U.S. patent number RE30,170 [Application Number 05/842,379] was granted by the patent office on 1979-12-18 for hydrolyzable polymers of amino acid and hydroxy acids.
This patent grant is currently assigned to Sutures, Inc.. Invention is credited to Murray Goodman, Gerald S. Kirshenbaum.
United States Patent |
RE30,170 |
Goodman , et al. |
December 18, 1979 |
Hydrolyzable polymers of amino acid and hydroxy acids
Abstract
Hydrolyzable film- and fiber-forming polymers having a plurality
of repeating units of the formula: ##STR1## wherein R is lower
alkyl, aryl, alkaryl and aralkyl; R.sub.1, R.sub.2 and R.sub.3 are
each selected from H or lower alkyl with the proviso that at least
one of R.sub.1, R.sub.2, R.sub.3 is H; and n is an integer of 0 to
2.
Inventors: |
Goodman; Murray (Brooklyn,
NY), Kirshenbaum; Gerald S. (Fanwood, NJ) |
Assignee: |
Sutures, Inc. (Coventry,
CT)
|
Family
ID: |
27073752 |
Appl.
No.: |
05/842,379 |
Filed: |
October 11, 1977 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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565076 |
Apr 4, 1975 |
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Reissue of: |
151577 |
Jun 9, 1971 |
03773737 |
Nov 20, 1973 |
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Current U.S.
Class: |
528/327;
264/290.7; 525/419; 528/328; 606/231 |
Current CPC
Class: |
C08G
69/44 (20130101) |
Current International
Class: |
C08G
69/00 (20060101); C08G 69/44 (20060101); C08G
069/10 (); C08G 069/44 () |
Field of
Search: |
;260/78A
;528/327,328 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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42-11672 |
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Jul 1967 |
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JP |
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1099184 |
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Jan 1968 |
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GB |
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Other References
Chem. Abstracts, vol. 67, 1967, 100555m, Ishida et al. .
Kirk-Othmer, Encyclopedia of Chem. Technology, 2nd Ed., vol. 16, p.
1. .
Your Choice of Suture (1970) and Deknatel Sutures. .
Webster's New World Dictionary, 2nd College Ed., 1972, p. 1435.
.
Webster's Third New International Dictionary, 1961, p.
2304..
|
Primary Examiner: Schain; Howard E.
Attorney, Agent or Firm: Larson, Taylor and Hinds
Parent Case Text
This is a continuation of application Ser. No. 565,076 filed Apr.
14, 1975 and now abandoned..Iaddend.
Claims
What is claimed is: .[.1. A hydrolyzable film- and fiber-forming
polymer having a plurality of repeating units of the formula:
##STR9## wherein R is lower alkyl, aryl, alkaryl, or aralkyl;
R.sub.1, R.sub.2 and R.sub.3 are each selected from H or lower
alkyl with the proviso that at least one of R.sub.1, R.sub.2 and
R.sub.3 is H; and n is an integer of 0
to 2..]. .[.2. A film- and fiber-forming polymer of claim 1 wherein
R is lower alkyl..]. .[.3. film- and fiber-forming polymer of claim
2 wherein the lower alkyl is methyl..]. .[.4. A film- and
fiber-forming polymer of claim 1 wherein the R is aralkyl..]. .[.5.
A film- and fiber-forming polymer of claim 1 wherein the aralkyl is
benzyl..]. .[.6. A film- and fiber-forming polymer of claim 1
wherein the repeating unit has the formula: ##STR10##
.[.7. A film- and fiber-forming polymer of claim 1 wherein the
repeating unit has the formula: ##STR11##
.[.8. A film- and fiber-forming polymer of claim 1 wherein the
repeating unit has the formula: ##STR12##
.[.9. A film- and fiber-forming polymer of claim 1 wherein the
repeating unit has the formula: ##STR13##
.[.10. A fiber of the polymer of claim 1..]. .[.11. A fiber of the
polymer of claim 6..]. .[.12. A fiber of the polymer of claim 7..].
