Note: Descriptions are shown in the official language in which they were submitted.
24,5~3
` 1052046
BACKGROUND OF ~E I~TION
This invention relates to unsymmetrically substituted
1,4-dioxane-2,5-diones, methods of making them, and more parti-
cularly to polymers, which polymers are either homopolymers of
the unsymmetrically substituted 1,4-dioxane-2,5-diones or
copolymers, ~nd which polymers are comp~tible with living
mammalian tissue, particularly human tissue, and which mater-
ials can be used surgically and are biologically degradable
into tissue compatible components which are absorbed by living
~tissues. It is presently postulated that the primary degrada-
tion of the polymer is by hydrolytic fission into products
which can be carried away by the living tissue and which
: products are degradable to excretable components or are them-
selves excretable. Because of the surgical demand for sutures,
absorbable fabrics, gauzes, bone pins, etc. whose absorption
and strength characteristics vary, it is desirable that a
spectrum of strength and absorbability be provided to meet
- surgical demands for various procedures.
- DESCRIPTION OF T~E PRIOR ART
U. S. Patent 2,518,456, Fein and Fisher, August 15,
1950, PREPARATIOI~ 0~ ACYLOXY CARBOXYLIC ACIDS FROM ESTERS OF
HYDROXY CARBOXYLIC ACIDS, discloses preparing
CH3
.
- ClC~ - C - O - CH - C - OH
.. . .,
O O
there called chloroacetoxypropionic acid (which may be also
properly named as O-(chloroacetyl)-lactic acid or -(chloro-
acetoxy)-propionic acid) by transesterification using an acid
catalyst such as concentrated sulfuric acid with chloroacetic
~ acid and ethyl lactate.
U. S. Patent 2,676,945, Higgins, April ~7, 1954,
COND~SATION POLYMERS OF HYDROXYACETIC ACID, discloses strong
, . -1- ~
J
~052046
orientable fibers of polyhydroxyacetic acid condensate (poly-
glycolic acid) having an intrinsic viscosity of 0.5 to 1.2.
U.S. Patent 2,758,987, Salzberg, August 14, 1956,
OPTICALLY AC~rVE HOMOPOLYMERS CONTAINING BUT ONE ANTIPODAL
SPECIES OF AN ALPHA-MONOHYDROXY MONOCARBOXYLIC ACID, discloses
forming high molecular weight optically active, cold-drawable,
polymers from one antipodal species of alpha-hydroxypropionic
acid (lactic acid).
U.S. Patent 3,268,487, Klootwijk, August 23, 1966,
PROCESS FOR POLYMERIZATION OF LACTIDES, discloses catalyst sys-
tems and the polymerization of symmetrical lactides to give
polymers with the recurring unit
Rl O Rl Q . .'
. ; I 11 1 11 ~
- . --C C--O--C-- C--,0_
. ~2 ~2
wherein Rl and R2 are hydrogen atoms or alkyl, cycloalkyl, hal- ~ -
oalkyl, hydroxyalkyl, alkoxy, phenol, alkaryl, hydroxyphenyl,
. or haloaryl radicals. Copolymers, including block copolymers
- are s~own. tCol. 1, lines 57-66).
t` 20 U-S- Patent 3,297,033, Schmitt and Polistina, January
10, 1967, SURGICAL SUTURES, discloses polyhydroxyacetic ester
absorbable sutures. The material is also called polyglycolic
acid, and is disclosed as permitting small quantities of como-
nomers to be present, such as dl-lactic acid, its optically
active forms, homologs and analogs. A small quantity is recog-
nized by the art as up to 15%, as shown by U.S. Patent 2,668,
162, Lowe, February 2, 1954, PREPARATION OF HIGH MOLECULAR
WEIGHT POLYHYDROXY-ACE~IC ESTER.
Many uses of polyglycolic acid for surgical purposes
are disclosed in said 3,297,033 and continuation-in-part there-
of including: 3,463,158, Infra; 3,620,218, Infra;
24, 583
~052046
3,739,773, June 19, 1973 - POLYGLYCOLIC PROSTHE~IC D~JICrS
and U. S. Serial No. 365,656, May 31-, 1973, SURGICAL DRESSINGS
OF ABSORBABLE POLYMERS.
U. S. Patent 3,303,177, Natta, Peraldo and Farina,
February 7, 1967, SUBST~TIALLY ~INEAR, REGULARLY HEAD-TO-
-TAIL POLYMERS OF DEUTERA~ED AND TRI~IATED MONOMERS ~D PRO-
; CESS FOR PRODUCING THE SAME, discloses the important cffect of
high regularity of steric structure ~s well as high regularity
- of chemical structure on the characteristics of polymers. A
nomenclature for such polymers is set forth.
U. S. Patent 3,463,153, Schmitt and Polistina, Au-
gust 26, 1969, POLYGLYCOLIC ACID PROSTHETIC D~JICES, discloses
surgical uses of polyglycolic acid, ~nd incorporates defini-
tions of some terms.
U. S. Patent 3,49?,325, Thompson, January 27, 1970,
PRODUCTIO~ OF ~-~DRO~Y ACIDS A~D ES~ERS, discloses the con-
version of ~-keto acetals into a~_hydroxy acids and esters,
~ . :
including lactides. ~he lactides produced are symmetrical.
U. S. 3,620,218, Schmitt and Polistina, November 16,
1971, CYLINDRICAL PROSTHETIC DEVICES OF POLYGLYCO~IC ACID,
; lists many surgical uses of polyglycolic acid.
U. S. Patent 3,6~6,948, Glick and McPherson, Decem-
ber 14, 1971, "Absorbable Polyglycolic Acid Suture Of En-
hanced In-Vivo Strength Retention" discloses heating under
vacuum, under specified conditions to remove volatile com-
ponents to give longer in-vivo strength retention to poly-
glycolic acid surgical protheses, including sutures.
U. S. Patent 3,~36,956, Schneider, January ~5,
- 1972, "Polylactide Sutures", discloses polylactides which
may contain up to 70 mole percent glycolide (Col. 12, line 4),
- ~nd mentions other comonomers, including tetramethyl glycolide~
~Column 2, line 21~). Lactide may be considered to be a sym-
~ . . . . . .... __ _ .. . .. . .. . ._ . ._ .. .. . _ . . _ ..... . . .
1052~46
metrical dimethylglycolide. Schneider prefers polylactides of one anti-
podal species, usually poly L(-) lactide.
United States Patent 3,736,646, Schmitt, et al., June 5, 1973,
METHOD OF ATTACHING S~GICAL NEEDLES TO MULTIFILAMENT POLYGLYCOLIC ACID
~BSORBABLE SUTURES, discloses surgical elements of a copolymer containing
from 15 to 85 1 percent glycolic acid and 85 to 15 mol percent lactic
acid.
United States Patent 3,763,190, Ross, Barrett, and HcDonald,
October 2, 1973, PREPRATION OF PURE GLYCOLIDE, discloses the ring closure
of O-chloroacetylglycolic acid as the sodium salt to give glycolide.
Sporz~nski, Kocay and Briscoe, A NEW METHOD OF PREPARING
GLYCOLlIDE, Recueil, 68, 613-618, (1949) relates the "thermal decomposition
of ~odium chloracetate under reduced pressure in the presence of copper
gave glycoll;de . . ." -
Chujo, Kobayashi, Suzuki, Tokuhara and Tanabe RING-OPENING POLY-
MERiZATION OF GLYCOLIDE, Die Makromolekulare Chemie, 100, 262_266, (1967)
shows the preparation of glycolide by the elim;nation of sodium chloride
from sodium monochloroacetate
2 ClCH2 COO~ ~ 2ClCH2 COONa ~
0 ~ 2 0=O + 2N Cl
CH2 0
The disclosures of the above patents and articles, particularly
on methods of manufacture and purification of components and of surgical
uses for hydrolytically degradable tissue absorbable polymers.
N MENCLATURE
Hydroxyacetic acid bears the trivial name of glycolic acid.
'~r:
~ _ 4 -
24,58, ~
lOSZ~46
2-Hydroxypropenoic acid, or a-hydroxypropanoic scid
beArs the trivial nsme Or l~ctic acid. ~ACtiC acid has the
~ormula CH~CHOHCOOH, and has an asymmctric carbon atom, and,
v~ hence, m~y exist in two different optically active forms, com-
monly called D(-)lactic acid and ~(~)lactic acid. Where not
otherwise specified or inco~porated from context, the term
lactic acid refers to the equi~olecular or racemic mixture.
A l~ctide is derined as the product from the inter-
nal cyclic esterification of two molecules of an ~-hydroxy
- 10 alXanoic acid. If the ~-hydrox~ alkanoic acid is lactic acid,
the product is lactide itself, which gives its name to the ~
series. Generically, the reaction is
R,
- 2 ~ -C-COOH ~
!- where ~ and ~ are each separately hydrogen or alkyl.
` ~rom the nature of the reaction, such lactide is
essentially symmetrical, that is~ it has two identical ~
groups and two identical ~ groups on the six-membered ring.
Ihe compounds in which ~ is hydrogen are much the more com-
mon.
These compounds may be nzmed by systematic nomen-
clature, for instance, the lactide of lactic acid, with
being methyl and ~ being hydrogen is properly named ~nd -
indexed as 3,6-dimethyl-1,4-dioxane-2,5-dione.
In the present invention, the substitution is not
sym~etrical and, hence, thc products are not properly classed
~8 l~ctides, but nre named ~s 3-, or ~,6-substituted 1,4-di-
oxane-2,5-diones.
Th~ simplest, and what can be considered ~s the
p~rent to t~e c1~6 i8 3-methyl-1,4-dioxane-2~5-dione, which
~ . .
~~
~4.~3
1052~46
can be given the trivial name of monomethylglycolide. Another
name is 3-methyl-2,5-diketo-1,4-dio~ane. m is compound has
part of the attributes of glycolide and some of lactide, but,
uniquely, is adapted to give controlled and ordered polymers
which empirically resembie a copolymer of glycolide and lac-
tide, but have an ordered structure imparting unique and de-
- æirable properties.
When glycolide is homopolymerized, the product is
called homopolymeric poly(hydroxyscetic acid) or poly(glyco-
lic acid) or polyglycolide. 'rhe individual units in thepolymer chain are oxyacetyl radicals
O , :
~.
~- - O - C~ - C -
which may be called glycolic acid residues, or glycolic acid
units, or glycolic acid radicals or glycolic acid linkages,
even though in polymerization water is eliminated in forming
the resultant polyester. For convenience, the term glycolic
acid unit is usually used herein.
