maleic anhydride.
[0045] Examples of monomers of formula (II) include
cyanopentadienoates and .alpha.-cyanoacrylates of the formula:
5
[0046] wherein Z is --CH.dbd.CH.sub.2 and R.sup.3 is as defined
above. The monomers of formula (III) wherein R.sup.3 is an alkyl
group of 1-10 carbon atoms, i.e., the 2-cyanopenta-2,4-dienoic acid
esters, can be prepared by reacting an appropriate 2-cyanoacetate
with acrolein in the presence of a catalyst such as zinc chloride.
This method of preparing 2-cyanopenta-2,4-dienoic acid esters is
disclosed, for example, in U.S. Pat. No. 3,554,990, which is hereby
incorporated in its entirety by reference.
[0047] Preferred .alpha.-cyanoacrylate monomers used in this
invention are alkyl .alpha.-cyanoacrylates including octyl
cyanoacrylate, such as 2-octyl cyanoacrylate; dodecyl
cyanoacrylate; 2-ethylhexyl cyanoacrylate; butyl cyanoacrylate such
as n-butyl cyanoacrylate; ethyl cyanoacrylate; methyl
cyanoacrylate; 3-methoxybutyl cyanoacrylate; 2-butoxyethyl
cyanoacrylate; 2-isopropoxyethyl cyanoacrylate; and
1-methoxy-2-propyl cyanoacrylate. More preferred monomers are
n-butyl and 2-octyl .alpha.-cyanoacrylate. Monomers utilized for
medical purposes in the present application should be very pure and
contain few impurities (e.g., surgical grade). Monomers utilized
for industrial purposes need not be as pure.
[0048] The composition may optionally also include at least one
plasticizing agent that imparts flexibility to the polymer formed
from the monomer. The plasticizing agent preferably contains little
or no moisture and should not significantly affect the stability or
polymerization of the monomer. Such plasticizers are useful in
polymerized compositions to be used for closure or covering of
wounds, incisions, abrasions, sores or other applications where
flexibility of the adhesive is desirable. Some thickeners, such as
poly-2-ethylhexylcyanoacrylate, can also impart flexibility to the
polymer.
[0049] Examples of suitable plasticizers include acetyl tributyl
citrate, dimethyl sebacate, triethyl phosphate,
tri(2-ethylhexyl)phosphate, tri(p-cresyl) phosphate, glyceryl
triacetate, glyceryl tributyrate, diethyl sebacate, dioctyl
adipate, isopropyl myristate, butyl stearate, lauric acid, trioctyl
trimellitate, dioctyl glutarate, and mixtures thereof. Preferred
plasticizers are tributyl citrate and acetyl tributyl citrate. In
embodiments, suitable plasticizers include polymeric plasticizers,
such as polyethylene glycol (PEG) esters and capped PEG esters or
ethers, polyester glutarates and polyester adipates.
[0050] The addition of plasticizing agents in amounts ranging from
about 0.5 wt. % to about 25 wt. %, or from about 1 wt. % to about
20 wt. %, or from about 3 wt. % to about 15 wt. % or from about 5
wt. % to about 7 wt. % provides increased elongation and toughness
of the polymerized monomer over polymerized monomers not having
plasticizing agents.
[0051] The composition may also optionally include at least one
thixotropic agent. Suitable thixotropic agents are known to the
skilled artisan and include, but are not limited to, silica gels
such as those treated with a silyl isocyanate. Examples of suitable
thixotropic agents are disclosed in, for example, U.S. Pat. No.
4,720,513, the disclosure of which is hereby incorporated in its
entirety.
[0052] The composition may also optionally include at least one
natural or synthetic rubber to impart impact resistance, which is
preferable especially for industrial compositions of the present
invention. Suitable rubbers are known to the skilled artisan. Such
rubbers include, but are not limited to, dienes, styrenes,
acrylonitriles, and mixtures thereof. Examples of suitable rubbers
are disclosed in, for example, U.S. Pat. Nos. 4,313,865 and
4,560,723, the disclosures of which are hereby incorporated in
their entireties.
[0053] The composition may also optionally include both at least
one anionic vapor phase stabilizer and at least one anionic liquid
phase stabilizer. These stabilizing agents inhibit polymerization.
Such stabilizing agents may also include mixtures of anionic
stabilizing agents and radical stabilizing agents. Any mixture of
stabilizers is included as long as the mixture does not inhibit the
desired polymerization of the monomer and is compatible with the
selected thickener under the selected sterilization conditions, as
discussed above.
