CA1329854C - Biodegradable polymeric materials based on polyether glycols, processes for the preparation thereof and surgical articles made therefrom - Google Patents
Biodegradable polymeric materials based on polyether glycols, processes for the preparation thereof and surgical articles made therefromInfo
- Publication number
- CA1329854C CA1329854C CA000568988A CA568988A CA1329854C CA 1329854 C CA1329854 C CA 1329854C CA 000568988 A CA000568988 A CA 000568988A CA 568988 A CA568988 A CA 568988A CA 1329854 C CA1329854 C CA 1329854C
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- Prior art keywords
- polymers
- biodegradable
- polymer
- vascular prosthesis
- absorbable
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/66—Polyesters containing oxygen in the form of ether groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L17/00—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
- A61L17/06—At least partially resorbable materials
- A61L17/10—At least partially resorbable materials containing macromolecular materials
- A61L17/12—Homopolymers or copolymers of glycolic acid or lactic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/58—Materials at least partially resorbable by the body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G18/00—Polymeric products of isocyanates or isothiocyanates
- C08G18/06—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen
- C08G18/28—Polymeric products of isocyanates or isothiocyanates with compounds having active hydrogen characterised by the compounds used containing active hydrogen
- C08G18/40—High-molecular-weight compounds
- C08G18/42—Polycondensates having carboxylic or carbonic ester groups in the main chain
- C08G18/4266—Polycondensates having carboxylic or carbonic ester groups in the main chain prepared from hydroxycarboxylic acids and/or lactones
- C08G18/4283—Hydroxycarboxylic acid or ester
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G2230/00—Compositions for preparing biodegradable polymers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/31504—Composite [nonstructural laminate]
- Y10T428/31551—Of polyamidoester [polyurethane, polyisocyanate, polycarbamate, etc.]
- Y10T428/31565—Next to polyester [polyethylene terephthalate, etc.]
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/31504—Composite [nonstructural laminate]
- Y10T428/31786—Of polyester [e.g., alkyd, etc.]
Abstract
BIODEGRADABLE POLYMERIC MATERIALS BASED ON POLYETHER GLYCOLS, PROCESSES FOR THE PREPARATION THEREOF
AND SURGICAL ARTICLES MADE THEREFROM
ABSTRACT OF THE DISCLOSURE
The invention provides poly(.alpha.-hydroxy-carboxylic acid)/
poly(oxyalkylene) polymers selected from multiblock polymers of the following repeating unit I
I
wherein R is an alkylene group, R1 is hydrogen or methyl groups, m is a positive integer, and a and b are zero or positive integers, the case where a and b are simultaneously zero being excluded, and chain extended multiblock polymers which polymers are bioabsorbable and biodegradable, these polymeric materials being derived from reacting diols in the form of polyether glycols w1th .alpha.-hydroxy-carboxylic acids. The invention also provides methods for the preparation of such polymeric materials and bioabsorbable surgical articles made therefrom,
AND SURGICAL ARTICLES MADE THEREFROM
ABSTRACT OF THE DISCLOSURE
The invention provides poly(.alpha.-hydroxy-carboxylic acid)/
poly(oxyalkylene) polymers selected from multiblock polymers of the following repeating unit I
I
wherein R is an alkylene group, R1 is hydrogen or methyl groups, m is a positive integer, and a and b are zero or positive integers, the case where a and b are simultaneously zero being excluded, and chain extended multiblock polymers which polymers are bioabsorbable and biodegradable, these polymeric materials being derived from reacting diols in the form of polyether glycols w1th .alpha.-hydroxy-carboxylic acids. The invention also provides methods for the preparation of such polymeric materials and bioabsorbable surgical articles made therefrom,
Description
1 3 2 9 ~
The present invention relates to new and useful bioabsorbable polymeric materials derived from reacting diols in the form of polyether glycols with ~-hydroxy-carboxylic acids, to methods for the preparation of such polymeric materials and products such as surgical articles derived therefrom.
The development of bioabsorbable polymers is an important area in the blomedlcal mater~als fleld. The most obvlous advantage ls that it ellmlnates the need of reoperatlon for prostheses removal followlng use. Such polymers can perform as a temporary scaffold for tlssue regeneratlon, as a translent barrier or in controlled drug release ~ ;
systems, :' ','. ' ". '.
The most lnd1spensable attribute of a blodegradable materlal re1ates to the blocompatlblllty of both the polymer at lmplantatlon t1me and the products of 1ts degradat1On process, Addltional parameters wh1ch play an tmportant role lnclude the mechanlcal propertles of the materlal and~ for most appllcatlons, the match~ng of the polymer blodegradatlon klnetlcs to that of the heallng process, The scarclty of polymers whlch meet these rather demandlng ~, requlrements has prompted a contlnuous search for new, lmproved blodegradable polymers.
, ~, . .
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1~98~4 Polyglycolic acid (PGA) was the first biodegradable polymer synthesized and is used mainly to prepare bioabsorbable sutures (E.E.
Schmitt and R.A. Polistina, U.S. Patent 3,297,033 (1967); E.J~ Frazza and E. E. Schmitt, J. Biomed. Mater. Res., 1 43-58 (1971); it was followed by polylactic acid (PLA) and copolymers of the two (A.K.
Schneider, (Du Pont), U.S. Patent 2,703,316. A.K. Schneider~ U.S.
Patent 3,636,956 (1975); R.K. Kulkarni, K.C. Pani, C. Neuman and F.
Leonard, J. Biomed, Mater. Res., 5, 169 (1971); D. Wasserman, U.S.
Patent 1,375,008 (1971); D. K. G~ld~ng and A. M. Reed, Polymer, 20, 1459-1464 (1979); A. M. Reed and D. K. G~ld1ng, Polymer, 22, 494-498 (1981)). These alpha polyesters have been 1nvest19ated for use as sutures and as implant mater1als for the repa1r of a var~ety of osseous and soft tissues (J.O. Holl1nger, J. Biomed Mater. Res., 17 71-82 (1983); D.E. Cutr19ht and E.E. Hunsuck, Oral Surg., 33 28-34 lg (1972); L. Audell, S. Bowald, C. Busch and I. Er~ksson, Acta Ch~r.
Scand. 146, 97-99 (1980), as well as ln susta1ned drug del1very appl1catons (T. M. Jakanlcz, H.A. Nash, D,L, W1se and J.B. Gregory Contracept1On, 8, 227 (1973); L.R. Beck, D,R, Cowsar, D.H. Lew~s, R.J, CoKgrove, C.T. R1ddle, S.L. Lowry and T. Epperly, Fert. Ster. 31, 545 ~1979)).
~
~ .
However, due to some character1st1cs of these o-hydroxy-carboxyllc ac1ds, more 1mportantly the1r slow degradat1On k1net1cs and the1r st1ffness, lt has long been recogn1zed that a need ex1~ts for new absorbable polymers, exhlb1t1ng the advantageous ~ `
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' 1~2~85~
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properties of strength, flexibility and absorbability needed for various biomedical applications.
There have been various prior art suggestions for modifying polyglycolic and polylactic acid, such as by copolymerization of glycolide or lactide mono~ers with other monomers, to produce a polymer possessing the requisite properties. For example, the work by C.X. Song and X. D. Feng, who developed a series of A6A triblock copolymers of E-caprolactone and DL-Lactide, Macromolecules, 17, 2764 (1984)), or the development of polyesteramides, by T.H. Barrows (U.S, Pat. No. 4,343,931). Other copolymers for use às bioabsorbable matertals have been disclosed~ Polyethylene oxide/polyethylene terephthalate copolymers have been disclosed as biodegradable elastomeric biomaterials in Reed et al., "Trans. Am, Soc. Artif, Intern. Organs", 1977, page lO9. U.S. Pat. No. 2,917,410 discloses ; -the condensation of glycolic acid with a polyethylene glycol mixture ~-to an ester with an average molecular weight of S105 for treating fabr1cs for improved tear strength and abrasion resistance. The ~-add1t10n of aromatic orthocarbonates during the formation of a flber-forming polyester by the reaction of a dicarboxylic ac;d or its funct10nal derivat1ve w1th a glycol is disclosed in U.S, Pat. No.
3.714,125, .'A . .
v ~ .. .. .
~ U,S, Pat, No, 4,070,347 discloses poly (orthoester) co- and -~ - homopolymers and poly~orthocarbonate) co- and homopo1ymers useful for ' ' :"., ', .
1329~4 forming delivery devices with drug dispersed therein for release by controlled polymeric erosion over a prolonged period of time. U.S.
Pat. No. 4,343,931 discloses poly(esteramides), which are condensation products of reacting a diamine with lactic or glycolic acid to form a diaminediol which is then reacted with a bischloroformate or a dicarboxylic acid. Important biodegradable polymers developed in recent years ;nclude a new class of bioerod;ble polyanhydrides, developed by Langer, especially for controlled drug delivery (H.B.
Rosen, J. Chang, G.E. Wnek, R.J. Linhardt and R~ Langer, Biomaterials, 4, 131(1983); K.W. Leong, B.C. Brott and R. Langer, J. Biomed. Mater.
Res" 19 (8), 941 (1985).
,;, ' .' Among the requ1rements of an ldeal absorbable polymeric material are that lt should have adequate strength and flex~b11ity, should be controllably unlform 1n propert1es, should be absorbable by l~v~ng t1ssue, pr~ferably at a constant rate regardless of the place of the body or the cond1t10n of the patlent, w~thout causlng unfavorable tlssue react10ns as wall1ng off, granuloma format10n, excess1ve edema, .
etc" 1t should cause m1n~mal thrombos1s 1n blood-contacting appl1cat10ns, 1t should have good handl1ng properties, and flnally 1t should be ster~l kable w~thout s19n~f1cantly affect~ng des~red propert1es of the mater1al. Add1t10nal requ1rements are d1ctated by 1ts spec1flc appl1cat10n. For example, the acceptab111ty of a suture 1s frequently determ1ned by the Young modulus (a measurement of ~ .', ' .' .
.
~: ., ' ' 1 3 2 ~ 8 ~
flexibility), the tensile strength and the percent elongation at the breaking point (a measure of extensibility).
According to the present invention there is now provided synthetic absorbable polymers having a high degree of softness and flex1bility, while covering a wide range of biodegradation kinetics.
Thus the present invention provides synthetic absorbable polymers hav1ng unigue and desirable properties not available with the b10degradable polymers of the prior art.
Mor~ specifically, the present invention prov~des copolymers from wh1ch can be manufactured absorbable surg1cal articles such as sutures, wound and burn dress1ngs and partially or totally b10degradable vascular grafts, possess1ng the des1red characterist1cs of flexlb111ty, strength, b10compat1b111ty, blodegradab111ty and st~r111zab111ty. Such ls achieved, accordlng to the lnvent~on, through the copolymertzatlon of lact1c or glycollc acld or comb1nat10ns of the two, w~th hydroxy-ended flex1ble cha~ns, most preferably poly(alkylene glycols) of var10us molecular welghts, to produce absorbable copolymers possess1ng lncreased flex1b111ty and ~ cover1ng a w1de range of blodegradat10n rates.
