CA2193968A1

CA2193968A1 - Ph-modified biocompatible monomer and polymer compositions

Info

Publication number: CA2193968A1
Application number: CA002193968A
Authority: CA
Inventors: Jeffrey G. Clark; Jeffrey C. Leung
Original assignee: Individual
Current assignee: Ethicon Inc
Priority date: 1994-06-28
Filing date: 1995-06-26
Publication date: 1996-01-11
Also published as: AU2913095A; MX9700169A; AU690303B2; US6143352A; EP0767819A4; WO1996000760A1; EP0767819A1; US6306243B1; JPH10502270A; BR9508139A

Abstract

The pH-modified monomer and polymer compositions are useful as biomedical and surgical adhesives, sealants, implants and bioactive agent release carriers or matrices. They comprise a monomer or polymer; and an effective amount of an acidic or basic pH mofifier effective to modify the pH of an immediate in vivo environment of the composition to a pH range at which the polymer biodegrades at a different rate then at physiologic pH. The invention also relates to in vivo applications in which surfaces are joined or treated with such pHmodified biocompatible compositions.

Description

P~NS 95/0~ 162 q3q(o - IPEAIlJs 03 JU~'199~

pH- MODIFIr D BIOCOr'!P.'.TI3LE MONOME~ AND ~OLV.~IER CO~IPOSITIONS

Fielà of the ~~vention -~ This invention relates to i...--oved co~positions useful as bio~edical adhesives, seal2~ts, implants and bloac~ive agen. relezse ~atrices. Ç:~is invention also relates to me~ical, surgical and othe- in viv~ appli-ca.ions in ~;~ic~ Doày .issue sur'2ces are joined or rèin.orced witn biocompatible compositions.
- ~:ac.~;cround The proàucts in p_imary use fc- ~ound closure are surgical su.ures and sta~les. Sutures z-e recognized to provi~de adeou2t2 ~ound supDor.. Ho~evor, sutures cause aàdi_ionzl ~ra~2 to the ~ound si.e (_~. ~e2son o_ .he need - fo- .he needle z~ suture to ?ass .:~.ro_-h .~ssue) znd are 1~ time-consuninc to place, and, at s~i~. level, can cause una.tr2ctive ~ou-.à closu~e mar~s. S~_--ical staples have been developed .o s~eed wound 2??csi_ion. ~owever, surqic21 sta~les 21so i~?ose addi.ion21 ~ound .rzumz and requlre the use ~f zncill2ry and o~te- e:.pensive devices ~3 fo- positioning znà Zpplyi?.g .he st2?'~s.
To ove-co~.e these d_ awDac~s ~ -2s _-2ct~ng sursic21 aQhes_v2s h2v_ -een ?-~?ose-. One c-c_- c~ SLC~ 2dheSlVeS
is ,:~e r.~o.70~e-i- _o-~s G- 2~?h2-c~2?.02~-. 2tss.
~ ~ ~efe-e.-cs ~s ,.. aàe, fo~ e~:a.~ e, ~o U.S. ?ztents 2~ Nos. 3,527j8'1 (h'ic~e- et al.); 3,722,5C9 (Rober.son et 21.); 3~,99~,6$1 (:~ronenth21 et al.); 2.-- _,9$0,3~2 (Over-hults),~ ~hich disclose that alph2-c~2,~02c-~12tes are ~use~u~ 2s sur~ic2i 2dhesives. ~11 of ~:-e fsregoins refer-e~ces are here_~ :nc~rpo~2.ed b~ -efe~ence herein.
T~ic '~1., ~~h.e~ se~ _s 2ches-.es 2nd seal2nts, ' C~2nc~ -' ztes 2-~ 2??1ie~ o-~-~- for. ~o .he s~ es ~~ ~e j~ -.e~ c~ sezle~, ~.~e-e -'. -_C2' i~-, '.~ situ ani~-. _ -ol~.--- _2.io?. - _:-e ~.o-~-.e~ ~_-_-s, gi-;in~ ~ise tc _~- ses_-e_ c-hesi-;e ~ ~ S~2 . _-.?12~,_s, SUC.. 2s 5~ .. 5shos, 5~-~- 5, 2~ es, -~ so _e o--led c-~ ~ 2 .~ ' ' ~ - ~.- 2 _ - _ ~ '.T. . ~ - S, - ~ - . e~ ~ . 5 ~ - 2- _ 2 -; _ , ~ _ ~ _ , __ ~ : ~ _ _; ~ _ ~ : -- _ _ _ ...

AMENDED SHEET

WO 96/00760 P~ 62 However, a drawback to the in vivo biomedical use of alpha-cyanoacrylate ~ ~ and polymers has been their potential for causing adverse tissue response. Por example, methyl alpha-cyanoacr~ylate has been reported to cause tissue ;nf~ m~-tion at the site of application.
The adverse tissue response to alpha-cyanoacry-lates appears to be caused by the products released during in vivo biodegradation of the polymerized alpha-cyanoacry-lates. It is believed that formaldehyde is the biodegrad-ation product most responsible for the adverse tissue response and, specifically, the high concentration of fnrmql~Phyde produced during rapid polymer biodegradation.
Reference is made, for example, to F. Leonard et al., Journal of Applied ~olymer Science, Vol. lO, pp. 259-272 (1966); F. Leonard, Annals New Yor~ Academy of Sciences, Vol. 146, pp. 203-213 (1968); Tseng, Yin-Chao, et al., Journal of Applied ~iomaterials, Vol. l, pp. 111-119 (1990), and to Tseng, Yin-Chao, et al., Journal of 3iomed-ical ~aterials Research, Vol. 24, pp. 1355-1367 (1990), which are hereby incorporated by reference herein.
For these reasons, cyanoacrylates have not come into widespread use for biomedical purposes.
Efforts to increase the tissue compatibility of alpha-cyanoacrylates have inrl~ modifying the alkyl ester group. For example, increasing the alkyl ester chain length to form the higher cyanoacrylate analogues, e.g., butyl-2-cyanoacrylates and octyl-2-cyanoacrylates, has been found to improve hlncrmratibility but the higher analogues biodegrade at slower rates than the lower aLkyl cyanoacrylates.
other examples of modified alpha-cyanoacrylates used in biomedical applications include carbalkoxyalkyl alpha-cyanoacrylates (see, for example, U.S. Patent No.

3,995,641 to Kronenthal et al.), fluorocyanoacrylates (see, for example, U.S. Patent No. 3,722,599 to P~obelLsol.
et al.), and alkoxyalkyl 2-cyanoacrylates (see, for example, U.S. Patent No. 3,559,652 to Banitt et al.).
Other e$forts have inoll~pd mixing alpha-cyanoacrylates W096/00760 I~ 162 r ~ 2 1 9 3 9 6 8 with dimethyl methylenemalonate and higher esters of 2-cyanoacrylic acid (see, for example, U.S. Patent No.
3,591,676 to Hawkins et al.).
; In other efforts t-o increzse the usefulness of alpha-cyanoacrylate adhesive compositions for surgical applications, certain viscosity modifiers have been used in combination with alkyl alpha-cyanoacrylate - ~, such as methyl alpha-cyanoacrylate. See, for example, U.S. Patents Nos. 3,564,078 (wherein the viscosity modi-fier is poly(ethyl 2-cyanoacrylate)) and 3,527,841 twherein the viscosity modifier is poly(lactic acid)), both patents being to ~icker et al.
In a related application, U.S.S.N. 08/040,618, filed March 31, 1993 (U.S. Patent 5,328,687), the entire contents of which are hereby incorporated by reference, the use of formaldehyde scavengers has been ~lu~osed to improve biocompatibility of alpha-cyanoacrylate polymers, whose biodegradation produces formaldehyde, for use in in vivo applications. It is known that various ~ 1~ can affect polymerization of alpha-cyanoacrylate ~, including acids to inhibit or slow polymerization (e.g., Leonard et al., U.S. Patent 3,896,077), and bases to accelerate polymerization (e.g., Coover et al., U.S.
Patent 3,759,264 and Dombroski et al., U.S. Patent 4,042,442).
SUMMARY OF THE INVENTION
It has not been known to regulate polymer biodegradation by regulating the pH of an immediate in vivo environment of a hi 1- , -tible composition. Such regulation would improve, for instance, the biocompati-~ bility of l,1-disubstituted ethylene polymers for in vivo applications, by controlling the rate of release of harmful byproducts (e.g., formaldehyde) and controlling the rate of degradation of the polymer in situ.
r in;ng the monomer composition with a hi~ -tible pH modifier effective to regulate the pH of an immediate environment of the in sit~ polymer will substantially improve the usefulness of polymers formed W096/00760 r~ l62 2 1 q 3 9 6 ~