[0054] The anionic vapor phase stabilizers may be selected from
among known stabilizers, including, but not limited to, sulfur
dioxide, boron trifluoride, and hydrogen fluoride. The amount of
anionic vapor phase stabilizer that is added to the monomer
composition depends on the identity of the liquid phase
stabilizer(s) chosen in combination with it, the monomer to be
stabilized, as well as the packaging material to be used for the
composition. Preferably, each anionic vapor phase stabilizer is
added to give a concentration of less than 200 parts per million
(ppm). In preferred embodiments, each anionic vapor phase
stabilizer is present from about 1 to 200 ppm, more preferably from
about 10 to 75 ppm, even more preferably from about 10 to 50 ppm,
and most preferably from 10 to 20 ppm. The amount to be used can be
determined by one of ordinary skill in the art using known
techniques without undue experimentation.
[0055] In embodiments, the vapor phase comprises, among other
things, an anionic stabilizer that is sulfur dioxide. In
embodiments, the vapor phase comprises, among other things, a
stabilizer that is boron trifluoride or hydrogen fluoride. A
combination of sulfur dioxide and boron trifluoride or hydrogen
fluoride is preferable in some embodiments.
[0056] In embodiments, the liquid phase anionic stabilizer is a
very strong acid. As used herein, a very strong acid is an acid
that has an aqueous pK.sub.a of less than 1.0. Suitable very strong
acidic stabilizing agents include, but are not limited to, very
strong mineral and/or oxygenated acids. Examples of such very
strong acids include, but are not limited to, sulfuric acid
(pK.sub.a-3.0), perchloric acid (pK.sub.a-5), hydrochloric acid
(pK.sub.a-7.0), hydrobromic acid (pK.sub.a-9), fluorosulfonic acid
(pK.sub.a<-10), chlorosulfonic acid (pK.sub.a-10). In
embodiments, the very strong acid liquid phase anionic stabilizer
is added to give a final concentration of 1 to 200 ppm. Preferably,
the very strong acid liquid phase anionic stabilizer is present in
a concentration of from about 5 to 80 ppm, more preferably 10 to 40
ppm. The amount of very strong acid liquid phase anionic stabilizer
to be used can be determined by one of ordinary skill in the art
without undue experimentation.
[0057] Preferably, the very strong acid liquid phase anionic
stabilizer is sulfuric acid, perchloric acid, or chlorosulfonic
acid. More preferably, the very strong acid liquid phase anionic
stabilizer is sulfuric acid.
[0058] In embodiments, sulfur dioxide is used as a vapor phase
anionic stabilizer and sulfuric acid is used as a liquid phase
anionic stabilizer.
[0059] The composition may also optionally include at least one
other anionic stabilizing agent that inhibits polymerization. These
agents are herein referred to as secondary anionic active agents to
contrast them with the strong or very strong liquid phase anionic
stabilizers, which are referred to hereinbelow as "primary" anionic
stabilizers. The secondary anionic active agents can be included in
the compositions to adjust the cure speed of the adhesive
composition, for example.
[0060] The secondary anionic active agent would normally be an acid
with a higher pK.sub.a than the primary anionic stabilizing agent
and may be provided to more precisely control the cure speed and
stability of the adhesive, as well as the molecular weight of the
cured adhesive. Any mixture of primary anionic stabilizers and
secondary active agents is included as long as the chemistry of the
composition is not compromised and the mixture does not
significantly inhibit the desired polymerization of the
composition. Furthermore, the mixture should not, in medical
adhesive compositions, show unacceptable levels of toxicity.
[0061] Suitable secondary anionic active agents include those
having aqueous pK.sub.a ionization constants ranging from 2 to 8,
preferably from 2 to 6, and most preferably from 2 to 5. Examples
of such suitable secondary anionic stabilizing agents include, but
are not limited to, phosphoric acid (pK.sub.a 2.2), organic acids,
such as acetic acid (pK.sub.a 4.8), benzoic acid (pK.sub.a 4.2),
chloroacetic acid (pK.sub.a 2.9), cyanoacetic acid, and mixtures
thereof. Preferably these secondary anionic stabilizing agents are
organic acids, such as acetic acid or benzoic acid. In embodiments,
the amount of acetic acid and/or benzoic acid is about 25-500 ppm.