.[.13. A fiber of the polymer of claim 8..]. .[.14. A fiber of the
polymer of
claim 9..]. 15. .[.A.]. .Iadd.An absorbable .Iaddend.surgical
suture .[.comprising polyfilaments of the polymer of clam 1.].
.Iadd.of a hydrolyzable film- and fiber-forming polymer having a
plurality of repeating units of the formula: ##STR14## wherein R is
lower alkyl, aryl, alkaryl or aralkyl; R.sub.1, R.sub.2 and R.sub.3
are each selected from H or lower alkyl with the proviso that at
least one of R.sub.1, R.sub.2 and R.sub.3 is H; and n is an integer
of 0
to 2.Iaddend.. 16. .[.A.]. .Iadd.The .Iaddend.surgical suture
.[.comprising polyfilaments of the polymer of claim 6.]. .Iadd.of
claim 15 wherein the repeating unit has the formula: ##STR15##
.Iaddend. 17. .[.A.]. .Iadd.The .Iaddend.surgical suture
.[.comprising polyfilaments of the polymer of claim 7.]. .Iadd.of
claim 15 wherein the repeating unit has the formula: ##STR16##
18. .[.A.]. .Iadd.The .Iaddend.surgical suture .[.comprising
polyfilaments of the polymer of claim 8.]. .Iadd.of claim 15
wherein the repeating unit has the formula: ##STR17##
.Iaddend. 19. .[.A.]. .Iadd.The .Iaddend.surgical suture
.[.comprising polyfilaments of the polymer of claim 9.]. .Iadd.of
claim 15 wherein the repeating unit has the formula: ##STR18##
.Iaddend.
Description
This invention relates to a novel class of high molecular weight
condensation polymers. More particularly, the present invention is
directed to hydrolyzable, high molecular weight, linear
polydepsipeptides in which ester bonds, derived from .alpha.-,
.beta.- and .gamma.-hydroxy acid residues, are incorporated at
intervals along an otherwise peptide backbone. The polymers of the
invention display excellent physical, chemical and biological
properties which make them useful as shaped structures such as
self-supporting films, fibers and the like. In particular, the
polymers of the invention possess unique hydrolysis characteristics
which make them especially useful in the preparation of synthetic
absorbable sutures.
The vast majority of absorbable sutures today are made from natural
proteinaceous polymeric materials such as a silk and reconstituted
collagen or gut. Ordinarily, breakdown and internal body absorption
of these materials requires a complex and unpredictable enzymatic
reaction which frequently poses a number of problems. Consequently,
efforts have been made to develop synthetic absorbable sutures
which breakdown by simple hydrolysis. The only sutures of this type
which have found any acceptance are those fabricated from
polylactides and polyglycolides. Sutures prepared from polylactides
and polyglycolides are not without their shortcomings, however, the
foremost of which is their ready hydrolysis. In other words,
sutures of these materials hydrolyze so quickly that they fail to
retain their tensile strength for a period of time considered
necessary by many for properly healing of the sutured wound or
incision.
It is an object of the present invention, therefore, to provide a
polymeric material which is decomposable by simple hydrolysis under
basic, neutral or acid conditions but which requires significantly
longer periods of time for such decomposition than found for
polylactides and polyglycolides of similar molecular weight.
Another object of the invention is to provide a polymer which while
possessing said hydrolyzable properties can be shaped into
self-supporting films and fibers characterized by high tensile
strength and other characteristics desirable of such films and
fibers.
Yet another object of the invention is to provide synthetic
absorbable sutures which retain the desired strength
characteristics for proper healing of wounds and incisions stitched
therewith but which will thereafter be broken down by simple body
hydrolysis.
These and other objects of the invention are obtained by a novel
group of polymers characterized by a repeating unit having the
following structural formula: ##STR2## wherein R is a lower alkyl,
say of 1 to 5 carbons, aryl, alkyaryl or aralkyl; R.sub.1, R.sub.2
and R.sub.3 are each selected from H or lower alkyl, with the
proviso that at least one of R.sub.1, R.sub.2 and R.sub.3 is H; and
n is the integer of 0 to 2.