` 20 Similarly, when lactide is homopolymerized, the
product is called homopolymeric poly(lactic acid) or poly-
(alpha-hydroxypropionic acid) or polylactide. '~he individual
units in the polymer chain are 2-oxypropionyl radic~ls
., ~,
- 0 - CH - C - .
'~hese can be called lactic acid residues or lactic acid units,
or lactic acid radicals, or lactic acid linkages.
For convenience, the term lactic acid unit is usu-
- ally used herein. m e steric configuration is specified if
~0
significant and not apparent from context. '~he steric con-
figuration Or the product is normally that of the starting
materials. If the additional regularity resulting from a
.. __ . ...... . .
24,583
~052~46
single antipode i9 desired, an appropriate starting material
: i8 selected.
When polymerized into chains, three consecutive
glycolic acid units are ~bbreviated -G-G-G- and three conse-
cutive lactic acid units are abbreviated -L-L_L_. A rcgularly
alternating polymer of glycolic acia units ~nd l~ctic acid
units is abbreviated -&-I-G-I_G-I-. Other orders are simi-
larly represented by the sequence o~ capital letters.
In places, hexafluoroacetone sesquihydrate is ab-
brevisted as HF~S; hexafluoroisopropanol is abbreviated as
HIPA; poly(glycolic acid) is abbreviated as PGA and 3-methyl-
-1,4-dioxane-2,5-dione can be abbreviated as MDD.
To be consistent, the name O-chloroacetyl-I-lactic
acid is used, with D,L_ or L or D being so designated where
appropriate for the formula
'! . '
ClC~ C - O - CH-C-OH
., , " , " .
- - O CH30
Other common names include I_2-(chloroacetoxy)-propionic acid
and I-a-(chloroacetoxy)-propionic acid.
In copolymerization of two monomers, depending upon
the catalyst used and-reaction conditions, the relative rates
of reactivity vary, and one of-the monomers usually tends to
polymerize more rapidly than the other.
For example, if an equimolecular mixture of glyco-
lide and lactide is polymerized, the glycolide tends to link
to the growing chains more readily giving relatively long
seguences of glycolic acid units with occasional short se-
quences Or lactic acid units and as the concentration Or the
3 unreacted components change, the ratio of lactide to glycolide
increases and the polymer being formed may contain more nearly~
equal numbers of glycolic acid units and lactic acid units.
-7-
1052~)46
If the polymerization is stopped before completion, a disproportionately
large amount of unreacted lactide is present in the reaction vessel. The
occurrence of pairs of glycolic acid units and pairs of lactic acid unit9
i~ basically random in nature with a bias towards the preponderance of gly-
colic acid l~ts in the first portions of chains formed and an increasing
proportion of lactic acid unit in those portions of the chains last formed.
If carried to completion, the last portions of chains formed are
predominantly of pairs of lactic acid units as a minimum of glycolide remains
to link to the chains.
Under the usual conditions of polymerization, a random order signi-
ficantly predominates and, hence, the product tends to have more of an
amorphous rather than crystalline character. For cry~tallinity to occur,
extensive lengths of the chain need steric regularity. For instance, a
regular brick wall can be easily built in any one of a number of patterns
from ordinary bricks which frequently have a size of 2" x 4" x 8" including ~-
the mortar. On the other hand, random stones or a multitude of sizes do not
so readily lend themselves to an ordered structure. Analogously with polymer
molecules, if the side groups occur in a strict~y random sequence, the cry-
stallinity of a product is decreased as compared with polymers for~ed with
strictly regular side group spacing.
The present invention relates to the use of unsymmetrically sub-
~tituted 1,4-dioxane,-2,5-diones which in polymerization gives two different
- uoits of alpha-hydroxy alkanoic acid precursors, but which are very well
; ordered.
The present invention provides a method of forming a polymer con-
taining more than 2% by weight of recurring units of the formula:
0 _ C -~C - O - C -~C
L CH3 Rl B H H
and the remaining units are
B ~ O H H
,,_~ l,
~ - 8 _
-
`~ ` 1052~46
where Rl and R2 are selected from the group consisting of hydrogen, and the
methyl radical which comprises heating, in the presence of a strongly acidic
catalyst selected from the group sulfuric acid, p-toluene sulfonic acid,
tin chloride dihydrate, and strongly acidic ion exchange resin, at least 2%
by weight of an unsymmetrically substituted 1, 4-dioxane-2, 5-dione of the
formula H
H3 ~
0 ~ 3
where Rl is selected from the group consisting of hydrogen, and the methyl
radical, and at least one compound of the formula
H5 ~ 0
~ R 3
where R2 is selected from the group consisting of hydrogen, and the methyl
ratical.
The present invention also provides a method as above which comprises
heating a compound of the formula
H 0
~r
. 0 0 ~ 3
wherein Rl is hydrogen or methyl with a glycolide or lactide in the presence
of tin chloride dihydrate to yield a polymer containing more than 2 mole
of recurring units of the formula
_ - O - C - C - O - C - C --_
1~
0 CH3 Rl 0 H H n
wherein Rl is hydrogen or methyl, wherein n is such that the weight average
molecular weights at least about 5,000.
The present invention also provides a polymer containing more than
2% by weight of recurring units of the formula:
~ 0 lH3 Rl 0 H H
.~
~ -8 ~
lOSZ~6
and the remaining units are
~ CH3 R2 and - O - C - C -
where Rl and R2 are separately selected from the group con~isting of hydro-
gen, and the methyl radical whenever prepared by the above process or by an
obvious chemical equivalent thereof.
Preferably the polymers of the present invention have a weight
average lecular weight greater than 5,000.
This invention relates to unsymmetrically substi-
- 8b -
~4,5~3
1052~46
tuted 1,4-diox~ne-~,5-diones, precursors of such dioxanediones,
and polymers formed from such dio~anediones. In the simplest
such uns~metrically substituted diox~nedioIle, 3-methyl-1,4-
-dioxane-2,5-dione, a lactic acid unit, antl a glycolic acid
unit, are in effect cyclized together, ~n~ in polymerization,
when such a ring is opened and added to a polymer chain, a
lactic acid unit and a glycolic acid unit are ~ddacent in the
polymer chain. If the ring opening and addition is strictly
uniform, the final product will have regularly alternating
lactic acid units and glycolic acid units. If polymerization
is random, because there is a glycolic acid unit ttached to ,~ --
each lactic acid unit, not more than two glycolic acid units
or two lactic acid units will be adj~cent in the chain formed.
Because hydrolytic fission of the polymer ch~in is
more probable adjacent a glycolic acid unit, and even more
probable between two such glycolic acid units, a minimum of
long blocks of lactic units gives more rapid hydrolytic fis-
sion, and polymers having adjacent glycolic ~cid units are
absorbed by tissue even more rapidly than polymers having
strictly alternating glycolic acid units and lactic acid
units.
Copolymerizntion of some glycolide with the 3-methyl-
-1,4-dioxane-~,5-dione increases susceptibility to hydrolytic
fission.
If polymerization of a mixture of glycolic acid
and lactic acid is used to form a copolymer s~ith remov~l of
water, the sequence of units in the final copolymer chain will
be somewhat random, with the first portions formed tending to
include more ~lycolic acid units. Because in polymerization
such chains are not always identical and because of the dif-
ficulty of analysis, it is not always readily possible to as- ~
certain the ex~ct order in a chain, but the general properties
_9_
~4, 5~
lOS2046
of the polymer are the items of interest and it is foun~ -
that the additional regularity imparted to the ch~in by the
use of the unsymmctrically substituted 1,4-dioxane-c,5-diones
results in polymers which are both ch~mically and steric~lly
more uniform.
The unsymmetrically substituted 1,4-dioxane-2,5-
-diones of this invention are of importance in the medical
field because their polymers, including homopol~ers and co-
poly~ers with various lactides including glycolide and l~ctide,
are useful as surgical elements as later described, but, addi-
tionally, the unsymmetrically substituted 1,4-dioxane-2,5-
-diones are excellent weak acidifying agents. They may be
used in such materials as baking powders or for the control
of pH in boiler waters. They may also be used in non-aqueous
systems for the ncutralization of alkali. Because the side
- chains may vary from methyl to long ch~in alkyl, including
branched chains, unsaturated chains, aryl or aralkyl, and
which may include halogen, alko~y, aryloxy, 3ralkoxy, ether,
ester and amide groups, as substituents on the side chains,
the relative distribution between aqueous ~nd solvent-compon-
ents in a system can be varied as well as water solubility or
oil and solvent solubility so that the 1,4-dioxane-~,5-dione
is distributed in a desired loc~tion and also bec~use the
size and location of the side chains affects the rate of hy-
drolysis, the acidity of the system, the rate of availabilityof acid can be varied over wide limits to meet the require-
ments of a system and the desires of the operator. The less
highly substituted materials are often preferred ~or medical
uses. The broader range of substituents permits more flexi-
3 bility in p~I control, and in biodegradable polymers for usein packaging, etc. The use of side chains with unsaturated -
link~ges permits cross-linked polymers to be formed. ~his
-10-
~4,5~3
, . .
1052046
uniformity re-ults in greater strength, more crystallinity,
and more readily reproducible and controll~ble characteristics,
which are of interest to a surgeon during use.
By copolymcri~ing the ~resent 1,4-tlioYane-.-,5-diones,
with either glycolide or lactide, the physic~l properties of
the polymer are altered to more closely resemble th~t of either
polygLycolic acid or polylactic acid respectively and the ab-
sorption characteristics may be varied. The lenGth of pol-~mer
chain, as shown by the inherent viscosity of the polymer, also
is important in determining the rate of hydrolytic degradation
in tissues and hence by adjusting both the inherent viscosity
and the ratio of components, there is provided a ~ide range
of tissue absorbable surgical components which may be tailored
to fit the desires of a surgeon for a particular procedurc.
~or many purposes, it is desired that the synthetic
tissue absorbable polymer maintain its stren~th for fro.m
2-60 days and then degr~de and be absorbed thereafter. Be-
cause the disappearance of strength is a gradual function, the
loss of strength is apt to start very early in the useful life,
but an adequate and useful proportion of strength is main-
tained for a surgically desirable period of time and the ulti-
mate absorption of the polymer occurs thereafter. Although the
polymers having glycolic and lactic acid units are often pre-
ferred, dioxanediones are useful in which the substituents
are ethyl, propyl, isopropyl, butyl, isobutyl, cyclohexyl and
phenyl radicals.