The concentration of acetic acid is typically 50-400 ppm,
preferably 75-300 ppm, and more preferably 100-200 ppm. When using
a stronger acid such as phosphoric acid, a concentration of 20-100
ppm, preferably 30-80 ppm, and more preferably 40-60 ppm may be
utilized.
[0062] Combinations of at least one vapor phase stabilizer and at
least one liquid phase anionic stabilizer are preferred. For
example, combinations of sulfur dioxide and sulfuric acid, sulfur
dioxide and perchloric acid, sulfur dioxide and chlorosulfonic
acid, boron trifluoride and sulfuric acid, boron trifluoride and
perchloric acid, boron trifluoride and chlorosulfonic acid, boron
trifluoride and methanesulfonic acid, hydrogen fluoride and
sulfuric acid, hydrogen fluoride and perchloric acid, hydrogen
fluoride and chlorosulfonic acid, and hydrogen fluoride and
methanesulfonic acid can be used. A combination of boron
trifluoride, sulfur dioxide, and sulfuric acid can also be used,
among other combinations. The two types of anionic stabilizers are
chosen in conjunction such that the stabilizers are compatible with
the chosen adhesive composition and each other stabilizer, as well
as with the packaging material and the equipment used to make and
package the composition. In other words, the combination of vapor
phase stabilizer(s), liquid phase stabilizer(s), and monomer should
be such that a stabilized, substantially unpolymerized adhesive
composition is present after packaging.
[0063] Medical compositions of the present invention may also
include at least one biocompatible agent effective to reduce active
formaldehyde concentration levels produced during in vivo
biodegradation of the polymer (also referred to herein as
"formaldehyde concentration reducing agents"). Preferably, this
component is a formaldehyde scavenger compound. Examples of
formaldehyde scavenger compounds useful in this invention include
sulfites; bisulfites; mixtures of sulfites and bisulfites; ammonium
sulfite salts; amines; amides; imides; nitriles; carbamates;
alcohols; mercaptans; proteins; mixtures of amines, amides, and
proteins; active methylene compounds such as cyclic ketones and
compounds having a b-dicarbonyl group; and heterocyclic ring
compounds free of a carbonyl group and containing an NH group, with
the ring made up of nitrogen or carbon atoms, the ring being
unsaturated or, when fused to a phenyl group, being unsaturated or
saturated, and the NH group being bonded to a carbon or a nitrogen
atom, which atom is directly bonded by a double bond to another
carbon or nitrogen atom.
[0064] Bisulfites and sulfites useful as the formaldehyde scavenger
compound in this invention include alkali metal salts such as
lithium, sodium, and potassium salts, and ammonium salts, for
example, sodium bisulfite, potassium bisulfite, lithium bisulfite,
ammonium bisulfite, sodium sulfite, potassium sulfite, lithium
sulfite, ammonium sulfite, and the like.
[0065] Examples of amines useful in this invention include the
aliphatic and aromatic amines such as, for example, aniline,
benzidine, aminopyrimidine, toluene-diamine, triethylenediamine,
diphenylamine, diaminodiphenylamine, hydrazines, and hydrazide.
[0066] Suitable proteins include collagen, gelatin, casein, soybean
protein, vegetable protein, keratin, and glue. The preferred
protein for use in this invention is casein.
[0067] Suitable amides for use in this invention include urea,
cyanamide, acrylamide, benzamide, and acetamide. Urea is a
preferred amide.
[0068] Suitable alcohols include phenols, 1,4-butanediol,
d-sorbitol, and polyvinyl alcohol.
[0069] Examples of suitable compounds having a b-dicarbonyl group
include malonic acid, acetylacetone, ethylacetone, acetate,
malonamide, diethylmalonate, or another malonic ester.
[0070] Preferred cyclic ketones for use in this invention include
cyclohexanone or cyclopentanone.
[0071] Examples of suitable heterocyclic compounds for use as the
formaldehyde scavenger in this invention are disclosed, for
example, in U.S. Pat. No. 4,127,382 to Perry, which is hereby
incorporated in its entirety by reference. Such heterocyclic
compounds include, for example, benzimidazole, 5-methyl
benzimidazole, 2-methylbenzimidazole, indole, pyrrole,
1,2,4-triazole, indoline, benzotriazole, indoline, and the
like.
[0072] A preferred formaldehyde scavenger for use in this invention
is sodium bisulfite.