The polymers of the invention may be prepared by polymerizing
condensible derivatives, such as the anhydrides or anhydrosulfites,
of .alpha.-amino acids having the structure: ##STR3## and hydroxy
organic acids having the structure: ##STR4## wherein R, R.sub.1,
R.sub.2, R.sub.3 and n have the values assigned above.
Advantageously, the polymers of the invention may be prepared by
reacting at least one N-carboxy-.alpha.-amino anhydride having the
structure: ##STR5## with at least one androsulfite of an hydroxy
organic carboxylic acid having the structure: ##STR6## wherein R,
R.sub.1, R.sub.2 and R.sub.3 have the values assigned above.
Illustrative of N-carboxy-.alpha.-amino compounds suitable for
preparation of the polymers of the invention may be included the
anhydrides of alanine, 2-amino-n-butyric acid, 2-aminoisobutyric
acid, 2-aminopentanoic acid, 2-amino-n-hexanoic acid, valine,
leucine, isoleucine, 2-amino-2-methylpropionic acid,
2-amino-2-ethyl-propionic acid, 2-amino-2-methyl-heptanoic acid,
2-amino-2-propylpropionic acid, 2-amino-2-phenyl-propionic acid,
2-amino-2-tolyl-propionic acid, phenylalanine and the like.
Exemplary of anhydrosulfite reactants suitable for use in the
preparation of the polymers of the invention are the
anhydrosulfites of 2-hydroxyethanoic acid, lactic acid,
2-hydroxypropanoic acid, 2-hydroxyheptanoic acid,
2-hydroxypentanoic acid, 2-hydroxyhexanoic acid, 2-hydroxyheptanoic
acid, hydroxyisobutyric acid, 2-hydroxy-2-ethylpropanoic acid,
2-hydroxy-2-ethylpropanoic acid, 2-hydroxy-2-propyl-propanoic acid,
2-hydroxy-2-butylbutanoic acid, etc.
Polymers of the invention may also be prepared by reacting at least
one of the aforementioned N-carboxy-.alpha.-amino anhydrides with a
lactone having the structure: ##STR7## wherein x is an integer of 1
to 2. Suitable lactones include for instance, .beta.-propiolactone
and .gamma.-butyrolactone.
Although polymers of the invention may be terpolymers or
interpolymers of three or more dissimilar monomers, they are
preferably copolymers of a single N-carboxy-.alpha.-amino acid
anhydride and a single hydroxy organic acid anhydrosulfite.
Infrared analysis and NMR (nuclear magnetic resonance) measurements
indicate the polymers of the invention be linear polymers composed
of block and/or alternating N-carboxy-.alpha.-amino acid residues
and hydroxy organic residues, the backbone of the polymer having
the aforementioned repeating units: ##STR8## wherein R, R.sub.1,
R.sub.2, R.sub.3 and n is defined as above. Hydrolysis tests
establish that the polymers are definitely copolymers and not
homopolymers. Furthermore, the polymers are found to be soluble in
benzene which shows them to be copolymers since the
homopolypeptides are not soluble in benzene.
The polymerization or condensation reaction can be conducted by
simply adding the reactants with or without a catalyst or initiator
to a suitable inert liquid diluent and heating the reactants under
preferably anhydrous conditions to reaction temperature. Generally
equimolar amounts of the reactants are used since a large excess of
one or the other limits the extent of polymerization and the
reaction carried out under reflux conditions.
In the preparation of the polymers of the invention, it is
preferred that the molecular weight of the resulting polymer be
such that its intrinsic viscosity be at least about 0.08 preferably
at least about 0.3 to 5.0. The intrinsic viscosity is measured at
30.degree. C. in trifluoroacetic acid.
The inert liquid diluents in the polymerization reaction are those
non-reactive with either of the starting materials or the polymer
product. Preferably the inert liquid diluent is an organic solvent
for the starting materials but a non-solvent for the polymeric
product. Suitable inert liquid diluents which can be used include,
for example, aromatic hydrocarbons such as benzene, toluene, xylene
and the like, chlorinated hydrocarbons such as chlorobenzene;
aliphatic hydrocarbons such as n-hexane, n-heptane; halogenated
aliphatic hydrocarbons such as dichloromethane, tetrachloroethane;
monohydric phenols such as phenol, m-cresol, p-cresol, xylenol and
the like. Other suitable diluents will be obvious to those skilled
in the art.
