CA1186438A - Polymers of di- (and higher functionality) ketene acetals and polyols - Google Patents

Abstract

ABSTRACT OF DISCLOSURE

This invention concerns ortho ester polymers having repeating mer units represented by the general formulas:

and The polymers are formed by a condensation reaction between ketene acetals having a functionality of two or more and hydroxyl containing compounds having a functionality of two or more.
Unlike most conventional condenastion reactions, the reaction between a ketene acetal andanalcohol proceeds without the evolution of small molecule by-products which must be removed by distillation in order to achieve high molecular weight. Hence, this new process produces high molecular weight poly (ortho esters) in short reaction times, at essentially room temperature and at atmospheric pressure. Furthermore, linear thermoplastic materials are produced when both the ketene acetal and alcohol have functionalities of two;and because no volatile materials are produced,void-free, thermoset materials are produced when either or both the alcohol and ketene acetal have functionalities greater than two and crosslinking occurs.
The polymers are bioerodible and are useful in the fabrication of devices and coatings for delivering beneficial agents.

Description

l ~ 3~

1 ~ SPECIFICATI~

2 ¦ ~Ihe invention disclosure described herein was made ln

3 the course of or under ~ational Institu-tes of Health Contract

4 No. l-~ID-7-2826 with the ~nited States Department of Health, Education and Welfare.
6 This lnvention relates to polymers which are bioerodible 7 ¦ and are suitable as carriers or matrices for drugs and other 8 ¦ beneficial agents used for therapeutic purposes and which, upon 9 1 contact with the environment in which they are used, degrade and 10 ¦release the drug or other biologically active agent. The 11 ¦invention also relates to methods of preparing such polymers, to 1?, ¦compositi.ons of matter comprising the polymer and biologically 13 ¦active agents and to fabricated articles such as implants 14 in which the polymer constitutes the matrix and contains a 16 biologically active material.

26 i 27 ' 29 '1 3U ,j rJ~

6~3~
There axe available drug delivery devices such as those described in U.S. Patent 4,069,307 in which a drug is included in a polymeric matrix from which it diffuses. There are also drug delivery devices in which a drug is contained in a capsule the walls of which are permeable to water and which, upon infusion of water, generate an internal osmotic pressure such as to force the drug through an orifice. Both types are implanted and require subsequent removal.

Another approach to drug delivery devices is typified by Choi and Heller U.S. Patent 4,093,709, which employs a bioerodible polymer in which a drug is incorporated and which undergoes degradation (called bioerosion) to release the drug.
Provided the degradation products are harmless, such an implant has the advantage that it does not require removal.
The bioerodible polymers of that patent are poly (ortho esters) or polycarbonates.

A typical example of such a polymer and its method of synthesis is given in Exa~ple 1 of the Choi and Heller Patent and is a polymer prepared from trans 1,4-cyclohexane dicarbinol and 2,2-diethoxytetrahydrofuran. The polymer has the formula _ _ -O f - CH ~ ~ CH2- _ _ ~ _ n 3~

wherein n is an integer from 10 to 1000. As dessribed in Example 1, of the Choi and Heller Patent this polymer is prepared by heating a mixture of the monomers and polyphosphoric acid, first at 110-115C for 1-1/2 to 2 hours with slow distillation of any liquid formed, then at 0.01 millimeter of mercury while the temperature is slowly increased to 180C. The reaction is allowed to continue at 1~0C for 24 hours.

~ here are several disadvantages to this procedure which are typical of a transesterification reaction and to the polymeric end~products resulting therefrom, among which are the following;

The reaction takes a considerable period of time, in this particular instance in excess of 24 hours. Furthermore, it is necesary to remove by distillation under high vacuum the volatile products formed as a result of condensation. The neces-sity to remove the volatile material precludes formation of nonporous, dense crosslinked products obtained by using alcohols having functionalities greater than two.

A further disadvantage of this procedure is the diffi-culty in achieving very high molecular weights. It is well known that typical polymers prepared by condensation reactions involving a transester fication reaction have molecular weights of about 30,000. Since this is an average molecular weight, it is apparent that the product contains a considerable proportion of polymer of much lower molecular weight. In many instances the presence of low molecular weight polymer chains adversely affects mechanical properties.

_5_ 3~il yet further disadvantage is the fact that a 2 transesterification reaction is an equilibrium reaction which 3 is driven to high polymer molecular weight by removal of a 4 volatile by-product with a consequent shift of equilibrium.
However, it is usually not possible to completely remove 6 the diol by-product and varying amounts of this diol are 7 very often found in the final polymer product.

9 Still another disadvantage is the fact that because of the high reaction temperatures and long reaction times, Il side-reactions can occur and the product is usually not pure 12 because extraneous linkages can be formed.

14 Yet another disadvantage is due to the propensity of diols having fewer than five carbon atoms to :Eorm monomeric 16 spiro structures which then need to be polymerized in a 17 separate step.

28 i 32jl The foregoing disadvantages are typical o~ bio-erodible polymers prepared by condensation of monomers which have been patented heretofore.

It is an object of the present invention to provide improvements upon bioerodible polymers suitable for use as matrices for drugs and other beneficial agents.

More particularly it is an object of the present invention to provide a bioerodible polymer which is useful for such purposes and which can be made by an improved process having few or none of the aforementioned disadvantages.

A particular object is to provide polymers whlch can be made by a process which proceeds rapidly at low temperatures, usu~lly below 40C, without the evolution of any by-products.
Therefore, either linear or dense, cross-linked matrices can be readily produced.

Another particular object is to provide a process of polymerization which is not an equilibrium reaction and whereby molecular weights as high as 200,000 can be routinely achieved.

, . . .

3~ 3~

Another object is to provide polymer structures having no significant ~mounts of unreacted monomers or extraneous linkages.