from such ~ ~, particularly in com~ination with use of fn~-l~Phyde s~cv~ s.
The present invention is also directed to methods of using the above-described~ monomers, copolymers and polymers made therefrom for hi~ -';r~l purposes.
The monomer compositions of this invention and polymers formed therefrom are useful as tissue adhesives, sealants for preventing bleeding or for covering open wounds, systems for delivery of therapeutic or other bioactive agents, and in other bi~ 'ir~l applications.
They find uses in, for example, apposing surgically incised or traumatically lacerated tissues; setting fractured bone structures; retarding blood flow from wounds; aiding repair and regrowth of living tissue; and serving as matrices for delivering bioactive agents and as implants.
DETAILED DESCRIpTION OF ~ ~kLU EMBODIMENTS
~mhn~ ;- ts of the present invention provide a biocompatible monomer composition, comprising an effective amount of at least one biocompatible pH modifier effective to regulate the pH of an immediate in vivo environment of the polymer to a pH range at which the polymer's in vivo biodegradation proceeds at a different rate than it does at physiologic pH.
In a further ~ho~;- L, the present invention is directed to a hi ~ , tible composition comprising a polymer whose in vivo biodegradation may produce formalde-hyde, and a pH modifier as described previously, and optionally including a fnrr~ hyde S~CY~IIg~L.
The ~ , used in this invention are polymeriz-able, e.g. anionically polymerizable or free radical polymerizable, to form polymers which biodegrade. In some embodiments, they form active fnrr~ hyde upon biodegradation.
Monomer compositions of this invention may be applied to a surface to be sealed or joined together with a second surface in vivo, where, typically, in sit~

wo g6/00760 r~ .t el62 anionic polymerization of the monomer occurs, giving rise ~ to the desired adhesive bond or seal.
Useful 1,1-disubstituted ethylene 0 include, but are not limited~ to, a of the formula:
S ( I ~ CHR=CXY
wherein X and Y are each strong electron withdrawing groups, and R iS H, -CH=CH2 or, provided that X and Y are both cyano groups, a C,-C4 alkyl group.
Examples of - ~ within the scope of formula (I) include alpha-cyanoacrylates, vinylidene cyanides, C,-C4 alkyl homologues of vinylidene cyanides, dialkyl 2-methylene malonates, acylacrylonitriles, vinyl sulfinates and vinyl sulfonates of the formula CH2=CX'Y' wherein X' is -S02R' or -503R' and Y' is -CN, -COOR', -COCH3, -So2R' or -503R', and R~ is H or hydrocarbyl.
Preferred monomers of formula (I) for use in this invention are alpha-cyanoacrylates. These ~ a are known in the art and have the formula CN

(II~ CHR2=C
CCoR3 wherein R2 is hydrogen and R3 is a hydrocarbyl or substi-tuted 11YdL~LbY1 group; a group having the formula -R~-O-R5-O-R6, wherein R~ is a 1,2-alkylene group having 2-4 carbon atoms, R5 i5 an alkylene group having 2-4 carbon atoms, and R5 is an alkyl group having 1-6 carbon atoms;
-R7- C -O_R8 or a group having the formula ~ , wherein R7 is ¦ , or -C(CH3)2-, and R3 is an organic radical.
-CH2 -, -CH -Examples of suitable hYdL~1bY1 and substituted hydrocarbyl groups include straight chain or branched chain alkyl groups having 1-16 carbon atoms; straight chain or branched chain C~-C~6 alkyl groups substituted with an acyloxy group, a haloalkyl group, an alkoxy group, a halogen atom, a cyano group, or a haloalkyl group;