Although the polymerization may often be conducted in the absence
of a catalyst or initiator, use of a catalyst is preferred and in
some instances necessary. Suitable catalysts include tertiary
amines such as tributyl amine, triamyl amine, triethyl amine,
pyridine, quinoline, N,N-dimethyl aniline, etc; alkali metal
alkoxides such as sodium methoxide, sodium ethoxide, potassium
propoxide and the like. The concentration of the catalyst may vary
widely but generally is employed in an anhydride reactant to
catalyst weight ratio of about 500 to 1,000.
Since in addition to the repeating ester units, the polymers of the
invention contain recurring amide linkages, it should be understood
that the polymer should contain a sufficient number of ester bonds
to endow it with the desired hydrolyzable properties. Generally,
the polymers of the invention will contain at least 15 mole percent
of the aforementioned repeating ester units based on the total
number of ester and amide units in the polymer. When the intended
use of polymers of the invention is for the preparation of fibers
for synthetic sutures fabrication, it is preferred that the polymer
contain no more than about 90 mole percent of said repeating ester
units since polymers containing in excess of 90 mole percent of the
ester units undergo too rapid hydrolysis. In most instances,
therefore, the preferred polymers of the invention contain about 40
to 60 mole percent of the defined repeating ester units. The
particular concentration of ester units in the polymer will depend
in part on the polymerization conditions, the reactants
polymerized, the activity of the particular monomers employed, the
presence or absence of catalyst and the particular catalyst
employed and its concentration.
The melting points of the polymers of the invention will vary
depending primarily upon the monomers employed and the proportions
of amide and ester residues in the polymer. In general, the
polymers have melting points of at least 150.degree. C. up to
350.degree. C. or more.
The following examples are included to further illustrate
preparation of the copolymers of the invention.
In the examples:
The infrared spectra were recorded on a Perkin-Elmer model 521
grating infrared spectrometer. The spectra were obtained in the
solid state as potassium bromide pellets, or as oils using sodium
chloride cells.
The nuclear magnetic resonance measurements were carried out on a
Varian Associates A-60 analytical NMR spectrometer and a Varian
Associates HR-220 high resolution NMR spectrometer.
Tetramethylsilane (TMS) was used as the internal standard.
Concentrations of 10% were used for the A-60 instrument, while
concentrations of 2-4% were used with the HR-220 instrument. All
spectra were recorded at room temperature.
The intrinsic viscosities of the polymers were determined using
standard Cannon viscometers (numbers 25, 50, and 100). The flow
times were recorded with a hand stopwatch which was calibrated to
0.1 second. The intrinsic viscosities were determined in
trifluoroacetic acid in accordance with the following equation:
in a thermostated, constant temperature water bath at
30.degree..
EXAMPLE I
Synthesis of the monomers
(a) L-alanine N-carboxyanhydride
(4-methyl-L-2,5-oxazolidinedione).-L-alanine (7.5 g., 0.084 mole)
was suspended in 300 ml. of dry tetrahydrofuran. The system was
purged with nitrogen for one hour. The suspension was then treated
with phosgene at 50.degree. for three hours until the L-alanine had
completely dissolved. The system was then purged with nitrogen for
two hours. The solvent and remaining gases were removed under
reduced pressure, and a white material was obtained which was
washed with hexane. This material was recrystallized several times
from ethyl acetate-hexane in a dry box. This reaction yielded 7.0
g. (73%) of the N-carboxyanhydride, M.P. 90.degree.-91.degree.
[lit. M.P.90.degree.].
(b) .alpha.-Aminoisobutyric acid N-carboxyanhydride
(4,4-dimethyl-2,5-oxazolidinedione).--This compound was prepared
according to the procedure in W. R. Sorenson and T. W. Campbell,
"Preparative Methods of Polymer Chemistry," 2nd ed., Interscience
Publishers, New York, 1968, p. 355 on a 0.15 mole scale. This
reaction furnished the desired product in 70% yield with a M.P.