One convenient method of making the unsymmetrically
substituted 1,4-dioxane-2,5-diones is by the reaction of ~
substituted acetic acid with an ~-hydroxy carboxylic acid to
form an acyloxy acid which is rin~ closed to form the 3,6-
-~ubstituted-1,4-diox~ne-2,5-dione or the 3-substituted-1,4-
-dioxsne-2,5-dione. The equations appear as follows:
~4, 5~3
1052046
X- C _ C- OH + HO ~ O~I Step on~
U Catalyst A
O R, O
(I~ (II) -
X- C- ~- O -C -C_ OH Step two
~ Reagën~t
- ~ O ~, O
(III)
X ~ --C__O _~ ~ - OH'N~ Step three
(IV)
El,, ' . .
R5 ~ ~
O=~
- (V)
in which ~ , ~ , R3 and ~ are each hydrogen, alkyl, aryl or
arylalkyl and which are chosen so that ~ and ~ are not the
same as ~ and ~ and at least one of ~1 and R~ has at least
one carbon atom. X is a halogen or R-C-O-,or RS02 O- where
R is H, alkyl or aryl or aralkyl and the catalyst A for the
~irst step is a strongly acidic catalyst such as concentrated
~5
sulfuric acid, p-toluene sulfonic acid, a strongly acidic
ion-exchange resin or other material which effectively acts
as a strong acid. The reagent B for the second step is con-
veniently a trialkylamine, such as triethylamine, but may be
sodium methylate in methyl alcohol, pyridine or a strongly
b~sic ion-exchange resin.. For clarity, a trialkylamine is
shown as reagent B in the equ~tion above. In the ring-
--1~--
24,5~3
1052~:146
-closing step, step three, heat is usually sufficient in the
presence or abs~nce of ~ solvent or diluent.
In view of the well known propensity for ~-hydroxy-
alkanoic acids in gencral to cyclize or polymerize and then
depolymerize or open the ring, it would be expected th~t un-
symmetrical 1,4-dioxane-c~5-diones would polymerize, depoly-
merize and split to form symmetric~l components which could
permit the formation of long blocks of similar units in the
final polymer. Fortunately, it is found that such randomi-
zation does not occur and that regularity of the acid units
in the polymer occurs so that the characteristics can be
adapted and tailored to specific uses and reproducibly ob-
tained.
Because of optical activity that can occur if ~
and ~ are different or if ~ and ~ are different, various
stereo isomeric components may be obtained and used. It is
particularly convenient to use 1- or DL or D,I-lactic acid
as a starting material. The optically active forms give
different melting points and changes in physic~l characteris-
tics. It is often convenient to use I-lactic acid ~s A start=
ing material in which case the polymer contains units with
the I-configuration. For instance, chloroacetic acid and
I-lactic acid may be used as starting materials to give the
~ form of 3-methyl-1,4-dioxane-2,5-dione.
c5 Other methods of preparing unsymmetrical 1,4-dioxane-
-2,5-diones include: (a) Cocondens~tion of two different
alpha-hydroxy acids A and B, with removal of water to form a
low-molecular weight random copolymer, and then heating this
copolymer with a transesterification catalyst to form a
mixture of cyclic dimers. The desired un~ymmetrical cyclic
dimer is isolated by fractional distilletion. (b~ Glycolide
is chlorinated to give 3-chloro-1,4-dioxzne-2,5-dione and
... . . . . ..
c4~5~3
105Z~46
and this is treated with A metal ~lkyl or met~l aryl to give
3-alkyl or 3-aryl-1,4-dioxarlc-~,5-dione.
In ~eneral, the sur~ical uses of thc polymers pro-
duced in accordance with the present invention ~re similar to
those previously taught for polyglycolic acid. These uses
are extremely varied.
For clarity and explanation, certain terms are de-
fined and representative uses given for the novel polymers
A "filament" is a single, long, thin flexible
structure of a non-absorbable or absorbable material. It may
be continuous or staple.
"Staple" is used to designate a group of shorter
filaments which are usually twisted together to form a longer
continuous thread.
An absorbable filament is one which is absorbed,
that is, digested or dissolved, in living ma~malian tissue.
- A "thread" is a plurality of filaments, either con-
tinuous or staple, twisted together.
A "strand" is a plurality of filaments or threads
twisted, plaited, braided, or laid parallel to form a unit
for further construction into a fabric, or used per se, or a
monofilament of such size as to be woven or used ind~pendently.
A "fabric" is a three dimensional asse~bly of fila-
ments, which may be woven, knitted, felted or otherwise formed
into a flexible sheet having two layer dimensions and a
thinner thickness dimension. A fabric may be cut to a desired
size before or at the time of use.
~ xcept where limited speciflcolly or by context,
the word fabric includes both absorbable and non-absorbable
3 cloth, or a fabric or cloth that is partially of absorbable
polymer.
A "dressin~" is a woven, knitte(l, felt~d or braided
~'~ . 5~3
lO5Z~6
fabric, of at least one layer, which is designed to protect
8 wound and favor its healing. As used herein, the term
dressing includes bandages, insofar as they contqct the
wound itself. The dressing may be entirely internal.
A "bandnge" is a strip of gau7e, or other material
used to hold a dressing in place, to apply pressure, to im-
mobilize a part, to obliterate tissue cavities or to check
hemorrhage. Except insofar as the bandage comes in contact
with a wound, or the exudate from a wound, there is no need
for the bandage to be of absorbable polymer. If the bandage
may be in a position where absorbability by living tissue of
at least part of the bandage is desirable, at least that part
should be of absorb~ble polymer.
A "respository" is a composite of a medic~ment and a
carrier whereby the medicament is placed in a desired loca-
tion, and released slowly by the carrier so that the effective
therapeutic action of the medicament is extended. Slowly di-
gestible drug release devices, including pills and pellets,
may be inserted subcutaneously, or orally, or into any body
cavity where slowed release of the medicament is desired.
Digestible carriers are preferred. The digestion may be in
the intestinal tract or in tissue depending on the desired
sdministrative site. An absorbable polymer is chosen ~.hose
digestive rate releases the medicament at a desired rate.
The dressing may be in part directive of growth,
as, for example, in nerve tissue, which grows slowly, and
as a result has regeneration impaired by the more rapid
growth of scar tissue which can block the growth of the
nerve tissue. With a wrap-around sheath of absorbable poly-
3 mer fabric or a split or solid tube used to support, place,
hold and protect; regeneration of nerve tissue and function
is greatly aided. Other f~ctors may inhibit regeneration of
-15-
2l~, 5$33
~052~46
nerve tissue or function, but with the exclusion Or scar
tissue, such other factors may be separately treated.
For different purposes and in different types of
tissue the rate of zbsorption may vary. In General, an ab-
sorbable suture or solid load bearing prosthesis should h.~ve
as high a portion o~ its original strength as possible for at
least three days, and sometimes as much as thirty days or
more, and preferably should be completely ~bsorbed by muscu-
lar tissue within from forty-five to ninety days or more de-
pending on the mass of the cross-section. ~he rate of .~bsorp-
tion in other tissues may vary even more.
~or dressings, strength is often a minim<~l require-
ment. Some dressings, as for instance, on a skin abrasion,
may need strength for only a few hours, until a scab forms,
and rapid decrease of strength and absorption is an advantage
so that when the scab is ready to fall off, the dressing does
not cause a delay. ~or burns, and larger lesions, strength and
reinforcement may be desired ror a longer period.
In com3lon ,Jith many biological systems, the require-
ments are not absolute and the rate of absorption as ~lell 2S ,,
the short-term strength requirement varies from patient to
patient and at different locations within the body, as well as
with the thickness of thc section of the pol~ner.
The absorbable polymer may be formed as tu~es or
sheets for surgical repair and may also be spun as thin fila-
ments ~nd woven or felted to form absorb~ble sponges or ab-
sorbable gauze, or used in conJunction with other compressive
structures as prostlletic devices within the body of a hum~n
or animal where it is desirable that the structure have
3 short-term strength, but be absorbablc. The useful embodi-
ments include tubes, inclu~ing branched tubes or Tees, for
artery, vein or intestinal rcpair, nerve splicing, tendon
. . ., ~ _
.sa3
105;~ 6
splicing, sheets for tying up arld supporting dama~ed kidney,
liver and other intestinal or~ans, protecting damaged surface
areas such as ~brasions, particularly major abrasions, or
areas where the skin and underlying tissues are ~ama~ed or
surgically re~oved.
In surgicRl techniques involving internal organs,
hemorrhage may be a major problem. Somc of the organs have
such tissue characteristics that it is very ~ifficult to usc
sutures or ligatures to prevent bleeding. For ex~mple, thc
human liver may suffer traumAtic damage or exhibit tumors or
for other reasons require surgery. In the past it has been
very difficult to excise part of the liver or to suture the
liver without the combined problems of the sutures cutting out
and hemorrhage at the surface causing such major complications
as to either prevent surgery or cause an unfavor3ble prognosis.
It is now found that a sponge or p~d or velour of
the present ~bsorbable polymer may be used to protect the sur-
face and permit new feats of surgical intervention. For in-
stance, fil~ments may be formed into a woven gauze or felted
cO sponge or a velour, preferably the construction is fairly
tight by textile standards, and such sponge may be placed on
the surface Or the bleeding organ such as the liver or a lung
with either gentle suturing or ~ith ties in thc nature of
li~atures to hold the element in position with a certRin
amount of body fluids flowing into the sponge ~nd being ab
sorbed, which results in hemostasis and prevention of ~urther
loss of body fluids. If a liver or lung is so repaired, the
organ may be replaced in the bo~y cavity and the ~lound closcd.
Where surgically useful, the sponge or fabric can
be used as a bolstcr to prevent ~ suture from cutting out. For
instance, if the livcr is to be suturcd, an absorbable poly~er
pad can be placed on the surfaces to rcinforce the tissue an(l
-17-
24,583
1052046
prevent the suture from cutting into rather than retaining the
tissue. ~uch pads of gauze or felt protect tissue from cutting.
Absorb~ble pads, bandages or sponges are cxtremely
useful in surgic~l techniques in ~hich it is the intent to re-
move the major portion or all of such sporlges, felt orp~ds
but, through inadvertencc or accident, p~rt of it may rem~in.
For instance, in a surgical operation one of the problems
which arises is the lint from cotton sponges remainirlg in the
wound. If absorbable polymer sponges ~rc used, any small
fragments which are accidcntally displaced ~re absorbed without
incident and even if a sponge is left in the wound, the de-
leterious effects are minimal.