W096/00760 r .,~ l 162 ~ 1 93968 v ~

straight chain or branched chain alkenyl groups having 2 to 16 carbon atoms; straight chain or branched chain alkynyl groups having 2 to 12 carbon atoms; cycloalkyl groups; aralkyl groups; alkylsryl groups; and aryl groups.
In the cyanoacrylate monomer of formula (II), R3 is preferably an alkyl group having 1-10 carbon atoms or a group having the formula -AoR9l wherein A is a divalent straight or branched chain alkylene or oxyalkylene radical having 2-8 carbon atoms, and R9 is a straight or branched alkyl radical having 1-8 carbon atoms.
Examples of groups ~Les~llLed by the formula -AoR9 include 1-methoxy-2-propyl, 2-butoxyethyl, 2-isopro-poxyethyl, 2-methoxyethyl, 2-ethoxyethyl and 3-methoxybutyl.
Especially advantageous alpha-cyanoacrylate monomers for use in this invention are methyl alpha-cyanoacrylate, butyl alpha-cyanoacrylate, 2-octyl alpha-cyanoacrylate, 1-methoxy-2-propyl cyanoacrylate, 2-butoxyethyl cyanoacrylate, 2-isu~Lu~u~y~Lhyl cyanoacrylate and 3-methoxybutyl cyanoacrylate. Equally advantageous are 2-methylene malonates, such as dimethyl 2-methylenemalonate.
The alpha-cyanoacrylates of formula (II) wherein R3 is a hydrocarbyl or substituted hydrocarbyl group csn be prepared according to methods known in the art.
Reference is made, for example, to U.S. Patents Nos.
2,721,858 and 3,254,111, each of which is hereby in.uL~uL~Led by reference herein. For example, the alpha-cyanoacrylates can be prepared by reacting an alkyl cyano-acetate with f~rr~ hyde in a non-aqueous organic solvent and in the presence of a basic catalyst, followed by pyrolysis of the anhydrous intermediate polymer in the presence of a polymerization inhibitor. The alpha-cyano-acrylate ~ ~ a prepared with low moisture content and essentially free of impurities are preferred for bi~ -~ic~1 use.
The alpha-cyanoacrylates of formula (II) wherein R3 is a group having the formula -R~-o-R5-o-R6 can be W096l00760 PCT~S95/08162 2 ~ 9 3 ~ ~8 prepared according to the method disclosed in U.S. Patent No. 4,364,876 (Kimura et al.), which is hereby incorporat-ed by reference herein. In the Kimura et al. method, the alpha-cyanoacrylates are prepared by producing a cyanoace-tate by esterifying cyanoacetic acid with an alcohol or bytransesterifying an alkyl cyanoacetate and an alcohol;
condensing the cy~nnAn~t~te and fnr~-lflPhyde or para-fnr~ r~hyde in the presence of a catalyst at a molar ratio of 0.5-1.5:1, preferably 0.8-1.2:1, to obtain a nnnrl~nc~te; depolymerizing the nnnrl~ncation reaction mixture either directly or after removal of the condensa-tion catalyst to yield crude cyanoacrylate; and distilling the crude cyanoacrylate to form a high purity cyanoacry-late.
The alpha-cyanoacrylates of formula (II) wherein -R7-C-o-R3 R3 is a group having the formula ~ can be prepared according to the procedure described in U.S.
Patent No. 3,995,641 (Kronenthal et al.), which is hereby incorporated by reference. In the Kronenthal et al.
method, such alpha-cyanoacrylate monomers are prepared by reacting an alkyl ester of an alpha-cyanoacrylic acid with a cyclic 1,3-diene to form a Diels-Alder adduct which is then subjected to ~lk~l ;nr hydrolysis followed by acidifi-cation to form the ~uLL~ ;ng alpha-cyanoacrylic acid adduc~. The alpha-cyanoacrylic acid adduct is preferably esterified by an alkyl bromoacetate to yield the corre-sponding carbalkoxymethyl alpha-cyanoacrylate adduct.
Alternatively, the alpha-cyanoacrylic acid adduct may be converted to the alpha-cyanoacrylyl halide adduct by reaction with thionyl chloride. The alpha-cyanoacrylyl halide adduct is then reacted with an alkyl hyd-~yacetate or a methyl substituted alkyl hydroxyacetate to yield the corr~pnnrl;ng carbalkoxymethyl alpha-cyanoacrylate adduct or rArh~lkn~y alkyl alpha-cyanoacrylate adduct, respec-tively. The cyclic 1,3-diene blocking group is finally removed and the carbalkoxy methyl alpha-cyanoacrylate adduct or the carbalkoxy alkyl alpha-cyanoacrylate adduct W096/00760 ~ r~ '2 2 1 93 9 ~
- ,3 -is converted into the corresponding carbalkoxy alkyl alpha-cyanoacrylate by heating the adduct in the presence of a slight deficit of maleic anhydride.
~xamples of r a of formula (II) include cyanopentadienoates and alpha-cyanoacrylates of the formula:
CN
(III) \CooR3 wherein Z is -CH=CHl and R3 is as de~ined above. The monomers of formula (III) wherein R3 is an alkyl group of 1-10 carbon atoms, i.e., the 2-cyanopenta-2,4-dienoic acid esters, can be prepared by reacting an appropriate 2-cyanoacetate with acrolein in the presence of a catalyst such as zinc chloride. This method of preparing 2-cyano-penta-2,4-dienoic acid esters is disclosed, for example, in U.S. Patent No. 3,554,990, which is incorporated by reference herein.
Compositions of this invention comprise an effective amount of a biocompatible pH modifier effective to regulate the pH of an immediate in situ environment of the polymer to a pH level at which the polymer's in vivo biodegradation proceeds at a different rate than it does at a physiologic pH ("effective amount"). An effective amount o~ a pH modifier effective to achieve the desired in situ pH modification will depend on the acidity or basicity (pKa or pKb) of the ~r~rol-n~ used, the pH of the polymer composition used when in situ, the in vivo environment's physiologic pH, and the release rate of biodegradation products resulting from the pH-modified biodegradation rate. An effective amount of pH modifier may be selected with regard to any formaldehyde a~v~llyel or other f ~rt added to control levels of biodegra-dation products released. As well, a non-toxic pH
modifier (e.~ , an acid) is preferably used, or the pH
modifier is used in an effective amount that minim;7~ any potential tox~c effect.

.

WO 96/00760 P~~ S. ~
2 1 ~396 .. , \ ~ t ~

In such P~ho~inPnt5, the pH modifier may include, for example, but is not limited to, an acidic ~ ul.d or anhydrous precursor thereof or a ~hP~;rAlly protected acid. For example, the pH modifier may comprise at least one member CPl P~t~ from the group consisting of: amino acids; carboxylic acids and salts thereof; di-acids and salts thereof; poly-acids and salts thereof; esters that are easily hydrolyzable in vivo; lactones that are easily hydrolyzable in vivo; organic carbonates; enolic compounds; acidic phenols; polyphenolic , luu--ds;
aromatic alcohols; ; 11~ compounds or salts thereof;
boron-containing compounds; sulfonic acids and salts thereof; sulfinic acids and salts thereof; phosphorus-containing '~; acid halides; chloroformates; acid gases; acid anhydrides; inorganic acids and salts thereof;
and polymers having functional groups of at least one of the preceding members. The pH modifier of this invention may, for example, comprise at least one member sPlPr~
from the group consisting of: glycine; alanine; proline;
lysine; glutaric acid; D-galacturonic acid; succinic acid;
lactic acid; glycolic acid; poly(acrylic acid); sodium acetate; diglycolic anhydride; succinic anhydride;
citraconic anhydride; maleic anhydride; lactide; diethyl oxalate; Meldrum's acid; diethyl carbonate; dipropyl carbonate; diethyl pyrocarbonate; diallyl pyrocarbonate;
di-tert-butyl dicarbonate; ascorbic acid; catechin;
ammonium chloride; D-glllrnsA~inp hydrochloride; 4 l-yd-u~y-ephedrine hydrochloride; boric acid; nitric acid; hydro-chloric acid; sulfuric acid; ethanesulfonic acid; and p-tolnPnPcn1fonic acid; 2-aminoethylrh~srhnric acid;
methylrhocphnni~ acid; dimethylrhnsFh;nic acid; methyl chloroformate; sulfur dioxide; and carbon dioxide.
Glutaric acid and diethyl u~LbullaLe are particularly preferred in P~hoS;~ Ls of the invention.
The pH modifier may alternatively be selected to modify, in vivo, a pH of an immediate in vivo environment of the polymer to a pH level at which in vivo _iodegradation of the in sit~ polymer proceeds more P~T/U~, 9 5 / 0 8 1 6 2 g For instance, in e~odi~ents of the invention, a non-encapsulated, acidic p~ modifier ~ay be present in an effective amount greater than 1% ~y weight of the composition. In microencaps'u'la'ted forms, the amount of p~
modifier added may be varied from a minimum effective amount up to 2 m~ um loading permitted by the microcap-sule and any toxicity limit, according to the particular monomer or polymer composition and application. At the same time, the pH modifier should not significantly affect (inhibit or accelerate) in vivo polymerization of the monomer composition or otherwise interfere with the composition' 9 efficacy for medical or surgical applications.
An acidic or basic pH moàifying compound, and its concentration in the composition, may be selected according to the in vivo pH range to be achieved in an immediate environment of the in situ polymerized or cross-linked adhesive co~position. The desired in situ p~ level depends on the particular monomer or ?olymer used and on whether that polymer's in vivo ~iodegradation rate is desired to be -lowe- or faster than ~ts biodegradation rate at the ?hysiologic pH of the ?articular in vivo application. One s~illed in the biocompatible monomer and poLymer -ield will be able, upon reading this disclosure and with some routine experimentation, to select the pH
~odifier best suited for a given polymer or monomer composition and the particular application for which it is used.
The pH modifier may be selected to modify, in vivo, the pH of an immediate in situ environment of the polymer to a p:i level at which -~ vivo biodegradation of the in situ polymer (and low molecul2r weight materials in the co~position) proceeds more slowly than it does at a physiologic pH. This results in .etarding the rate of release of formaldehyde and other deqradation products, thereby -edu~i~g their .oxic effec~s since, e.g., formaldeAyde _2?. be more completel~ eLiminated before substan'iai, -oxi~ concentrations sccur ~n situ.