,-, Thus accord1n~ to the present lnventlon there are now prov1ded ~ poly~o-hydroxy-carboxyl1c ac1d)/poly(oxyalkylene)s selected from:
.~
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a) multiblock polymers of the following repeating unit I
~( ~ IH )b (O-fH-C-)a (O R ) R1 Rl wherein R is an alkylene group, R1 iS hydrogen or methyl gro~ps, m is a positive integer, and a and b are zero or positive integers, the case where a and b are simultaneously zero being excluded, and . .' '' b) a chain extended multiblock polymer of the following formula II: --~(0 - ~H - ~ ~ (O - R)_ 0-(~ - ~H - O)y ~ -~ - R' -~ - C~
where1n R represents an alkylene gro~p, R1 is hydrogen or methyl groups and R' 1s hexamethylene, 4,4'-d1phenylmethane, toluene, I
naphtalene, 4,4'-dtcyclohexylmethane, cyclohexyl, 3,3'-dlmethylphenyl, ~y~. 3,3'-d1methyl-dlphenylmethane, 4,6'-xylylene, 3,5,5-tr1methylcyclohexyl, 2,2,4-tr~methyl-hexamethylene and p-phenylene, or d11socyanate-terminated polyalkylene glycol chains compr1s1ng~ a central polyalkylene glycol chain capped by two :.
dll~ocyanate co~ounds of formula NCO-R'-NCO wherein R' is ..
a8 d-~lned above, or : 1:
X ~
- 8 - 1 3 2 ~ ~ ~ 4 ... ..
c) a chain extended multiblock polymer of the following formula I I I
'' ','.`'"'-:.,; "''-.' . .- ~ ~ ..
~(O - fH - t )x (OR)m 0-~C - fH - O)y e R -R1 R1 ;-~ ~
''. ':':' .".
where1n R represents an alkylene group, R1 is hydrogen or methyl .. . .
groups, R" is a saturated or unsaturated alkylene group, or an ~
, .", . .
aromatic r1ng, x and y are ldentical or different positive integers, and m 1s a pos1tive 1nteger.
"'';~''. :':
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The copolymers of this 1nvention are multiblock copolymers obt~1ned through the polyesterficat1On of the ~hydroxycarboxylic ac1d 1n the presence of hydroxyl-ended poly(alkylene glycol) chains of ~- var1Ous molecular we19hts. The degree of polymer1zatlon of the copolymer was var1ed depend1ng on var1Ous exper1mental parameters.
Most notlcèably temperature, pressure and t1me, A preferred poly~alkylene glycol) 1s poly(ethylene glycol), preferably 1n the lS 600-6000 molecular welght range, ~, ..
; The lnvent1On also provldes a method of polymer1zat1On for produclng sa1d poly(~-hydroxy-carboxyl~c ac1d)/poly(alkylene glycol) block copolymers, ;
. , ,;,: .
s'~ ~ . .. ... .
... ~ . . .
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~ ' 13~98~ -g .:, As indicated hereinbefore the polymers of the invention find advantageous utility in the manufacture of surgical articles and pharmaceutical compositions as is known in the art for polymers, àbsorbable in living animals. Thus, ~he present invention also provides surgical articles including a suture or ligature, -particularly in the form of flexible monofilaments~ a suture in the form of a needle and a suture combination, a surgical clip or staple, a surg~cal prosthesis, a part;ally or totally biodegradable vascular graft, wound and burn covering, text~le structures, couplings, tubes, supports, pins, screws or other forms of support. Yet further objects of thls 1nvent1On ~nclude a self-supporting film, hollow tube, beads -or gel, conta~n~ng a un1formly dispersed drug for controlled cont1nuous adm1nistration, manufactured from polymers of the present lnvent10~
Thus the 1nventton also prov~des surg1cal articles comprlsed of:
(1) a mult1block polymer of the followlng repeat~ng unlt:
, .,' " ' .
9 )b (~IH~~!)D~(o-R-)m ~ 1 Rl : ~' whereln R ls an alkylene group, R1 ls hydrogen or methyl groups, m ls posltlve lnteger, and n and b are zero or pos1t1ve lntegers, the case where a and b ~re s1multaneously zero be~ng excluded~
' ~ ':':, '.:, 1 3 ~ 9 ~
- ''- ''' ' The copolymers of this invention are obtained by the .
polycondensation reaction of monomeric -hydroxy-carboxylic ac~ds, .
having the formula -HO-CH-COOH .-wherein R1 is hydrogen or methyl groups, in the presence of hydroxyl-ended poly(alkylene glycol) chains having the general formula : -H-(OR-)m-OH wherein R is an alkylene group such as ethylene, .
propylene, butylene or combinat1,ons of them, ln the presence of an .:: .
esterflcation promoting catalyst such as Sb203, to produce the copolyme;. ~.
Add~,t10nal d1hydroxy compounds that can be used ~nclude the already ment10nèd poly~alkylene glycols) and also ethylene glycol; : ;:
. 1,3-propaned101; 1,4-butaned101; 1,5-pentaned~,ol; 1,6-hexanedlol;
1,7-heptanedJ,ol; 1,8-octaned~ol; 1,9-nonanediol; 1,1O-decaned~,ol: .
- 15 l,ll-undecaned101; 1,12-dodecaned101; 1,13-trldecaned~ol~~ -tetradecaned{,ol; 1,15-pentadecaned101; 1,16-hexadecaned~,ol:
.~ oxaal1phAtlc d101s, d~am~ned101s, hydroxy-term~nated polyd~methyl s110xane polymers and copolymers, and poly(butad1ene, hydroxyl .;
term1nated).
~ ~. , . -A part1cularly pre~erred poly~alkylene glycol) ls polyethylene :
glycol ~other commonly used nt,mes are poly(oxyethylene) and poly .:
thylon0 ox1de); therefore, the followlng descrlpt10n and f~rst ~" ~
''~' '''"'''"
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1 3 ~
" ~ -examples, which are presented by way of illustration, are directed primarily to the synthesis of copolymers comprising polyethylene glycol chains, it being understood that certain variations may apply to other poly(alkylene glycols) encompassed by the general formula of the invention (described in less detail in later examples) as will be readily apparent to those skilled in the art.
, :' ' PELA is the generic name used to denote this family of polyethylene glycol (PEG) and lactic acid (LA) copoly (ether-esters).
The average molecular welght of the PEG chalns ls listed after the name, th1s belng followed by x, the segmental degree of polymerization of the LA sequences (e.g., PELA3400/209).
, "
The one-step synthesls of the multlblock copolymer ~s exempllfied as follows, for a polytethylene glycol)/polylact1c acld, PELA
copolymer. ~
, . .. . .
Durlng thls flrst stage of the reactlon, an ABA trlblock polymer 1s formed, lts overall molecular we19ht and the length of the dlfferent segments be1ng determlned by the molecular welght of the polyalkylene glycol cha1n, by the feed of lactlc acld lnto the system ~;
and by reDctlon tlme. RDlslng the temperature of the system was expected, ~s lt would be readlly Dpparent to those skllled ln the art, to lncreDse the rcDctlon rate. Surprlslngly, however, ralslng the temperDture cDused a drastlc change ln the reactlon mechanlsm, a :, ' :'' :.':,' ' ; .;
6 . S ~ ~ ~
- 12 - 13298~ `
completely unexpected and rather unusual pathway being now available for further increase of the molecular weight. Most probably an ester ~: -alkyl-oxygen scission mechanism of lactoyl units is responsible for .
the large increase in molecular weight and the consequent dramatic -.
changes in the polymers' properties. The second stage of the reaction .
yields a polymer of the following general repeating unit: ~ .
O p ' ,.
H-(-O-ICH-C-)X-(-O-CH2CH2-)m-0-(C-fH-O-)yH .:
H3CH3 :
~ . .. .
~., -., . I sb23 ~'''. :.
~(0- l fH-)b-(O-fH~C~)a~(~O~CH2~CH2~)m3 (AB)z multlblock Copolymer .~
wher~1n m Is a pos1tlve lnteger, and a and b are zero or poslt~ve . :.
1nteg~rs, prov1ded A and b ~re not slmultaneously zero~ ~
.
~ ,.
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13~98~
U.S. Pat. No. 4,452,973 discloses poly(glycolic acid)/poly(oxy-ethylene) triblock copolymers and method of manufacturing the same, while U.S. Pat. No. 4,438,253 describes a poly~glycolic acid)/poly (alkylene glycol) block copolymer and the method of manufacturing the same. These multiblock copolymers are synthesized via a three-steps process, whereby triblock copolymers comprising a poly(alkylene glycol) chain and two poly(glycolic acid) (PGA) blocks are chain extended by an aromat~c orthocarbonate such as tetra-p-tolyl orthocarbonate. The substant1al st1ffness of the copolymers prepared accordlng wlth the teachings of thls reference (a 2.75 GPa modulus ~s presented ln Example 6 of U.S. Pat. No. 4,438,253 as illustrating the greater flex~bllity of the materlals developed), makes these materials unsu1table for use as flex1ble surg1cal art~cles and concluslvely ~;
precludes the~r use ~n a var1ety of b~omed1cal appl1cat1Ons. The large PGA content (80-85%) read11y explalns the r19~dity of the mater~als obta~ned, their st~ffness be~ng comparable to that of, for example, polymethyl methacrylate, tw~ce that of polypropylene and approxlmately twenty-f1ve tlmes that of s111cone rubber, The h~gh PGA content ~s also respons1ble for the h19h meltlng po1nt of these crystall1ne materlals (Tm - 217-220) and can be assumed, w~11 also result ~n severely 11m1ted solublllty propert1es. It ls also 1mportant notlclng thc extremely norrow composlt1Onal range covered by the polymers dlsclosed by the ~nventlon (8~-85% PGA), result1ng, therefore, 1n a str1k1n~1y 11m1ted range of b1Odegradatlon processes, the mater~als devoloped follow1ng ~n essent1ally slmllar degradat~on klnet~cs. It ~b~
132~8~
should also be stressed, that the process comprises the transesteri-fication reaction of PGA and hydroxy-terminated poly(alkylene glycol) chains (U.S. Pat. No. 4,438,253, claim 7), the polymerization of monomeric GA to produce PGA, being a previous and separate reaction.
Finally, the addition of an aromatic orthocarbonate chain extender is a th1rd step, requlred to increase the molecular weight of the polymer ~ ;
and reduce lts br1tlleness. -~ -Clearly contrasting with thls description of the invention d1sclosed in U,S. Pat. No. 4,438,253, it is readily apparent that the rather speclal chem1stry ~nvolved 1n the fundamental stage of the process of the present ~nvent~on, plays a cruc~al role ln allowing a very s1mple one-step full polymer1zat10n process, and resulted 1n a v~r1ety of polymer1c mater1als exhib~tlng very speclal mechan1cal features (most 1mportantly, the~r extremely hlgh flexlb111ty, att~ln1ng E~5 MPa and eF~1100% values, In some 1nstances) and coverlng a w1de range of degradatlon k1net1cs. In llght of these flndlngs, 1t 15 apparent that the present ~nventlon provides synthet~c absorbable polymers h~v1ng un1que and des1rable propert1es not ava11able wlth the b10degradable pol~mers of the pr10r art, and that the method present~d hereby 1s markedly more advantageous than that of the pr10r art.
.: .
Alternat1vely, the degree of polymer1zatlon of the ABA Copolymer 1s 1ncrensed by ' .
' ;~''' '' "..' -:
!c, ~ "i~, ,~
1~2~8~ -: 1 ~
(a) reacting various di-isocyanates such as hexamethylene diisocyanate (HDI),4,4'-diphenylmethane diisocyanate (MDI), ~-4,4'-dicyclohexylmethane diisocyanate (H12MDI), cyclohexyl diisocyanate (CHDI) and 2,4 toluene diisocyanate (TDI), of the following formula~
', . .
NCO
OCN-CH2-CH2-CH2-CH2-CH2-CH2-NCOOCN ~ CH3 NCO OCN
HDI TDI CHDI -~
- / CH2-CH ~ /CH2-CH ~
OCN~ ~ -CH2- ~ NCO OCN-CH\ / CH-CH2-C\H / CH-NCO
, H1 2MDI .'' .
w1th the termtnal hydroxyl groups of the ABA type polymer.