The use of a synthetic absorbable polymer as ~
sponge or p~d is particularly advantageous for surface abra-
sions. In the past it has been necessary to put on ~ dress- ;
ing and avoid having the non-absorbable dressing grow into
the tissue at all costs. If elements of ~n zbsorbable polymer
gauze are beneath the regeneratin~ tissue lcvel, the tissue
will regenerate and absorb the polymer with the residual poly-
mer in the scab falling off when the scab is displaced.
- The dressing that contacts tissue should be sterile.
A strippable sterile package is a convenient storage system
to maintain sterility between the time of mRnufacture and
time of use.
Even in cosmetic surgery or skin surgery, where in
the past it has been quite customary to use silk suturés and,
after the tissue is regener~ted sufficient to be self retain-
ing, remove the sutures so that they do not leave sc~rs, the
use of synthetic absorbable polymer sutures now permits im-
plant2tion of sutures through the skin with tlle p~rt below
the skin surface being absorbed and the part above the skin
surrace falling off. Thc resulting minimal degree of sc~r-
. . . . _ . , . . , .. __. _ .. , , ~
~ 24,~33
1052~ 6
ring at the skin surface is highly 3dvantageous.
In surgery various tissues need to be retained in
position during healin~. Defects and wounls of the abdomin~l
wall, chest wall and other such tissucs need to be rccon-
structed. For a hernia, a perm.~nellt splice or reinforcemerltis often desired ~s shown in Usher, 3,054,406, SURGICAL M~H,
or 3,1~4,136, ~IE~HOD 0~' REP~IRING BODY TIS~UE. For some
surgical procedures, a temporary rcinforcing is desired to
provide strength while body tissues are healing; and after
the body tissues have assumed the load, foreign components
are no longer dcsired. ~issue retention using the gener~l
techniques disclos~d in the Usher patents, supra, are readily
accomplished using either an absorbable synthetic pol~ncr
monofilament or polyfilament fabric or mesh or by using a non-
-absorbable material such as polyethylene or polypropylene or
polyester woven as a bicomponent mesh or kit with ~n absorbable
synthetic polymer. The use of a bicomponent fabric has the
advantage of giving additional early strength for holding the
tissues in position during initial regeneration with the
absorbable portions being absorbed, thus permitting body
tissues to invade and reinforce the permanent mesh.
In common with other surgical procedures, it is
often desirable that a bicomponent structure be used which
provides the spacing desired for non-absorb~ble elements, with
the ~bsorbable synthetic polymer element holding the struc-
ture in a desired geometrical configuration .~t the st~rt o~
the he~ling process. As the element is ~bsorbed, regener~tirlg
tissue invades ~nd replaces the dissolved synthetic polymer
so that the non-absorbed element is left in a desired con-
3 figuration, interlaced with living tissue in a stress-trans-
ferring relationship.
m e clloice of a non-absorba~le reinforcement, a par-
-19-
c4,5~
1052~)4.6
tially absorbnble reinforcement, or a completely absorbable
reinforcement is a mfltter of surgical judgment, based upon
the condition of the patient, the body structure under treat-
ment, and other medical factors.
For instance, a synthetic absorbnble poly~er sponge
may be used in a cavity aftcr tooth e~trection to stanch the
- flow of blood. ~he sponge is either absorbed by re~enerating
tissue, or disintegr~tes into the mouth, permitting improved
recovery after extractions.
The medical uses of the polymers of the present in-
vention include, but are not necess~rily limited to:
A. Absorbable pol~mer alone
1~ Solid Products, molded or machined
a. Orthopedic pins, clamps, screws and
plates
b. Clips (e.g., for use as hemostat)
c. Staples
d. Hooks, buttons and snaps
e. Bone substitute (e.g., mandible
prosthesis)
f. Needles
g. Non-permanent intrauterine devices
(spermicide)
h. Temporary draining or testing tubes
or capillaries
i. Surgical instruments
j. Vascular implants or supports
k. Vertebral discs
1. ~xtracorporeal tubing for kidney and
hear~-lung machines
. Flbrill~r Product~, knitted or woven, in-
cluding velours
a. Burn dressings
b. Hernia patches
c. Absorbent paper or swabs
- d. Medicated dressin6s
e. Facial ~ubstitutes
f. G~uze, fabric, sheet, felt or sponge
for liver hemostasis
g. Gnuze bnndages
h. Dental packs
i. Surgical sutures
3. Miscellaneous
a. Flake or powder for burns or abrasions
b. ~`oam 2S absorbable prosthesis
c. Substitute for wire in fixations
d. Film spray for prosthetic devices
^O
2~,5~3
1052046
B. Absorbable ~olymer in Combin~tion with other
~ro~ucts
1. Solid Products, molded or machined
a. Slowly dig~stible ion-cxchange rcsin
b. Slowly di~estiblc drug r~lease device
(pill, pellet) as ~ -epository, oral
or impl~nte~ or intrav2~inal
c. Reinforced bone pins, needle~, etc.
2. Fibrillar Products
a. Arterial graft or substituents
b. Bandages for skin surf~ces
c. Burn dressings (in combin~tion with
other polymcric films)
d. Coated sutures (i.e., ~ coating on a
suture of this polymcr~
e. A coating of the present polymer on a
suture of other material
f. A two component suturc, one being the
present polymer, the components being
spun or braided to~ether
g. Multicomponent fzbrics or gauzes, the
other component of which may be non-
-absorbable, or more r~pidly absorbable.
~he synthetic character and hence predictable form-
ability and consistency in characteristics obtainable from a
controlled process are highly desirable.
One convenient method of sterilizing synthetic ab-
sorbable polymer prosthesis is by heat under such conditions
that any microorganisms or deleterious materials are rendered
inactive. Another com~on method is to sterilize using a gas-
eous sterilizing agent such as ethylene oxide. Other methods
of sterilizing include radiatiorl by ~ rays~ gamma rays,
neutrons, electrons, etc., or high intensity ultrssonic vi-
brational energy or combinations of these methods. The pre-
sent synthetic absorbnble polymers may bc sterilized by any of
these me~hods, although there m~y be an appreciable but ac-
ceptable change in physical characteristics.
Controlled release rates are very desirable. Some
3 drugs are injected with the intention that the faster the
drug is absorbed, the better. Others n~ed to be emplaced
under such conditions that the maximum concentration release
-21-
1052~46
is within desired limits, and yet the drug i5 made available
over an extended period of time so that a single implantation
can last for whatever length of time is desired for a parti-
cular medical procedure. For instance, as ? birth control
pill, the blood levels of certain steroids are to be main-
tained at R low level for prolonged periods. The steroid
m.~y be dissolved in chloroform? the present polymers added,
the mixture dried and tabletted. The polymer, its molecular
weight and hydrolytic history affect the relative rate of
drug release and absorption of the carrier.
~ or contraceptive purposes, an effective storage
bank may be desired with a prolonged release time. ~le medi-
cament containing absorbable polymer m~y be shaped and used
as an intrauterine contraceptive device, having the advantDges
f both shape and the released medicament, and additionally
an inherently limited effective life. ~ith other steroids
used for the treatment of pathological conditions, the choice
may be that the entire dosage is released uniformly over a
period of from 1 to 30 days, or so. For other drugs the re-
lease period desired may be even more widely v~riable. For
; some antibiotics an effective concentration for 1 or 2 days
is pre~erred for control of some pathogens.
Additional materials such as silicones may beco~ted upon the polymer repository where it is ~esired that
the release rate be further delayed. For instance, there
are pathological conditions under ~hich the release of a drug
or hormone m~y be desired for the remaining life of a subject.
Sterility is essential in the subcutaneous implants,
and desirable in oral forms. If the medicament is adaptable
to radiation, heat, or ethylene oxi~e sterilizing cycles,
such may be used. For more labile medicaments, the absorbable
repository forms are made using steril~ t~chniqlles from
-22-
L4~5~33
105Zi:~46
sterile componcnts, or a sterilization procedurc is chosen
which is compatible with the medic~ent char~cteristics.
Othcr subst~nces may be present, such as dyes, anti-
biotics, ~ntiseptics, anAcsthctics, and antioxidants. Surfaces
can be coated ~tith a silicone, beeswax, and the likc to modify
handling or absorption rate.
The absorbnble polymer can be spun into fibers and
used to form str~nds. Fibers of about 0.002 inch diametcr are
particularly convenient for fabricntion. Sheets, or tubes
from these absorbable polymer are wr~pped around nerves, traU
matic.ally severed, to protect such nerves from-invasive scar
tissue growth, while the nerve is regcner~ting.
The ends or edges of mono-component or bi-component
fabrics containing absorbable polymer may be rendered rigid
by molding such edges, with or without addition~l solid ab-
sorbable polymer to a desired configuration. It is often
easier to insert and retain a flexible f~bric prosthetic
tube if the end of the tube is of a size and shape to be in-
serted into the severed end of a vessel.
Becoming of increasing interest and importance is
the implantation of cos~etic devices. ~`or example, some
women, due to partial surgical removal of bre~st tissue be-
cause of malignancies or traumatic injuries, are left with
smaller breasts than are considered desirable. ~dditionally,
some women are not as well naturally endowed as may be re-
quired by the styling trends or fashion at ~ particular time.
In the past, among the first surgical contributions to in-
flation were injcctions of silicones. The silicones enlar~e
the appcarance of the breast, but inherently remain shiftable
3 ~nd hcnce the silicone is apt to migr~te from the desired
location to some other less str3tegic area.
A non-mi~rating prosthctic implantation has been
.. . .. .
24, 5~33
105Z~)46
used which consists of a plastic sponge or ~ pl~stic bag
partially filled with a liquid having ~ viscosit~ adjusted to
simulate that of natur;~l tissue. The bag is implanted through
a slit under the brenst, to raise the mamm~ry tissue ~way from
the underlying chest w~ll which permits sur~ic~l reconstruction
which has a very natural appear~nce and resilience. See U. S.
Patent 3,559,.14 for surgical dctails.
- A difficulty th~t is encountered is the possibility
of displacement of such an implanted b~g from the location of
choice from the effects of gravity or pressure.