95.degree.-96.degree. [lit. M.P. 95-97].
(c) .alpha.-Hydroxyisobutyric acid anhydrosulfite.--This compound
was prepared using the procedure in Sorenson and Campbell, supra;
p. 359 on a 0.20 mole scale. This reaction furnished the desired
product in 40% yield with a B.P. 55.degree. at 10 mm. Hg [lit. B.P.
53.degree.-55.degree. at 16 mm Hg]. The compound was prepolymerized
prior to use.
(d) S-lactic acid anhydrosulfite. This compound was prepared using
the procedure in Sorenson and Campbell, supra; for the
.alpha.-hydroxyisobutyric acid anhydrosulfite. Instead of purifying
this monomer by prepolymerization, it was distilled three times
under reduced pressure. The reaction furnished the desired product
in 40% yield with a B.P. 71.degree.-72.degree. at 16 mm. Hg [lit.
B.P. 72.degree.-74.degree. at 19 mm. Hg].
In the synthesis of the copolymers prepared in the examples below,
unless otherwise indicated, the following general procedure was
employed:
A round-bottom flask was dried in the oven for three hours. To the
flask, which was cooled under nitrogen, was added 40 ml. of
benzene. In order to make sure that the system was completely dry,
about 20 ml. of the benzene was distilled from the reaction vessel.
The flask was cooled under nitrogen in an ice-salt bath until the
benzene had frozen, and the reactants were then added to the flask.
The reaction mixture was refluxed for several days under nitrogen
to give a cloudy colorless gel. The gel was separated by filtration
to give a solid polymer.
EXAMPLE II
Copolymers of L-alanine and S-lactic acid--Reaction 1
L-alanine N-carboxyanhydride (1.0 g., 0.0087 mole), S-lactic acid
anhydrosulfite (1.0 ml.) and dry triethylamine (0.00243 ml.,
1.74.times.10.sup.-5 mole, anhydride-to-initiator ratio of 500)
were added to the reaction flask. This was refluxed for four days
under nitrogen. A white precipitate was obtained which was isolated
by filtration. This powder was washed with hot benzene to eliminate
any polylactic acid homopolymer that might have been formed during
the polymerization. The white powder was dissolved in hot
chloroform. However, the product only partially dissolved, and
therefore a soluble fraction (sample 1) and an insoluble fraction
(sample 2) were isolated by filtration. The insoluble fraction was
reprecipited from trifluoroethanol-petroleum ether, while the
soluble fraction was reprecipitated from chloroform-petroleum ether
and then trimethyl phosphate-petroleum ether. Integration of the
NMR spectra showed that sample 1 consisted of three lactic acid
residues for each alanine residue, while sample 2 had one alanine
residue for each lactic acid residue. Both samples decomposed
between 250.degree.-280.degree.. The reaction furnished about
100-200 mg. of each sample. The infrared spectra of both compounds,
exhibited an ester peak at 1755 cm..sup.-1, an amide II peak at
1540 cm..sup.-1, and a split amide I peak at 1655 and 1625
cm..sup.-1. There was not enough material to have elemental
analysis performed on the insoluble fraction. However, elemental
analysis was performed on the soluble fraction, sample I.
Analysis.--Calcd. (for the monomer ratio as determined from the
integration of the NMR spectrum) (percent): C, 50.46; H, 6.59; N,
13.09. Found (percent): C, 44.79; H, 5.87; N, 3.92.
Reaction 2.--This reaction was performed exactly as in reaction 1
except in this case the anhydride-to-initiator ratio was 50. A
white precipitate was isolated by filtration. The powder was washed
with hot benzene to eliminate any polylactic acid homopolymer that
might have formed during the polymerization. The white powder was
insoluble in hot chloroform. This reaction furnished about 0.75 g.
of the copolymer. Integration of the NMR spectrum showed that this
copolymer contained two alanine residues for each lactic acid
residue. The material decomposed between 210.degree. and
260.degree.. The infrared spectrum exhibited an ester peak at 1745
cm..sup.-1, an amide II peak at 1525 cm..sup.-1, and an amide I
peak at 1655 cm..sup.-1 with a shoulder at 1625 cm..sup.-1. The
intrinsic viscosity in trifluoroacetic acid at 30.degree. was
0.191. Hydrolysis data showed that the material was a copolymer and
not two homopolymers.