AMEND~D SttE~T

W096/00760 I~ 162 ~ 2 1 3968 quickly than it does at a physiologic pH. Basic pH
modifiers allow the use of polymer materials otherwise degrading slowly or not at all in vivo, e.g., butyl alpha-- cyanoacrylate or 2-octyl alpha-cyanoacrylate. The pH
5modifier is added in an amount sufficient to accelerate the polymer's biodegradation, but the accelerated release of biodegradation products ~e.g., formaldehyde) must remain within physiologically tolerable ranges. In this aspect, a formaldehyde scavenger may also be added to keep 10fnrr~l~Phyde levels within tolerable levels, for instance, in the manner of related application, U.S.S.N. 08/040,618.
In such Pmhn~; r Ls ~ the pH modifier may include a basic compound or anhydrous precursor thereof, andlor a chemically protected base. For example, the pH modifier 15may comprise at least one member selected from the group consisting of: hydroxides; ~1 kn~ c; basic carbonates;
nitrogen-containing nnmrmln~c; amines; alkaloids;
hydrides; organolithium ~ ; Grignard reagents;
carbanions; and polymers having functional groups of at 20least one of the preceding members. The pH modifier (whether single or in combination) may be, for example, selected from the group consisting of: sodium hydroxide;
potassium hydroxide; sodium methoxide; potassium t-butoxide; sodium ~c.~u,-ate; calcium carbonate;
25dibutylamine; tryptamine; sodium hydride; calcium hydride;
~utyllithium; and ethylmagnesium bromide.
The present invention ~r c~es situations in which f nrr- l~rhyde is released zs a byproduct cr in situ biodegradation of the hi~ -tible polymer. A formalde-30hyde cu"c~"LL~tion-reducing agent or fnrr~l~hyde scavenger, e.g., sodium bisulfite, may be added to the compositions and methods of this invention to control fnrr-l~rhyde release in situ and to min;mi7~ harmful effects therefrom, as disclosed in related application, 35U.S.S.N. 08/040,618, in~u.~u.cted herein by reference.
However, an acid pH modifier-containing composition herein ~; ~rl ns~ can further minimize active formaldehyde cu..ce..LLctions in situ in the following manner. The pH

W096/00760 r~ t :162 ' ~ 12 -- 2 ~ 9 s 9 6 8 modifier regulates the immediate pH environment of the in situ polymerized composition such that the polymer's in situ biodegradation is slowed, thereby keeping in situ formaldehyde concentrations~at a level that can be handled physiologically and that will not, in an initial burst, overwhelm any formaldehyde scavenger that is present.
The pH modifier used in this invention may either be in free form or in a protected form. For instance, it may be in a form that is insoluble in the monomer of a monomer composition, such as a free acid or a micro~nrnrs--lated form, or may be in a rhrmirAlly protected form that may be soluble or insoluble in such monomer compositions. Once in vivo, the pH modifier may diffuse through the mi~Lu~p~ule or be released by bioerosion of the microcArclllrr into the in situ polymer.
The microcapsule may be formulated so that the pH modifier is released from the microcapsule continuously over a period of time during the biodegradation of the in situ polymer. Alternatively, the microencapsulated pH modifier may be formed to release rapidly and transiently, after a time delay, or even intermittently, vis-~-vis the life of the in situ polymer, ~rr~n~ing on when the pH modifier is desired to have effect. For example, delayed release of 2 basic pH modifier may be desired to cause the polymer to begin to degrade rapidly after it has served a significant portion of its useful life. As well, pH modifiers may be used in combination, allowing, e.g., quick release of an acidic pH modifier followed by later release of a basic pH
modifier, for more refined control of the polymer's biodegradation.
For purposes of this invention, the microencapsu-lated form of the pH modifier is advantageous because this ~mhQ~i L prevents or substantially reduces pre-application effects of the pH modifier, e.g., a basic pH
modifier, thereby increasing shelf-life and facilitating hAn~l;ng of the monomer composition during use.
MicrornrArs~llAtion of the pH modifier can be achieved by many known micro~nrAr~nlation techniques. For W096J00760 ~ l 162 example, micropnr~rcnl~tion can be carried out by dissolving a coating polymer in a volatile solvent, e.g., methylene chloride, to a polymer ~u-,cen-~tion of about 6~
by weight; adding a pH modifying cu~uuu--d ~selected to be acidic or basic according to the pH level to be achieved in situ) in particulate form to the coating polymerlsolvent solution under agitation, to yield a pH
modifier cu..c~l.L.~tion of 2~ to 10~ by weight; adding the resulting polymer dispersion to a methylene chloride solution containing a phase inducer, such as silicone oil, under agitation; allowing the mixture to equilibrate for about 20 minutes; further adding the mixture slowly to a non-solvent, such as heptane, under rapid agitation;
allowing the more volatile solvent to evaporate under agitation; removing the agitator; separating the solids from the silicone oil and heptane; and washing and drying the microparticles. The size of the microparticles will range from about 0.001 to about 1000 microns.
The microPnr~rs~ ting coating polymer should be able to undergo in vivo bioerosion or to permit diffusion of the pH modifier, and should have low inherent moisture content. Bioerosion preferably occurs at rates greater than or similar to the rate of degradation of the base polymer. Such "bioerosion" can occur as a result of the physical or rhP~;r~l breakdown of the Prr~rqlll~ting material, for example, by the ~nr~rsl~lating material passing from solid to solute in the presence of body fluids, or by biodegradation of the ~nr~rslll~ting material by agents present in the body.
Examples of coating materials that can be used to microPnr~r~ te the pH modifier include, but are not limited to: polyesters, such as polyglycolic acid, polylactic acid, copolymers of polyglycolic acid and polylactic acid, polycaprolactone, poly-~-hydlu~ybuLy.~te, copolymers o~ ~-caprolactone and 6-valerolactone, copolymers of ~-caprnl~rtrnP and D~-dilactide, and polyester hydrogels; polyvinylpyrrolidone; polyamides;
gelatin; albumin; proteins; collagen; poly(orthoesters);