[0073] In practicing the present invention, the formaldehyde
concentration reducing agent is added in an effective amount to the
cyanoacrylate. The "effective amount" is that amount sufficient to
reduce the amount of formaldehyde generated during subsequent in
vivo biodegradation of the polymerized cyanoacrylate. This amount
will depend on the type of active formaldehyde concentration
reducing agent, and can be readily determined without undue
experimentation by those skilled in the art.
[0074] The formaldehyde concentration reducing agent may be used in
this invention in either free form or in microencapsulated form.
When microencapsulated, the formaldehyde concentration reducing
agent is released from the microcapsule continuously over a period
of time during the in vivo biodegradation of the cyanoacrylate
polymer.
[0075] For purposes of this invention, the microencapsulated form
of the formaldehyde concentration reducing agent is preferred
because this embodiment prevents or substantially reduces
polymerization of the cyanoacrylate monomer by the formaldehyde
concentration reducing agent, which increases shelf-life and
facilitates handling of the monomer composition during use.
[0076] Microencapsulation of the formaldehyde scavenger can be
achieved by many known microencapsulation techniques. For example,
microencapsulation can be carried out by dissolving a coating
polymer in a volatile solvent, e.g., methylene chloride, to a
polymer concentration of about 6% by weight; adding a formaldehyde
scavenger compound in particulate form to the coating
polymer/solvent solution under agitation to yield a scavenger
concentration of 18% by weight; slowly adding a
surfactant-containing mineral oil solution to the polymer solution
under rapid agitation; allowing the volatile solvent to evaporate
under agitation; removing the agitator; separating the solids from
the mineral oil; and washing and drying the microparticles. The
size of the microparticles will range from about 0.001 to about
1000 microns.
[0077] The coating polymer for microencapsulating the formaldehyde
concentration reducing agent should be polymers which undergo in
vivo bioerosion, preferably at rates similar to or greater than the
cyanoacrylate polymer formed by the monomer, and should have low
inherent moisture content. Such bioerosion can occur as a result of
the physical or chemical breakdown of the encapsulating material,
for example, by the encapsulating material passing from solid to
solute in the presence of body fluids, or by biodegradation of the
encapsulating material by agents present in the body.
[0078] Examples of coating materials which can be used to
microencapsulate the formaldehyde concentration reducing agent
include polyesters, such as polyglycolic acid, polylactic acid,
poly-1,4-dioxa-2-one, polyoxaltes, polycarbonates, copolymers of
polyglycolic acid and polylactic acid, polycaprolactone,
poly-b-hydroxybutyrate, copolymers of epsilon-caprolactone and
delta-valerolactone, copolymers of epsilon-caprolactone and
DL-dilactide, and polyester hydrogels; polyvinylpyrrolidone;
polyamides; gelatin; albumin; proteins; collagen;
poly(orthoesters); poly(anhydrides); poly(alkyl-2-cyanoacrylates);
poly(dihydropyrans); poly(acetals); poly(phosphazenes);
poly(urethanes); poly(dioxinones); cellulose; and starches.
[0079] Examples of surfactants which can be added to the mineral
oil include those commercially available under the designations
Triton X-100.TM. (Rohm and Haas) (octoxynol), Tween 20.TM. (ICI
Americas) (polysorbate), and Tween 80.TM. (ICI Americas)
(polysorbate).
[0080] To improve the cohesive strength of adhesives formed from
the compositions of this invention, difunctional monomeric
cross-linking agents may be added to the monomer compositions of
this invention. Such crosslinking agents are known. U.S. Pat. No.
3,940,362 to Overhults, which is hereby incorporated in its
entirety by reference, discloses such cross-linking agents.
Examples of suitable crosslinking agents include alkyl
bis(2-cyanoacrylates), triallyl isocyanurates, alkylene
diacrylates, alkylene dimethacrylates, trimethylol propane
triacrylate, and alkyl bis(2-cyanoacrylates). A catalytic amount of
an amine activated free radical initiator or rate modifier may be
added to initiate polymerization or to modify the rate of
polymerization of the cyanoacrylate monomer/crosslinking agent
blend.