The reactlon ytelded a ser1es of poly(etherester urethanes). The reactlon 1s carrted out 1n dry solvents such as tetrahydrofuran or ~ dtmethylformamlde or ~n the melt, 1n presence of an appropriate f~ urethanlzatton promottng catalyst such as d~butyltln d11aurate. The chaln extonston step ts exempltfled as follows for a polyethylene s glycol contalntng copolymer:
., .,, , ', .:
~ ' ' ";~' . ' : . ,:, .
1 3 2 ~
O O ':: ' H-(-O-CH-C-)X-(ocH2cH2-)m-o-(c-~H-o-) 1 R1 - ~ ~
~`,'.. ,' OCN-R -NCO l cat.
_l-(o-fH-c-)~-(-ocH2cH2-)~-o-(-c-lcH-o-)y-c-~ R
Poly(etherester urethane) .. `
wherein R1 represents hydrogen or methyl groups and R' may be ;: .
hexamethylene, 4,4'-diphenylmethane, toluene, napthalene, .
4,4'-dicyclohexylmethane, cyclohexyl, 3,3'- dimethylphenyl, 3,3'-dimethyl-diphenylmethane, 4,6'-xylene, 3,5,5-tr1methylcyclohexyl, 2,2,4-trimethyl-hexamethylene and p-phenylene, or diisocyanate terminated polyalkylene glycol chains comprising a central polyalkylene chain, capped by two di1socyanate compounds of formula NCO-R'-NCO wherein R' i8 a~ defined above, and b) react1ng a compound selected from the group consisting of d~carboxylic acids, methyl and ethyl esters of dicarboxylic acids, d1~ac1d chlorldes ~nd anhydrides of a dicarboxylic acid. D~carboxyl~c . .
ac1ds a~nd der1vat1ves useful in the synthesis of polymers by the above m~thods 1nclude those der1ved from the d~carboxylic acids l~sted . ~;
r ' :
: - . ,: ' ~ ~" _.. ~
_17_ 13298~
below. In addition the free acids can also be used. They are, for example, oxalic acid, malonic acid; succinic acid; -~
2,3-dimethylsuccinic acid; glutaric acid; 3,3-dimethylglutaric acid;
The present invention relates to new and useful bioabsorbable polymeric materials derived from reacting diols in the form of polyether glycols with ~-hydroxy-carboxylic acids, to methods for the preparation of such polymeric materials and products such as surgical articles derived therefrom.
The development of bioabsorbable polymers is an important area in the blomedlcal mater~als fleld. The most obvlous advantage ls that it ellmlnates the need of reoperatlon for prostheses removal followlng use. Such polymers can perform as a temporary scaffold for tlssue regeneratlon, as a translent barrier or in controlled drug release ~ ;
systems, :' ','. ' ". '.
The most lnd1spensable attribute of a blodegradable materlal re1ates to the blocompatlblllty of both the polymer at lmplantatlon t1me and the products of 1ts degradat1On process, Addltional parameters wh1ch play an tmportant role lnclude the mechanlcal propertles of the materlal and~ for most appllcatlons, the match~ng of the polymer blodegradatlon klnetlcs to that of the heallng process, The scarclty of polymers whlch meet these rather demandlng ~, requlrements has prompted a contlnuous search for new, lmproved blodegradable polymers.
, ~, . .
. ~ . , : , .. :.
, . . . . .
1~98~4 Polyglycolic acid (PGA) was the first biodegradable polymer synthesized and is used mainly to prepare bioabsorbable sutures (E.E.
Schmitt and R.A. Polistina, U.S. Patent 3,297,033 (1967); E.J~ Frazza and E. E. Schmitt, J. Biomed. Mater. Res., 1 43-58 (1971); it was followed by polylactic acid (PLA) and copolymers of the two (A.K.
Schneider, (Du Pont), U.S. Patent 2,703,316. A.K. Schneider~ U.S.
Patent 3,636,956 (1975); R.K. Kulkarni, K.C. Pani, C. Neuman and F.
Leonard, J. Biomed, Mater. Res., 5, 169 (1971); D. Wasserman, U.S.
Patent 1,375,008 (1971); D. K. G~ld~ng and A. M. Reed, Polymer, 20, 1459-1464 (1979); A. M. Reed and D. K. G~ld1ng, Polymer, 22, 494-498 (1981)). These alpha polyesters have been 1nvest19ated for use as sutures and as implant mater1als for the repa1r of a var~ety of osseous and soft tissues (J.O. Holl1nger, J. Biomed Mater. Res., 17 71-82 (1983); D.E. Cutr19ht and E.E. Hunsuck, Oral Surg., 33 28-34 lg (1972); L. Audell, S. Bowald, C. Busch and I. Er~ksson, Acta Ch~r.
Scand. 146, 97-99 (1980), as well as ln susta1ned drug del1very appl1catons (T. M. Jakanlcz, H.A. Nash, D,L, W1se and J.B. Gregory Contracept1On, 8, 227 (1973); L.R. Beck, D,R, Cowsar, D.H. Lew~s, R.J, CoKgrove, C.T. R1ddle, S.L. Lowry and T. Epperly, Fert. Ster. 31, 545 ~1979)).
~
~ .
However, due to some character1st1cs of these o-hydroxy-carboxyllc ac1ds, more 1mportantly the1r slow degradat1On k1net1cs and the1r st1ffness, lt has long been recogn1zed that a need ex1~ts for new absorbable polymers, exhlb1t1ng the advantageous ~ `
. . .
,~ , :
' 1~2~85~
': .
properties of strength, flexibility and absorbability needed for various biomedical applications.
There have been various prior art suggestions for modifying polyglycolic and polylactic acid, such as by copolymerization of glycolide or lactide mono~ers with other monomers, to produce a polymer possessing the requisite properties. For example, the work by C.X. Song and X. D. Feng, who developed a series of A6A triblock copolymers of E-caprolactone and DL-Lactide, Macromolecules, 17, 2764 (1984)), or the development of polyesteramides, by T.H. Barrows (U.S, Pat. No. 4,343,931). Other copolymers for use às bioabsorbable matertals have been disclosed~ Polyethylene oxide/polyethylene terephthalate copolymers have been disclosed as biodegradable elastomeric biomaterials in Reed et al., "Trans. Am, Soc. Artif, Intern. Organs", 1977, page lO9. U.S. Pat. No. 2,917,410 discloses ; -the condensation of glycolic acid with a polyethylene glycol mixture ~-to an ester with an average molecular weight of S105 for treating fabr1cs for improved tear strength and abrasion resistance. The ~-add1t10n of aromatic orthocarbonates during the formation of a flber-forming polyester by the reaction of a dicarboxylic ac;d or its funct10nal derivat1ve w1th a glycol is disclosed in U.S, Pat. No.
3.714,125, .'A . .
v ~ .. .. .
~ U,S, Pat, No, 4,070,347 discloses poly (orthoester) co- and -~ - homopolymers and poly~orthocarbonate) co- and homopo1ymers useful for ' ' :"., ', .
1329~4 forming delivery devices with drug dispersed therein for release by controlled polymeric erosion over a prolonged period of time. U.S.
Pat. No. 4,343,931 discloses poly(esteramides), which are condensation products of reacting a diamine with lactic or glycolic acid to form a diaminediol which is then reacted with a bischloroformate or a dicarboxylic acid. Important biodegradable polymers developed in recent years ;nclude a new class of bioerod;ble polyanhydrides, developed by Langer, especially for controlled drug delivery (H.B.
Rosen, J. Chang, G.E. Wnek, R.J. Linhardt and R~ Langer, Biomaterials, 4, 131(1983); K.W. Leong, B.C. Brott and R. Langer, J. Biomed. Mater.
Res" 19 (8), 941 (1985).
,;, ' .' Among the requ1rements of an ldeal absorbable polymeric material are that lt should have adequate strength and flex~b11ity, should be controllably unlform 1n propert1es, should be absorbable by l~v~ng t1ssue, pr~ferably at a constant rate regardless of the place of the body or the cond1t10n of the patlent, w~thout causlng unfavorable tlssue react10ns as wall1ng off, granuloma format10n, excess1ve edema, .
etc" 1t should cause m1n~mal thrombos1s 1n blood-contacting appl1cat10ns, 1t should have good handl1ng properties, and flnally 1t should be ster~l kable w~thout s19n~f1cantly affect~ng des~red propert1es of the mater1al. Add1t10nal requ1rements are d1ctated by 1ts spec1flc appl1cat10n. For example, the acceptab111ty of a suture 1s frequently determ1ned by the Young modulus (a measurement of ~ .', ' .' .
.
~: ., ' ' 1 3 2 ~ 8 ~
flexibility), the tensile strength and the percent elongation at the breaking point (a measure of extensibility).
According to the present invention there is now provided synthetic absorbable polymers having a high degree of softness and flex1bility, while covering a wide range of biodegradation kinetics.
Thus the present invention provides synthetic absorbable polymers hav1ng unigue and desirable properties not available with the b10degradable polymers of the prior art.
Mor~ specifically, the present invention prov~des copolymers from wh1ch can be manufactured absorbable surg1cal articles such as sutures, wound and burn dress1ngs and partially or totally b10degradable vascular grafts, possess1ng the des1red characterist1cs of flexlb111ty, strength, b10compat1b111ty, blodegradab111ty and st~r111zab111ty. Such ls achieved, accordlng to the lnvent~on, through the copolymertzatlon of lact1c or glycollc acld or comb1nat10ns of the two, w~th hydroxy-ended flex1ble cha~ns, most preferably poly(alkylene glycols) of var10us molecular welghts, to produce absorbable copolymers possess1ng lncreased flex1b111ty and ~ cover1ng a w1de range of blodegradat10n rates.
,-, Thus accord1n~ to the present lnventlon there are now prov1ded ~ poly~o-hydroxy-carboxyl1c ac1d)/poly(oxyalkylene)s selected from:
.~
, . ~ ~ . . , : . " .
. ~
~ ' , " '' "' ' _ 7 ~ 3 ~ 9 8 ~
a) multiblock polymers of the following repeating unit I
~( ~ IH )b (O-fH-C-)a (O R ) R1 Rl wherein R is an alkylene group, R1 iS hydrogen or methyl gro~ps, m is a positive integer, and a and b are zero or positive integers, the case where a and b are simultaneously zero being excluded, and . .' '' b) a chain extended multiblock polymer of the following formula II: --~(0 - ~H - ~ ~ (O - R)_ 0-(~ - ~H - O)y ~ -~ - R' -~ - C~
where1n R represents an alkylene gro~p, R1 is hydrogen or methyl groups and R' 1s hexamethylene, 4,4'-d1phenylmethane, toluene, I
naphtalene, 4,4'-dtcyclohexylmethane, cyclohexyl, 3,3'-dlmethylphenyl, ~y~. 3,3'-d1methyl-dlphenylmethane, 4,6'-xylylene, 3,5,5-tr1methylcyclohexyl, 2,2,4-tr~methyl-hexamethylene and p-phenylene, or d11socyanate-terminated polyalkylene glycol chains compr1s1ng~ a central polyalkylene glycol chain capped by two :.
dll~ocyanate co~ounds of formula NCO-R'-NCO wherein R' is ..
a8 d-~lned above, or : 1:
X ~
- 8 - 1 3 2 ~ ~ ~ 4 ... ..
c) a chain extended multiblock polymer of the following formula I I I
'' ','.`'"'-:.,; "''-.' . .- ~ ~ ..