A further object is to provide a process in which there is no limitation on the number of carbon atoms in the diol whereby polyols having fewer than five carbon atoms may be employed, and such diols do not form monomeric spiro structures.

The above and other objects of the invention will be apparent from the ensuing description and the appended claims.

In accordance with the present invention, a ketene acetal having a functionality of two or more is reacted with a polyol, which term includes alcohols and phenols.

By "functionality" as applied to a ketene acetal is meant the ketene acetal group _ C < or ' > C

,~

3~

Thus a diketene acetal has a functionality of two, a triketene acetal has a functionality of three, etc. Similarly where the term "functionality" is used in connection with a polyol, it refers to the hydroxyl groups.

Such polymers have a number of advantages as matrices or carriers for drugs as explained below.

The monomeric polyols can be represented generally by the formula HOIOH

(OH)y wherein y is zero or a positive integer. These are described below.

The monomeric ketene acetals are of two types as follows:

_ype I Monomers ,~C=C~ ,/C=C/I

wherein the terminal R groups are the same or different, and can be ~ or essentially hydrocarbon groups, primarily alkyl, aryl, cycloaliphatic or aralkyl groups, and may be saturated or unsaturated, and ~ is a quadrivalent grouping or atom.

_g_ 43~

The grouping --O\ / O--/(~ \
;~ ~ o_ ;~
may be a spiro structure or it may be a non-spiro grouping.
A subgroup of Type I monomer is exemplified by Compounds XIII
through XVIII in Table II below.

By "essentially hydrocarbon" is meant that the groups R may contain hetero atoms provided they do not inhibit poly-merization with a polyol to an unacceptable degree, do not inhibit degradation of the polymer to an unacceptable degree and do not give rise to toxic or difficulty metabolizable degradation products. The formulation R--R indicates that the :
two R groups may be joined together to form a cyclic group or may be separate, unconnected groups.

'~

~ ~ 3~

2 Type II Monomers 3 R - O ~ RI' / O R
4 ~ / C - C - R" - C ~ C \

7 Wherein the terminal R groups are the same or different 8 essentially hydrocarbon groups, the R' groups are hydrogen or 9 essentially hydrocarbon groups (defined as above) and R" is a bivalent organic grouping which is also essentially hydrocarbon il (similarly defined).

13 The Type I monomers condense with diols HO - R - OH, 14 R belng an essentially hydrocarbon (similarly defined) bivalent 16 group to produce linear polymers as follows:

20 ¦ -- R-- K

24 wherein ~ is derived fron: the polyol and n ls an intege~
25 1l greater than one and usually l00 to 300 or greater.

27 The Type II monomers polymerize with diols HO - R - OH
~ , (defined as above) to produce linear polymers as follows:

3:~ i li rl- ~

6 ~38 ~ O ~ H - R' ~ H -JC - O - R L

_ and n are similarly defined.

It will be understood that where the polyol and/or the ketene acetal has or have functionalities greater than two, crosslinked polymers will result. As noted below crosslinking may also be achieved by other crosslinking agents.
.~

Certain of the diketene acetals which can be used in ; the present invention are described in the literature, among which are the following:

I Diketene Acetals ~0 - C 1~ H ~-O ~
Cll2 = C/ \ / C/ \ / C _ C~2 O -CH C~2 O

lQ This compound and its synthesis are described in Yasnitskii et al in Zhurnal obshchei Khimii 34, 1940-45 (1964)~

, ~

3~

Type II Ketene Acetals __ RO\ ~R
~ = CH - CH _ C <
R OR

(R = methyl, ethyl, n-butyl, CH3-CH-CH2-) C~3 Scheeren and Aben, Tetrahedron Letters, 12, 1019-1020 (1974) CH3 ~ OCH3 f _ CH - CH CH CH _ ~
~ CH30 OCH3 ; Scheeren et al., J. Royal Netherlands Chemical Society, 94, 1 196-8 (1975). The centrally located double bond may be employed to bring about crosslinking of lihear ketene~diol polymers-Suitable crosslinking agents for this purpose are free radical type crosslinking agents such as benzoyl peroxide.

- ~ 3~ 1 ethods oE preparatloll o~ othcr poly~unctional ketellc 2 acetals which are not described in the literature and are believed 3 to be novel are descri~ed in thc c~amples Lelow. r'~amplc.s of 4 such ketene acetals and general metho~.s of synthesis are as 511follows: ;
6, IC2H5 7 ~ . HO ~ - OH Cll~2 IH
~iii HO ~ OH Br C2H5 9 I , 1' ¦ CH2 - CH \ ~ 1 \CH - CH2 ____~

C~2 =~ = C~2 20i' 222 ll , ~ 23il 24!

' ~ 2~ii 29 I .
: 30 l l 31li .
3Z'~
, ,,, - ~

~ 3~

1 2. HO--CH2 fH2H jC2~5 2 E~O--CH CH--- OH + CH2--CH
4 CH2--CH2 Cl C2H5 6 I \ f l \C H--C H 2 7 Cl O--CH CH--O Cl g ~o CH2 _ c~ f ¦ , 2 12 O--C~ ~CII--O
13 CH2 (~1]2 fH3 ~OC2H5 HO~-OH
16 3. CH2_ C--CH HO--~/LOH

2 Cll~=C--CH ~ CH--C--Cll? ---3 23 ~ C~ O--~ ~CH3 :~6 ~C=C ~ o/C=C\

29 i' --~ ~ 3~

1 I / Il()--C11,~ 112 4. CH2=C - CH + C

C~H2C 3 /O--CH2~CH2 ~ CH2CH3 6 CH2 C -- CH \C ~CH--C= C~2 9 CH2CH3 O--CH2 ~CH2 ~ ~CH2CH3 12 C --C = C C ~C=C--CH3 1~

26 ,1 31 , l~j 3~3 The condensation of a glycol with diethylbromoacetals is described by R. M. Roberts, J. Corse, R. Boschaw, D. Seymour and S. Winstein in J. Am. Chem. Soc. 80, 1247-1254 (1958) and the deyhdrohalogenation by F. Beyerstedt and S. M. McElvain in J. Am Chem. Soc. 58, 529-53 (1936). Isomerization of the double bond has been described by F. J. Corey and J. W. Suggs in J. Org. Chem. 38, 3224 (1973).