- If the bag to be used is constructed from a physio-
logically inert material such as polypropylene or a silicone
film, the b~g can be formed wit~l a surface roughness in which~
through loops, or fusion of filaments of polypropylene or
other material there is formed a bag to which the non-ab-
sorbable filament are attached. If tissue absorbable pol-~mer
fibers as a bi-component matcrial nre stitched, woven, felted
or otherwise formed into such appendant structures, the ele-
ments may be readily ¢mplaced ~nd the tissue absorbable poly-
~ mer portions are dissolved out with n~tur311y occurring tissuerepl~cing the absorbable polymer ænd thus becoming intermeshed
with the elements attached to thc prosthetic bng which inter-
locks the bag in location in the body tissues, prim~rily the
chest wall, ~nd hence the implanted prosthetic device is
firmly lockcd into the tissues and protected from accidentel
displacement, m~intairling a desired configurntion with comfort
to the paticnt.
In one embodiment, the implanted prosthetic device
is an implantable bag containing viscous liquid therein, which
3 may be a single cell or a sub-divided cell, ~ith a puncturnble
area in ~ selected loc~tion so thnt nfter implantntion, n
hypodermic needle may be used ~o puncture through the skin
-24-
.. . ... _ _ _ .. _ . . . . .... . .. .. . . . . . . . _ _ _ _ _, .. .
~4,5~
1052046
and intervening tissues, the puncturable area and into the
main volume of the prosthetic device which permits hypodermic
removal or additlon of infl~ting liquid so that with 3 mini-
mum inconvenience, ti~e and expenst, thc enh~ncing volume m~y
be modified with ch~nging f~shions or the desires of the user.
A similarly constructe(l element using the same con-
joint bi-component displacing techllique is useful to fill out
other areas in which extern~l tissuc contours are to be chan~ed.
For example, an individual may have been involved in an c?Uto-
mobile accident or the victim of a tumor and ~ith the removal
of certain tissues, a disfiguring surface configuration re-
mains. By filling in with a prosthetic element of suitable
size and shape, the surface configuration can be reconstructed
to the great psychological benefit of the subject.
Similar, but solid, devices may be implanted in the
nose, chin or ears to modify, restore or correct the surface
configuration of the subject. In some instAnces, it is found
that the psychological benefit to the subject far overshado~s
nny surgical risks, costs or inconveniences resulting from
' the operative technique.
A bi-component system can be used to aid in retain-
ing i~planted devices such as internal pacemakers or hearing
aids. See U. S. Patent 3,557,775, supra, for details of the
surgical aspects.
In the case cf extensive superficial a~rasions,
dressings, frequently gauze, pads or wrappings absorb blood
or lymph and present a problem because the gauze dressings
stick to the wound or are infiltrc~ted by regener~tecl tissue.
In the past, it has been custom~ry to chc~n~e ~ress.ings fre-
3 quently to prevcnt such infiltration. ~emoving ~n adherent
dressing can bc quite painful.
Extensive surface abrhsions such as from sliding on
-25-
.' ~
24,5~ '
1052046
a concr~tc surfacc after falling off a motorcyclo can be de-
brided and wrapped with a 6auze synthetic absorbable polymer.
Ihe wound shows a tendency to bleed into the absorbable poly-
mer gauze but t~c porosity of the gauze aids in rapidly stop-
ping the flow of blood. By usin~ se~eral l~yers and permittin~the blood to ~t least partially ~arden, a minimum a~ount of
the absorbable poly~er gauze is required ard the main pro-
tective dressing is of ordinary cotton gauze wrapped around
the injured area. A mininum of changing the dressing is re-
quired. The outer cotton g2uze may be removed for inspectionto be sure that infection does not occur, but the absorbable
polymer gauze is allowed to re~air. in position, Ar.d partly
heals into the tissue, and p~rtly remains abo~e the tissue.
~ewer ~anipulative steps aid in preventing the entrance of new
pathogens. After healing, the gauze below the new skin sur-
f~ce absorbs in the body and the non-absorbed gauze and the
scab separate readily.
Details of representative syntheses are set forth
in the following ex~ples, in which parts are by weight u~n-
less otherwise cle~rl~ indicated.~ ple 1
Synthesis of ~-meth~ 4-dio~ane-2~5-Dione
One mole of chloroacetic acid (94.5 gms.), one mole
of D,I-l~ctic aci~ (107.0 ~ms. of 85% water solution), and 8
gm5. of Dowex 50W-X ion exchan~e resin (equivalent to 1 ml.
conc. ~ S0~), and ~00 ml. benzene were refluxed and the theo-
retical ~mount of w~ter collccted in a Dean-Stark tr~p. The
solution was nllowcd to cool to room tcmperature and the ion
exch~nco resin WR5 filtQred 0~. The bcnzene was removed on
n rotary evaporator with vacuum. The unreacted chloro~cetic
ncid ~as ~ublimed out ~t 0.~ - 0.4 torr. Thc 0-chloroacetyl-
D,I_lactic acid W8S distilled at 108 - 118C. at 0.2 - 0. 3
torr (b.p. ref: U.S.~. 2,51a,JJ56, supr~, 113-11~C. ~t 0.~ -
-26-
24,5~7 ?
, . .
105Z046
torr,) m.p.: 73-74C). After recrystallization from toluene
the 0-chloroacetyl-D,L-lactic acid had a m.p. of 72-74C.
3.34 g. (0.02 mole~ 0-chloroacetyl-D,I_lactic acid
and 2.0~ ~. (0.02 mole) triethylamine were dissolved in 670
ml. dim~thyl for~mide. The solution was heated to 100 ~
5C. for six hours and allowed to cool to room temperature.
~he solvent was distilled off under vacuum ~ieldin6 ~ reddish
colored semisolid residue. The product ~ras removed by ex-
traction with acetone leaving solid triethylamine hydrochlo-
ride.
Ihe acetone extract was evaporated yielding a red-
dish colored oil which solidified on st2nding to a red~ish
yellow solid. It was recrystallized by dissolving in warm
isopropanol and cooling to -25C. The D,I_3-methyl-1,4-
15 -dioxane-2,5-dione had a melting point of 64-65C. (0.7 g.).
It was further purified by sublimation at 0.01 torr. at
50-60C. The yield ~as 0.3 g., m.p. 63.8-64.2C. ,~ Carbon
.. .. , ; .,.
found was 46.57 vs. 46.10 calc'd. ~ Hydrogen found was 4.73
vs. 4.60 calc'd. ~he proton nucle~r magnetic resonance spec-
20 trum of this product in CDC13 gave the following absorptions
where ~ (delta) = ppm shift downfield from tetramethyl silane
reference absorption; doublet, '~ protons (1.~6, 1.72 delta,
J ~ 6 Ez); qu~rtet 1 proton ( (4.97~, 5.0~, 5.10, 5.16 delta,
J ~ 6-7 Hz~; quartet, 2 protons (4.78, 4.94, 4.96, 5.12 delta,
25 J ~ 16 Hz), confirming the structure as 3-rnethyl-1,4-~iox2ne-
-2,5-dione. The product is essentially racemic ~s would be
cxpected.
NMR Spectrum of 3-meth~1-1,4-dioxsr~e-2~5-~ione
Thc proton nucle~r magnctic resonance spectrum of
30 a chemical compound reveals t~e number of protons in the mole-
cule that are locsted in ~ifrerent chemical environments by
~ series of ab~orPtion peaks whose aren~ nre proportional to
-27-
24,5~
~052~46
th~ number of protons. (See, ~or example, F. A. Bovey, High
Resolution ~R of M~cro~olecules, Ch~pter 1, Academic Press,
.Y., 197~). Furthermorc, the absorptions are split into
, multiple pea'~s by nei~hborin~ protons in characteristic ways
whic~ furthcr aid in assigning peaks to specific chemical
structures. (Bovey, pg. 30-32). The spectru~ of 3-~ethyl-
-1,4-dioxane-2,5-dione:
~d
' ~ ~b'
O~C~O,~
" . .
obtained on 8 100 megaherz Varian ~A-100 spectro~eter shows
the following absorptions grouped to indicate the splittings
of single absorptions into ~ultiplets.
TAB~E I
Positi~n ofSplittin Relative
Line Delt~ ( S~(Herz~ AreaAssiF~n~ent
1.66 1
1.72J 6 Hz ~3 Ha proto~s
5~3 ~
5 16 ,~ 6 ~Iz ¦ ~b protons
4.78?
4,9l~J lG Hz ~ 3Hc or Hd
4.96~ I
5.12~ 16 ~z J H~ or Hd
A H atom attached to a carbon bearin~ an oxygen
0 atom, such as Ha, i5 expected to absorb at 1.3-2 delta
(Bovey pg. 29). Thc absorption should be split into two lines
8cp~r~ted by 2-13 Ilerz. (Bovey, p~. 3~). The values observed
-28-
c4~5~3
1052046
are 1.69 delta taver~ge of doublet) ~nd ~ Herz.
A proton in the environmcnt of Hb should absorb
.
at hi~her delt~ than CH~C- or CH3 -O- bec~use it is influenced
0
by both the -C- and -0- groups, each o which causes a down-
field shift from C~ ~b should be split into 4 lines with
a splitting of 6 Hz corresponding to the splitting observcd
in the CH3 protons. Actually, only ~ lines are observed,
but the expected position of the fourth line, (5.0~-.06)=~.97
coincides with anothcr strong line of a dif~erent origin.
Thus, the 3 lines at 5.03, 5.10 and 5.1G delta ~re ~ssigne~
to Hb
Protons in the environmen~ of ~Ic and Hd should ab-
sorb at about the szme delta as Hb and at ~irst glance ~Ic and
Hd would appe~r to have identical environments and give a
single line. Actually, one must be some~rh~t nearer than the
other to the CH3 group on the opposite side of the ring so
the environments differ. The spectrum sho~Js a quartet of
lines due to this pair as is expected for two difrerent in-
teracting protons. The splitting of 16 Hz between the first
and secon~ lines and between the third and fourth lines is con-
sistent with splittings observed between protons on the same -~
stom. (Bovey, pg. 35). Quartets of this type are not ob-
served in the spectrum of either glycolide or lactide which
are tabulated below for comparison.
-29-
( ~ J
1052046
?ABLE II
CompoundPe~k Positions
3_~ethyl-1,4- 1.66 5.03 4.78
-dloxane-2,5- 1.72 5.10 4 94
-dione . 5.16 4.96
5.12
lactide 1.66 4.94
1.72 5.01
5 17
glycolide 4.94
qhus, the ~MR spectrum of 3-methyl-1,4-dioxane-2,5-
-dione is co~sistent with the assigned structure and incon-
sistent with an~ mixture of glycolide and lactide.
EXample 2
Homopol~merization of ~-meth~ 4-dioxane-2,5-d one, at 125C.