~(O - fH - t )x (OR)m 0-~C - fH - O)y e R -R1 R1 ;-~ ~
''. ':':' .".
where1n R represents an alkylene group, R1 is hydrogen or methyl .. . .
groups, R" is a saturated or unsaturated alkylene group, or an ~
, .", . .
aromatic r1ng, x and y are ldentical or different positive integers, and m 1s a pos1tive 1nteger.
"'';~''. :':
.~,. . .
The copolymers of this 1nvention are multiblock copolymers obt~1ned through the polyesterficat1On of the ~hydroxycarboxylic ac1d 1n the presence of hydroxyl-ended poly(alkylene glycol) chains of ~- var1Ous molecular we19hts. The degree of polymer1zatlon of the copolymer was var1ed depend1ng on var1Ous exper1mental parameters.
Most notlcèably temperature, pressure and t1me, A preferred poly~alkylene glycol) 1s poly(ethylene glycol), preferably 1n the lS 600-6000 molecular welght range, ~, ..
; The lnvent1On also provldes a method of polymer1zat1On for produclng sa1d poly(~-hydroxy-carboxyl~c ac1d)/poly(alkylene glycol) block copolymers, ;
. , ,;,: .
s'~ ~ . .. ... .
... ~ . . .
- , ,, :,, .:: .
~ ., .,- ;.
~ ' 13~98~ -g .:, As indicated hereinbefore the polymers of the invention find advantageous utility in the manufacture of surgical articles and pharmaceutical compositions as is known in the art for polymers, àbsorbable in living animals. Thus, ~he present invention also provides surgical articles including a suture or ligature, -particularly in the form of flexible monofilaments~ a suture in the form of a needle and a suture combination, a surgical clip or staple, a surg~cal prosthesis, a part;ally or totally biodegradable vascular graft, wound and burn covering, text~le structures, couplings, tubes, supports, pins, screws or other forms of support. Yet further objects of thls 1nvent1On ~nclude a self-supporting film, hollow tube, beads -or gel, conta~n~ng a un1formly dispersed drug for controlled cont1nuous adm1nistration, manufactured from polymers of the present lnvent10~
Thus the 1nventton also prov~des surg1cal articles comprlsed of:
(1) a mult1block polymer of the followlng repeat~ng unlt:
, .,' " ' .
9 )b (~IH~~!)D~(o-R-)m ~ 1 Rl : ~' whereln R ls an alkylene group, R1 ls hydrogen or methyl groups, m ls posltlve lnteger, and n and b are zero or pos1t1ve lntegers, the case where a and b ~re s1multaneously zero be~ng excluded~
' ~ ':':, '.:, 1 3 ~ 9 ~
- ''- ''' ' The copolymers of this invention are obtained by the .
polycondensation reaction of monomeric -hydroxy-carboxylic ac~ds, .
having the formula -HO-CH-COOH .-wherein R1 is hydrogen or methyl groups, in the presence of hydroxyl-ended poly(alkylene glycol) chains having the general formula : -H-(OR-)m-OH wherein R is an alkylene group such as ethylene, .
propylene, butylene or combinat1,ons of them, ln the presence of an .:: .
esterflcation promoting catalyst such as Sb203, to produce the copolyme;. ~.
Add~,t10nal d1hydroxy compounds that can be used ~nclude the already ment10nèd poly~alkylene glycols) and also ethylene glycol; : ;:
. 1,3-propaned101; 1,4-butaned101; 1,5-pentaned~,ol; 1,6-hexanedlol;
1,7-heptanedJ,ol; 1,8-octaned~ol; 1,9-nonanediol; 1,1O-decaned~,ol: .
- 15 l,ll-undecaned101; 1,12-dodecaned101; 1,13-trldecaned~ol~~ -tetradecaned{,ol; 1,15-pentadecaned101; 1,16-hexadecaned~,ol:
.~ oxaal1phAtlc d101s, d~am~ned101s, hydroxy-term~nated polyd~methyl s110xane polymers and copolymers, and poly(butad1ene, hydroxyl .;
term1nated).
~ ~. , . -A part1cularly pre~erred poly~alkylene glycol) ls polyethylene :
glycol ~other commonly used nt,mes are poly(oxyethylene) and poly .:
thylon0 ox1de); therefore, the followlng descrlpt10n and f~rst ~" ~
''~' '''"'''"
~ . : . .
1 3 ~
" ~ -examples, which are presented by way of illustration, are directed primarily to the synthesis of copolymers comprising polyethylene glycol chains, it being understood that certain variations may apply to other poly(alkylene glycols) encompassed by the general formula of the invention (described in less detail in later examples) as will be readily apparent to those skilled in the art.
, :' ' PELA is the generic name used to denote this family of polyethylene glycol (PEG) and lactic acid (LA) copoly (ether-esters).
The average molecular welght of the PEG chalns ls listed after the name, th1s belng followed by x, the segmental degree of polymerization of the LA sequences (e.g., PELA3400/209).
, "
The one-step synthesls of the multlblock copolymer ~s exempllfied as follows, for a polytethylene glycol)/polylact1c acld, PELA
copolymer. ~
, . .. . .
Durlng thls flrst stage of the reactlon, an ABA trlblock polymer 1s formed, lts overall molecular we19ht and the length of the dlfferent segments be1ng determlned by the molecular welght of the polyalkylene glycol cha1n, by the feed of lactlc acld lnto the system ~;
and by reDctlon tlme. RDlslng the temperature of the system was expected, ~s lt would be readlly Dpparent to those skllled ln the art, to lncreDse the rcDctlon rate. Surprlslngly, however, ralslng the temperDture cDused a drastlc change ln the reactlon mechanlsm, a :, ' :'' :.':,' ' ; .;
6 . S ~ ~ ~
- 12 - 13298~ `
completely unexpected and rather unusual pathway being now available for further increase of the molecular weight. Most probably an ester ~: -alkyl-oxygen scission mechanism of lactoyl units is responsible for .
the large increase in molecular weight and the consequent dramatic -.
changes in the polymers' properties. The second stage of the reaction .
yields a polymer of the following general repeating unit: ~ .
O p ' ,.
H-(-O-ICH-C-)X-(-O-CH2CH2-)m-0-(C-fH-O-)yH .:
H3CH3 :
~ . .. .
~., -., . I sb23 ~'''. :.
~(0- l fH-)b-(O-fH~C~)a~(~O~CH2~CH2~)m3 (AB)z multlblock Copolymer .~
wher~1n m Is a pos1tlve lnteger, and a and b are zero or poslt~ve . :.
1nteg~rs, prov1ded A and b ~re not slmultaneously zero~ ~
.
~ ,.
, ~ , .
13~98~
U.S. Pat. No. 4,452,973 discloses poly(glycolic acid)/poly(oxy-ethylene) triblock copolymers and method of manufacturing the same, while U.S. Pat. No. 4,438,253 describes a poly~glycolic acid)/poly (alkylene glycol) block copolymer and the method of manufacturing the same. These multiblock copolymers are synthesized via a three-steps process, whereby triblock copolymers comprising a poly(alkylene glycol) chain and two poly(glycolic acid) (PGA) blocks are chain extended by an aromat~c orthocarbonate such as tetra-p-tolyl orthocarbonate. The substant1al st1ffness of the copolymers prepared accordlng wlth the teachings of thls reference (a 2.75 GPa modulus ~s presented ln Example 6 of U.S. Pat. No. 4,438,253 as illustrating the greater flex~bllity of the materlals developed), makes these materials unsu1table for use as flex1ble surg1cal art~cles and concluslvely ~;
precludes the~r use ~n a var1ety of b~omed1cal appl1cat1Ons. The large PGA content (80-85%) read11y explalns the r19~dity of the mater~als obta~ned, their st~ffness be~ng comparable to that of, for example, polymethyl methacrylate, tw~ce that of polypropylene and approxlmately twenty-f1ve tlmes that of s111cone rubber, The h~gh PGA content ~s also respons1ble for the h19h meltlng po1nt of these crystall1ne materlals (Tm - 217-220) and can be assumed, w~11 also result ~n severely 11m1ted solublllty propert1es. It ls also 1mportant notlclng thc extremely norrow composlt1Onal range covered by the polymers dlsclosed by the ~nventlon (8~-85% PGA), result1ng, therefore, 1n a str1k1n~1y 11m1ted range of b1Odegradatlon processes, the mater~als devoloped follow1ng ~n essent1ally slmllar degradat~on klnet~cs. It ~b~
132~8~
should also be stressed, that the process comprises the transesteri-fication reaction of PGA and hydroxy-terminated poly(alkylene glycol) chains (U.S. Pat. No. 4,438,253, claim 7), the polymerization of monomeric GA to produce PGA, being a previous and separate reaction.
Finally, the addition of an aromatic orthocarbonate chain extender is a th1rd step, requlred to increase the molecular weight of the polymer ~ ;
and reduce lts br1tlleness. -~ -Clearly contrasting with thls description of the invention d1sclosed in U,S. Pat. No. 4,438,253, it is readily apparent that the rather speclal chem1stry ~nvolved 1n the fundamental stage of the process of the present ~nvent~on, plays a cruc~al role ln allowing a very s1mple one-step full polymer1zat10n process, and resulted 1n a v~r1ety of polymer1c mater1als exhib~tlng very speclal mechan1cal features (most 1mportantly, the~r extremely hlgh flexlb111ty, att~ln1ng E~5 MPa and eF~1100% values, In some 1nstances) and coverlng a w1de range of degradatlon k1net1cs. In llght of these flndlngs, 1t 15 apparent that the present ~nventlon provides synthet~c absorbable polymers h~v1ng un1que and des1rable propert1es not ava11able wlth the b10degradable pol~mers of the pr10r art, and that the method present~d hereby 1s markedly more advantageous than that of the pr10r art.
.: .
Alternat1vely, the degree of polymer1zatlon of the ABA Copolymer 1s 1ncrensed by ' .
' ;~''' '' "..' -:
!c, ~ "i~, ,~
1~2~8~ -: 1 ~
(a) reacting various di-isocyanates such as hexamethylene diisocyanate (HDI),4,4'-diphenylmethane diisocyanate (MDI), ~-4,4'-dicyclohexylmethane diisocyanate (H12MDI), cyclohexyl diisocyanate (CHDI) and 2,4 toluene diisocyanate (TDI), of the following formula~
', . .
NCO
OCN-CH2-CH2-CH2-CH2-CH2-CH2-NCOOCN ~ CH3 NCO OCN
HDI TDI CHDI -~
- / CH2-CH ~ /CH2-CH ~
OCN~ ~ -CH2- ~ NCO OCN-CH\ / CH-CH2-C\H / CH-NCO
, H1 2MDI .'' .
w1th the termtnal hydroxyl groups of the ABA type polymer.
The reactlon ytelded a ser1es of poly(etherester urethanes). The reactlon 1s carrted out 1n dry solvents such as tetrahydrofuran or ~ dtmethylformamlde or ~n the melt, 1n presence of an appropriate f~ urethanlzatton promottng catalyst such as d~butyltln d11aurate. The chaln extonston step ts exempltfled as follows for a polyethylene s glycol contalntng copolymer:
., .,, , ', .:
~ ' ' ";~' . ' : . ,:, .
1 3 2 ~
O O ':: ' H-(-O-CH-C-)X-(ocH2cH2-)m-o-(c-~H-o-) 1 R1 - ~ ~
~`,'.. ,' OCN-R -NCO l cat.
_l-(o-fH-c-)~-(-ocH2cH2-)~-o-(-c-lcH-o-)y-c-~ R
Poly(etherester urethane) .. `
wherein R1 represents hydrogen or methyl groups and R' may be ;: .
hexamethylene, 4,4'-diphenylmethane, toluene, napthalene, .