There is another, somewhat less satisfactory method which involves an imino ether hydrochloride intermediate.

: C1~33 CH30H CH3 NH~HCl

5. CH3 - CH - CN ) CH3 - CH - C - OCH3 ~ICl CH3 IlH~Hcl HO ~ OH _ CH3 - CH - C - OCH3 HO ~ OH

` .
CH CH
~ ,0 ~ ~ 3 CH3 - CH ¦c ~o_ ~ ~ C--CH - CH3 ~ OCI~3 3\ '^`` ~ C - C
CH3 ~ \ CH3 The reaction of imino ether hydrochlorides with diols has been described by S, M. McElvain and C. C. Aldridge in J. Am. Chem. Soc. 75, 3993-3996 (1975). The dealcoholation has been described by S. M. McElvain and J. T. Venerable in J. Am. Chem. Soc. 72, 1661-1669 (1950).

The procedures thu,s described in the cited literature may be adapted to synthesize the diketene acetals set forth above and below.

The addition of monohydric alcohols to mono ketene acetals has been intensely studied and described in the literature by McElvain and co-workers, In J. Am. Chem. Soc.
commencing in 1936, e.g. Beyerstedt and ~IcElvain, JoA.C.S. 58, 529 (1936), McElvain and Weyna J.A.C.S. 81, 2579 (1979) and in many papers in the same Journal between those dates.
Most of these studies involve the addition of a monohydric alcohol to a mono ketene acetal, Scheexen and Aben, Tetrahedron Letters 12, 1019-1020 (1974) describe the addition of several monohydric alcohols to diketene acetals; see above. No descrip-tion of polymers of polyols and polyfunctional ketene acetals i5 known and such are believed to be broadly novel.

~8~;~3~

Exemplary polyols suitable as reactants include diols, triols and the like that can enter into the polymerization reaction without adversely effecting it or the polymeric product.
The polyols are known to the art ln reported synthesis and they are commercially available. Generally,they include aliphatic diols, triols and the like of the straight or branched chain type. Representative polyols are alkane polyols having a terminal hydroxyl group at the terminus of an alkylene chain of the formula HO- R ~OH
(OH)y wherein R is an alkylene chain of 2 to 12 carbon atoms and y is 0 to 6. Typical diols, named as the glycols, include 1,5 pentylene glycols; 1,6-hexylene ylycol; 1,7-heptylene glycol;
l,9-nonylene glycol; 2,3-dimethyl-1,6- hexylene glycol; 3,6-diethyl-l,9-nonylene glycol; 1,12-dodecamethylene glycol; and the like.

Polyols containing more than 2 reactive hydroxyl radicals suitable for use herein include polyhydroxyl compounds such as 1,2,3,4~5,6-hexanehexol; 1,2,3-propanetriol; 1,2,5-pentanetriol; 1,3,5-pentanetriol; 1,2,4-butanetriol; 2-methyl-1, 2,3-propanetriol; 2-methyl-2(hydroxymethyl) 1,2-propanediol;
1,4,7-heptanetriol; 1,5,10-decanetriol; 1,5,12-dodecanetriol;

and the like.

Other polyols suitable for snythecizing the polymers include polyglycols ccn~ning a repeating glycol monoether moiety--OCH2(CH2)poH wherein p is 1 to 5, and the polyglycols are diglycols, triglycols, tetraglycols, and the like. Typical 1.9-3~

poyglycols include diethylene glycol, triet~ylene glycol, tetraethylene glycol, bis(4 hydroxybutyl) ether, bis(3-hydroxypropyl) ether, and the like.

dditional polyols thht can be used in accordance with the invention are polyhydroxyl compounds having 2 or more reactive hydroxyl groups such as pentaerythritol; dipen~aerythritol;
~ methylglycerol; 1,4-cyclohexane dicarbinol in the cis, trans isomeric configuration or mixtures thereof; 2,2,~,4-tetramethyl cyclobutane 1,3-diol; adonitol; mannitol; 2,5-dipropyl-1,4-phenyldipropanol; 1,3-cyclopropanol; 2-propenyl~1,4-cyclohexane dipropanol; trimethylol propane; sorbitol; penacol; 2-methyl-1,4-cyclohexanedicarbinol; 3-isopropoxy~1,4-cyclohexane dipropanol;
2-ethenyl-1,3-cyclopentane dicarbinol; 1,4-phenyldicarbinol; 2-pro-pyl-1,4-phenyldiethanol; 3-butoxy-1,4-phenyldibutanol; and the like. The preparation of the above polyols is known to the art in Acta Pharm. Jugaslav. Vol 2 pages 134 to 139, 1952; Ann. Vol.
¦ 594, pages 76 to 88, 1955; J. Am. Chem. 5Oc. Vol. 71, pages 3618 to to 3621l 1949; ihid., Vol. 74, page~, 2674 to 2675, 1952; Chem.
Abst., Vol. 42, pages 8774 to 8775, 1948; ibid., Vol. 43 pages 571 to 573 and 6652, 1949; ibid., Vol 44, pages 255~ and 7231, 1950;ibid., Vol. 46, page 9585, 1952; ibid., Vol. 47, page 7575, 1953; ibid., Vol. 48, page 106, 1954, ibid., Vol. 49, pages 6098 to 6099, 1955; Encyclopedia of Chemical ~echnology, Kirk-Othmer, voL 10, pages 638 to 678, 1966, publis~ed by Interscience Publi-shers, New York.
Also, phenol;c polyols (two or more phenolic hydroxyl groups) and mixed phenolic-alcoholic polyols may be employed.
Also mixtures of two or more polyols may be employed. Examples of polyols and of mixed phenolic-alcoholic polyols are as follows:

