U.S. patent application number 10/931126 was filed with the patent office on 2005-02-24 for stabilized polyester/cyanoacrylate tissue adhesive formulation.
Invention is credited to Shalaby, Shalaby W..
Application Number | 20050042197 10/931126 |
Document ID | / |
Family ID | 32324390 |
Filed Date | 2005-02-24 |
United States Patent
Application |
20050042197 |
Kind Code |
A1 |
Shalaby, Shalaby W. |
February 24, 2005 |
Stabilized polyester/cyanoacrylate tissue adhesive formulation
Abstract
The present invention is directed to adhesive/hemostatic
formulations of 2-alkoxyalkyl cyanoacrylate, an absorbable liquid
or solid polymeric modifier, and a general stabilizer against
premature anionic polymerization of cyanoacrylates. The present
adhesive formulations are useful as tissue adhesives/sealants,
hemostatic agents, or as a means of patching and anastomotic
coupling of damaged organs.
Inventors: |
Shalaby, Shalaby W.;
(Anderson, SC) |
Correspondence
Address: |
LEIGH P. GREGORY
ATTORNEY AT LAW
PO BOX 168
CLEMSON
SC
29633-0168
US
|
Family ID: |
32324390 |
Appl. No.: |
10/931126 |
Filed: |
August 31, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10931126 |
Aug 31, 2004 |
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10300076 |
Nov 20, 2002 |
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10300076 |
Nov 20, 2002 |
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09932628 |
Aug 17, 2001 |
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6723114 |
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09932628 |
Aug 17, 2001 |
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09439167 |
Nov 12, 1999 |
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6299631 |
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60102868 |
Nov 12, 1998 |
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60115836 |
Jan 14, 1999 |
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Current U.S.
Class: |
424/78.27 ;
525/295 |
Current CPC
Class: |
A61L 24/001 20130101;
A61L 24/06 20130101; A61L 24/043 20130101; A61L 24/06 20130101;
A61B 17/11 20130101; A61B 17/00491 20130101; A61L 24/043 20130101;
C08L 35/04 20130101; C08L 35/04 20130101 |
Class at
Publication: |
424/078.27 ;
525/295 |
International
Class: |
A61K 031/785; A61L
015/16; C08F 267/08 |
Claims
1. A stabilized cyanoacrylate-based composition comprising at least
about 1 ppm of at least one physically compatible acid selected
from the group consisting of phosphorous-containing acid, monobasic
organic sulfonic acid and precursors thereof, wherein the acid
stabilizes the reactive double bond of the cyanoacrylate against
premature anionic polymerization.
2. A cyanoacrylate-based composition as in claim 1 wherein the acid
comprises a phosphorous-containing acid selected from the group
consisting of phosphoric acid, phosphorous acid anhydride,
pyrophosphoric acid, and polyphosphoric acid.
3. A cyanoacrylate-based composition as in claim 1 wherein the acid
comprises an organic sulfonic acid-based moiety selected from the
group consisting of p-toluene sulfonic acid, methane sulfonic acid,
and trifluoroacetic acid.
4. A cyanoacrylate-based composition as in claim 1, comprising
methoxypropyl cyanoacrylate admixed with a liquid or compliant
solid copolyester modifier and comprising pyrophosphoric acid as
the stabilizer.
5. A cyanoacrylate-based composition as in claim 4, that is
radiochemically stabilized and suitable for use as an absorbable,
sterile, tissue adhesive or sealant in repairing internal wound or
redirecting the function of internal organs.
6. A cyanoacrylate-based composition as in claim 5, that can be
applied to surgically, accidentally, or pathologically compromised
skin or internal sites using a delivery device or catheter having
covalently linked acidic groups.
7. A cyanoacrylate-based composition as in claim 6, used in wound
repairs associated with endoscopic procedures.
8. A cyanoacrylate-based composition as in claim 1, comprising at
least one alkyl cyanoacrylate monomer selected from the group
consisting of methyl-cyanoacrylate, ethyl-cyanoacrylate,
n-propyl-cyanoacrylate, isopropyl-cyanoacrylate,
n-butyl-cyanoacrylate, isobutyl-cyanoacrylate,
isooctyl-cyanoacrylate, and n-octyl-cyanoacrylate.
9. A cyanoacrylate-based composition as in claim 8, that is
radiochemically sterilized and packaged as a sterile product.
10. A cyanoacrylate-based composition as in claim 9, for use as a
tissue adhesive, sealant, or blocking agent.
11. A cyanoacrylate-based composition as in claim 8 for use as an
intravascular sealant or blocking agent, wherein its delivery
system comprises an intravascular flexible catheter having
covalently bound sulfonic groups on its surface.