4,4'-dicyclohexylmethane, cyclohexyl, 3,3'- dimethylphenyl, 3,3'-dimethyl-diphenylmethane, 4,6'-xylene, 3,5,5-tr1methylcyclohexyl, 2,2,4-trimethyl-hexamethylene and p-phenylene, or diisocyanate terminated polyalkylene glycol chains comprising a central polyalkylene chain, capped by two di1socyanate compounds of formula NCO-R'-NCO wherein R' i8 a~ defined above, and b) react1ng a compound selected from the group consisting of d~carboxylic acids, methyl and ethyl esters of dicarboxylic acids, d1~ac1d chlorldes ~nd anhydrides of a dicarboxylic acid. D~carboxyl~c . .
ac1ds a~nd der1vat1ves useful in the synthesis of polymers by the above m~thods 1nclude those der1ved from the d~carboxylic acids l~sted . ~;
r ' :
: - . ,: ' ~ ~" _.. ~
_17_ 13298~
below. In addition the free acids can also be used. They are, for example, oxalic acid, malonic acid; succinic acid; -~
2,3-dimethylsuccinic acid; glutaric acid; 3,3-dimethylglutaric acid;
3-methyladipic acid; adipic acid; pimelic acid; suberic acid; azela~c acid: sebacic acid: 1,9-nonanedicarboxylic acid:
1,10-decanedicarboxylic ac1d; l,ll-undecanedicarboxylic acid;
1,12-dodecaned1carboxyl1c acid; 1,13-tridecaned;carboxylic acid;
1,14-tetradecaned~carboxyl1c acid; 1,1~pentadecanedicarboxylic acid;
1,16-hexadecaned~carboxyl1c acid; maleic acid; trans- - hydromuconic ac1d; fumar1c ac1d; d~glycol1c acid; 3,3'-oxydiproplonic acid;
1,10-decanedicarboxylic ac1d; l,ll-undecanedicarboxylic acid;
1,12-dodecaned1carboxyl1c acid; 1,13-tridecaned;carboxylic acid;
1,14-tetradecaned~carboxyl1c acid; 1,1~pentadecanedicarboxylic acid;
1,16-hexadecaned~carboxyl1c acid; maleic acid; trans- - hydromuconic ac1d; fumar1c ac1d; d~glycol1c acid; 3,3'-oxydiproplonic acid;
4,4'-oxydlbutyr1c ac1d; 5,5'-oxyd1valer1c ac1d; 6,6'-oxydicaproic ac1d; 8,8'-oxyd1capryl1c ac1d; 6-oxaundecanedio~c ac1d; 5-oxaazelaic ac1d; 5- oxasebac1c acld; ~oxaundecaned~o1c acid; -~
5-oxadodecaned101c acld; 5-oxatetradecaned101c ac1d:
5-oxahexadecaned101c ac1d: 6-oxadodecaned10~c ac1d;
5-oxahexadecaned101c ac1d: 6-oxadodecaned10~c ac1d;
6-oxatr1decanedloic ac1d: 6-oxapentadecaned101c ac1d;
6-oxaheptadecaned101c acld: 7-oxapentadecaned101c acid:
10-oxanonadecaned101c acld and other oxa-al1phat~c d1carboxyl1c ac~ds phthal1c acld; 1sophthal1c ac1d: terphthal1c acld and other aromat1c dlcarboxyllc aclds7 1,2-cyclobutanedlcarboxyl1c ac1d; l,4-cyclohexane-- tlcarboxyllc acld, poly(butad1ene, carboxyl term1nated), poly~oxyalkylene, carboxyl term1nated), carboxy-ended polyd1methyl s110xane polymers and copolymers.
, .. ,, ~
p ..: :' ' ~; ~
- 18 - 1 32985g Poly~eric analogs of the above carboxylic acid derivatives conta;ning reactive groups, like esters or anhydrides, can also be used; therefore, polyester or polyanhydrides segments can be successfully incorporated into the copolymeric chain, resulting in higher molecular weights and significantly affecting the properties of the products. The multiblock polymers obtained by carboxylic acids and der1vatives have the tollowing formula:
~(o - fH - ~ )X (OR)m O-(C - IH - O ~ ~ - Rn- C~~ III
R1 Rl where1n R represents an alkylene group, Rl 1s hydrogen or methyl groups, R" 1s an alkylene saturated or unsaturated group or an -~ aromat1c ring, accordlng to the carboxyl1c ac1d and der1vat1ves 11sted ! .. . .
above, x and y are 1dent1cal or d1fferent pos1t1ve 1ntegers, and m 1s a poslt1ve 1nteger.
~: .' ' . ' - ; The hydroxyl-ended poly~alkylene glycol) useful 1n the ~nvention lS may advantageously compr1se, among others, hydroxyl-term1nated -~~ polyethylene ox1de, polypropylene oxlde, poly~oxyethylone-co-oxypropylene) and polytetramethylene ox1de cha1ns.
Gono nlly the poly~alkylene)ox1des must be water soluble so that they c~n bo excroted by the body onc0 the copolymer1c b10mater1al has .', ~ . .
j . ,'",' ' ' 19- 1329~
~ , -degraded~ Examples of poly(alkylene glycols) capable of producing linear polymers are poly(oxyethylene glycols), poly(oxypropylene)-poly(oxyethylene)-glycols block copolymers and - -poly(oxybutylene) glycols. The foregoing are commercially available in a variety of molecular weights. ;
D~hydroxy compounds that can be used include the previously ment10ned poly(alkylene glyco1s) and also ethylene glycol;
1,3-propanedlol: 1,4-butanedlol; l,~-pentaned101; 1,6-hexanedlo1; ;`
1,7-heptanedlol: 1,8-octaned~o1; 1,9-nonanediol; 1,10-decanediol;
l,ll-undecanedlol, 1,12-dodecanediol; 1,13-trldecanedlol;
1-14-tetradecaned~ol: 1,15-pentadecaned101; 1,16-hexadecaned101 oxaallphatlc dlols, dlam1ne d101s, hydroxy-term1nated polyd1methyl ;~
s110xane polymers and copolymers, poly(butad1ene, hydroxyl term1nated), .. .,,::
~: ., . ':
~- 15 The polymerlc mater1als of th1s 1nvent10n can be fabr1cated 1nto -~ f11ms and f1bers by melt extenslon. Such materlals have been -~ 1mplanted subcutaneously 1n mlce and have been found to be non-1rr1t~t1n0 and compatlble with the 11vlng t1ssue over the tlme sp~n of many months, Substantlal amounts of the polymer are absorbed - ~20 by the 11vlng tlssue, the degratlon klnetlcs vary1ng wlth composltlon, ;;~
structure ~nd molecul~r welght of the polymer.
, ;.~"' ~,, ~ ~ : ' -," '' ' ;,' - - 20 - ~ 3298~ -- The polymers of the present invent;on are also useful in the manufacture of cast and/or extruded films and molded solid surgical aids, Thus, cylindrical pins, screws, reinforcing plates, etc. may be machined from the cast or molded polymer having the aforementioned in v1vo absorption characteristics.
The polymers are melt extruded through a splnneret in a conventlonal manner to form one or more filaments which are subsequently drawn about three to s1x times in order to achieve :
molecular orlentatlon and improve tensile propertles, The resulting or1ented f~laments have good tens~le and dry knot strength and good in vlvo strength retentlonO
, , ,:
To ~urther lmprove dlmenslonal stablllty and tenslle strength retentlon, the orlented f11aments may be subJected to an aneallng treatment, by heatlng them at varlous temperatures for dlfferent tlme perlods, whlle preventlng the fllaments from measurable shrlnklng.
.
The present lnventlon prov~des synthetlc absorbable sutures hav1ng a h1gh degree of softness and flex~b111ty whlle at the same t1mo allowlns the sutures to be used 1n monofllamQnt form. Whlle mult1f11~ment sutures manuf~ctured from polymers such 8S lactlde and glycol1de fulf111 most of the requ1rements of a suture, monof11ament sutures of these mater1als are cons1derably less flex1ble than catgut . ...
~nd these synthetlc sutures are accord1ngly generally 11mited to a , . .. .... . .
, ''~,'. ''' -: "; ";':
multifilament braided construction. Braided sutures have the disadvantage of causing trauma upon being pulled through tissue due to a sawing action, also known as tissue drag. It is accordingly an ob~ect of the present invention to provide synthetic absorbable ~
sutures hav1ng unique and desirable properties, as monofilaments or in ~ -bra1ded structure, not available with the sutures of the prior art.
: .:
B1component f11aments composed of two separate materials, at least one of them being one of the polymers of the invent10n were ~;
developed as well.
..~ . . .
Fabr1cs compr1stng polymeric mater1als of th1s invent10n, alone or 1n comb1nat10n w1th other polymers, have been developed by text11e and non-texttle techn1ques. Mult1component fabrtcs, woven, kn1tted, felted, adheslvely un1ted or otherw1se, compr1s~ng at least two d1fferent polymers, at least one of them belng accordtng to the present 1nventton were prepared. Also fabr1c tubes hav1ng separate strands of blcomponent mater1als or strands of two separate components, wherein at least one 1s accord1ng to the 1nvent10n, were produced. A coated fabr1c, compr1s1ng a substant1ally cont1nuous sheet of a second mater1al or mater1als was prepared by hot melt coat~ng. A
co~ttng from a solvent system or wtth coat1ng rolls, the base fabr~c ~- of wh1ch may bq wholly non-absorbable although 1t may conta1n an ~bsorbable component, were produced.
., , ;,;:
, .; ;, :"' ';' - 22 - 13298~
While the invention will now be described in connection with certain preferred embodiments in the following examples so that aspects thereof may be more fully understood and appreciated~ it is not intended to limit the invention to these particular embodiments.
On the contrary, it is intended to cover all alternatives, modifications and equivalents as may be included wlthin the scope of the ~nvention as defined by the appended claims. Thus, the following examples wh1ch ~nclude preferred embodiments will serve to illustrate the practice of th1s invention, lt belng understood that the partlculars shown are by way of example and for purposes of 111ustratlve d~scusslon of preferred embodiments of the present 1nvent~on only and are presented in the cause of provid1ng what is bel1eved to be the most usefu1 and read11y understood descr1ption of formulatlon procedures as well as of the pr1nc1ples and conceptual - 15 aspects of the lnvent10n.
, Examele 1 Pre~rat10n o~ PELA3400/209 copolymer , 17 gr PEG(mw-3400) (0.005 mole) were placed 1n a 250 ml three-necked flask f1tted w1th a mechan1cal st1rrer and a n1trogen flow 1nlet, together w1th 0.12 gram Sb203 and 0.75 gram H2P04. The systom was flushed w1th dry n1trogen and heated up to 120C. 108 grams LA (1.20 mole) were added dropw1se dur1ng 2 hours, wh11e the -~ temperaturo was ra1sed gradu~lly to 160C, and ma1antain~d there for ~ 16 hours, Then the temporature was ra1sed further, to 200C for ,~
another 16 hours. During all these stages of the polymerization process the reaction vessel was permanently flushed with dry nitrogen.
Finally, the temperature was lowered to 135C, while a 5 mm Hg vacuum was applied to the system, for another 4 hours.
.
Example 2 Preparation of PELA3400/71 ~
:
The procedure of Example 1 was following uslng 17 gr PEG ;
~mw-3400) 72 gr LA, 0,08 gr Sb203 and 0.56 gr H3P04.
~ ,` ' . '. .