~ 3~

1 4,4'-isopropylldenediphenol (bisphenol ~);
2 4-hydroxybenzylalcohol;
3 4-hydroxy-3-methoxybenzylalcohol;
4 p-hydroxyphenethylalcohol;
5 1 4,4'-dihydroxydiphenyl,

6 4,4'-dihydroxydiphenylmethane;

7 2,4-dihydroxybenzaldehyde; catechol; resorcinol;

8 hydroquinone;

9 2,2'-dihydroxybenzophenone;
2,4-dihydroxybenzophenone; and 11 3,4-dihydroxymethylcinnamatei also 12 non-phenolic polyols having aromatic linking groups between 13 the hydroxyl groups, e.g. l,4-dihydroxymethylbenzene.
14 Furthermore, tri- (and higher) hydric phenols may be used such as pyrogallol; hydroxyhydroquinone; ?hloruglucinol;
16 1 and propyl gallate.
17 , ]9 11 20 1l The following specific examples will serve further 21 1¦ to illustrate the practice of the invention. Table I
22 !1 immediately following identifies the ketene acetals of the 23 1 Examples (Compounds I through XII) and it also identifies 24 1 ketene acetals of a sub-group of ~ype I which may be used.

26 i 30 !
31 ' 32 i 2i ~ l 1~ 3~3 l 1 TAF~Lr~ I

3 ' Structures of_ Ketene Acetals_of_Type I

S ll Compound I
5 il /O CH2\ ,, CH2 ~
7 ¦I CH2 C ~ , C , C----CH 2 8 1¦ ~0 CH2/ \CH O~
9 ~I Compound 0~ ~0/
3 l 15 ,, Compound I I T
16 Ij ~ CIH2 fH2 ~~ .
17 CH C ~ l l C~ -CH
18 ¦ ~ O CH ~ CH -- O
19 1 Compound IV `~ CH -CH
20 CH3\\ /~ f ~ / \ " C~3 2111 ~C=-C~ /C----C'~
22 il CH3 ~ ~ " CH3 23 l 24 ,I Compound v 25 il CH2CH3 /o_ CEi2\ /CH ~ - o\ fH2CH3 25 1 CH3----C==C\ / ~ /C ------C ~ - CH3 '' 7 ll O CEI 2 CH 2 28 lli 29 l¦ Compound vI
30 ¦ CH3~ /o CH2\ / 2 \ ~CH3 31 1I jC~ C~ ~C~ ~ C=- C ~
32 !I CH3 \ O--CH / 2 \CH3 Il Il ... ..

3~ ~

~ Structures of Ketene Acetals of Type II
I
2 ~ :

4¦Compound VII
51~ CH 3f loCH 3 6ll C CH CH - 7 7 !I CH 30 OCH 3 ~ I
9 ¦Compound VIII

10 I

11 1 O-f f-O

12 C~ CH - CH--- C

15¦ Compound IX

17 > C ~ C <
~8jl CH30 OCH3 19 ~
20 l 21¦¦Compound X

23Ç ¦ > C CH ~ CH~ C \

26 11 , 27 ¦I Compounds XI and XII and methods of preparation are as ~`31~follows:

301,!

I!
2 ~`

~ 3~

2 Compound XI
3 ~ OCH3 H ~ / O
4 f f f CH - fH2 S ¦ ClOCH3 Cl O O Cl 6 C~1 7 CH2Cl 8 1 K tert. butoxide/
; 9 1 tert. butanol lV ~O--C
Il CH2.--C O
\O - C/
: 13 ~ C1~2 :~ 15 Compound XII
: 16 OH

. 17 /,OCH3 HO - ~ - OH
~: f~2 - CH HO - ~ - OH
19 Cl "OCH3 oll 23 l CH CH2 Cl C
24 ¦ ~ ~ tert. butoxide 1 ¦
26 1 /~ ' \ ' '' ~ \~
27 1 / ~ \ tert. butanol ~ 1 1 \
28 1 O O O O o O O O
29 ! CHl Cll C C

C~l2 cl2 1112 Cl-~

i 2'~

, L3~

Example 1 10.00 grams (0.0543 moles) of Compound I and 6.40 grams (0.0543 moles) of 1,6-hexanediol were weighed into a 200 ml 3-necked, paddle stirred flask under rigorously anhydrous condi-tions. The anhydrousconditions were maintained while 50 ml of dried tetrahydrofuran was added to the flask and the stirrer activated. After a very brief induction period, the reaction mixture spontaneously warmed up to 43C and then gradually return-ed to room temperature. After stirring at room temperature for about one hour the high molecular weight poly ~ortho ester) was isolated by either precipitation into n-hexane which contained a small amount of triethylamine followed by filtration of the ~hite solid, or by evaporation of the tretrahydrofuran in a Teflon coated pan placed in a vacuum chamber.

The polymer had the following structure 2 \ f H2 \ / CH3 C\ /C~
--O O - C~I2 CH2 - O O - (CH2) 1 6 ¦

The infrared spectrum is shown in Figure 1 and the C13 NMR
spectrum in Figure 2. The weight average molecular weight obtain-ed by light scattering was 166,000 and the poly-dispersity obtain-ed from gel permeation chromatography 1.52O The degree of polymerization, n, was 335O

-2S.

,~, 3~3 1 ~ ~5 3 Following the procecll~re of ExamDle 1, hut replacinq 4 1,6-hexanediol with: trans-1,4-cyclohexane dicarhinol; 1,2-5 ¦ propanediol; ethylene glycol; 2-methyl - ],3-propanediol, the 7 ~ following polymers àre formed:

9 ~ ~ C C C
10 ~ Lo O--CH2 CH2--_o --CH2 ~ ( ~ -CH

12 ~C~O--CH2f H2 .~ 3 I H 3 ~ 2 CH2 0 - CH2 - CH

18 ~ ¦--C~ O--CH2 CH2-- ~ CH3 1 9 1 --~--CH2CH2-- O--(CE~2 ) 24 t--CH2 CH2-- `o--CH2-- I H--CH2J

2G 'l n ?9 ` I
, . . .

