Initiation of Polymerization - ACS Publications - American Chemical

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Downloaded by UNIV OF MICHIGAN ANN ARBOR on February 18, 2015 | http://pubs.acs.org Publication Date: April 19, 1983 | doi: 10.1021/bk-1983-0212.ch027

Synthesis of Biodegradable Polymers for Biomedical Utilization J. H E L L E R SRI International, Polymer Sciences Department, Menlo Park, CA 94025

Polymer bioerosion is defined as the conversion of an initially water-insoluble material to a water-soluble material and is discussed in terms of three distinct mechanisms denoted as Type I, II, or III. Solubilization by Type I erosion involves hydrolytic bond cleavage occurring in water-soluble polymers that have been insolubilized by covalent crosslinks. Solubilization by Type II erosion involves reactions of pendant groups, and solubilization by Type III erosion involves backbone cleavage. Solubilization by simple dissolution is not considered. Each type of bioerosion is illustrated with specific examples that include gelatin-based surgical aids, enteric-type coatings, erodible sutures, surgical adhesives, oviduct blocking agents, and controlled drug release. Polymer bioerosion can be defined as the conversion of an initially water-insoluble material to a water-soluble material and does not necessarily signify a major chemical degradation. In this review we do not consider a simple dissolution process, and we classify the various bioerosion mechanisms into the the three distinct types shown in Figure 1 . In general terms, Type I erosion encompasses water-soluble polymers that have been insolubilized by hydrolytically unstable crosslinks. Type II erosion includes polymers that are initially water-insoluble and are solubilized by hydrolysis, ionization, or protonation of a pendant group. Type III erosion includes hydrophobic polymers that are converted to small watersoluble molecules by backbone cleavage. Clearly, these three types represent extreme cases, and actual erosion can be a combination of these types. Thus, it is 0097-6156/83/0212-0373$06.00/0 © 1983 American Chemical Society In Initiation of Polymerization; Bailey, F., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1983.

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p o s s i b l e to develop a combination of Type I and Type I I I e r o s i o n i n which i n i t i a l h y d r o l y s i s i n v o l v e s c r o s s l i n k cleavage with subsequent backbone cleavage o f the high molecular weight waters o l u b l e polymer. S i m i l a r l y , a combination o f Type I I and Type I I I e r o s i o n can be developed i n which i n i t i a l s o l u b i l i z a t i o n i s by i o n i z a t i o n , protonation, or h y d r o l y s i s , followed by backbone cleavage of the s o l u b l e polymer.