Analysis.--Calcd. (for the monomer ratios as determined from the
integration of the NMR spectrum) (percent): C, 50.46; H, 6.59; N,
13.09. Found (percent): C, 47.75; H, 5.87; N, 11.79.
EXAMPLE III
Copolymer of L-alanine and .alpha.-hydroxyisobutyric acid
L-alanine N-carboxyanhydride (1.0 g., 0.0087 mole),
.alpha.-hydroxyisobutyric acid and anhydrosulfite (1.0 ml.) and dry
triethylamine (0.0243 ml., 1.74.times.10.sup.-4 mole,
anhydride-to-initiator ratio of 50) were added to the reaction
flask. This was refluxed for four days under nitrogen. A white
precipitate was obtained which was isolated by filtration. The
compound was washed with hot benzene and hot chloroform in order to
eliminate any homopolyester that might have been formed during the
reaction. The reaction furnished about 0.6 g. of the copolymer. The
material did not melt or decompose below 275.degree.. Integration
of the NMR spectrum showed that the copolymer contained three
residues of alanine for each .alpha.-hydroxyisobutyric acid
residue. The intrinsic viscosity of the polymer in trifluoroacetic
acid at 30.degree. was 0.084. The infrared spectrum exhibited a
medium ester peak at 1745 cm..sup.-1, an amide II peak at 1525
cm..sup.-1, and a strong amide I peak at 1650 cm..sup.-1 with a
shoulder at 1625 cm..sup.- 1. Hydrolysis data showed that the
material was a copolymer and not two homopolymers.
Analysis.--Calcd. (for the monomer ratio as determined from
integration of the NMR spectrum) (percent): C, 52.16; H, 7.07; N,
14.04. Found (percent): C, 49.09; H, 6.87; N, 13.45.
EXAMPLE IV
Copolymer of S-lactic acid and .alpha.-aminobutyric acid
.alpha.-Aminoisobutyric acid N-carboxyanhydride (0.2 g., 0.00155
mole), S-lactic acid anhydrosulfite (0.2 ml.), and dry
triethylamine (0.00432 ml., 3.1.times.10.sup.-5 mole,
anhydride-to-initiator ratio of 50) were added to the reaction
flask. This was refluxed under nitrogen for one week but no
precipitate had formed. A small amount of petroleum ether was
added, and a white precipitate immediately formed. This material
was isolated by filtration. Upon adding more petroleum ether and
cooling in the refrigerator overnight a second precipitate had
formed. This second crop proved to be polylactic acid homopolymer.
The copolymer was reprecipitated from benzene-petroleum ether and
about 150 mg. of the polymer was obtained. The copolymer appeared
to soften between 133.degree.-140.degree. and underwent total
decomposition by 230.degree.. Integration of the NMR spectrum
showed that the copolymer contained three lactic acid residues for
each .alpha.-aminoisobutyric acid residue. The infrared spectrum
exhibited a very strong ester peak at 1755 cm..sup.-1, and weak to
medium amide peaks at 1655 and 1528 cm..sup.-1.
Analysis:--Calcd. (for the monomer ratios as determined from
integration of the NMR spectrum (percent): C, 51.82; H, 6.36; N,
4.65. Found (percent): C, 36.69; H, 4.32; N, 2.05.
EXAMPLE V
Copolymers of L-alanine and .beta.-propiolactone
In each of the following reactions L-alanine N-carboxy anhydride (1
mole) was stirred in .beta.-propiolactone (2 moles) at room
temperature. The polymers were isolated and purified. The infrared
spectra exhibited a strong ester peak at 1738 cm..sup.-1, an amide
II peak at 1525 cm..sup.-1 for each copolymer. The copolymers did
not melt or decompose below 300.degree.. Hydrolysis data showed
that these compounds were indeed copolymers.