3~

-Example 6 Using the same conditions as in Example 1, 15.00 grams (0.0781 moles~ of compound II and 9.22 grams (0.0781 moles) of 1,6-hexaned~ol are dissolved in 90 ml of tetrahydrofuran and 3 ml of a solution containing 1 x 10 6 moles of iodine per ml of pyridine are added. There is an immediate temperature rise to 52C after which it gradually returns to room temperature.
After stirring at room temperature for about one hour, the polymer is isolated as described in Example 1, and has the follow-ing structure where n is 10 to 1000.

O~C\o-~ /\c\ ~ ) ~

n Example 7 Using the same condition as in Example 1, 42.00 grams (0.1567 moles) of Compound V and 14.10 grams (0.1567 moles) of 1,4-butanediol are dissolved in 200 ml of 1,2-dimethoxyethane and 1 ml of solution containing 1 x 10 4 mole of p-toluenesulfunic acid monohydrate per ml of tetrahydrofuran is added~ After the slight temperature rise subsides,the mixture is stirred a~ room temperature for about one hour and the polymer i5 isolated as described in Example 1.
The polymer has the following stucture where M~7 is 196,900 and the M~7/M~ is 1.48.
The pol~mer has the following structure.

" ~

31~

/ - CH2 \ /CH2 - ~ CH - CH2 - Cll3 ¦ 2 C~2 o O - (CH2)4 ~ n Examp-le 8 ~':
Repeating the procedure of Example 7, but replacing Compound V and 1,4-butanediol with 40.00 grams ~0.1667 molel of Compound VI and 19.67 grams (C.1667 mole~ of 1,6-hexanediol, thefollowing polymer is obtained.

~ ~ \ / 2~ / 2 ; ~ O / ~ O - CH2 C~2 - O (CH2)6 1 _ n ;

Example 9 Repeating the procedure of Example 6, but replacing Compound II and 1,6-hexanediolwith 12.00 grams (0.0652 moles) of Compound I and 7.43 grams (0.0652 moles) of trans-1,4-cyclohexanediol, the followiny polymer is obtained:

~.

~ ~ C~ \C C
to O_ CH2 \ CH2-- 0/ ~0--0 Example 10 Repeating the procedure of Example 6, but replacing Compound II and 1,6-hexanediol with 35~00 grams Co.1768 moles) of Compound III and 25.11 grams ~0.1763 moles) of trans-1.4-cyclohexanedicarbinol, the following polymer is obtained.

C ~ ~
t - CH - CH2 - CH2 - CH _ O O ~ CH2 - ~ - CH21 n Example 11 Repeating the procedure of Example 6, but replacing Compound II and 1,6-hexanediol with 2S.00 grams (0.1437 moles) of Compound VII and 20.41 grams ~0.1437 moles) of trans-1,4-cyclohexanedicarbinol, the following polymer is obtained:
r I CH2 C~2 1 0 C~12 c ~ ~ c 2 OCH3 OCH3 n i ¦ Example 12 Repeating the procedure of Example 6, but replacing Compound II and 1,6-hexanediol with 30.00 grams (0.0673 moles) of Compound VIII and 6.0Ç grams (0.0673 moles) of 1,4~butanediol, the following polymer i5 obtained:

. - ~ 'I O -. -O - C C3~ ~ CH2 - C - o - (CH2)4-n Example 13 Repeating the procedure of Example 6, but replacing Compound II with 28.00 grams (0.1228 moles) of Compound IX and using 14.49 grams ~0.1228 moles) of 1,6-hexanediol, the following polymer is obtained:

~: O--C--O--C--O--( C H 2 ) 6~

CH30 C~3 n Example 14 ,, ; Repeating the procedure of Example 7, but replacing Compound V and 1,4-butanediol with 30.00 grams (0.1220 moles~ of Compound X and 9.27 grams (0.1220 moles) of 1,2~propanediol, the following polymer is obtained:

~, 6~31~

2 L\ CEI2 ~ C~2 - C -- O-- CH - CH

5 11 ~ O ~ O O ~

6 ~_ n 8 Example 15 Repe~ting th~ ~roced~lro ~f ~xamplo 1 b~lt oml~L~ying Il a mixture (0.02715 moles each) of 1,6-hexanediol and trans-1,4-

13 cyclohexane dicarbinol, the following polymer is obtained:

14 ~ / \ / \ __ / \

16 ~ O - CH2 C~l2 ~ C~

18 ~ C~ / O CH2 /~C 2 ~ 3 21 - CH2 - CH `CH O (CH2)6 ¦--22 1 The two diol residues are randomly located in the chain and 24 are shown as alternating merely for convenience.

226 ~xample 16 27 1 Repeating the procedure of Example 6, but replacing 28 il Compound I and 1,6-hexanediol with a mi~ture of 7 00 grams 29 l (0.0380 rnoles) of Compound I and 7.30 grams (0.0380 moles) of 3~il Compound II and 4.71 grams (0.0760 moles) of ethylene 31 l glycol, the folloiling polymer is obtained:
32 ~i 364~

2~¦ ~ 3 / C 2, f~ 2 ~ / 3 3~ ~ O / O - CH2 CH2 ~ (CH2)2 -61 ~c/-O-\c/cf3 ~ ~

7 ISimilarly the groups derived from the t~70 ~i~etene aceta]s are 8 Irandomly located.

~ ~c~m~ 17 Repeating the procedure of ~xamp]c 6,~ t t-`pl.~Cil~y 11 ~ompound II and 1,6-he.Yanecliol with 25.00 grams (~.L35~ molecj) 12 of Compound I and 30.g8 grams (0.1359 moles) of bisphe~ol~

13 the follo~7ing polymer is o~tained.