In a glass tube was charged 1.0 g. of 3-methyl-1,4-
-dioxane-2,5-dio~e prepared as in Example 1 and 0.80 ml. of
an ether solution containing 0.1 mg. of SnCl2 2~ 0 per ml.
The ether was vaporized off, and the tube sealed under vacuum.
qhe tube was then placed in a i25C. oil bath for 80 hours.
The tube was cooled, broken open and the contents dissolved in
10 ml. of hexafluoracetone sesquihydrate (H~AS). This solu-
tion was added dropwise to 100 ml. of methanol and the re-
~ulting precipitated polymer was dried in vacuo for two days
at room temper~ture. The resulting polymer weighed 0.6 g.
(67~o conYersion) and had a meltin~ point by differenti~l
thermal analysis of 100C. and an inherent viscosity in ~AS
of 0.38 dl/g (0.5 g./100 ~1.) at 30C. ~he proton NMR spec-
trum measured in hexnfluoracetone sesquideutcrate gave thc
Sollowin~ ~bsorptions ~lhere ( ~ )delta=ppm shift downfield
from tetrAmethylsilnne reference absorption: 5.402~ 5.~32
4.90~, 1.676, 1.605 delt~.
-3
24,y
1052~6
Inherent viscosity as used herein is ~ inh=ln ~ rel
where ~ rel is the ratio of the viscosity Or a O.~;~('J/V) solu-
tion of the polymer in hexafluoracetone sesquihydrate to the
~iscosity of thst solvent alone, and c - 0.5 gr.~ms per lO0 ml.
~MR S~trum of Pol~ Meth~l-l,4-Dio~ane-2~5-Dione-
The proton nuclear magnetic resonance spectrum of
O
poly~ers containing glycolic acid units (-O-C~-C-) and lactic
C,H3,0,
acid units (-0-C~-C-) reve21s the number of protons which
exist in each of the different chemical environments in the
polymer chain. For poly(D,I,lactic acid) the methine (-C~
proton appears as a guartet the center of which is located
at 5.286 delta (where delta is the parts per million chemical
shift to lower magnetic field from the absorption of the
~ethyl groups in the tetramethyl silane reference standard.)
The area of the quartet absorption is one third the area of
the methyl absorption as expected. ~he quartet structure
arises due to spin-spin coupling with the proto~s of the ad-
~oining -CH3 group and further substantiates the assignment.
In a copolymer of D,I-lactide and glycolide con-
tsining 52 lactic acid units- for each 48 glycolic acid units,
two overlapping quartets are seen in the -CH re~ion l~ith
centers ~ocated as sho-m in ~able III. The quartet centered
at 5.~76 falls close to that in poly(lactic acid) (5.~86) and
can be assigncd to thc methine proton in the center lactic
acid unit of the -I,I,L- sequcnce:
CH~ CH3 o .CH3 0
,. ., .
-- O -- C -- C -- O -- C -- C -- O -- C -- C -- .
.
~ H
-31-
2~.5~3
~ OS2046
The second quartet in thc copolymer is centered at 5.310,
very close to the center of the only quartet seen in a ~/92
lactic ~cid unit/glycolic acid unit copolymer where isolated
pairs of lactic acid units should predominate. The 5.310
quartet can thus be assigned to the center methine proton of
either a -GLL- or -LLG- sequence:
. 0 CH3 0 C~3 0
.. . .. . ..
-- O -- C~ C -- O -- C -- C -- O -- C -- C --
H H
.
or
.~ , .
CH3 0 CH 0 0
.. . ..... . - .
-- O -- C -- C -- O -- C -- C -- O -- C~ C --
H H
The spectrum of poly(3-methyl-1,4-dioxane-2,5-
-dione) prepared as in Example 2 shows a quartet absorption
centered at 5.367, significantly shifted from absorptions as-
~O .
signed to the -LLI-, -GLL- or -LLG- sequences. The 5.367
absorption can logically be assigned to the center methine
proton of the GLG sequence, which is the only other possible
sequence of three residues. '~his is the sequence expected to
predominate if polymerization of this monomer occurs by suc-
cessive attack of the active end group on the least hindered
carbonyl group of 3-methyl-1,4-dioxane-~,5-dione to yield
-G-L~G-I-G-I- chains. m e prcsence of minor ~mounts of
-GLL- ~nd -LLG- sequences is not ruled out by the ~IR spectra
as minor absorption at 5.307-5.~10 could be maked by the
principal methine absorption.
~4.5~3
105Z~46
Thu.s, the position of the lactic acid unit methine
absorption reflects the chemic~l nature of two neighl~oring
units. As the neighbors ch~nge from two lactic ~cid units to
one lactic acid unit ~nd then no lactic ~cid unit, thcre is
progressive downficld (higher delt~) shift of the ~ethine
absorption.
-32a-
~4,583
~OSZ~)46
a~
~o ~ ~ cr~
_
~D ~D
. . .
C~
_ , . . . .. . ..
a
~ U~ , oo o C~
H ~: V
H O
~ ~ _ '
~ 0 C~ - ~
~_
rES~, ,_
.'. ~ ~ ~, 0~
~ h ~ ~ c~ I Ld ~1
H c~ u~
~ lll
U~ I
a~
~ O X
h~ ~ o
~ O ~ ~
o,~ ~ o ^ 0
~:1 p. bO O 0 ~1 ~
~1 0 ~ h I ~;
0 C) ~ bO P~
~ ~ Ul
t~ ~æ ~
.,1 a~ Q~ d 0--`
~ O-rl ~ I ~ 0
h 0 13 4 o a) -o o
~ 0
u 4 P~ I ~
o o (U~ ~ C~ o ~ ~
o 0 ,~ ~ ~ cn
--33--
24~
105Z~46
~ mple
~ymeriz~tion of D~ meth~1-1,4-diox~ne-~ 5-dione-~t 220C.
Io a glass tube was charged 0.5 g. of 3-methyl-1,4-
-dioxane-2,5-dione and 0.1 ml. of an ether solution containing
0.1 mg. of SnCl2 2~ 0 per ml, and 0.06 ml. of an ether solu-
tion cont~i~ing 20 mg. of lauryl alcohol per ml. The ether
was vaporized off and the tube sealed under vacuum. m e tube
was placed in an oil bath at 220C. for 2 hours. The tube was
cooled, broken open, and the contents dissolved in 5 ml. H~AS.
This solution w~s added dropwise to 50 ml. of metha~ol and
the resulting precipitated polymer was dried in vacuo for two
days at 50C. The resulting poly(D,I,3-methyl-1,4-diox~e-
-2,5-dione) weighed 0.14g. and had a~ inherent viscosity in
H~AS of 0.65 dl./g. (0.5 g./100 ml.) at 30C.
~xample 4
Pol~merization Or D,I,~-meth~1-1,4-dioxane-2,5-aione at 1~0C.
~o a glass tube was added 2.0 g. D,I,3-methyl-1,4-
-dioxane-2,5-dione and 0.4 ml~ of an ether solution containin~
0.1 mg. of SnCl2 2~ 0 per ml. The ether was vaporized and
removed and the tube sealed under vacuum. ~he tube was placec
in an oil bath at 180 ~ 5C. and heated for 24 hours. The
tube is cooled, broken open and the co~tents dissolved in
40 ml. of hexafluoroisopropanol (HIPA). ~his solution was
added dropwise to 400 ~1. of methanol and the resulting pre-
cipitated poIy(D,I,3-methyl-1,4-dioxane-~,5-dione) was dried
in vacuo for 16 hours at 50C. The resulting polymer weighed
1.65 G. Rnd had an inhcrent viscosity in HFAS o 0.~3 dl/g
(0.5 g./100 ml.) at 30C.
E~ample 5
Extrusion Or Poly(D,I,3-methyl-1,4-dioxane-2,5-dione) as
Monofil~ments
A 0.5 g. sample o the polymer Or Exa~ple 4 was
,
_3~_
24~c~a~ , ., ,' -
105%046
placed in the barrel (1 cm i.d.) of a melt-index appsratus
(Custom Scientific) fitted with a bottom plug 1 cm. in height
and having a 0.5 mm. vertical central hole. A close-fitting
weighted piston (4700~) was placed in the barrel which had
been preheated to 160C. The monofilament which extruded
trom the hole had a diameter in the range of 0.002 to 0.005
inches (0.05 to 0.15 mm.) and was rather weak. The filaments
were drawn by hand to four times their original length on a
hot plate having a surface temperature of 50-60C. ~he~ be-
co~e much stronger, showing a tensile strength at break of
17,000 to 21,000 psi. ~1,200-11470 Rg/cm2).
ExamPle 6
~ y~eri~gtion of D,I,3-meth~ 4-dio~?ne-2,5-dione 2t 180C.
- ~o a glass tubç was added 6 0 g. of D,I_7-methyl-
-1,4-dioxane-~,5-dione and 1.2 ml. of an ether solution con-
taining 0.1 mg. of SnCl2 2~ 0 per ml. The ether was vaporized
~nd removed, and the tube sealed. The sealed tube was placed
in an oil bath at 180 ~ 2C. for 4 hours, coolcd and brol~en.
The cooled tube contents were dissolved in 120 ml. of boiling
acetone and the solution added dropwise to 1200 ml. of
methanol. The resulting precipitated poly(D,I-3-methyl-1,4-
-dioxane-2,5-dione) was dried in v~cuo for ~ days at 25C.
Ihe resulting polymer wei~hed 1.4 g. (23,~ conversion) and had
an inhercnt viscosity in HFAS of 1.19 dl/g(0.5g/100~1) at
-30C
Ex~mples 7, a, and 9
Copoly~eri7ation of D,I,3-methyl-1,4-dioxane-2,5-dione with
G1YCO1ide
"
The amounts of D,I,3-methyl-1,4-dioxane-2,5-dione
~nd ~lycoli~e indicated in Table IV w~re combined in ~lass
3o
tubes with 0. ao ml. of an ether solution containing 0.1 mg.
ot SnCl2 2H20 per ml. ~nd 0.5 ml. o~ an ether solution con-
tsinin~ 2 m~. lauryl alcohol per ml. The ether was v~porized
~35-
~J
~s~c ~ ~
1~35Z~)46
and removed an~ the tubes sealed undcr vacuum. The tubes
were placed in an oil bath at 2~0~C. for 2 hours. The con-
tents of each cooled a~nd broken tube ~ere dissolved in ~EFAS
and precipitated in methanol. The prccipitated polymer was
dried 2 days in vacuo at 50UC.