Reaction 1.--No catalyst was used in this reaction. Integration of
the NMR spectrum showed that the copolymer contained three alanine
residues for each .beta.-propiolactone residue. The intrinsic
viscosity of the copolymer in trifluoroacetic acid at 30.degree.
was 0.352.
Analysis.--Calcd. (for the monomer ratio as determined from
integration of the NMR spectrum) (percent): C, 50.48; H, 7.06; N,
14.93. Found (percent): C, 50.52; H, 6.71; N, 14.73.
Reaction 2.--Sodium methoxide was used as a catalyst with
anhydride-to-initiator ratio of 1000. The integration of the NMR
spectrum showed that the copolymer contained one alanine residue
for each .beta.-propiolactone residue. The intrinsic viscosity of
the copolymer in trifluoroacetic acid at 30.degree. was 0.345.
Analysis.--Calcd. (for the monomer ratio as determined from
integration of the NMR spectrum) (percent): C, 50.50; H, 6.04; N,
10.21. Found (percent): C, 50.35; H, 6.34; N, 9.79.
Reaction 3.--Benzylamine was used as a catalyst with an
anhydride-to-initiator ratio of 1000. The integration of the NMR
spectrum showed that the copolymer contained three alanine residues
for every two .beta.-propiolactone residues. The intrinsic
viscosity of the copolymer in trifluoroacetic acid at 30.degree.
was 0.415.
Analysis.--Calcd. (for the monomer ratio as determined from
integration of the NMR spectrum) (percent): C, 50.24; H, 6.84; N,
11.57. Found (percent): C, 50.42; H, 6.49; N, 11.76.
EXAMPLE VI
Alternating copolymer of L-phenylalanine and hydracrylic acid
This polymer had a softening point between 110.degree. and
120.degree.. The infrared spectrum exhibited a strong ester peak at
1740 cm..sup.-1 and strong amide peaks at 1650 and 1525 cm..sup.-1.
Integration of the NMR spectrum showed that the copolymer consisted
of one residue of L-phenylalanine for each residue of hydracrylic
acid.
The hydrolysis experiments were carried out in the examples below
in the following manner:
The polymer (approximately 150 mg.) was placed in concentrated
hydrochloric acid (5 ml.), and was allowed to stir at room
temperature for five days. The viscosity and infrared spectra of
the initial polymers were compared to those of the resulting
compounds after the hydrolysis experiments. Any portion of the
polymer that did not dissolve in the acid was isolated by
filtration and investigated.
HYDROLYSIS OF POLYMERS AND COPOLYMERS
EXAMPLE VII
Poly-S-lactic acid
Poly-S-lactic acid (152 mg.) was placed in concentrated
hydrochloric acid (5 ml.), and after five days, the polymer had
completely dissolved in the acid. The intrinsic viscosity of the
starting polymer in benzene at 30.degree. was 0.14, and the
intrinsic viscosity of the polymer after hydrolysis was 0.0066 in
hydrochloric acid at 30.degree.. The solution was evaporated to
dryness, and an oil was obtained. The infrared spectrum of this oil
exhibited a very broad absorption region between 3500 and 2900
cm..sup.-1 and a broad band at 1735 cm..sup.-1. These peaks are
typical of acids. The initial polymer had a sharp peak at 1755
cm..sup.-1, an ester peak, and no broad absorption region above
3000 cm..sup.-1. The data indicate that poly-S-lactic acid was
completely hydrolyzed during the hydrolysis experiment.
EXAMPLE VIII
Poly-L-alanine
Poly-L-alanine (164 mg.) was placed in concentrated hydrochloric
acid, and after five days, hardly any of the polymer had dissolved.
This material was separated by filtration furnishing over 60 mg. of
the undissolved material. The remaining solution was evaporated to
dryness. The infrared spectrum of the undissolved material was
identical to that of poly-L-alanine. The viscosity (n.sub.sp./c.)
of the undissolved solid was 0.446 in dichloroacetic acid at
30.degree. compared to that of the initial polymer, 0.645. The
infrared spectrum of the oil, obtained from evaporation of the
solution, exhibited very weak amide peaks. These results indicate
that poly-L-alanine is only slightly hydrolyzed by treatment with
hydrochloric acid for five days at room temperature.