14 i 1$ ~ C C C Cll l6 I - ~ o / \ O - Clf2/ \ Clf~ - O/ ~ o~

~n ~I T:~ample 18 21l The procedure or E~ample 7 is repeated exce?t that 22 Ino solvent is used and instead the reaction mi.~ture ii he,?.~ed 23¦~to 7noC in order to ac~ieve a homogeneous solution. Compound V
24¦1and 1,4-hutanediol used in E~ample 7 are replaced 7ith 3:3.n6 25~1grams (0.1333 moles) of ~omPound IV ancl a mixture or 9 f~rj ~Jram 26ll~(0.1000 moles~ grams 1,4-butanediol ar)d 5.39 grams (~ ~3333 mo]e~) , 27,iof 1,2,6-he~anetriol. The follo~7iny crosslinke-:l polv~l,er ;-j !
28l¦o~,t;~ined:

30ill 3l i~864;1~

2 C ~ CH3 C ~ / CH3 3 C ~ C
5 _ O O \ ~ O O - CH2 fH (CH2) 8 ~ \ fH ~

C ~""`1 c 11 O / \ O ~ ~ ~ O / \ O (CH2)4 - _ 2 n 14 As in the case of Examples lS and 16, -the residues of the diol and the triol are randomly located. The joint use of 16 a diol and a triol enables one to control the density of 17 crosslinking.

Example 19 21 ¦ The procedure of Example 6lis repeated except that 22 ¦ no solvent is used and instead the reaction mixture is heated 23 ~ to 65C in order to achieve a homogeneous solution. Compound II
~4 ¦ and 1,6-hexanediol used in Example 6 are replaced with 25 ~ 25.00 grams (0.1263 moles) of Compound III and 16.92 grams 26 ; (0.1263 moles) of trimethylolpropane. The following cross-linked 27 1 polymer is obtained:

3o 1!

l 33 ~L386~38 2 ~ I \ C / CH2 - \ / 3 CH3 4 ~ T (CH2)2 0~ CH --- C ~ CH -6 ~ L

8 / \ CH2 - \ CH3 CH3 I O \ ( CH 2 ) / O--CH 2 1 - CH 2 -~

12 ~ _ In In Examples 18 and 19 the pendant valence bonds indicate 16 crosslinking to similar chains.

23 Ij ~7 1 3'~

li~6~8 1 r.xample 20 3 The procedure of Example 6 is repeated except that 4 no solvent is used and instead the mixture is heated to 60~C
S in order to achieve a homogeneous solution. Compound II
6 and 1,6-hexanediol are replaced with 10.00 grams (0.0794 moles) 7 of Compound XI and 7.38 grams (0.1191 moles) of ethylene 8 glycol. The following polymer is obtained:

I O ~o C--O--CH 2--CH 2 ' 12 _ -CH2 - CH2-- O ~ C \ ~ O

6 l CH o - C - O - CH2 - CH

17 Example 21 19 The procedure of Example 6 is repeated except that ZO no solvent is used and instc~d thc mixture i~ hc~tcd to asoc 21 ¦ ln order to achieve homogeneous solution. Compound II and 22 ~ 1,6-hexanediol are replaced with 15.00 grams (0.0490 moles) 23 1 of Compound XII and 6.62 grams (0.0731 moles) or 1,4-butanediol.
24 ¦ The following polymer is obtained:

~ j O (C~12) 4 - --~ \3 / o~

!
"

1~ '138 1 The follo~ing example is illustrative of t~e usr of the r~o]Ymers ? of this invention as carriers or matrices ~or a drug.

4 ~xample 22 6 ~ ~elivery devices ~ere prepared hy putting 7.2 grams 7 ¦ of the polymer of Example 1 on a Teflon coated ~an heated ~ ¦ to a surface temperature of about 150~ to provide a melt con-9 ¦ sistency permitting mixing to produce a thorou~h d;snersion o~
10 ¦ 0.8 grams of micronized ~la2C03 and 2.0 grams of micronized ll I norethindrone into the ~lymer melt. ~heets o~ the polymer 12 ¦mixture 20 mil and 40 mil in thickness 3" x 3" s~uare were 13 ¦pressed at 135C (275F), and 1~,000 psi bet~leen sheets of 14 ¦ Teflon covered foil using the appropriate thic]cness mold

15 ¦ spacers. 1/4" discs were punched from these sheets. These

16 ¦ discs are suitable as implants.

17 I ,

18 ~lternativeLy, the drllg may be incorporat,ecl in the l9 mixture of monomers before polymerization. In the case of crosslinked polymers such as those of ~xamples 18 to 21 t~is 21 ~ill he done because the polymers are infusible and insoluble 22 in solvents.
23 ~he same procedure rnay be employed ~!ith any of the 24 polymers of the present invention such as those of Fxample 2 25 l~ to 21.
26 ll 27 'I Other drugs may be similarlv incorporated in the 7,8 polymers of the invention. ~mong others these drugs or 29 ~ enc:ficial agents rnay inclu~e any Or those merltiolle~l in 30 'IChoi and lleller ~1. .S. Patent 4,093,209 column 2~, line 45 to 3l Icolumn 30, line 37; also insecticides and other ~ioloqically 32~1active agents.
, V,~
ll . . .