Example 3 Preparat~on of PELA3400/19 ~`
. :.- ., . . :-.~, , The procedure of Example 1 was followed us1ng 17 gr PEG
~mw-3400), 54 gr LA, 0.06 gr Sb203 and 0.42 gr H3P04, ,'"'. :,'.":.' ..
Example 4 Preparat1On of 6000/277 "'',",; :' The procedure of Example 1 was followed using 17 gr PEG
(mw 6000), 108 gr LA, 0.12 gr Sb203 and 0.75 gr H3P0~
, :
ExamPle 5 PreParat1on of PELA6000/196 , ,:
The procedure of Example 1 was followed us1ng 17 gr PEG
~mw~6000), 90 gr LA, 0.10 gr Sb203 and 0.70 gr H3P04.
........
.''.' . . ' ','' ': ' '',' 1~298~
- -Example 6 Preparation of PELA1500/179 . : -The procedure o~ Example 1 was followed using 7~5 gr PEG
(mw=1500), 90 gr LA, 0.10 gr Sb203 and 0.70 gr H3P04. :
Example 7 Preparation of PELA 1500/45 .
'..', . ' "' 5The procedure of Example 1 was followed using 17 gr PEG .;
(mw-1500), 90 gr LA, 0.10 gr Sb203 and 0.70 gr H3P04.
Example 8 Preparation of PELA600/24 , . .
The procedure of Example 1 was fol1Owed using 17 gr PEG (mw~600), . :
90 gr LA, 0~10 gr Sb203 and 0.70 gr H3P04 10ExamPle 9 Preparatlon of PELA600/16 " . "
The procedure 1n Example 1 was followed us~n~ 17 gr PEG (mw~600), : .
72 gr LA, 0.06 gr Sb203 and 0.56 gr H3P04.
.
~ . .
',',' '"' ,".
~ 'i':.
~ ' ''',''"'" ".
,.....
, .
, . .
.
- 25 _ 13298~4 ~:~
Example 10 Preparation of PELA3400/141/urethane copolymer ~
, .
The procedure in Example 1 was followed using 17 gr PEG - : ~
:.. ~. . :..
(mw-3400), 90 gr LA, 0.10 gr Sb203 and 0.70 gr H3P04, the last step ;.
(135C, 5 mm Hg) being shortened to 2 hours. The temperature was then .~
5lowered to 125C and 1.68 gr (0.01 mole) hexamethylene diisocyanate .~ .. -;
was added; the system was kept at these conditions for 3 hours. :~ ~ ~
.,`.' :'.' '',.
Example 11 Preparation of PPLA2000/65 (PPG2000/LA) copolymer , :":,: ;.. -The procedure of Example 1 was followed uslng 20 gr PPG .
(polypropylene glycol) (mw-2000), 90 gr LA, 0.10 gr Sb203 and 0.7 gr 10H3P0~
.,~,.,..,,"" ,.
. ; ,... . .
Some properties of the block copolymers produced according to the above examples, compared to those of polylact~c acld are set forth in Table I, `"' ' ' '~' , . ':
: - , ~ .:
~: ' ' ' ' ` '' . . :, : , ,. .:
, :., ~ , . ...
... ..
13~9~4 ~
~: ' Table I
Properties of PE0/LA Block Polymers ;., ~ ' Example MW wt%
PEG PE0 Tml(C) Tm2C) - ~ -by NMR
., ~:, 1 3400 18 - 135 ~ -4 6000 23 ~ 142 :
6-oxaheptadecaned101c acld: 7-oxapentadecaned101c acid:
10-oxanonadecaned101c acld and other oxa-al1phat~c d1carboxyl1c ac~ds phthal1c acld; 1sophthal1c ac1d: terphthal1c acld and other aromat1c dlcarboxyllc aclds7 1,2-cyclobutanedlcarboxyl1c ac1d; l,4-cyclohexane-- tlcarboxyllc acld, poly(butad1ene, carboxyl term1nated), poly~oxyalkylene, carboxyl term1nated), carboxy-ended polyd1methyl s110xane polymers and copolymers.
, .. ,, ~
p ..: :' ' ~; ~
- 18 - 1 32985g Poly~eric analogs of the above carboxylic acid derivatives conta;ning reactive groups, like esters or anhydrides, can also be used; therefore, polyester or polyanhydrides segments can be successfully incorporated into the copolymeric chain, resulting in higher molecular weights and significantly affecting the properties of the products. The multiblock polymers obtained by carboxylic acids and der1vatives have the tollowing formula:
~(o - fH - ~ )X (OR)m O-(C - IH - O ~ ~ - Rn- C~~ III
R1 Rl where1n R represents an alkylene group, Rl 1s hydrogen or methyl groups, R" 1s an alkylene saturated or unsaturated group or an -~ aromat1c ring, accordlng to the carboxyl1c ac1d and der1vat1ves 11sted ! .. . .
above, x and y are 1dent1cal or d1fferent pos1t1ve 1ntegers, and m 1s a poslt1ve 1nteger.
~: .' ' . ' - ; The hydroxyl-ended poly~alkylene glycol) useful 1n the ~nvention lS may advantageously compr1se, among others, hydroxyl-term1nated -~~ polyethylene ox1de, polypropylene oxlde, poly~oxyethylone-co-oxypropylene) and polytetramethylene ox1de cha1ns.
Gono nlly the poly~alkylene)ox1des must be water soluble so that they c~n bo excroted by the body onc0 the copolymer1c b10mater1al has .', ~ . .
j . ,'",' ' ' 19- 1329~
~ , -degraded~ Examples of poly(alkylene glycols) capable of producing linear polymers are poly(oxyethylene glycols), poly(oxypropylene)-poly(oxyethylene)-glycols block copolymers and - -poly(oxybutylene) glycols. The foregoing are commercially available in a variety of molecular weights. ;
D~hydroxy compounds that can be used include the previously ment10ned poly(alkylene glyco1s) and also ethylene glycol;
1,3-propanedlol: 1,4-butanedlol; l,~-pentaned101; 1,6-hexanedlo1; ;`
1,7-heptanedlol: 1,8-octaned~o1; 1,9-nonanediol; 1,10-decanediol;
l,ll-undecanedlol, 1,12-dodecanediol; 1,13-trldecanedlol;
1-14-tetradecaned~ol: 1,15-pentadecaned101; 1,16-hexadecaned101 oxaallphatlc dlols, dlam1ne d101s, hydroxy-term1nated polyd1methyl ;~
s110xane polymers and copolymers, poly(butad1ene, hydroxyl term1nated), .. .,,::
~: ., . ':
~- 15 The polymerlc mater1als of th1s 1nvent10n can be fabr1cated 1nto -~ f11ms and f1bers by melt extenslon. Such materlals have been -~ 1mplanted subcutaneously 1n mlce and have been found to be non-1rr1t~t1n0 and compatlble with the 11vlng t1ssue over the tlme sp~n of many months, Substantlal amounts of the polymer are absorbed - ~20 by the 11vlng tlssue, the degratlon klnetlcs vary1ng wlth composltlon, ;;~
structure ~nd molecul~r welght of the polymer.
, ;.~"' ~,, ~ ~ : ' -," '' ' ;,' - - 20 - ~ 3298~ -- The polymers of the present invent;on are also useful in the manufacture of cast and/or extruded films and molded solid surgical aids, Thus, cylindrical pins, screws, reinforcing plates, etc. may be machined from the cast or molded polymer having the aforementioned in v1vo absorption characteristics.
The polymers are melt extruded through a splnneret in a conventlonal manner to form one or more filaments which are subsequently drawn about three to s1x times in order to achieve :
molecular orlentatlon and improve tensile propertles, The resulting or1ented f~laments have good tens~le and dry knot strength and good in vlvo strength retentlonO
, , ,:
To ~urther lmprove dlmenslonal stablllty and tenslle strength retentlon, the orlented f11aments may be subJected to an aneallng treatment, by heatlng them at varlous temperatures for dlfferent tlme perlods, whlle preventlng the fllaments from measurable shrlnklng.
.
The present lnventlon prov~des synthetlc absorbable sutures hav1ng a h1gh degree of softness and flex~b111ty whlle at the same t1mo allowlns the sutures to be used 1n monofllamQnt form. Whlle mult1f11~ment sutures manuf~ctured from polymers such 8S lactlde and glycol1de fulf111 most of the requ1rements of a suture, monof11ament sutures of these mater1als are cons1derably less flex1ble than catgut . ...
~nd these synthetlc sutures are accord1ngly generally 11mited to a , . .. .... . .
, ''~,'. ''' -: "; ";':
multifilament braided construction. Braided sutures have the disadvantage of causing trauma upon being pulled through tissue due to a sawing action, also known as tissue drag. It is accordingly an ob~ect of the present invention to provide synthetic absorbable ~
sutures hav1ng unique and desirable properties, as monofilaments or in ~ -bra1ded structure, not available with the sutures of the prior art.
: .:
B1component f11aments composed of two separate materials, at least one of them being one of the polymers of the invent10n were ~;
developed as well.
..~ . . .
Fabr1cs compr1stng polymeric mater1als of th1s invent10n, alone or 1n comb1nat10n w1th other polymers, have been developed by text11e and non-texttle techn1ques. Mult1component fabrtcs, woven, kn1tted, felted, adheslvely un1ted or otherw1se, compr1s~ng at least two d1fferent polymers, at least one of them belng accordtng to the present 1nventton were prepared. Also fabr1c tubes hav1ng separate strands of blcomponent mater1als or strands of two separate components, wherein at least one 1s accord1ng to the 1nvent10n, were produced. A coated fabr1c, compr1s1ng a substant1ally cont1nuous sheet of a second mater1al or mater1als was prepared by hot melt coat~ng. A
co~ttng from a solvent system or wtth coat1ng rolls, the base fabr~c ~- of wh1ch may bq wholly non-absorbable although 1t may conta1n an ~bsorbable component, were produced.
., , ;,;:
, .; ;, :"' ';' - 22 - 13298~
While the invention will now be described in connection with certain preferred embodiments in the following examples so that aspects thereof may be more fully understood and appreciated~ it is not intended to limit the invention to these particular embodiments.
On the contrary, it is intended to cover all alternatives, modifications and equivalents as may be included wlthin the scope of the ~nvention as defined by the appended claims. Thus, the following examples wh1ch ~nclude preferred embodiments will serve to illustrate the practice of th1s invention, lt belng understood that the partlculars shown are by way of example and for purposes of 111ustratlve d~scusslon of preferred embodiments of the present 1nvent~on only and are presented in the cause of provid1ng what is bel1eved to be the most usefu1 and read11y understood descr1ption of formulatlon procedures as well as of the pr1nc1ples and conceptual - 15 aspects of the lnvent10n.
, Examele 1 Pre~rat10n o~ PELA3400/209 copolymer , 17 gr PEG(mw-3400) (0.005 mole) were placed 1n a 250 ml three-necked flask f1tted w1th a mechan1cal st1rrer and a n1trogen flow 1nlet, together w1th 0.12 gram Sb203 and 0.75 gram H2P04. The systom was flushed w1th dry n1trogen and heated up to 120C. 108 grams LA (1.20 mole) were added dropw1se dur1ng 2 hours, wh11e the -~ temperaturo was ra1sed gradu~lly to 160C, and ma1antain~d there for ~ 16 hours, Then the temporature was ra1sed further, to 200C for ,~
another 16 hours. During all these stages of the polymerization process the reaction vessel was permanently flushed with dry nitrogen.
Finally, the temperature was lowered to 135C, while a 5 mm Hg vacuum was applied to the system, for another 4 hours.
.
Example 2 Preparation of PELA3400/71 ~
:
The procedure of Example 1 was following uslng 17 gr PEG ;
~mw-3400) 72 gr LA, 0,08 gr Sb203 and 0.56 gr H3P04.