W096/00760 r~ ,''0 l62 i 9 3 9 6 ~

poly(anhydrides); poly(alkyl-2-cyanoacrylates);
poly(dil,ydL~yl~ns); poly(acetals); poly(rhnsph~70n~c);
poly(urethanes); poly(~;nYinnnoc); rolllllnce; and starches.
Examples of a phase inducer that can be added include ~;l; rnno oil, mineral oil, polyethylene, polyisobutylene, and polybutadiene.
Compositions of this invention may further contain a stabilizer and/or one or more adjuvant substances, such as thickening agents, plasticizers, or the like, to improve its medical utility for particular medical applications.
Examples of suitable stabilizers include sulfur dioxide, sulfonic acid, lactone, boron trifluoride, hydroquinone, hydroquinone monomethyl ether, catechol, pyrogallol, benzoquinone, 2-hydroxybenzoquinone, p-methoxy phenol, t-butyl catechol, organic acid, butylated hydroxy anisole, butylated hydroxy toluene, t-butyl hydroquinone, alkyl sulfate, alkyl sulfite, 3-sulfolene, alkylsulfone, alkyl sulfoxide, mercaptan, and alkyl sulfide.
Suitable thickeners include, for example, poly-cyanoacrylates, polylactic acid, polyglycolic acid, lactic-glycolic acid copolymers, polycaprolactone, lactic acid-caprolactone copolymers, poly-3-hydLu~ybuLyLic acid, polyorthoesters, polyalkyl acrylates, copolymers of alkylacrylate and vinyl acetate, polyalkyl methacrylates, and copolymers of alkyl methacrylates and butadiene.
Examples of suitable plasticizers include dioctyl phthalate, dimethyl sebacate, triethyl phosphate, tri(2-ethylhexyl)phosphate, tri(p-cresyl~ rhnsFh~te~
glyceryl triacetate, glyceryl tributyrate, diethyl sebaca-te, dioctyl adipate, isopropyl myristate, butyl stearate, lauric acid, dibutyl phthalate, trioctyl trimellitate, and dioctyl glutarate.
To improve the cohesive strength of adhesives formed from the compositions of this invention, difunc-tional monomeric cross-linking agents may be added to compositions or used in methods of this invention in vivo W096/00760 P~l/u~ 'l 162 2 ~ 9 3 9 6 8 or ex vivo. Such crossl;nking agents are known.
Reference is made, for example, to U.S. Patent No.
3,940,362 (Overhults), which is hereby incorporated by -, reference herein. Exampres of suitable crosslinking agents include alkyl bis(2-cyanoacrylates), triallyl isocyanurates, alkylene diacrylates, alkylene dimethacryl-ates, trimethylol propane triacrylate, and alkyl bis(2-cyanoacrylates). When used ex viVo~ a catalytic amount of a free radical initiator is added to initiate polymerization of the cyanoacrylate monomer/crosslinking agent blend. Such compositions can be molded or otherwise formed to provide preformed implants and prosthetic devices for surgical use, such as rods, meshes, plates, screws, and fasteners.
The compositions of this invention may further contain fibrous reinforcement and colorants, e.g., dyes and pigments. Examples of suitable fibrous reinfu~. L
include PGA microfibrils, collagen microfibrils, cellu-losic microfibrils, and olefinic microfibrils. ~Y~mploc of suitable colorants include 1-hydroxy-4-[4-methylphenyl-amino]-9,lO anthracenedione (FD&C violet No. 2); ~;co~illm salt of 6-hydroxy-5-[(4-sulfophenyl)axo~-2-naphthalene-sulfonic acid (FD&C Yellow No. 6); 9-(o-carboxyphenyl)-6-hydroxy-2,4,5,7-tetraiodo-3H-xanthen-3-one, ~ico~ m salt, monohydrate (FD&C Red No. 3); 2-(1,3-dihydro-3-oxo-5-sulfo-2H-indol-2-ylidene)-2,3-dihydro-3-oxo-lH-indole-5-sulfonic acid ~;co~inm salt (FD&C Blue No. 2); and [phtha-locyaninato (2-)] copper.
The biocompatible adhesive compositions of this invention can be used, for example, to join together two surfaces, at least one of the surfaces being body or living tissue, by applying the composition to at least one of the surfaces. ~or~n~ing on the particular re~uirements of the user, the compositions of this invention can be applied by known means, such as with a glass stirring rod, sterile brush, ';~ino dropper, spray bottle or other non-aerosol means. However, in many situations, a pressurized aerosol dispensing package is advantageous, in W096l00760 P~~ 162 2 ! 9 3 9 6 8 which the adhesive composition is in solution with a compatible anhydrous or other aerosol propellant. Aerosol application of the - ~ is particularly advantageous for use in hemostasis. The compositions of this invention may also be stored in and dispensed from a two-phase container, in which the pH modifier is kept apart from the monomer composition until shortly before or at the moment of applying the adhesive composition in situ to the in vivo surfaces to be bonded. If a fnrr~ hyde cu.lc~"Ll~tion-reducing agent is also present, it may be present in either of the above two phases, or in a separate third phase of a multi-phase container.
In one ~mhn~ st, the present invention is directed to a method of joining together in vivo two surfaces, one or both of which may be a body tissue, which comprises (a) applying to at least one of said surfaces a biocompatible composition of this invention, and (b) main-taining the surfaces in contact until said composition ~oins together the two surfaceS (e.g., by polymerization of the monomer composition). One of said surfaces can be body tissue and the other surface a prosthetic device or the like, or both surfaces may be body tissue. As one example of a composition which may be used to practice this method, said composition may comprise: (1) at least one monomer (e.g., a monomer of formula (I)) which forms a polymer whose in vivo biodegradation proceeds at a physiologic pH (and may release fnrr~l~hyde); and (2) an effective amour,t of a h; nrn~p~tible pH modifier effective to regulate the pH of an immediate in situ environment of the biocompatible polymer to a pH level at which said polymer biodegrades at a different rate than it does at said physiologic pH. The pH modifier may be selected to slow or to accelerate the polymer's biodegradation.
Various methods for repairing or strengthening damaged living tissue to prevent the escape of fluids th~let~ h exist which may employ a composition of the invention. For example, a method for repairing or dressing living tissue may comprise: (a) applying to the W096/00760 r~ 62 tissue a surgical sealant comprising the biocompatible composition including a pH modifier of this invention; and (b) allowing the composition to polymerize. A method for - stemming the flow of blood from small vessels may comprise applying to said vessels a surgical sealant or hemostatic agent comprising a biocompatible monomer composition ;nr~ ing a p~ modifier. A method of dressing burns to promote the healing thereof may comprise (a) covering said burn with a biocompatible composition of this invention;
and ~b) allowing the composition to polymerize in situ;
and methods of dressing wounds to promote the healing thereof may comprise (a) covering said wound with a biocompatible composition of this invention; and (b) allowing the composition to polymerize.
~epairing injured tissues (for example, to control bleeding) may comprise, for example, sponging to remove superficial body fluids and subsequent application to the exposed tissue of a composition of the invention. For example, a monomer composition polymerizes to a thin film of polymer while in contact with the tissue surface. For bonding separate surfaces of body tissues, the monomer is applied to at least one surface, and the surfaces are brought quickly together while the monomer polymerizes in contact with both surfaces.
In another PrhoA; r -nt, the present invention may be used in a method for effecting in vivo administration of a bioactive agent, comprising introducing into a body a composition of this invention, which may comprise: (a) a polymer whose in vivo biodegradation may or may not release formaldehyde; (b) an effective amount of a ~ biocompatible pH modifier; and (c) a bioactive amount of a bioactive agent, wherein biodegradation of the polymer or diffusion of the bioactive agent effects its in vivo release. The bioactive agent may be encapsulated in a suitable biodegradable material for controlling release of the bioactive agent. The polymer may be one degrading slowly or not at all or may be hydrolytically sensitive, at an in vivo physiologic pH. In the former case, a basic W096~00760 P~ 162 pH modifier may be added to promote biodegradation of the polymer. The composition may also include an effective amount of at least one biocompatible agent effective to reduce active fnrr~ hyde ~concentration levels, e.~., a fn~ yde S~ve~
The compositions may be used further to administer therapeutic agents into the body. The composition will form a matrix for the therapeutic agent, with the thera-peutic agent being released in vivo from the matrix by diffusion or by biodegradation, over time, of the polymer.
For example, a composition comprising the monomer (or polymer form of the monomer, since in this application, polymerization need not occur in situ), a biocompatible p~
modifier of this invention, an optional biocompatible formaldehyde s~vel~ge" and a therapeutic agent are introduced into the body where the polymer undergoes biodegradation, gradually r~ q;ng the therapeutic agent.
Alternatively, the therapeutic agent may diffuse out from the composition, into the body, be~ore polymeric 2C biodegradation ends or even begins.
The ~ are readily polymerized to addition-type polymers and copolymers.
In most bonding applications using compositions of this invention, polymerization of the monomers is catalyzed by small amounts of moisture on the surface of the adherents. Therefore, desired bonding of tissues and hemostasis proceed well in the presence of blood and other body fluids. The bonds formed are of adequate flexibility and strength to withstand normal movement of tissue. In addition, bond strength is maintained as natural tissue healing proceeds ~u.,uu, Le-.Lly with polymer ~c5im;1~tion Compositions employed in the invention are steril-izable by conventional methods such as by autoclave or by aseptic filtration techniques.
The invention is further illustrated by the following non-limiting examples.