3~

l l~xarnpl~s 18 ~nd 19 illu~tratc t~lC usc oE p~lyol-J
2 having a functionality greater than two and Examples 20 and 3 21 illustrate the use of ketene acetals having a functionality 4 greater than two. As stated above, where crosslinking is S desired, it is preferred to use tri- and higher unctionality 6 polyols because of their greater availability. Mixtures of 7 polyols of different functionality, e.g. 2 and 3 and/or 8 mixtures of ketene acetals of differen-t functionality, e.g 9 2 and 3 may be used. By using, for example, a mixture of diol and triol the density oE crosslinking can he controlled hy the 12 ratio of diol to triol.

l6 l7 2S ,j 3l' l ~i ,_ , . I

6~;1B

1 1 As noted abo~e, a sub-c3roup of rype I polym~r.. ,~re 3 ~ derived from ketene acetals of the formula:

_ ¦ ~ ~C=C C=C~

8 That is, the grouping ~ may contain no single radical as in 9 Compound I to which all four of the interior acetal o.Yygen atoms are attached. EYamples of such Type I ketene acetals and ll resulting polymers are as follows:

Compound XIII

17 ,1 / OCH3 C~1301 18 1 CH --C C ~-C112

19 ¦ \ O --CH -- CH ---O /

22l l Compound XIV

~5 11 \0~ CH 2--26 Ij 27 ,1 Compound XV

~ C - < / \C = C /
31 1 / O - CH2 ~ CH2 - O CH3 1 3~3 ., ~

` 1~8~,~3~

2 Compound XVI

'~ ~ ~C=C~ ~C=C~

8 Compound XVII

10 ¦ ~C= C/ ~C--C~

13 Compound XVIII

6 1H2-- C ~ / O - CH2 - ~ / CH2 -1H2 17 l CH2 ~12 CH2 CH ---CH

The corresponding polymers are as follows, in 2] 11~ which R represents the polyol resldue:

23 ¦ Ketene Acetal Polymer 24 OiC~I3 OCH3 XIII_ -- O - f_ o _ CH2_ CH2 - o f o_ R- _ ~
26 'I CH3 CH3 n 30 i r - cH2 o~ - -1 3~ / I ~f \O - C112 ~3 n etene ~cetal Po]y1n~r fC~13 fC113 -3 XV _-- O--f _o_ CH2_ CH2_ o_ f-- o_Rt 4 CH3 CH3 / `~

6 n 8 ~ /O--CH 2 ~
9 XVI --~ O ~ f, ,f--o--R--_ CH3 ` CH3 CH3 C~13 ]2 _ _ n XVII ~ O_- C~ O--CH2--CH2~ O~ C--O-- R--_ 16 /CH\ /CH\
17 ` f 2 2 18 CH 2--CH2 CH2--C~2 19 ¦ _ n

20 1 _

21 ~ O - CH2 - 0 .6 XVIII If \o CH o /¦ t 27 CH2 1H2 CH2 C~l2 28 _ _ n 29 ,It will be understood that crosslinked polymers 30 l~ of CompoundsvIII through XVII may be produced by using 3~ l tri- and higher functionality polyols, and/or by using 32 I ketene acetals of tri- or higher functionality.
~(,) I

I ¦ ~mony th~ advan~acJes o~ my novel ~olym~r-~ ar~
following: Being prepared by a reaction between a ketene 3 acetal and polyol, they do not require removal hy heat and distillation of small molecules. Also, -the reaction proceeds to a high degree of polymerization at low temperature.
6 Therefore, a drug, even one that is sensitive to elevated 7 temperatures, can be incorporated in the mixture of monomers and will appear in the polymer without degradation. This is ~ especially advantageous in the case of crosslinked polymers.
These are infusible and insoluble, and therefore are not ll susceptible to incorporation o~ a drug after t~ polymeriza~ion 12 process is complete, but this disadvantage is overcome by 13 adding the drug to the mixture of monomers and carrying out 14 the reaction, if need be, in a mold which molds the polymer with the drug incorporated to the desired shape and size as 16 it is formed. Also, the polymer structure is pure and the 17 finished product does not contain unreacted monomer.
1~
19 It will be apparcnt from ~he Spc~iric cx~m~ h~
the reactions of ketene acetals with polyols are facile.
21 1 They proceed at room temperature and heing exothermic~ they

22 are allowed to rise in temperature as the reaction proceeds

23 1 to completion. Suitable solvents are polar aprotic solvents,

24 ¦ e.g. glyme, diglyme, dimethylacetamide, dimethyl

25 ¦ sulfoxide, dimethylformamide, acetonitrile, pyrrolidone,

26 1 and methy~butyl ether. When crosslinking occurs, solvents

27 ! are not used. Catalysts are not required but when used,

28 ~~ suitable catalysts are iodine in pyridine,

29 p-toluensulfonic acid; also Lewis acids such as boron

30 il trich]oride, boron trifluoride, boron -trichloride etherate,

31 l boron trirluoride etherate, stannic oxychloride, phosphorous 3~ ¦ ox.ychloride,zinc chloride, phosphorous pentachloride, , *l 1 antimony pentafluoride, stannous octoate, stannic chloride, 2 diethylzinc, and mixtures thereof; also, Bronsted cat~lysts 3 ¦ in addition to p-toluene sulfonic acid such as poly-phosphoric 4 ¦ acid, crosslinked polystyrene sulfonic acid, acidic silica gel, and mixtures thereof. The amount of catalyst used may 6 be about one part catalyst to about 500 parts of the ketene 7 acetal monomer. Smaller or larger amounts can also be ~ used, such as 0.005~ to about 2.0% based on the weight of the 9 starting monomer.