~ ,` ' . '. .
Example 3 Preparat~on of PELA3400/19 ~`
. :.- ., . . :-.~, , The procedure of Example 1 was followed us1ng 17 gr PEG
~mw-3400), 54 gr LA, 0.06 gr Sb203 and 0.42 gr H3P04, ,'"'. :,'.":.' ..
Example 4 Preparat1On of 6000/277 "'',",; :' The procedure of Example 1 was followed using 17 gr PEG
(mw 6000), 108 gr LA, 0.12 gr Sb203 and 0.75 gr H3P0~
, :
ExamPle 5 PreParat1on of PELA6000/196 , ,:
The procedure of Example 1 was followed us1ng 17 gr PEG
~mw~6000), 90 gr LA, 0.10 gr Sb203 and 0.70 gr H3P04.
........
.''.' . . ' ','' ': ' '',' 1~298~
- -Example 6 Preparation of PELA1500/179 . : -The procedure o~ Example 1 was followed using 7~5 gr PEG
(mw=1500), 90 gr LA, 0.10 gr Sb203 and 0.70 gr H3P04. :
Example 7 Preparation of PELA 1500/45 .
'..', . ' "' 5The procedure of Example 1 was followed using 17 gr PEG .;
(mw-1500), 90 gr LA, 0.10 gr Sb203 and 0.70 gr H3P04.
Example 8 Preparation of PELA600/24 , . .
The procedure of Example 1 was fol1Owed using 17 gr PEG (mw~600), . :
90 gr LA, 0~10 gr Sb203 and 0.70 gr H3P04 10ExamPle 9 Preparatlon of PELA600/16 " . "
The procedure 1n Example 1 was followed us~n~ 17 gr PEG (mw~600), : .
72 gr LA, 0.06 gr Sb203 and 0.56 gr H3P04.
.
~ . .
',',' '"' ,".
~ 'i':.
~ ' ''',''"'" ".
,.....
, .
, . .
.
- 25 _ 13298~4 ~:~
Example 10 Preparation of PELA3400/141/urethane copolymer ~
, .
The procedure in Example 1 was followed using 17 gr PEG - : ~
:.. ~. . :..
(mw-3400), 90 gr LA, 0.10 gr Sb203 and 0.70 gr H3P04, the last step ;.
(135C, 5 mm Hg) being shortened to 2 hours. The temperature was then .~
5lowered to 125C and 1.68 gr (0.01 mole) hexamethylene diisocyanate .~ .. -;
was added; the system was kept at these conditions for 3 hours. :~ ~ ~
.,`.' :'.' '',.
Example 11 Preparation of PPLA2000/65 (PPG2000/LA) copolymer , :":,: ;.. -The procedure of Example 1 was followed uslng 20 gr PPG .
(polypropylene glycol) (mw-2000), 90 gr LA, 0.10 gr Sb203 and 0.7 gr 10H3P0~
.,~,.,..,,"" ,.
. ; ,... . .
Some properties of the block copolymers produced according to the above examples, compared to those of polylact~c acld are set forth in Table I, `"' ' ' '~' , . ':
: - , ~ .:
~: ' ' ' ' ` '' . . :, : , ,. .:
, :., ~ , . ...
... ..
13~9~4 ~
~: ' Table I
Properties of PE0/LA Block Polymers ;., ~ ' Example MW wt%
PEG PE0 Tml(C) Tm2C) - ~ -by NMR
., ~:, 1 3400 18 - 135 ~ -4 6000 23 ~ 142 :
7 1500 32 - 113 . :~
; 8 600 26 105 .. :
PLA ,',, - : ".' , . . .
Ex~mple 12 ~' ~ ' ' ' ' ' Solvent cast fllms were prepared and standard str~ps for tenslle :::
test1ng, ware preparet. The mechan1cal analysls of the developed . ;.
~ ,. .
~ , ,:, .
"': , '"' :.' .
~ . . .-, .
1 ~ 2 9 ~
- 27 - ~
'':~''. ~.
copolymers revealed that, when compared with PLA, they show a substantial decrease in stiffness and a large increase in the -elongation at break. Of special interest were highly f1exible PELA
polymers, exhibiting an elastomeric-like behavior, with d modulus of 5 MPa and elongation at break of 900%. ^
:
It will be evident to those skilled in the art that the invention ;is not limited to the details of the foregoing i11ustrative examples and that the present invention may be embodied in other specific forms without departlng from the essential attributes thereof, and it is therefora desired that the present embodiments and examples be considered ~n all respects as ~llustrative and not restrictive, :`reference being made to the appended claims, rather than to the forego1ng descr1pt10n, and all changes wh1ch come w1th1n the mean~ng and range of equ~valency of the cla~ms are therefore 1ntended to be embraced there~n.
.. ' ' .
' ' ', ':'' ., ';:
,: .
"' ',''''" ' . . . . . .
: ' :;.' , ' .: . ' ~ .
:~,' ':
.,,,., ~"~, '.,',' .
,, '
; 8 600 26 105 .. :
PLA ,',, - : ".' , . . .
Ex~mple 12 ~' ~ ' ' ' ' ' Solvent cast fllms were prepared and standard str~ps for tenslle :::
test1ng, ware preparet. The mechan1cal analysls of the developed . ;.
~ ,. .
~ , ,:, .
"': , '"' :.' .
~ . . .-, .
1 ~ 2 9 ~
- 27 - ~
'':~''. ~.
copolymers revealed that, when compared with PLA, they show a substantial decrease in stiffness and a large increase in the -elongation at break. Of special interest were highly f1exible PELA
polymers, exhibiting an elastomeric-like behavior, with d modulus of 5 MPa and elongation at break of 900%. ^
:
It will be evident to those skilled in the art that the invention ;is not limited to the details of the foregoing i11ustrative examples and that the present invention may be embodied in other specific forms without departlng from the essential attributes thereof, and it is therefora desired that the present embodiments and examples be considered ~n all respects as ~llustrative and not restrictive, :`reference being made to the appended claims, rather than to the forego1ng descr1pt10n, and all changes wh1ch come w1th1n the mean~ng and range of equ~valency of the cla~ms are therefore 1ntended to be embraced there~n.
.. ' ' .
' ' ', ':'' ., ';:
,: .
"' ',''''" ' . . . . . .
: ' :;.' , ' .: . ' ~ .
:~,' ':
.,,,., ~"~, '.,',' .
,, '
Claims (43)
1. A poly( .alpha.-hydroxy-carboxylic acid)/poly(oxyalkylene) polymer selected from:
a) a multiblock polymer of the following repeating unit I
I
wherein R is an alkylene group, R1 is hydrogen or methyl groups, m is a positive integer, and a and b are zero or positive integers, the case where a and b are simultaneously zero being excluded, or b) a chain extended multiblock polymer of the following formula II:
II
wherein R represents an alkylene group, R1 is hydrogen or methyl groups and R1 is hexamethylene, 4,4'-diphenylmethane, toluene, naphtalene, 4,4'-dicyclohexylmethane, cyclohexyl, 3,3'-dimethylphenyl, 3,3'-dimethyl-diphenylmethane, 4,6'-xylylene, 3,5,5-trimethylcyclohexyl, 2,2,4-trimethyl-hexamethylene and p-phenylene, or diisocyanate terminated polyalkylene glycol chains comprising a central polyalkylene glycol chain capped by two diisocyanate compounds of formula NCO-R'-NCO wherein R' is as defined above, or c) a chain extended multiblock polymer of the following formula III
III
wherein R represents an alkylene group, R1 is hydrogen or methyl groups, R" is a saturated or unsaturated alkylene group, or an aromatic ring, x and y are identical or different positive integers, and m is a positive integer.
a) a multiblock polymer of the following repeating unit I
I
wherein R is an alkylene group, R1 is hydrogen or methyl groups, m is a positive integer, and a and b are zero or positive integers, the case where a and b are simultaneously zero being excluded, or b) a chain extended multiblock polymer of the following formula II:
II
wherein R represents an alkylene group, R1 is hydrogen or methyl groups and R1 is hexamethylene, 4,4'-diphenylmethane, toluene, naphtalene, 4,4'-dicyclohexylmethane, cyclohexyl, 3,3'-dimethylphenyl, 3,3'-dimethyl-diphenylmethane, 4,6'-xylylene, 3,5,5-trimethylcyclohexyl, 2,2,4-trimethyl-hexamethylene and p-phenylene, or diisocyanate terminated polyalkylene glycol chains comprising a central polyalkylene glycol chain capped by two diisocyanate compounds of formula NCO-R'-NCO wherein R' is as defined above, or c) a chain extended multiblock polymer of the following formula III
III
wherein R represents an alkylene group, R1 is hydrogen or methyl groups, R" is a saturated or unsaturated alkylene group, or an aromatic ring, x and y are identical or different positive integers, and m is a positive integer.
2. A multiblock copolymer useful for the manufacture of bioabsorbable surgical articles, having a general repeating unit I
II
wherein R is an alkylene group, R1 is hydrogen or methyl groups, m is a positive integer, and a and b are zero or positive integers, the case where a and b are simultaneously zero being excluded.
II
wherein R is an alkylene group, R1 is hydrogen or methyl groups, m is a positive integer, and a and b are zero or positive integers, the case where a and b are simultaneously zero being excluded.
3. A multiblock copolymer as claimed in claim 1 where R is ethylene.
4. A mult1block copolymer as claimed in claim 1 where R1 is hydrogen.
5, A mult1block copolymer as claimed in claim 1 where R1 is methyl.
6. A multiblock copolymer as claimed in claim 1 wherein along the copolymeric cha1n some R1s are hydrogen and some are methyl groups.
7. A multiblock copolymer having the following general formula;
wherein R represents an alkylene group, R1 is hydrogen or methyl groups and R' is hexamethylene, 4,4'-diphenylmethane, toluene, naphtalene, 4,4'-dicyclohexylmethane, cyclohexyl, 3,3'-dimethylphenyl, 3,3'-dimethyl-diphenylmethane, 4,6'xylylene, 3,5,5-trimethylcyclohexyl, 2,2,4-trimethyl-hexamethylene and p-phenylene, or diisocyanate-terminated polyalkylene glycol chains comprising a central polyalkylene glycol chain capped by two diisocyanate compounds of formula NCO-R'-NCO wherein R' is as defined above, x and y are identical or different positive integers and m is a positive integer.
wherein R represents an alkylene group, R1 is hydrogen or methyl groups and R' is hexamethylene, 4,4'-diphenylmethane, toluene, naphtalene, 4,4'-dicyclohexylmethane, cyclohexyl, 3,3'-dimethylphenyl, 3,3'-dimethyl-diphenylmethane, 4,6'xylylene, 3,5,5-trimethylcyclohexyl, 2,2,4-trimethyl-hexamethylene and p-phenylene, or diisocyanate-terminated polyalkylene glycol chains comprising a central polyalkylene glycol chain capped by two diisocyanate compounds of formula NCO-R'-NCO wherein R' is as defined above, x and y are identical or different positive integers and m is a positive integer.
8. A multiblock copolymer as claimed in claim 7, wherein R is ethylene and the diisocyanate is hexamethylene diisocyanate (HDI), the polymer being of the formula wherein R1, x, y and m are as defined in claim 1.
9. A multiblock copolymer as claimed in claim 7, wherein the diisocyanate is 4,4'-diphenylmethane diisocyanate (MDI), the polymer being of the formula
10. A multiblock copolymer according to claim 1, wherein said copolymer is in the form of at least one filament.
11. A surgical article selected from the group consisting of a suture, ligature, needle and suture combination, surgical clip, surgical staple, surgical prosthesis, textile structure, coupling, tube, support, screw or pin, where at least one of the components of each of said articles is a polymer as claimed in claim 1.