12. A cyanoacrylate-based composition as in claim 9 for use as an
intravascular sealant or blocking agent, wherein its delivery
system comprises an intravascular flexible catheter having
covalently bound sulfonic groups on its surface.
Description
[0001] This is a divisional application of U.S. Ser. No. 10/300,076
filed Nov. 20, 2002, which is a continuation-in-part application of
U.S. Ser. No. 09/932,628, filed Aug. 17, 2001, which is a
divisional application of U.S. Ser. No. 09/439,167, filed Nov. 12,
1999, now issued as U.S. Pat. No. 6,299,631, which claimed the
benefit of two provisional applications, U.S. Ser. No. 60/102,868,
filed Nov. 12, 1998, and U.S. Ser. No. 60/115,836, filed Jan. 14,
1999.
BACKGROUND OF THE INVENTION
[0002] The prior art on absorbable alkoxyalkyl cyanoacrylate-based
tissue adhesive/sealant formulations dealt with polymeric modifiers
such as oxalate polymers of trimethylene glycol (U.S. Pat. No.
5,350,798), oxalate polymers of polyethylene glycol (U.S. Pat. No.
6,299,631), and trimethylene carbonate-based polymers (U.S. Pat.
No. 6,299,631). All of these formulations were shown to exhibit
clinically significant properties. However, it has been noted that
upon packaging these formulations in market-acceptable and user
friendly forms, occasional premature anionic polymerization of the
cyanoacrylate component, and subsequent reduction or loss of these
intended properties can be encountered in the presence of a trace
amount of water or basic compounds that may be brought into contact
with said formulations, inadvertently. Obviously, this can
compromise the shelf-stability of the respective tissue
adhesive/sealant in the final marketable form. Accordingly, this
invention deals with the prevention of premature anionic
polymerization and reduction or loss of intended adhesive/sealant
properties by the incorporation of certain stabilizers into the
absorbable cyanoacrylate formulation. The use of such stabilizers
can also be extended to non-absorbable cyanoacrylate adhesives.
Addition of such stabilizer is intended to achieve adequate
shelf-stability of packaged products as well as to prevent any
changes in the formulations during their preparation due to
extraordinary exposure to water vapor or a similar anionic
initiator.
SUMMARY OF THE INVENTION
[0003] The principle aspect of this invention is directed to a
bioabsorbable adhesive formulation, which is an admixture of an
alkoxyalkyl cyanoacrylate, an absorbable liquid or solid polymeric
modifier, and a stabilizer against premature anionic polymerization
of the cyanoacrylate components, wherein said stabilizers are one
or more miscible acidic compounds, including either
phosphorus-containing acids and precursors thereof such as
pyrophosphoric acid, polyphosphoric acid, and phosphoric acid, or
monobasic organic sulfonic acids such as p-toluene sulfonic acid,
trifluoroacetic acid, and methanesulfonic acid at a concentration
exceeding 1 ppm. The absorbable polymeric liquid or solid modifier
can be one or more of the polymers described in U.S. Pat. Nos.
5,350,798 and 6,299,631.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0004] This invention deals with absorbable tissue adhesive/sealant
formulations that are stabilized against premature anionic
polymerization based on combinations of 2-cyanoacrylate ester and
one or more absorbable liquid or compliant solid copolyester
modifier of the types disclosed in U.S. Pat. Nos. 5,350,798 and
6,299,631, in the presence of one or more miscible acidic compounds
or precursors thereof including either phosphorus-containing
compounds such as phosphoric acid, pyrophosphoric acid, and
polyphosphoric acid, or monobasic organic sulfonic acids such as
p-toluene sulfonic acid, methanesulfonic acid, trifluoroacetic
acid, at a concentration that exceeds 1 ppm.
[0005] One specific aspect of this invention deals with
adhesive/sealant formulations of 2-methoxypropyl cyanoacrylate and
one or more amorphous or low-crystallinity polyaxial copolyesters,
such as those described in U.S. Pat. No. 6,462,169 and
pyrophosphoric acid as the stabilizer. Another specific aspect of
this invention deals with adhesive/sealant formulations of
2-methoxypropyl cyanoacrylate and one or more absorbable,
hydrogel-forming, self-solvating liquid copolyesters of those
described in U.S. Pat. No. 6,413,539, after acylation of the
hydroxyl end-groups of their chains and pyrophosphoric acid.