W096/00760 r~ l62 ~ $~ 2 1 9 3 9 6 ~

EXA~p~ .c , In the Examples below, the following terms are defined as follows:
IPECA - 2-isu~Lu~u~y~Lhyl cyanoacrylate DMM - dimethyl 2-methylenemalonate 3MBCA - 3-methoxybutyl cyanoacrylate 20CA - 2-octyl cyanoacrylate monomer(s) - refers generically to IPECA, DMM, 3MECA
and/or 2OCA
Examples 1-18 and Control ExamPles lC-18C
Examples 1-18 and Control Examples lC-18C
illustrate the effect of a biocompatible pH modifier on the biodegradation of a 1,1-disubstituted ethylene monomer polymerized in situ. The compositions of Examples 1-18 each contain a p~ modifier (in free or micro~n~rc~ ted form) while the compositions of Control Examples lC-18C
contain sodium chloride (NaCl), polycaprolactone microcapsules, or no additive.
The formulations of the compositions prepared in Examples 1-18 and Control Examples lC-18C are shown in Tables IA and IB, respectively.
The compositions of the examples are prepared as follows. Appropriate weight ratios of the monomer and an additive are mixed thoroughly by shaking. (solid p~
modifiers and sodium chloride are ground or milled to a fine particle size before mixing.) The resulting mixture is quickly poured onto a glass plate equipped with a 4 cm x 8 cm boundary. The glass plate is pre-treated with chlorotrimethylsilane and the boundary is fabricated with caulking cord material. The mixture is spread evenly to all edges. Polymerization of the monomer mixture is then accelerated by spraying with a 1% aqueous sodium h;rArhnn~te solution (Examples 1-3, 5, 9-18, lC-3C, 5C, and 9C-18C) or a 1:2:97 triethylamine/methanol/heptane mixture (Examples 4, 6-8, 4C, and 6C-8C). The hardened polymer film is gently scraped off the glass plate, cut away from the boundary and dried. It is further cut into two halves, each of 2 cm x 8 cm, for duplicate runs.

W096/00760 r~~ 162 ~ {~ 2 1 q 3 q 6 8 In Examples 13-15, the additive is sprinkled evenly on the glass plate and the monomer is then carefully added, instead of the two ~eing mixed directly.
In vitro ~iodegradation (simulating in vivo biodegradation) of each 2 cm x 8 cm polymer film is then carried out as follows. The polymer film, encaged in aluminum mesh, is placed in a pH 7.4 huffer (e.g., h~; r potassium phosphate and dipotassium phosphate).
Biodegradation is carried out at 37_2~C for 168 hours 10(Examples 1-9, 13-18, lC-9C, and 13C-18C) or at 37+2~C for 192 hours (Examples 10-12, and lOC-12C). The partially degraded film is separated from the huffer solution and dried. The huffer solution is subjected to formaldehyde determination.
15~et~rrin~tion of the amount of formaldehyde generated during hiodegradation of the polymer films may be accomplished as disclosed in related application U.S.S.N. 08/040,618 (U.S. Patent 5,328,687).
In the following ta~les, the term "~g fnrr~ hyde aetected per g polymer" means the amount of fnrr~ hyde generated in micrograms divided oy the original polymer weight in grams (excluding the weight of the pH modifier or control additiYe).

WO 96l00760 PCTIUS95/08162 2 1 q 3 9 6 8 Table IA
r les 1-18 ~ ~g Formaldehyde X Chnnge of Example AWitive Deeec~ed per g Formaldehyde No. Monomer AWi~ive Ueicht X Polymer Detected 1 IPECA diethyl carbona~e 2.5 1652 - 77.4 Z IPECA diethyl carbcnDte 5.C 1278 - 87.0 3 IPECA diethyl cnrbonnte 7.5 88C6 - 14.4 4 IPECA Inctide 7.0 1161 ~ 73.3 S IPECA glucosamine 9.0 6C82 - 19.9 hydrochloride l 0 6 IPECA ascorbic acid 2.0 5226 - 66.7 7 IPECA glutaric Dcid 1.0 13,78B ~ 7.3 8 IPEU qlu~aric acid/ 8.0 3023 - 20.0 polycnprolactcne micrccaxules g 3H8CA glycine 8.0 1909 - 8.7 DHH diethyl oxalnte 6.0 1723 - 61.4 1 5 11 OHM tryp~nmine 3.0 2538 I 2Z.6 lZ DHH po~ossium cnrbona~e 2.0 2372 I 16.2 13 IPECA L", 'r~lycnpro- 4.0 10,376 1 53.4 Incnone m~crocaxules 14 IPECA L" , tt~lycnpro- 6.0 9961 I a.7 I-ceone micrccaosules IPECA t", t~_lyc-prc 8.0 9094 + 46.9 Inctone micrccaDsules 2 0 16 IPECA sodium cnrbone~e/poly 10.0 6949 1 63.6 cnprclnceone m~crocnpsules 17 3HBCA sodium me~hoxide S.O 4389 ~856.2 18 20CA sodium hvdrcxide 8.5 2351 ~1379.C

W096/00760 r~ l62 ' , ~' 2 t 9 3 9 ~ 8 TAhle IB
Control ~YA~les lC-18C

~9 FormaLdehy~e X Change o~
Example Additive Detected per g Forma~dehyde ho Monpmer Additive ~eight % Polymer Detected 1C IPECA sodium chLoride 2 5 7295 0 2C IPECA sodium chloride 5 0 Y856 0 3C IPECA sodium chloride 7 5 tO,293 D
4C IPECA sodiur chloride 7 0 4355 0 SC IPECA sodlum chloride 9 0 7595 0 1 0 6C IPECA sodium chloride 2 0 15,698 0 7C IPECA sodium chloride 1 0 14,880 0 8C IPECA sodium chloride 8 D 378D D
9C 3MacA sodium chloride 8 D 2091 D
lDC DMM sodlum chloride 6 D 4466 0 1 5 lC DMM sodium chloride 3 0 2D70 0 12C DMM sodium chlorlde 2 D 2041 0 13C IPECA polyc-prol~ctone 4 0 6764 D
microcapsules 14C IPECA polyc-prolactone 6 D 6D85 D
micrpc~Ku~es 15C IPECA polyc~prolactone 8 D 6189 D
microcapsules 16C IPE U polycaprolrctpnelD D 4248 D
microcapsules 17C 3MECA none D 459 D
18C 2DCA npne D 159 D

The monomer IPEC~ is polymerized by azoisobutyronitrile (AI8N~ at 70~C to give a polymer of approximately 25,000 molecular weight. In the following Examples, poIymer(s~ refers cJenerically to the IPECA
polymer ~L ~al_d in this manner.
Exam~les 19-20 and Control Exam~les l9C-20C
Examples 19-20 and Control Examples l9C-20C
illustrate the e~ect of a biocompatible pH modifier on the biodegradation of a 1,1-disubstituted ethylene polymer. The compositions of Examples lg-20 each contain a pH modifier while the compositions of Control Examples l9C-20C contain sodium chloride (NaCl~.