EXAMPLE IX
Copolymer of L-alanine and .alpha.-hydroxyisobutyric acid
The copolymer (170 mg.), which contained three alanine residues for
each .alpha.-hydroxyisobutyric acid residue, was placed in
concentrated hydrochloric acid, and after five days, nearly all of
the copolymer had dissolved. Some undissolved material (10-15 mg.)
was isolated by filtration. The remaining solution (the filtrate)
was then evaporated, and an oil was obtained. The infrared spectrum
of the solid sample was identical to that of poly-L-alanine. The
viscosity (n.sub.sp./c.) of this solid was 0.0538 at 30.degree. in
trifluoroacetic acid, while the value for the initial copolymer was
0.108 under the same conditions. The infrared spectrum of the oil,
obtained from evaporation of the solution, exhibited a very broad
acid region at 3500-3000 cm..sup.-1, a broad acid peak at 1720
cm..sup.-1, but no amide peaks. The facts that only 10-15 mg. of
material did not dissolve and that the infrared spectrum of the oil
did not contain any amide peaks, but only acid peaks, indicate that
the polymer was definitely a copolymer. The solid that was obtained
was either a small amount of homopolymer that had not been
separated from the copolymer, or some very long blocks of alanine
that did not hydrolyze.
EXAMPLE X
Copolymer of L-alanine and S-lactic acid
The copolymer (172 mg.), which contained two residues of alanine
for each lactic acid residue, was placed in hydrochloric acid, and
after five days, nearly all of the polymer had dissolved. Some
undissolved material (10 mg.) was isolated by filtration. The
infrared spectrum of this material was identical to that of the
initial copolymer. The spectrum exhibited amide peaks at 1630 and
1530 cm..sup.-1, an ester peak at 1750 cm..sup.-1, and an N-H peak
at 3280 cm..sup.-1. The viscosity (n.sub.sp./c.) of this material
was 0.0196 in trifluoroacetic acid at 30.degree., compared to a
value of 0.196 for the starting material under identical
conditions. Since most of the copolymer dissolved, it appears that
the starting material was a copolymer.
The polymers of the invention are a valuable source of synthetic
fibers which may be melt spun or extruded through suitable dies or
orifices. The extruded filaments or fibers may be cooled by air or
by a non-solvent cooling medium after which they may be wound on a
reel. The fibers may be drafted between rolls operated at
differential speeds, for example, at peripheral speed ratios in the
ranges from 4 to 1 to 6 to 1. Better results are usually obtained
by allowing the drafting to occur at elevated temperatures.
Hydrolyzable threads or sutures may be prepared from fibers of the
polymers of the invention as will be illustrated by the following
Example XI.
EXAMPLE XI
Fibers prepared by melt spinning each of the copolymers of Examples
II, III, IV, V and VI are each twisted and braided into a
polyfilamentous suture on a New England Butt braider machine. This
machine is a well known braider and has 8 to 12 carriers in readily
available models. Any type of braider is of course suitable. Such
machines by varying the number of individual fibers and tensions
can provide a wide variety of sutures.
The braided sutures are then hot stretched by pulling the thread
under tension over a heated platen maintained at a temperature of
about 300.degree. F. This operation serves to substantially reduce
elasticity and eliminate memory (that tendency of the fiber to
return to its original length). While elongation may vary from
about 10 to 15 percent, a braid preferred for surgical use will
usually be stretched about 40% during the process. Any suitable
device providing the necessary tension and heat is suitable for
this step. The thread stretched about 40 to 50 percent is then
gathered into a skein.
Samples of each of the sutures prepared are immersed in an aqueous
solution maintained at a pH of 7.3 by a standard buffer to
approximate the pH conditions of human body fluids. Each of the
sutures dissolves in 4 to 6 weeks while retaining a high degree of
tensile strength in the interim weeks.
Although the polymers of the invention have been described
primarily with regard to their utility as fibers it should be
understood that they may also be dissolved in a suitable solvent
and cast into hydrolyzable films in accordance with casting methods
well known in the art.
* * * * *