12. A compound vascular prosthesis in which a non-biodegradable graft is coated w1th a polymer or polymers as claimed in claim 1, the prosthesis being blood tight at implantation, and becoming, in time, sufficiently porous to facilitate tissue ingrowth and biological healing.
13. A compound vascular prosthesis as claimed in claim 12, where a knitted Dacron graft is coated w1th a multiblock copolymer as claimed in claim 1.
14. A substantially biodegradable vascular prosthesis comprising non-absorbable polymers and polymers as claimed in claim 1.
15, A substantially biodegradable vascular prosthesis comprising a non absorbable component selected from polyethylene terephthalate and/or polyether urethanes and/or polyether esters and/or polydimethyl siloxane polymers or copolymers, and polymers as claimed in claim 1 as the absorbable component.
16. A totally biodegradable vascular prosthesis manufactured by textile and non-textile techniques, comprising polymers as claimed in claim 1.
17.A partially biodegradable wound or burn covering comprising non-absorbable polymers and polymers as claimed in claim 1.
18. A biodegradable wound or burn dressing, comprising polymers as claimed in claim 1.
19. A process of producing a multiblock copolymer having a general repeating unit I
I
wherein R is an alkylene group, R1 is hydrogen or methyl groups, m is a positive integer, and a and b are zero or positive integers, the case where a and b are simultaneously zero being excluded, produced by adding monomeric .alpha.-hydroxy carboxylic acids of the formula to hydroxyl-ended poly(alkylene glycol) chains, the polycondensation reaction taking place in the presence of an esterification promoting catalyst at a temperature of about 120°
to 160°C, subsequently raising the temperature to about 200°C for about 16 hours, with constant flow of dry nitrogen and then lowering the temperature to about 135°C while a 5 mm Hg vacuum is applied for about 4 hours.
I
wherein R is an alkylene group, R1 is hydrogen or methyl groups, m is a positive integer, and a and b are zero or positive integers, the case where a and b are simultaneously zero being excluded, produced by adding monomeric .alpha.-hydroxy carboxylic acids of the formula to hydroxyl-ended poly(alkylene glycol) chains, the polycondensation reaction taking place in the presence of an esterification promoting catalyst at a temperature of about 120°
to 160°C, subsequently raising the temperature to about 200°C for about 16 hours, with constant flow of dry nitrogen and then lowering the temperature to about 135°C while a 5 mm Hg vacuum is applied for about 4 hours.
20. A process according to claim 19 wherein said catalyst is Sb2O3.
21. A process for chain extending triblock copolymers of formula IV
IV
wherein R and R1 are as defined in claim 1, x and y are identical or different positive integers, and m is a positive integer, said triblock polymers, which are produced by the polycondensation reaction of monomeric .alpha.-hydroxy carboxylic acid, having the formula , in the presence of hydroxyl-terminated poly(alkylene glycol) chains, are extended by adding to the polymers produced thereby, a diisocyanate chain extension agent of general formula OCN-R'-NCO, wherein R' is hexamethylene, 4,4'-diphenylmethane, toluene, naphtalene, 4,4'-dicyclohexylmethane, cyclohexyl, 3,3'-dimethylphenyl, 3,3'-dimethyl-diphenylmethane, 4,6'-xylylene, 3,5,5-trimethylcyclohexyl, 2,2,4-trimethyl-hexamethylene and p-phenylene, or diisocyanate-terminated polyalkylene glycol chains comprising a central polyalkylene glycol chain capped by two diisocyanate compounds of formula NCO-R'-NCO wherein R' is as defined above.
IV
wherein R and R1 are as defined in claim 1, x and y are identical or different positive integers, and m is a positive integer, said triblock polymers, which are produced by the polycondensation reaction of monomeric .alpha.-hydroxy carboxylic acid, having the formula , in the presence of hydroxyl-terminated poly(alkylene glycol) chains, are extended by adding to the polymers produced thereby, a diisocyanate chain extension agent of general formula OCN-R'-NCO, wherein R' is hexamethylene, 4,4'-diphenylmethane, toluene, naphtalene, 4,4'-dicyclohexylmethane, cyclohexyl, 3,3'-dimethylphenyl, 3,3'-dimethyl-diphenylmethane, 4,6'-xylylene, 3,5,5-trimethylcyclohexyl, 2,2,4-trimethyl-hexamethylene and p-phenylene, or diisocyanate-terminated polyalkylene glycol chains comprising a central polyalkylene glycol chain capped by two diisocyanate compounds of formula NCO-R'-NCO wherein R' is as defined above.
22. A process as claimed in claim 21, where R is ethylene, R1 is methyl and R' is hexamethylene.
23. A multiblock copolymer having the following general formula III
III
wherein R represents an alkylene group, R1 is hydrogen or methyl groups, R" is an alkylene saturated or unsaturated group or an aromatic ring, x and y are identical or different positive integers, and m is a positive integer.
III
wherein R represents an alkylene group, R1 is hydrogen or methyl groups, R" is an alkylene saturated or unsaturated group or an aromatic ring, x and y are identical or different positive integers, and m is a positive integer.
24, A multiblock copolymer as claimed in claim 23, where R is ethylene, R1 is methyl and R" is ethylene.
25. A multiblock copolymer as claimed in claim 24, where R" is an unsaturated CH=CH group.
26. A process for chain extending the triblock copolymers presented in claim 21 by adding to them carboxylic acids and derivatives as chain extension agents, the multiblock copolymers produced thereby having the following formula III
III
wherein R represents an alkylene group, R1 is hydrogen or methyl groups, R" is an alkylene saturated or unsaturated group or an aromatic ring, x and y are identical or different positive integers, and m is a positive integer.
III
wherein R represents an alkylene group, R1 is hydrogen or methyl groups, R" is an alkylene saturated or unsaturated group or an aromatic ring, x and y are identical or different positive integers, and m is a positive integer.
27. A surgical article selected from the group consisting of a suture, ligature, needle and suture combination, surgical clip, surgical staple, surgical prosthesis, textile structure, coupling, tube, support, screw or pin, where at least one of the components of each of said articles is a polymer as claimed in claim 7.
28. A compound vascular prosthesis in which a non-biodegradable graft is coated with a polymer or polymers as claimed in claim 7, the prosthesis being blood tight at implantation, and becoming, in time, sufficiently porous to facilitate tissue ingrowth and biological healing.
29. A compound vascular prosthesis as claimed in claim 28, where a knitted Dacron graft is coated with a multiblock copolymer as claimed in claim 7.
30. A substantially biodegradable vascular prosthesis comprising non-absorbable polymers and polymers as claimed in claim 7.
31. A substantially biodegradable vascular prosthesis comprising a non-absorbable component selected from polyethylene terephthalate and/or polyether urethanes and/or polyether esters and/or polydimethyl siloxane polymers or copolymers, and polymers as claimed in claim 7 as the absorbable components.
32. A totally biodegradable vascular prosthesis manufactured by textile and non-textile techniques, comprising polymers as claimed in claim 7.
33, A surgical article selected from the group consisting of a suture, ligature, needle and suture combination, surgical clip, surgical staple, surgical prosthesis, textile structure, coupling, tube support, screw or pin, where at least one of the components of each of said articles is a polymer as claimed in claim 23.
34. A compound vascular prosthesis in which a non-biodegradable graft is coated with a polymer or polymers as claimed in claim 23, the prosthesis being blood tight at implantation, and becoming, in time, sufficiently porous to facilitate tissue ingrowth and biological healing.
35. A compound vascular prosthesis as claimed in claim 34, where a knitted Dacron graft is coated with a multiblock copolymer as claimed in claim 23.
36, A substantially biodegradable vascular prosthesis comprising non-absorbable polymers and polymers as claimed in claim 23.
37. A substantially biodegradable vascular prosthesis comprising a non absorbable component selected from polyethylene terephthalate and/or polyether urethanes and/or polyether esters and/or polydimethyl siloxane polymers or copolymers, and polymers as claimed in claim 23 as the absorbable components.
38. A totally biodegradable vascular prosthesis manufactured by textile and non-textile techniques, comprising polymers as claimed in claim 23.
39. A partially biodegradable wound or burn covering comprising non-absorbable polymers and polymers as claimed in claim 7.
40. A biodegradable wound or burn dressing comprising polymers as claimed in claim 7.
41. A partially biodegradable wound or burn dressing comprising non-absorbable polymers and polymers as claimed in claim 23.
42. A biodegradable wound or burn dressing comprising polymers as claimed in claim 23.
43. A pharmaceutical composition comprising a self-supporting film, hollow tube, beads or gel, manufactured from a multiblock copolymer as claimed in claim 1 and containing a uniformly dispersed drug contained therein.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000616519A CA1332035C (en) | 1987-03-17 | 1992-11-17 | Pump with heat exchanger |
| CA000616520A CA1332034C (en) | 1987-03-17 | 1992-11-17 | Pump with heat exchanger |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IL82834A IL82834A (en) | 1987-06-09 | 1987-06-09 | Biodegradable polymeric materials based on polyether glycols,processes for the preparation thereof and surgical artiicles made therefrom |
| IL82834 | 1987-06-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1329854C true CA1329854C (en) | 1994-05-24 |
Family
ID=11057876
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000568988A Expired - Fee Related CA1329854C (en) | 1987-03-17 | 1988-06-08 | Biodegradable polymeric materials based on polyether glycols, processes for the preparation thereof and surgical articles made therefrom |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US4826945A (en) |
| EP (1) | EP0295055A3 (en) |
| JP (1) | JPH01195862A (en) |
| CA (1) | CA1329854C (en) |
| IL (1) | IL82834A (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2917410A (en) * | 1955-06-20 | 1959-12-15 | American Cyanamid Co | Polyglycol-polyacid ester treatment of textiles |
| US4355133A (en) * | 1981-07-27 | 1982-10-19 | Celanese Corporation | Polyester of 6-hydroxy-2-naphthoic acid, 4-hydroxy benzoic acid, 1,4-cyclohexanedicarboxylic acid, and aromatic diol capable of readily undergoing melt processing to form articles possessing high impact properties |
| US4438253A (en) * | 1982-11-12 | 1984-03-20 | American Cyanamid Company | Poly(glycolic acid)/poly(alkylene glycol) block copolymers and method of manufacturing the same |
| US4452973A (en) * | 1982-11-12 | 1984-06-05 | American Cyanamid Company | Poly(glycolic acid)/poly(oxyethylene) triblock copolymers and method of manufacturing the same |
| ES2098217T3 (en) * | 1986-05-14 | 1997-05-01 | Takiron Co | POLYURETHANES OF ANPHYPHILIC SEGMENTS. |
-
1987
- 1987-06-09 IL IL82834A patent/IL82834A/en not_active IP Right Cessation
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1988
- 1988-06-02 US US07/201,403 patent/US4826945A/en not_active Expired - Lifetime
- 1988-06-07 EP EP88305187A patent/EP0295055A3/en not_active Withdrawn
- 1988-06-08 CA CA000568988A patent/CA1329854C/en not_active Expired - Fee Related
- 1988-06-08 JP JP63139583A patent/JPH01195862A/en active Pending
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|---|---|
| US4826945A (en) | 1989-05-02 |
| JPH01195862A (en) | 1989-08-07 |
| IL82834A (en) | 1990-11-05 |
| EP0295055A3 (en) | 1990-05-02 |
| IL82834A0 (en) | 1987-12-20 |
| EP0295055A2 (en) | 1988-12-14 |
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