W096/0076n E~ 162 ~ t 3 9 6 8 The formulations of the compositions prepared , in Examples 19-20 and Control Examples l9C-20C are shown in Table II.
The compositions~of the examples are prepared as follows. The polymer is dissolved in methylene chloride to give a polymer concentration of about 15%.
The resulting polymer solution and an additive (either a pH modifier or sodium chloride) are mixed thoroughly in the appropriate weight ratio by shaking. (solid p~
modifiers and sodium chloride are ground or milled to a fine particle size before mixing.) The resulting mixture is quickly poured onto a glass plate e~uipped with a 4 cm X 8 cm boundary. The glass plate is pre-treated with chlorotrimethylsilane and the boundary is fabricated with r~nlk;ng cord material. The inside border is painted with melted paraffin wax. The mixture is spread evenly to all edges. Following evaporation of solvent, the polymer film is gently scraped off the glass plate, cut away from the boundary and dried. It is further cut into two halves, each of 2 cm x 8 cm, for duplicate runs.
In vitro biodegradation (simulating in vivo biodegradation) of the polymer films and formaldehyde ~t~r~in~tion are carried out using the same ~Lu~cuULes followed in Examples 1-9 and 13-18 and Control ~xamples lC-9C and 13C-18C. The results of Examples 19-20 and Control Examples l9C-20C are shown in Table II.
Table IT
EYF~mnles 19-20 and Control ExamDles l9C-20C

~9 Formaldehyde X Charge o~
E~ar4ie Addit~ve Detected per g Forr~idehyde 3 0 Uo. Polvmer Additive iJeight X Polymer Detected 19 IPECA hydrochioric acid 1.0 329 -37.0 IPECA methylohosphoric acid 5.0 906 -55.1 19C IPECA sodium chioride 1.0 SZ2 0 20C IPECA sodium chloride 5.0 2018 0 i h)~ J~ fA.~'

Claims

We claim:

1. A method comprising:
(a) applying to an in vivo surface a biocompatible composition comprising: (1) at least one monomer which forms a polymer in situ at a physiologic pH;
and (2) an effective amount of at least one biocompatible pH modifier effective to modify the pH of an immediate in vivo environment of said polymer to a pH range at which said polymer biodegrades at a different rate than it does at physiologic pH, without said pH modifier significantly affecting the monomer's polymerization in situ; and (b) allowing the monomer composition to polymerize in situ.

2. The method of claim 1, wherein said composition is an adhesive composition, and said surface is maintained in contact with another surface in vivo until the monomer composition polymerizes.

3. The method of claim 2, wherein one of the surfaces is body tissue and the other surface is a prosthetic device.

4. The method of claim 2, wherein both surfaces are body tissue.

5. The method of claim 1, wherein said composition is applied to damaged or exposed tissue.

6. The method of claim 5, wherein said tissue comprises a blood vessel, and said method stems flow of blood from said blood vessel by applying to said blood vessel a hemostatic agent comprising said composition.

7. The method of claim 5, wherein said tissue has been burned or is living tissue exposed in a wound.

8. The method of claim 1, wherein the effective amount of a non-encapsulated, acidic pH modifier is at least 1 % by weight of the composition.

9. The method of claim 1, wherein the pH
modifier is soluble in the monomer.

10. The method of claim 1, wherein the polymer's in vivo biodegradation proceeds faster than it does at physiologic pH.

11. The method of claim 1, wherein the polymer's in vivo biodegradation proceeds slower than it does at physiologic pH.

12. The method of claim 1, wherein the polymer degrades slowly or not at all at a physiologic pH and the pH modifier is a basic compound.

13. The method of claim 1, wherein the polymer comprises at least one member selected from the group consisting of butyl alpha-cyanoacrylate and octyl alpha-cyanoacrylate, and said pH modifier is a basic compound.

14. The method of claim 1, wherein the composition further comprises: (3) at least one biocompatible agent effective to reduce active formaldehyde concentration levels.

15. The method of claim 10, wherein the composition further comprises: (3) at least one biocompatible agent effective to reduce active formaldehyde concentration levels.

16. The method of claim 1, wherein the monomer is an alpha-cyanoacrylate or a 2-methylene malonate.

17. The method of claim 16, wherein the alpha-cyanoacrylate is methyl cyanoacrylate, butyl cyano-acrylate, 2-octyl cyanoacrylate, 1-methoxy-2-propyl cyanoacrylate, 2-butoxyethyl cyanoacrylate, 2-isopropoxy-ethyl cyanoacrylate or 3-methoxybutyl cyanoacrylate.

18. The method of claim 1, wherein the pH
modifier is microencapsulated in a material that has a low inherent moisture content and that undergoes in vivo bioerosion.

19. The method of claim 1, wherein the pH
modifier is microencapsulated in a material and is capable, in vivo, of diffusing through the material.

20. The method of claim 1, wherein the pH
modifier comprises at least one member selected from the group consisting of:

amino acids;
carboxylic acids or salts thereof;
di-acids or salts thereof;
poly acids or salts thereof;
esters that are easily hydrolyzable in vivo;
lactones that are easily hydrolyzable in vivo;
organic carbonates;
enolic compounds;
acidic phenols;
polyphenolic compounds;
aromatic alcohols;
ammonium compounds or salts thereof;
boron-containing compounds;
sulfonic acids or salts thereof;
sulfinic acids or salts thereof;
phosphorus-containing compounds;
acid halides;
chloroformates;
acid gases;
acid anhydrides;
inorganic acids or salts;
chemically protected acids; and polymers having functional groups of at least one of the preceding members.

21. The method of claim 1, wherein the pH
modifier comprises at least one member selected from the group consisting of: glycine; alanine; proline; lysine;
glutaric acid; D-galacturonic acid; succinic acid; lactic acid; glycolic acid; poly(acrylic acid); sodium acetate;
diglycolic anhydride; succinic anhydride; citraconic anhydride; maleic anhydride; lactide; diethyl oxalate;
Meldrum's acid; diethyl carbonate; dipropyl carbonate;
diethyl pyrocarbonate; diallyl pyrocarbonate; di-tert-butyl dicarbonate; ascorbic acid; catechin; ammonium chloride; D-glucosamine hydrochloride; 4-hydroxyephedrine hydrochloride; boric acid; nitric acid; hydrochloric acid;
sulfuric acid; ethanesulfonic acid; p-toluenesulfonic acid; 2-aminoethylphosphoric acid; methylphosphonic acid;
dimethylphosphinic acid; and methyl chloroformate.

22. The method of claim 1, wherein the pH
modifier comprises at least one member selected from the group consisting of:
hydroxides;
alkoxides;
basic carbonates;
nitrogen-containing compounds;
amines;
alkaloids;
hydrides;
organolithium compounds;
Grignard reagents;
carbanions; and chemically protected bases; and polymers having functional groups of at least one of the preceding members.

23. The method of claim 1, wherein the pH
modifier comprises at least one member selected from the group consisting of: sodium hydroxide; potassium hydroxide; sodium methoxide; potassium t-butoxide; sodium carbonate; dibutylamine; tryptamine; sodium hydride;
calcium hydride; butyllithium; and ethylmagnesium bromide.

24. A method of regulating a rate of in vivo biodegradation of a polymer formed in vivo from at least one monomer which forms a polymer at a physiologic pH, comprising:
combining said at least one monomer with an effective amount of at least one biocompatible pH modifier effective to modify a pH of an immediate in situ environment of the polymer to a pH range at which the polymer's biodegradation proceeds at a different rate than it does at physiologic pH;
allowing the polymer to form in vivo; and maintaining the thus-formed polymer in vivo for a time sufficient to effect biodegradation of the polymer.

