CA1052046A - Unsymmetrically substituted 1,4-dioxane-2,5-diones - Google Patents

Abstract

ABSTRACT
Unsymmetrically 3,6-substituted 1,4-dioxane-2,5--diones may be polymerized to give living-tissue absorbable, hydrolytically degradable surgically useful polymers. These polymers have predominantly regular rather than random spacings of side chains, may be stereoregular and tend toward higher cryatallinity than radomly sequenced polymers. A polymer of 3-methyl-1,4-dioxane-2,5-dione has the same empirical formula as an equimolecular copolymer of lactic and glycolic acid but has unique physical properties resulting from its more regu-lar steric configuration. Polymers and copolymers of 3- and 3,6-unsymmetrically substituted 1,4-dioxane-2,5-diones have surgically useful mechanical properties. On implantation, in living mammalian tissue, the polymers are absorbed, and re-placed by living tissue.

Description

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 .
- 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 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
., , " , " .

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.

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 ~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 ~4,5~3 , . .

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 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 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 24,583 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-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 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 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 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 .. . ... _ _ _ .. _ . . . . .... . .. .. . . . . . . . _ _ _ _ _, .. .

~4,5~

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 .' ~

24,5~ ' 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.~ -24,5~7 ?

, . .

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 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 c4~5~3 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 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.

( ~ J

?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 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~.

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

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 .~ , .

.. . ..... . - .
-- 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 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 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 ?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.

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.

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.

. . 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 - ~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 . . , ., , ~

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 ~ .

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 ) o ~ ~
O~ O ~ ~D ~ O, (U g O 9 .

~U

~ 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.

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-24,5 "`

.

-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 .
~ .
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~

.

~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.

Claims (14)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A method of forming a polymer containing more than 2% by weight of recurring units of the formula:

and the remaining units are and 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:

where R1 is selected from the group consisting of hydrogen, and the methyl radical and at least one compound of the formula where R2 is selected from the group consisting of hydrogen, and the methyl radical.

2. A polymer containing more than 2% by weight of recurring units of the formula:

and the remaining units are and where R1 and R2 are separately selected from the group consisting of hydrogen, and the methyl radical, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.

3. A method according to claim 1 which comprises heating 3-methyl-1, 4-dioxane-2,5-dione in the presence of tin chloride dihydrate to yield a polymer of the formula:

where n is such that the weight average molecular weight is at least about 5,000.

4. The polymer of claim 2 which has the formula:

where n is such that the weight average molecular weight is at least about 5,000, whenever prepared by the process according to claim 3 or by an obvious chemical equivalent thereof.

5. A method according to claim 1 which comprises heating 3,3-dimethyl-1,4,-dioxane-2,5,-dione in the presence of tin chloride dihydrate to yield a polymer of the formula wherein n is such that the weight average molecular weight is at least about 5,000.

6. A method according to claim 1 which comprises heating a compound of the formula wherein R1 is hydrogen or methyl with a glycolide or lactide in the presence of tin chloride dehydrate to yield a polymer containing more than 2 mole %
of recurring units of the formula wherein R1 is hydrogen or methyl, wherein n is such that the weight average molecular weight is at least about 5,000.

7. A method according to claim 1 or 6 which comprises heating 3-methyl-1,4-dioxane-2,5-dione with 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:

the remaining units being where R3 is CH3- or H -.

8. A method according to claim 1 or 6 which comprises heating 3,3-dimethyl-1,4-dioxane -2,5-dione with glycolide or lactide in the presence of tin chloride dyhydrate to yield a polymer containing more than 2 mole % of recurring units of the formula and the remaining units being wherein R3 is CH3 or H.

9. A polymer according to claim 2 containing more than 2 mole % of recurring units of the formula:

the remaining units being where R1 is CH3- or H -, whenever prepared according to claim 1 or 6 or by an obvious chemical equivalent thereof.

10. A polymer according to claim 2 containing more than 2 mole % of recurring units of the formula the remaining units being wherein in R3 is hydrogen or methyl, wherever prepared according to claim 1 or 5 or by an obvious chemical equivalent thereof.

11. A method according to claim 1 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 ex-change resin, unsymmetrically substituted 1,4-dioxane-2,5-dione of the formula:

where R1 is selected from the group consisting of hydrogen, and the methyl radical and glycolide to yield a polymer containing 50 or more % by weight of recurring units of the formula:

the remaining units being predominantly of the formula:

and having a weight average molecular weight of at least 10,000, where R1 is selected from the group consisting of hydrogen, and the methyl radical.

12. A method according to claim 1 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 ex-change resin, unsymmetrically substituted 1,4-dioxane-2,5-dione of the formula:

where R1 is selected from the group consisting of hydrogen, and the methyl radical and lactide to yield a polymer containing 50 or more % by weight of recurring units of the formula:

the remaining units being predominantly of the formula:

and having a weight average molecular weight of at least 10,000, where R1 is selected from the group consisting of hydrogen, and the methyl radical.

13. A polymer containing 50 or more % by weight of recurring units of the formula the remaining units being predominantly of the formula:

and having a weight average molecular weight of at least 10,000, where R1 is selected from the group consisting of hydrogen, and the methyl radical, when-ever prepared by a process according to claim 11 or by an obvious chemical equivalent thereof.

14. A polymer containing 50 or more % by weight of recurring units of the formula the remaining units being predominantly of the formula:

and having a weight average molecular weight of at least 10,000, where R1 is selected from the group consisting of hydrogen, and the methyl radical, when-ever prepared by a process according to claim 12 or by an obvious chemical equivalent thereof.