[0006] Another aspect of this invention deals with stabilized
cyanoacrylates used as absorbable or non-absorbable tissue
adhesives or as industrial adhesives, wherein the cyanoacrylate
components can be one or a combination of these used as tissue
adhesives/sealants or an industrial adhesive and the stabilizer
being one or more of the acidic compounds or a precursor of acidic
compounds. Among cyanoacrylate formulations suitable for
stabilization are those comprising methyl cyanoacrylate, ethyl
cyanoacrylate, isopropyl cyanoacrylate, n-propyl cyanoacrylate,
n-butyl cyanoacrylate, isobutyl cyanoacrylate, isooctyl
cyanoacrylate, and n-octyl cyanoacrylate.
[0007] Another aspect of this invention deals with minimizing or
eliminating the chance of premature polymerization of
cyanoacrylates or their formulations upon transfer to the
application site during their use in a typical industrial
application or use as tissue adhesives/sealants, wherein
stabilization against premature polymerization is achieved through
modifying the surface of the delivery apparatus in direct contact
of the cyanoacrylate. A more specific aspect of this invention
deals with a polymeric catheter or container made of polyethylene,
polypropylene, or any similar polymer capable of surface
sulfonation or phosphonylation to introduce covalently bonded acid
groups on the cyanoacrylate-contacting surface as described in U.S.
Pat. Nos. 5,558,517 and 5,491,198. Accordingly, the delivery device
used to administer the cyanoacrylate-based system will be
phosphonylated or sulfonated to introduce covalently bonded
sulfonic or phosphonic groups on the contacting surface that will
prevent premature anionic polymerization of the cyanoacrylate
components. Another aspect of this invention deals with
radiochemical sterilization (described in U.S. Pat. No. 5,422,068)
of packaged cyanoacrylate formulations using a combination of 5 to
7.5 kGy of gamma radiation and radiolytically generated gaseous
formaldehyde, wherein the liquid formulation is contained in an
ampoule with a tapered neck made of a suitable polymer, such as
polyethylene and enclosed in a hermetically sealed, secondary
package containing a gas permeable fabric pouch containing
radiolytically labile polyformaldehyde (as a precursor of
formaldehyde). Radiochemically sterilized cyanoacrylate
formulations, such as that of methoxypropyl cyanoacrylate,
containing an absorbable copolyester modifier and stabilized
against premature polymerization were shown to be fully sterile
and, hence, suitable for internal surgical applications. Another
aspect of this invention is a method of delivering radiochemically
sterilized cyanoacrylate formulation for internal or external
applications at surgical or wound repair sites. Another aspect of
this invention is the use of radiochemically sterilized
cyanoacrylate formulation endoscopically through polymeric delivery
catheters or devices whose cyanoacrylate-contacting surface is
chemically modified to introduce an acid group, such as phosphonic
or sulfonic ones.
[0008] Another aspect of this invention deals with a
cyanoacrylate-based composition colored with an organic dye.
[0009] Further illustrations of the present invention are provided
by the following examples, which deal with the preparation of
typical polymeric modifiers and their incorporation in tissue
adhesive formulations with different cyanoacrylates in the presence
of small amounts of polyphosphoric acid (PPA) as the
stabilizer.
EXAMPLE 1
Preparation of a Polyethylene Glycol Copolyester (GF) Acetylated
Derivative (AC-GF)
[0010] A copolyester of polyethylene glycol 400 (PEG-400) was
prepared by end-grafting the PEG-400 (15 g) with a 60/40 molar
ratio of dl-lactide/glycolide (85 g) at 150.degree. C. in the
presence of a catalytic amount of stannous octanoate until
practically complete conversion is achieved. The resulting GF was
isolated, purified, and characterized as described in U.S. Pat. No.
6,413,539. The purified product was then acylated by treating with
a four-fold excess (based on Mn determined by GPC) of acetic
anhydride at 120.degree. C. for four hours. Unreacted anhydride and
the acetic acid by-product were removed by distillation under
reduced pressure above 80.degree. C. The acetylated GF (AC-GF) was
characterized for identity (IR and NMR) and molecular weight
(GPC).
EXAMPLE 2
Preparation and Characterization of Polyaxial Copolyester (PAX)
[0011] A polyaxial polymeric initiator was first prepared by
copolymerization of 5/20/25 (molar) of glycolide (G),
.epsilon.-caprolactone (CL), and trimethylene carbonate (TMC) in
the presence of stannous octoate and trimethyl propane as a
catalyst and monomeric initiator, respectively, as described in
U.S. Pat. No. 6,462,169. The polyaxial polymeric initiator was then
grafted with 1-lactide (LL) to yield a segmented, partially
crystalline polymer comprising sequences derived from G, CL, TMC,
and LL at a ratio of 5/20/25/50. The segmented copolymer was
isolated and purified as per U.S. Pat. No. 6,467,169, and then
characterized for identity (IR and NMR) molecular weight (GPC) and
thermal properties (DSC).