25. The method of claim 24, wherein the polymer is a 1,1-disubstituted ethylene.

26. The method of claim 24, wherein the polymer is hydrolytically sensitive in vivo at a physiologic pH.

27. The method of claim 24, wherein the polymer biodegrades slowly or not at all at a physiologic pH, and the pH modifier is a basic compound.

28. The method of claim 24, wherein the polymer comprises at least one member selected from the group consisting of butyl alpha-cyanoacrylate and octyl alpha-cyanoacrylate, and said pH modifier is a basic compound.

29. A biocompatible monomer composition, comprising:
a) at least one monomer comprised of a 1,1-disubstituted ethylene, which forms a polymer in vivo at a physiologic pH; and b) an effective amount of a biocompatible pH modifier effective to regulate, after in vivo polymerization of the monomer in situ, the pH of an immediate in vivo environment of the polymer to a pH range at which the polymer biodegrades in vivo at a different rate than it does at physiologic pH, without significantly affecting in situ polymerization of the monomer.

30. The composition of claim 29, wherein the polymer biodegrades in vivo at physiologic pH.

31. The composition of claim 29, wherein the pH
modifier is in a form that is substantially insoluble in the monomer.

32. The composition of claim 29, wherein the pH
modifier is soluble in the monomer.

33. The composition of claim 29, wherein the pH
modifier is microencapsulated in a coating polymer that has a low inherent moisture content and that undergoes in vivo bioerosion.

34. The composition of claim 33, wherein the pH
modifier is capable, in vivo, of diffusing through the coating polymer.

35. The composition of claim 29, wherein the pH
modifier is effective to promote than that occurring at physiologic pH.

36. The composition of claim 29, wherein the pH
modifier is effective to promote a slower in vivo biodegradation of the polymer than that occurring at physiologic pH.

37. The composition of claim 29, wherein said pH modifier is a non-encapsulated acidic pH modifier comprises at least about 1% by weight of the composition.

38. The composition of claim 29, wherein the at least one monomer is an alpha-cyanocrylate or a 2-methylene malonate.

39. The composition of claim 37, wherein the alpha-cyanoacrylate is methyl cyanoacrylate, butyl cyanoacrylate, 2-octyl cyanoacrylate, 1-methoxy-2-propyl cyanoacrylate, 2-butoxyethyl cyanoacrylate, or 2-isopropoxyethyl cyanoacrylate or 3-methoxybutyl cyanoacrylate.

40. The composition of claim 29, further comprising an effective amount of at least one biocompatible agent effective to reduce active formaldehyde concentration levels.

41. The composition of claim 29, wherein the pH
modifier is a chemically protected acid or an acid or anhydrous precursor thereof.

42. The composition of claim 29, wherein the pH
modifier comprises at least one member selected from the group consisting of:
amino acids;
carboxylic acids or salts thereof;
di-acids or salts thereof;
poly acids or salts thereof;
esters that are easily hydrolyzable in vivo;
lactones that are easily hydrolyzable in vivo;
organic carbonates;
enolic compounds;

acidic phenols;
polyphenolic compounds;
aromatic alcohols;
ammonium compounds or salts thereof;
boron-containing compounds;
sulfonic acids or salts thereof;
sulfinic acids or salts thereof;
phosphorus-containing compounds;
acid halides;
chloroformates;
acid gases;
acid anhydrides;
inorganic acids or salts; and polymers having functional groups of at least one of the preceding members.

43. The composition of claim 29, wherein the pH
modifier comprises at least one member selected from the group consisting of: glycine; alanine; proline; lysine;
glutaric acid; D-galacturonic acid; succinic acid; lactic acid; glycolic acid; poly(acrylic acid); sodium acetate;
diglycolic anhydride; succinic anhydride; citraconic anhydride; maleic anhydride; lactide; diethyl oxalate;
Meldrum's acid; diethyl carbonate; dipropyl carbonate;
diethyl pyrocarbonate; diallyl pyrocarbonate; di-tert-butyl dicarbonate; ascorbic acid; catechin; ammonium chloride; D-glucosamine hydrochloride; 4-hydroxyphedrine hydrochloride; boric acid; nitric acid; hydrochloric acid;
sulfuric acid; ethanesulfonic acid; p-toluenesulfonic acid; 2-aminoethylphosphoric acid; methylphosphonic acid;
dimethylphosphinic acid; and methyl chloroformate.

44. The composition of claim 29, wherein the pH
modifier is a chemically protected base or a base or anhydrous precursor thereof.

45. The composition of claim 29, wherein the pH
modifier comprises at least one member selected from the group consisting of:
hydroxides;
alkoxides;

basic carbonates;
nitrogen-containing compounds;
amines;
alkaloids;
hydrides;
organolithium compounds;
Grignard reagents;
carbanions; and polymers having functional groups of at least one of the preceding members.

46. The composition of claim 29, wherein the pH
modifier comprises at least one member selected from the group consisting of: sodium hydroxide; potassium hydroxide; sodium methoxide; potassium t-butoxide; sodium carbonate; dibutylamine; tryptamine; sodium hydride;
calcium hydride; butyllithium; and ethylmagnesium bromide.

47. The composition of claim 29, wherein the polymer biodegrades slowly or not at all at physiologic pH.

48. The composition of claim 47, wherein the polymer comprises at least one member selected from the group consisting of butyl alpha-cyanoacrylate and octyl alpha-cyanoacrylate.

49. The composition of claim 47, further comprising an effective amount of at least one biocompatible agent effective to reduce active formaldehyde concentration levels.

50. A surgical adhesive comprising the composition of claim 29.

51. A surgical sealant comprising the composition of claim 29.

52. A method of joining together two surfaces in vivo, at least one of the surfaces being body tissue, which comprises applying to at least one of the surfaces a composition of claim 29 and maintaining the surfaces in contact until said composition polymerizes in situ.

53. A biocompatible composition, comprising:

(2) a polymer whose in vivo biodegradation produces formaldehyde; and (b) an effective amount of at least one biocompatible pH modifier effective to modify the pH of an immediate environment of the biocompatible composition in situ to a pH range at which the polymer's in situ biodegradation proceeds at a rate different than at physiologic pH.

54. The composition of claim 53, wherein the pH
modifier is an acid or anhydrous precursor thereof or a chemically protected acid.

55. The composition of claim 53, wherein the pH
modifier is a base or anhydrous precursor thereof or a chemically protected base.

56. The composition of claim 53, wherein the polymer is formed in vivo.

57. The composition of claim 53, wherein the polymer is formed ex vivo.

58. The composition of claim 53, wherein the polymer can biodegrade at a physiologic pH and the pH
modifier is an acid or anhydrous precursor thereof or a chemically protected acid.

59. The composition of claim 53, wherein the polymer biodegrades slowly or not at all at physiologic pH
and the pH modifier is a base or anhydrous precursor thereof or a chemically protected base.

60. The composition of claim 53, further comprising at least one biocompatible agent effective to reduce active formaldehyde concentration levels.

61. A delivery system for a therapeutic agent, comprising:
(a) a suitable carrier or matrix comprising the composition of claim 53; and (b) a therapeutic agent deposited on or within the carrier or matrix.

62. A cross-linked monomer surgical implant molded from the composition of claim 53 further comprising at least one difuntional monomeric cross-linking agent.

63. The implant of claim 62, comprising a prosthetic device.

64. The implant of claim 63, comprising a tissue fastener.

65. A method according to claim 1, wherein said at least one biocompatible pH modifier is thoroughly mixed with said at least one monomer.

66. A biocompatible monomer composition according to claim 29, wherein said biocompatible pH modifier is thoroughly mixed with said at least one monomer.