[0081] The compositions of this invention may further contain
fibrous reinforcement and colorants such as dyes, pigments, and
pigment dyes. Examples of suitable fibrous reinforcement include
PGA microfibrils, collagen microfibrils, cellulosic microfibrils,
and olefinic microfibrils. Examples of suitable colorants include
1-hydroxy-4-[4-methylphenyl-amino]-9,10 anthracenedione (D+C violet
No. 2); disodium salt of
6-hydroxy-5-[(4-sulfophenyl)axo]-2-naphthalene-sulfo- nic acid
(FD+C Yellow No. 6); 9-(.alpha.-carboxyphenyl)-6-hydroxy-2,4,5,7--
tetraiodo-3H-xanthen-3-one, disodium salt, monohydrate (FD+C Red
No. 3);
2-(1,3-dihydro-3-oxo-5-sulfo-2H-indol-2-ylidene)-2,3-dihydro-3-oxo-1H-ind-
ole-5-sulfonic acid disodium salt (FD+C Blue No. 2); and
[phthalocyaninato (2-)] copper.
[0082] Other compositions contemplated by the present invention are
exemplified by U.S. Pat. Nos. 5,624,669; 5,582,834; 5,575,997;
5,514,371; 5,514,372; and 5,259,835; and U.S. patent application
Ser. No. 08/714,288, the disclosures of all of which are hereby
incorporated in their entirety by reference.
EXAMPLES
[0083] In order to find a polymer (thickening agent) that is stable
in both dry heat and electron beam sterilization cycles,
formulations of 2-octylcyanoacetate with several different polymers
were prepared. In particular, 2-octylcyanoacetate was mixed with
one of poly(butylmethacrylate) (PBMA),
poly(butylmethacrylate-co-methylmethacryl- ate) (PBMAMMA),
poly(vinylacetate) (PVAc), and poly(2-ethylhexylmethacryla- te)
(PEHMA). See Tables II-V. The data in Tables II-V show that the
polymers are relatively stable to the dry heat cycle at 160.degree.
C. (DH). The effect of the electron beam radiation on viscosity
increases with the level of exposure. Polymer formulations exposed
to 20 kGy of electron beam radiation showed less of a decrease in
viscosity compared to polymer formulations exposed to 30 kGy of
electron beam radiation. Therefore, the degradation of the polymer
increases and the viscosity of the formulation decreases, as the
exposure level increases. However, the degradation of the polymers
(and thus the percentage differences) shown in Tables II-V is much
less significant than the degradation of poly(2-octylcyanoacetate)
(P2OCA) shown in Table I.
2TABLE II Poly(butyl methacrylate) (PBMA) PBMA Thickened
Formulations Viscosity (cps) Run % 20 % 30 % # Control DH Change
kGy Change kGy Change 1 197 179 -9.1 161 -18.3 141 -28.4 2 203 184
-9.4 163 -19.7 139 -31.5 3 196 194 -1.0 158 -19.4 143 -27.0 4 195
199 2.1 171 -12.3 142 -27.2 5 198 189 -4.5 156 -21.2 144 -27.3 6
197 185 -6.1 158 -19.8 142 -27.9 7 197 199 1.0 160 -18.8 141 -28.4
8 191 192 0.5 152 -20.4 143 -25.1
[0084]
3TABLE III Poly(butyl methacrylate-co-methyl methacrylate)
(PBMAMMA) PBMAMMA Thickened Formulations Viscosity (cps) Run % 20 %
30 % # Control DH Change kGy Change kGy Change 1 205 ND ND 201 -2.0
186 -9.3 2 196 ND ND 203 3.6 185 -5.6 3 198 ND ND 202 2.0 189 -4.5
4 198 ND ND 190 -4.0 184 -7.1 5 194 ND ND 207 6.7 183 -5.7 6 196 ND
ND 197 0.5 185 -5.6 7 199 ND ND 203 2.0 186 -6.5 8 207 ND ND 195
-5.8 187 -9.7 ND means "no data".