EXAMPLE 3
Preparation of an 85/15 Tissue Adhesive Formulations of Undyed
Methoxypropyl Cyanoacrylate (MPC) and AC-GF
[0012] In a predried glass reactor equipped for mechanical
stirring, AC-GF (5.3 g from Example 1), and an equal amount of MPC
(5.3 g) containing small amounts of pyrophosphoric acid (2 mg),
were mixed under a dry nitrogen atmosphere. The mixture is then
heated to 110.degree. C. and maintained at that temperature until
complete mixing is achieved. The mixture was then cooled to
60.degree. C. and an additional amount of MPC (24.7 g) was added
and the mixing continued for about one hour and then allowed to
reach room temperature to yield a uniform clear liquid. This was
characterized for identity by infrared and adhesive strength using
the fabric peel test [as described by J. D. Kline et al., Sixth
World Biomaterials Congress, Trans. Soc. Biomat., III, 1062
(2000)].
EXAMPLE 4
Preparation of Dyed 85/15 Tissue Adhesive Formulation of MPC and
AC-GF
[0013] This was conducted as in Example 3 with the exception of
mixing D & C Violet #2 at 0.05% concentration with the final
liquid formulation.
EXAMPLE 5
Preparation of Undyed Tissue Adhesive Formulations of 95/5, MPC and
PAX
[0014] In a predried glass reactor equipped for mechanical
stirring, PAX (20 g from Example 2) and MPC (20 g) containing a
small amount of pyrophosphoric acid (8 mg) were mixed under a dry
nitrogen atmosphere. The mixture is then heated to 110.degree. C.
and maintained at that temperature until complete mixing is
achieved. The mixture was then cooled to 60.degree. C. and an
additional amount of MPC (360 g) was added and the mixing continued
for about one hour and allowed to cool to room temperature to yield
a uniform clear liquid. The product was characterized as described
in Example 3.
EXAMPLE 6
Preparation of Dyed 95/5, MPC/PAX Formulation
[0015] This was conducted as in Example 5 with the exception of
mixing D & C Violet #2 t 0.05% concentration with the final
liquid formulation.
EXAMPLE 7
Preparation of Undyed 97/3, MPC/PAX Adhesive Formulation
[0016] This was conducted as in Example 5 with the exception of
using 7.5 g of PAX (from Example 2) and 7.5 g of MPC containing 2.5
mg pyrophosphoric acid in the first stage, and 235 g of MPC in the
second stage.
EXAMPLE 8
Packaging and Sterilization of Undyed 97/3, MPC/PAX
[0017] Polyethylene ampoules with tapered nicks were filled under
dry nitrogen with undyed aliquots (0.2 ml) of the formulation from
Example 7. Eighteen of these ampoules were packaged under dry
nitrogen atmosphere in a hermetically sealed secondary package
containing a porous, heat-sealed polyester pouch containing 200 mg
of unstabilized polyformaldehyde powder (Celcon M-90). The
secondary package and its contents were radiochemically sterilized
using 5 kGy at a dose rate of 32 kGy/hour. The sterilized
formulation was tested for identity (by IR), adhesive property
(using the fabric peel test as in Example 3), and for sterility.
Using standard microbiological assays, the liquid formulation and
the surface of the sealed ampoule were tested after more than one
month post-irradiation, and were shown to be sterile. The adhesive
strength of the sterilized formulation was slightly lower than that
of the same formulation before sterilization.
EXAMPLE 9
Preparation of Undyed 97/3 Tissue Adhesive Formulations of Ethyl
Cyanoacrylate (EC) and AC-GF
[0018] This was conducted as in Example 7 with the exception of
using ethyl cyanoacrylate instead of MPC.
EXAMPLE 10
Evaluation of Shelf-life Stability of Stabilized Cyanoacrylate
Formulations
[0019] The shelf stability at 4.degree. C. of the formulations of
Examples 3 through 9 at 3, 6, 9, or 12 months were tested in terms
of changes in typical group frequencies (using IR) and adhesive
strength (using the fabric peel test). No discernable changes in
properties were observed for all formulations, which exhibited
acceptable one-year shelf stability.
[0020] Although the present invention has been described in
connection with the preferred embodiments, it is to be understood
that modifications and variations may be utilized without departing
from the principles and scope of the invention, as those skilled in
the art will readily understand. Accordingly, such modifications
may be practiced within the scope of the following claims.
Moreover, Applicant hereby discloses all subranges of all ranges
disclosed herein. These subranges are also useful in carrying out
the present invention.
* * * * *