TABLE IV
~xam- Exam- Exam-
ple 7 ple 8 ple
Mole X D,L,3- 10 25 5
_methyl-1,4-
dioxane-~,5-dione
Weight of glycolide
used (g) 3-58 2.96 1.86
Weight of D,L-3-
-methyl-l ~4-(lioxane-
-2,5-dione used ~g? 0 44 1.10 2.0
,o Conversion to
Polymer 80 79 25
Melting Point,
(~isher-Johns
Apparatus) 212C 1~C 13cC
Inherent Viscosity
in HFAS(0.5 mg./ml.)
30C 0.45 0.32 0.1
Mole ,o D,I-3-
-methy~ 4-dioxane-
-2,5-dione in Poly- ~
mer (by ~MR) 4.8 16.2 31.7
Examples 10 and 11
Implantation of Glycolide/D,L-3-Methyl-l,'~-Dio~ane-2,5-Dione
- Copol ~er in Rabbits
m e copolymers of Examples 7 and ~ (and poly~lycolic
acid (PGA), 0.~9 inherent viscosity) wexe formed into strips
nt room temperature by distributin~ 0.4 g~ of powdered p?ly-
mer in a die 3/4" deep by 1/2" wide by 3" long ~1.9 ~ 1.27
x 7.62 cm) and exerting a hydraulic pre6sure of 16,000 pounds
(7,2GOkg) on the matched plunger for 30 seconds b~ means of
a Carver hydraulic prcss. ~liS lar~e 2ressed piece was cut
-36-
?4,'~
~352046
into 4 strips, each approximately 1.5" long, 1/4" wide
(3.8 x 0.63 c~.) and weighing approximately 0.1 g. Each ~trip
was placed in a plastic envelope, vacuum dried, heat sealed,
8terilized with ethylene oxide o~ernight and the residual
ethylene oxide was pumped off. Individual strips were ther.
~mplanted subcutaneously in rabbits. At intervals the rabbits
were sacrificed and observed for tissue reaction at the im-
plantation site. The extent of absorption was estimated
visually. ~issue reaction was unremarkable in each case. ~he
estimated extent of absorption is shown in ~able V.
!I!ABIE V
PGA ~xam- Exam-
Control E~ Z Ple 8
Mole Ratio of -~
Polymer of D,I-
-3-methyl-1,4-
-dioxane-2,5-dione/
glycolide 0/100 4.8/95.2 16.2/83.8
~bsorption at
15 days 5~,-b 40-50~`0 '25,~
Absorption zt
30 days 90-1007'o lOO,o 90-100;;~
Absorption at
45 days 100~ 100~ lOOio
Example 12
Implantation Or Poly(D,I-3-meth~1-1,4-Diox~ne-2,5-Dione
~ollowing the procedure of Examples 10 and 11, strips
of thc poly(D,I_3-methyl-1,4-dioxane-2,5-dione) of Ex2mple 6
were prepared and implanted in rabbits. Tissue reaction was
unremarkable in each case. The estimated extent of absorption
Or duplicflte samples of thesc strips ~nd of polyglycolic acid
(PGA~ control strips is shown in Table YI.
-37-
24 Z ~ !
..
lOSZ~46
~AB~E VI
Poly(D~3-
-Methyl-1,4-
-Dioxane-2,5-
PGA -Dione
Absorption at 15 d~ys 50~ 50~o 0,0%
Absorption at 30 days 85~85~o 50,50~o
~bQorption at 45 days 100,100~~ 85 ~ lOO~o
Ex~mPle 1~
PrePar~tion of 0-Chloro~cet~ ctic Acid
Into a 2-liter, 2-necked round bottom flask equipped
with a magnetic stirrer and a Dean-Stark trap was placed
750 ml. of benzene and 8.0 g. Dowex 50W-~ resin. ~o this
~uspension 262.2 g. (2.78 mole) of monochloroacetic acid was
added. The mixture was reflu~ed until rLo further water was
collecte~. -
To this was then added 100 g. (1.11 mole~ of cry-
stalline I-lactic acid in ten equal portio~s at a rate such
that a subsequent portion was not added until the theoretic21
amount of water was collected from the preceding portion.
Whe~ all water had been collected, heating was dis-
continued and the resin removed by filtration from the hot
solution. The resin was then washed with two 50 ml. portions
of hot benzene. ~he washings were added to the reaction mix-
ture, and the solvcnt`removed in vqcuo.
ffl e crude oil which remained was then carefully dis-
tilled to rcmove excess monochloroacetic acid. The rem~ining
oil w~s th~n distillcd at 95-105C./0.05 torr. to ~ive 143.3 e
(7~.3%) Or 0-chloroacetyl-I,lactic acid. This was then r~-
3o distillcd, to ~ive 130 ~r2ms (70.3X~ of product, b.p.
94-100C./0.05 torr.
-38-
24,5
1 ~ 5 ~ ~4
Calculated for ClC~ -C-0-CH-C-0
n n
O ~ Found
-- C ~6.05 35.86
4.24 4.41
Cl 21.29 20.74
- MW 166.56 173
t~]D ~ -60 + 0.7 (C = 1.34, CHCl~)
IR Pea~s 3050 cm~l, 2975 cm~l, 1750 cm 1,
1460 cm~l, 1412 cm~l, 1378 cm~l,
1345 cm~l, 1315 cm~l, 1183 cm~
1135 cm 1, 1095 cm 1, 1043 cm 1,
957 cm~l, ~30 cm~l, 833 cm~l, -
788 cm~l. .
~MR (CD~13, ~MS) singlet 9.53 ~ , quartet
5.33, 5.26, 5.19, 5.12 ~ , singlet
4.16 ~ , doublet 1.64, 1.56- ~,
~xamPle 14
Prepar~tion of I-~-meth~l-1,4-dio~ne-2,5-dione
Forty-five grams (0.270 mole) of 0-chloro~cetyl-
-I,lactic acid was dissolved in 4500 ml. of amine-free, dry
dimethylformamide. To this solution was added 35.83 ml.
(26.0 grams, 0.256 mole) of dry triethylamine. The solution
2S W8S then heated to 100C. and kept at this temperature for
four hours. At the end of this time, the heating was dis-
continued and the solvent removed in v~cuo to ~ive an oily-
-semi-solid residue.
The residue wns treated with one liter of dry di-
ethyl ether nnd thc insoluble triethylamine hydrochloride
riltered of~. Thc ether was then removcd in vacuo and the
oil taken up in 100 ml. of bcnzene. The bcnzene w~s then
cxtr~cted wit~ 50 ml. of cold distilled water whose ~H wa~
~39~
.
24,5~.
105;~0~6
adiusted to c . 5 with ~ICl. The berlzene solutior~Jas then
quickly dried over anhydrous sodium sulfate ~nd then dried
for one hour over moleGul~r sieves. Th~ sieves were filtered
off, washed well with 50 ml. of dry benzene, the co~bined
solvent and ~rashings were then removed in v2cuO to give 1~.9
grams (51~o) of an oil which was crystalli ed fro~ isopropanol
at -20C. The semi-solid w~s filtered cold and quickly re-
crystallized from a minimum volume of boiling isopropanol.
Two addition~l recrystalliz~tions from isopropallol gave a
white solid, I-3-meth~1-1,4-dioxane-2,5-dione, ~.p. ~-39C.,
8.0 grams (24~o).
IR Peaks 3450 cm~l, 1775 cm~l, 144~ um~l,
1378 cm~l, 1345 cm~l, 1296 cm~l,
1225 cm 1, 1195 cm~l, 1130 cm~l,
1099 cm~l, 105~ cm 1, 103~ cm~l'
95~ cm~l, 849 cm~l,
[~]D = -245 (~1.0) (C=0.988, benzene)
MMR (CD~13,~IS) Quartet (5.00, 5.06, 5~14,
5.20 5 ), ~oublet (4.9~, 4.94 5 ~,
doublet (1.70, 1.64 ~ )
Ex~mple 15
Preparation o~ Poly-L-2-meth~1-1,4-dioxane-Z,5-dione
~ ` D o CH3
l I H ~ ~C}~ -C-O-C-C-O~-n
~ ~ C~ H
0.5 grams of L-3-methyl-1,4-diox~ne-2,5-dione from
Example 1l~ was polymerized in the presence of 0.002 weight
per cent of st~nnous chloride dihydr~te o~er a twenty-four
hour period ~t 180C. to give 0.5 gr~ms of polymer, IV=0.33,
and softening poirrt 56-G0C.
0--
. . t
24,5~- )
.
10 5 ~ 0 4 6
Ex~mples 16 ~nd 17
CoDol~merization of I~ methzl-1~4-dio~ne-2~5-dione with
lycoli e
.
Polymerization tubes were charged with the quanti-
ties of monomers indicsted in Table VII and O.OOcSo SnCl2 2~ 0
by weight based on total monomers was added in 8~ ethereal
soiution. The ether was evaporated and the tube sealed under
-vacuum. The tubes were heated in an oil bath for 24 hours at
190C
- ~he tubes were removed, chilled in dry ice-acetone,
- cracked open and dissolved in ~AS. The pol~mer was then pre-
-cipitated from solution with methanol, filtered and dried
~overnight in a vacuum oven.
--~ - TABLE VII
Exam- x2m-
ple 16 ple 17
Mole % of I,3-methyl-1,4-
-dioxsne-2,5-dione 15 - 25
-Mole a,o Glycolide 85 75
Gms. I-3-methyl-1,4-
-dioxsne-2,5-dione 0.5 0.5
Gms. glycolide - 2.53 1.34
Melting Point (Differ-
ential Thermal Analysis
at 10C./min.) 196C. 175C.
Inherent Viscosity in H~AS
(0.5 mg./ml.) 30C. 0.53 0.60
5 Mole % I_3-methyl-1,4-
-dioxane-2,5-dione in
Copolymer 7.2 12.4
Yield ~ 78 83
-41-
. . , ., , ~
24, J ~_
0 5~.~ 46
Ex~m~le 18
PrePar~tion of ~ dimeth~1-1,4-diox~ne-?,5-dione
Ib a flask cont~ining two liters of chlorofor~,
1 mole of 2-hydroxy-isobu~Tic acid (104.1 gms.) and 2.2
~oles of triethylamine (224 gms.), cooled in an ice bath, was
810wly added 1 mole of chloroacetyl chloride (127 gms.). Ad-
dition took one hour. The chloroform was evapor2ted to yield
a reddish semi-solid which was triturated several times with
acetone followed by decantation Or the reddish acetone ex-
tract. The white solid residue was triethylamine hydrochlo-
ride. The acetone extracts were combined and concentr~ted
under vacuum to a red oil which was distilled under vacuum.