[0085]
4TABLE IV Poly(vinyl acetate) (PVAc) PVAc Thickened Formulations
Viscosity (cps) Run % 20 % 30 % # Control DH Change kGy Change kGy
Change 1 388 393 1.3 344 -11.3 331 -14.7 2 376 362 -3.7 339 -9.8
320 -14.9 3 403 435 7.9 355 -11.9 345 -14.4 4 395 385 -2.5 344
-12.9 320 -19.0 5 393 363 -7.6 363 -7.6 311 -20.9 6 404 ND ND 335
-17.1 314 -22.3 7 392 396 1.0 358 -8.7 329 -16.1 8 396 376 -5.1 342
-13.6 317 -19.9
[0086]
5TABLE V Poly(2-ethylhexyl methacrylate) (PEHMA) PEHMA Thickened
Formulations Viscosity (cps) Run % 20 % 30 % # Control DH Change
kGy Change kGy Change 1 198 186 -6.1 178 -10.1 155 -21.7 2 195 178
-8.7 173 -11.3 157 -19.5 3 201 201 0.0 182 -9.5 159 -20.9 4 203 203
0.0 168 -17.2 156 -23.2 5 198 191 -3.5 171 -13.6 155 -21.7 6 200
189 -5.5 175 -12.5 154 -23.0 7 197 198 0.5 174 -11.7 152 -22.8 8
198 198 0.0 170 -14.1 151 -23.7
[0087] Three different monomer formulations were prepared using
2-octylcyanoacrylate (2OCA), containing a fixed sulfur dioxide
content (15 ppm) and hydroquinone content (1500 ppm) as the base
monomer. Varying amounts of BHA, sultone and TFA as stabilizers
were then added to this base monomer to provide three different
stabilized monomers (see Table VI below). Each of the three
stabilized monomers was then formulated with a series of several
different polymers. These materials were ampoulized and exposed to
dry heat and electron beam radiation sterilization cycles.
[0088] Thickened formulation controls were tested to get a baseline
before exposure to any of the sterilization cycles. Samples were
then exposed to either a 160.degree. C. dry heat cycle, or 20 or 30
kGy of electron beam radiation. Samples were then tested, after
exposure (t=0), to determine the effect of the sterilization cycles
on the formulations. The t=0 post exposure data for the three
monomer sets is shown in Tables VII-IX below.
6 TABLE VI Formulation Sultone (ppm) BHA (ppm) TFA (ppm) K1 1000
3000 500 Q 1500 3000 1000 S 1500 5000 5000
[0089]
7TABLE VII Post Exposure Data (t = 0) Formulation K1 Initial
Results Formulation K1 Viscosity Modified Monomers Viscosity (cps)
Sample Dry ID Polymer Control Heat 20 kGy 30 kGy 1 None 6.6 6.7 8.4
9.4 2 PBMA 194 212 312 435 3 PBMAMMA 216 223 403 623 4 PVAc 319 309
369 407 5 PEHA 57.5 56 402 100 6 PEHMA 207 205 298 376
[0090]
8TABLE VIII Post Exposure Data (t = 0) Formulation Q Initial
Results Formulation Q Viscosity Modified Monomers Viscosity (cps)
Sample Dry ID Polymer Control Heat 20 kGy 30 kGy 1 None 6.8 6.7 8.6
9.2 2 PBMA 197 215 317 433 3 PBMAMMA 190 190 304 447 4 PVAc 293 299
347 369 5 PEHA 59 60 427 102 6 PEHMA 192 193 256 307
[0091]
9TABLE IX Post Exposure Data (t0) Formulation S Initial Results
Formulation S Viscosity Modified Monomers Viscosity (cps) Sample
Dry ID Polymer Control Heat 20 kGy 30 kGy 1 None 6.5 ND 8.4 9.4 2
PBMA 203 214 298 374 3 PBMAMMA 217 232 366 516 4 PVAc 295 306 357
369 5 PEHA 54 54 74 88
[0092]
10TABLE IX Post Exposure Data (t = ) Formulation S Initial Results
Formulation S Viscosity Modified Monomers Viscosity (cps) Sample
Dry ID Polymer Control Heat 20 kGy 30 kGy 6 PEHMA 207 207 309
350
[0093] The data shows that the dry heat cycle has a minimal effect
on the sample formulations. As stated above, exposure to electron
beam radiation has an effect on the formulation viscosity such that
the viscosity increases with increasing exposure level. However,
the effect appears to be formulation dependent, since there is
significant variation in the viscosity change when the formulation
sets are compared.
[0094] The data indicates that the chosen polymers are stable to
the dry heat sterilization cycle and do not have any significant
change in viscosity after exposure. Exposure of the formulations to
electron beam radiation indicates that the degradation of the
polymer has an effect on the formulation viscosity. A 50-100%
increase in viscosity is acceptable in the thickened formulation as
long as the formulation is stable and the increase is
reproducible.
[0095] While the invention has been described with reference to
preferred embodiments, the invention is not limited to the specific
examples given, and other embodiments and modifications can be made
by those skilled in the art without departing from the spirit and
scope of the invention.
* * * * *