Il Referring to the Type I and Type II polymers, there 12 are various organic groups such as those in the R _ O - groups, 13 those forming parts of pendant groups such as R~ R

17 1 those forming linking groups or parts of linkiny groups such 18 1 as ~ and ~0 1 21 1¦ --CH--R '-- ~H ---22 li and the polyol residue R. Referring to these groups collectively 23 1 as "R groups", the following observations are in order: In 24 1 some instances, the "R groups" may be hydrogen. Where they 25 l¦ are not hydrogen, they are essentially hydrocarbon groups as 26 ' defined above; iOe., they do not exclude groups containing 27 hetero atoms provided the presence of the hetero atom or atoms 28 Il is not incompatible with the intended use and with bioerodibility, 2~ l and do not give rise to toxic or non-metabolizable degradation 30 I products. ~.n instance of such permissible groups containing 31 hetero atoms is the case where R ~the polyol residue) is

32 l derived from a polymer of an alkylene oxide (e.g. ethylene oxide, 11191`~13~3 ~

I propylene oxide, butylene oxide, tetrahydrofuran ~nd the like) 2 in which case R has the formula 6 t ( 2)~ C ~
7 in which X is 1, 2 or 3, R is hydrogen or alkyl, and n is 8 an integer equal to one or more. Another case is that of 9 hydroxy terminated polyesters represented by the general for~ula O ~ ~--C--o 3~ R ' ~0--C--R~}, O--11 16 ¦~ in which case R is represented by the formula 19 -~ O ~ C-- ~ R '--- r--C--llt 20 ~ b 22 1l wherein a and b are positive integers. Examples of such 23 ¦j polyesters are the glycolides and lactides.

25 ,I The "R g-oups" as defined above may be of low 26 ! molecular weight, e.g. methyl, ethyl, CH2 - CH2 - , etc., 27 jl or they may be of high or intermediate molecular weight.
28 1 Practical considerations will influence the choice of 29 , molecular weight. For example, "R groups" of high molecular weight which are pendant groups, or ~"hich form linking groups 31 1 or pa~ts of linking groups, or are parts of R - O - groups, 32 or which are deriv~d from high molecular weight polyols, l 4v I

3~3 may ~e available onl~ ~rom expens~ve start~ng materials, or may impart less desirable characteristics to t~e polymer.

; ~/

Claims (30)

WE CLAIM:

1. Polymers of polyols and ketene acetals having a functionality of two or more.

2. Polymers according to Claim 1 wherein the polyol and/or the ketene acetal has a functionality greater than two and the resulting polymer is crosslinked.

3. Polymers according to Claim 2 wherein at least some of the polyol reactant has a functionality greater than two.

4. Polymers according to Claim 3 wherein the polyol reactant is a mixture of a diol and a polyol having a functionality greater than two.

5. Polymers according to Claim 2 wherein the ketene acetal has a functionality greater than two.

6. Linear polymers according to Claim 1 wherein both the polyol and the ketene acetal have a functionality of two.

7. Polymers having the repeating mer unit:

wherein n is an integer substantially greater than 10; wherein R1 and R2 are hydrogen or the same or different essentially hydrocarbon groups and may be separate groups or may form parts of a cyclic group; ? is a quadrivalent organic grouping; R3 and R4 are hydrogen or the same or different essentially hydrocarbon groups and may be separate groups or may form parts of a cyclic group; R5 is an essentially hydrocarbon group which is the residue of a polyol R5(OH)a wherein a is an integer equal to two or more, such polyol being a single molecular species or a mixture of molecular species; and wherein such linear chain may he crosslinked with other similar chains.

8. Polymers according to Claim 7 wherein ? is a single quadrivalent radical attached to all of the interior acetal-forming oxygen atoms.

9. Polymers according to Claim 8 wherein ? is a spiro structure.

10. Polymers according to Claim 8 wherein ? is an open chain aliphatic group.

11. Polymers according to Claim 8 wherein ?
contains a carbocyclic group.

12. Polymers according to claim 7 wherein R5 in at least some of the mer units is alkylene or contains a carbocyclic group.

13. Polymers according to Claim 7 wherein R5 in at least some of the mer units is derived from a polyol of greater functionality than three and the polymers are crosslinked.

14. Polymers according to Claim 13 wherein some of the R5's are derived from diols and others are derived from polyols of greater functionality.

15. Polymers having the repeating mer unit wherein n is an integer substantially greater than 10; wherein R1, R2, R3 and R4 are the same or different essentially hydrocarbon groups, R1 and R2 being separate groups or parts of a cyclic group and R3 and R4 being separate groups or parts of a cyclic group; R5 is an essentially hydrocarbon group which is the residue of a polyol R5(CH)a wherein a is an integer equal to two or more, such polyol being a single molecular species or a mixture of molecular species; R6 is a valence bond or an essentially hydrocarbon group; R7 and R8 are hydrogen or essentially hydrocarbon groups which may be separate groups or may form parts of a cyclic group;
and wherein such linear chains may be crosslinked to similar chains.

16. Polymers according to Claim 15 wherein the group is selected from the class consisting of alkylene and groups containing a carbocylic ring.

17, Polymers according to Claim 15 wherein R5 in at least some of the mer units is alkylene or contains a carbocyclic group.

18. Polymers according to Claim 15 wherein R5 in at least some of the mer units is derived from a polyol having a greater functionality than three and the polymers are crosslinked.

19. Polymers according to Claim 18 wherein some of the R5's are derived from diols and others are derived from polyols of greater functionality.

20. A method of producing poly (ortho esters) which comprises polymerizing a mixture of a polyol and a ketene acetal having a functionality greater than one.

21. The method of Claim 20 wherein the polymerization is carried out at a temperature not greatly in excess of the temperature to which the reaction mixture rises by reason of the heat of reaction.

22. The method of Claim 20 wherein the reaction is carried out in the substantial absence of a solvent.

23. The method of Claim 20 wherein a beneficial agent is incorporated in the mixture of monomers before they are polymerized.

24. The method of Claim 23 wherein at least one of the monomers has a functionality greater than two and the resulting polymer is crosslinked.

25. Polymers of Claim 1 in admixture withbiologically active agents.

26. Polymers of Claim 7 in admixture withbiologically active agents.

27. Polymers of Claim 15 in admixture with biologically active agents.

28. Polymers of Claim 25 in shaped form fitted for end use.

29. Polymers of Claim 26 in shaped form fitted for end use.

30. Polymers of Claim 27 in shaped form fitted for end use.