The fraction distilling at 103-110C./0.7-0.9 torr. was col-
lected. ~his fraction solidified to a green semi-solid which
was recrystallized from isopropyl alcohol and then sublimed
at 75C./0.1 torr. to yield 15 grams of ~hite solid, m.p.
82-83C. ~his was dissolved in 3000 ml. of benzene at 10C.
and extracted successively with three ~00 ml. portions of
0.01 N HCl solution saturated with sodium chloride in a
separatory funnel, and the benzene layer quickly dried by
filtration through a bed of anhydrous sodium sulfate into a
fl~sX containing anhydrous magnesium sulfate. After the re-
moval of the magnesium sulfate by filtration and the benzene
under vacuum, the solid 3,3-dimethyl-1,4-dioxane-2,5-dione
w~s recrystallized from isopropyl alcohol ~nd sublimed at
75C/0.1 torr. to yield 1~ grams of solid, m.p. 85-86~C.,
C found ~ 50.00 vs. 50.00 c~lcul~ted, ~o H found = 5.52
V8. 5.G0 calculated.
The proton NMR spectrum of this sample in CDCl~
gave the following nbsorptions where ~= ppm shift downfield
~rom the t~tr~methylsilane reference nbsorption: singlet,
6 protons ~t 1.72 ~ ~nd 5ingl~t~ 2 protons At 5.02 ~ .
-42 -
24,5~ ` ,!
,.~
lOSZ~46
Exemplcs 19, 20 ~nd 71
CoPoly~ri7~tion o~ Gl~colide ~nd ~ Dimethyl-1~4-diox~ne-
-c ~-dione
. .
50 3 glsss tubes were added the amounts of glyco-
lide and 3,3-dimethyl-1,4-dioxane-2,5-dione indicated in
Table VIII. To each tu~e was added 1.2 ml. Or an ether solu-
tion of SnCl2 2~ 0 (0.1 mg./ml.) ~nd 0.75 ml. of an ether
solution of lauryl alcohol (10 mg./ml.~. The ether was evapo-
rated off, and tubes were evacuated and sealed, then keated
for two hours at 220C. in an oil bath. After cooling and
breaking, the tube contents were dissolved in 20 ml. of hexa-
fluoroacetone sesquihydrate per gram Or recovered solid. The
polymer solution was added to 10 times its volume of methanol.
Ihe precipitated polymer was then extracted for two days in
--a Sohxlet extracter with acetone. The undissolved polymer
was vacuum-dried at 50C. for 24 hours.
-~3~
24,5 )
1052046
0
o ~ ~
O~ O ~ ~D ~ O,
(U g O 9
.
~U
- 0
~ o u~ o
H 1~ ;~ ~i ~0 0
H . :
~ cr
. ~ C c~ ~ O ~
.. . ~ U~ O.~ OtU
,
~d
.
o .~ H . ~ -
O~ ~
,0
~o ~ h
1 0 a~
h `~
o
3 ~ ~ æ ~ ~
.
24~5~
10520~
_ ~mple ~2
CoP ol:~nn eri z a t i~
~ ione in ~r10 Inole ~tlO
qo ~ pol~neriz~tion tube was added 0.54 gr~ms of
D,l_3-methyl-1,4-diox~ne-c,5-dione (0.00415 mole) and 5.41 g.
of D~I-lactide (0.0376 nolc), 1.~0 ml. of an ether solution
of SnCl2 2~ 0 (0.1 mg.~ml.) and 0.75 ml. of an ether solution
of lauryl alcohol (10 ~g./ml.). The ether was vaporized and
removed. The tube was ev~cuated, sealed 2nd heated for ~4
hours at 180C. The cooled tube contents were dissolved in
boiling 2cetone and the resulti~g solution was added to metha-
nol. ~he resulting solid was collected and vacuum dried at
90C. for 24 hours. The conversion of monomers to polymer
was 79~o by weight and the polymer inherent viscosity was 1.36.
The mole ~,'o of D,I-3-methyl-1,4-dioxane-2,5-dione units in the
polymer was 7.9 by NMR.
ExamPle 2~ -
Copol~merization of D,l-~actide with D,I-~-Meth~l-1,4-Dioxane-
~ 2~-Dione in ~0/20 ~lole ~atio
To a polymerization tube was added 1.21 g. of D,I,
2~ -3-methyl-1,4-dio~ne-~,5-dione t0.00931 mole) and 4.86 g. o~
D,I-lactide (0.033~ mole). ~he procedure was then identical
to Example 22. The conversion of monomers to polymer was 74~o
by wei~ht, and the polymcr inherent viscosity was 1.24. The
polymer contained 14.7 mole percent of units derived from
D~I-3-methyl-1s4-diox~ne-2,5-dione by N~îR.
Ex~mple 24
Copolym~rizRtion of I-Lactide with D,l-~-Meth~1-1,4-Dioxane-
~-Dione in 90/10 ~201e ~atio
Exa~ple 22 w~s repe~ted substituting L(-) lactide
for D~l-lactide. Convcrsion was 78~, inherent viscosity 0.73
3 and the polymer cont~inc~ 7.G mole ~o Or ~nits dcrivcd from
D,I,3-aethyl-1,4-dioxane-2,5-dione by MMR.
-45-
24, ~Q~
105;~ 6
Ex~mple ?5
Copolymerization ef I-Lact ~ th D I,~-Meth~1-1.4-Dioxane-
-2 ~- ion~ in ~ o e atlO
Example 23 was repeated substituting ~ lacti~e
Sor D,I-l~ctide. Conversion was 75~, inherent viscosity
0.61 and the polymer contained 10.2 mole ~o of units derived
Srom D,I-3-methyl-1,4-dioxane-2,5-dione b~ NMR.
Example 26
Preparation of 0-Chloroacet~l-I,Lactic Acid
~ mixture of 57.6 gra~s (0.4 mole) of sublimed
I-lactide, 378.0 grams (4.0 mole) of monochloroacetic acid
and 2.8 grams of antimony trioxide was heated in an oil bath
ror 8 hours at 1~0C., then for 24 hours at 1~0C., and finall~
for five hours at 185C. The excess monochloroacetic acid
was then distilled off in vecuo and the 0-chloroacetyl-I-
-lactic 2cid produced distilled at 90-110C./0.05 torr. to
give 109.~ gr~ms (82~ of product. Ihe product was then
810wly redistilled at 94-100C./0.05 torr. to give 100.5 grams
(75.4%) of 0-chloroacetyl-I-lactic acid, identical to that
prepared from I_lactic acid and monochloroacetic acid.
If ~.1 grams of titanium dioxide is used in place
of antimony trioxide, the yield is 69.2 gra~s of product
(51.9~ etraisopropyl titanate m~y also be used 25 a catalysT
Ex~mple 27
-Lactic hcid
530.1 ~ms. (5.55 ~ole) of monochloro~cctic acid,
100 gms. tl.39 equiv.) of poly-D,I,lactic acid and 1.5 ~ms.
Or antimony trioxidc was heated with stirring at 160C. for
twenty-four hours. ~le excess monochloroacetic acid w~s th~n
distilled off in v~uo and thc product distilled at ~5-lOO~C/-
0.075 torr. to 6ive 122.5 ~ms. (53~o) Or 0-chloroacetyl-D,I-
-46-
24,5 "`
105Z046
.
-l~ctic acid. The material so recovered W8S identical to that
prepared from D~I-lactic acid and monochIoroacetic acid.
, ample ~8
PrePzration of D,I~ Methyl-1,4-Dioxane-?,5-Dione fro~ Gl~co-
lic ~Cl an D L-Lactic Acid
_v , ,
To 543 g. of 70~ aqueous solution of glycolic acid
was addcd 276 g. of a~ 85$ aqueous solution of D,I-lactic acid.
This mixture ~JaS heated in a distillation apparatus at atmo-
spheric pressure until water had ceased to distill. ~hen, 6 g.
of antimony trioxide was added and heating was continued at
lO torr. until 350 g. of distillate was obt~ined (head tempe~z-
ture range 120-180C.). This distillate W85 refraction ted
using a Vigreaux colum~ at lO torr. to give 40 g. of fraction
A (b.p. 114-140C.) and 160 g. of fractio~ B (b.p. 142-153C.).
Fraction B partially solidified at 5C. and was recrystallized
from 320 ml. of isopropyl alcohol.
Ihe recrystallized material was further fractio~ated
using a Vigreaux column to yield the fractions shown ir.
Table I~. $he fractions were analyzed by a gas chrom~tographic
method.
_~.7_
4 , 53 3
105Z046
.
~ .
c)a
p~ . O C~
~ t~
~ . .
~ a~ ' .,
o ~ (U ff~
J~ ~ ~ ~1 , . .
~ t)
o~
:~ ~
H ~ -rl
:~ ~ O C~ , , ,
1~ ~ C) ~1 ~1
.
_ . .
h
E~l ,J r~ ~ ' '
' . ~,.o ~
m ,,~
.
~ ~ .
,q u~
,bO ~ O ~ O
~ ~ .
:~ ~ . ~ .
C> ~t, ~, ~I ~ .
Ii~
.
--48--
~4,5E~
~ - 1 0 5 2 0 4 6
~mpl e 29
Preparation of D,I~3-Methyl-1 4-D 0~2ne-~, ~Dione from Gls~co-
collc Acid an , ~actic Acld
Example 28 is repeatcd until Fraction B is obtained
by distillation. This fr~ction is then fractionated in a
high-efficiency distillation apparatus to obtain D,I,3-methyl-
-1,4-dioxane-2,5-dione with a purity greater than 9~ percent
as measured by gas chromato~raphy.
The choice Or $,, D-, or D, I, components in the
feed to the polymerization determines the optical activity of
the units in the polymer. The properties tend toward those
resulting from greater crystallinity if a single opticzl
ifiomer is used in the polymer.
The rate of tissue absorption in living mammals is
affected by the hydrolytic history of the poly~ers before im-
plantation, the molecular weight, and the size and shape of
the implanted polymer, as well as the chemical composition of
the polymer. In general, subject to the effect of these other
~ariables, the higher proportion of glycolic acid units, the
more rapid the absorption. The drier the polymer is kept, the
slower the absorption, and the higher the molecular weight,
the stronger the polymer.
Ihe use of the present homopolymers and co-polymers
per~its an increase in the range Or absorption characteristics
~vail~ble for surgical devices.
-49-