Type I E r o s i o n The most widely used polymer system that bioerodes by Type I erosion or by a combination o f Type I and Type I I I e r o s i o n i s g e l a t i n that has been i n s o l u b i l i z e d by heat treatment, aldehyde treatment, or chromic a c i d treatment. Aside from the photographic i n d u s t r y , i n s o l u b i l i z e d g e l a t i n a l s o f i n d s a p p l i c a t i o n as s u r g i c a l a i d s such as dusting powder for s u r g i c a l gloves or as sponges or f i l m s . Dusting powders are prepared by heating g e l a t i n at 142°C f o r 25 hours, and i n s o l u b i l i z a t i o n i s b e l i e v e d to occur by formation of i n t e r c h a i n amide l i n k s (2). S u r g i c a l sponges or f i l m s are u s e f u l i n a r r e s t i n g s u r g i c a l hemorrhage and are prepared by t r e a t i n g s t e r i l e g e l a t i n with formaldehyde. Although d e t a i l s are p o o r l y understood, i n s o l u b i l i z a t i o n occurs by r e a c t i o n o f g e l a t i n amino groups with formaldehyde followed by r e a c t i o n of the hydroxymethylamino groups Q , j^, Formaldehyde c r o s s l i n k e d g e l a t i n has a l s o been used as a matrix i n c o n t r o l l e d drug r e l e a s e a p p l i c a t i o n s . However, because i n s o l u b i l i z a t i o n of water-soluble polymers by c r o s s l i n k i n g produces hydrogels that are completely permeated by water, they are c l e a r l y unable to immobilize small molecules having a p p r e c i a b l e water s o l u b i l i t y . Consequently, u s e f u l n e s s of these m a t e r i a l s i s l i m i t e d to molecules having extremely low water s o l u b i l i t y or to macromolecules that can be p h y s i c a l l y entangled i n the hydrogel so that they can not d i f f u s e out of the matrix even though they are f r e e l y s o l u b l e i n water. An example of the f i r s t a p p l i c a t i o n i s shown i n F i g u r e 2, which shows r e l e a s e of the h i g h l y w a t e r - i n s o l u b l e hydrocortisone acetate from a g e l a t i n matrix c r o s s l i n k e d with formaldehyde (JO. As i n d i c a t e d by the f i r s t - o r d e r dependence, drug i s released by a simple d i f f u s i o n a l process and the c r o s s l i n k e d g e l a t i n simply provides cohesiveness f o r the drug p a r t i c l e s . Even though r e l e a s e k i n e t i c s are not constant, u s e f u l r e l e a s e over many days i s achieved. The f i r s t - o r d e r drug r e l e a s e a l s o i n d i c a t e s that matrix erosion makes l i t t l e or no c o n t r i b u t i o n to drug r e l e a s e , and, because e r o s i o n of a formaldehyde-crosslinked g e l a t i n i s slow, drug d e p l e t i o n can occur before s i g n i f i c a n t matrix e r o s i o n i s noted. Such a device may be u s e f u l i n a p p l i c a t i o n s where z e r o order k i n e t i c s are not important and removal of the expended device i s not convenient or d e s i r a b l e .

In Initiation of Polymerization; Bailey, F., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1983.

27.

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Synthesis of Biodegradable

375

Polymers

TYPE I

"X

®

φ

I


TYPE I I —I—Γ-

Α

—ι—Γ

Β

Α

C

A

represents a hydrophobic substituent and

Β -> C

represents hydrolysis, ionization or protonation

TYPE I I I

Figure 1. Schematic representation of bioerosion mechanisms. (Reprinted with permission from Réf. 1. Copyright 1980.)

40i

30h

2 20h σ

lOh

-M—b 24

48

72 Time (doys)

96

120

144

Figure 2. Release of hydrocortisone acetate from a cross-linked gelatin matrix. (Reprinted with permission from Réf. 1. Copyright 1980.)


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Release o f macromolecules from b i o e r o d i b l e hydrogels has received r e l a t i v e l y l i t t l e a t t e n t i o n , and most past e f f o r t s have been devoted t o the immobilization o f macromolecules i n hydrogels by p h y s i c a l entanglement (6). However, because o f the growing r e c o g n i t i o n o f the therapeutic p o t e n t i a l o f macromolecules, t h e i r entanglement i n a hydrogel matrix and c o n t r o l l e d r e l e a s e by matrix e r o s i o n i s becoming recognized as an important methodology (7, S).


Type I I E r o s i o n Because t h i s type s o l u b i l i z a t i o n i n v o l v e s the r e a c t i o n o f a pendant group, b i o e r o s i o n proceeds without s i g n i f i c a n t changes i n molecular weight. Therefore, unless the polymer backbone a l s o undergoes b i o e r o s i o n , polymers i n t h i s category are only u s e f u l i n t o p i c a l a p p l i c a t i o n s where e l i m i n a t i o n o f high molecular weight, water-soluble macromolecules proceeds with no difficulty. An important c l a s s o f polymers that undergo Type I I e r o s i o n are polymers c o n t a i n i n g c a r b o x y l i c a c i d f u n c t i o n s . These s o l u b i l i z e by i o n i z a t i o n and consequently are i n s o l u b l e a t low pH and s o l u b l e a t high pH. A major a p p l i c a t i o n f o r such polymers i s as e n t e r i c coatings, designed t o p r o t e c t therapeutic agents during passage through the a c i d i c stomach and t o a b r u p t l y d i s s o l v e i n the higher pH environment o f the i n t e s t i n e s . An i n t e r e s t i n g example i s the p a r t i a l e s t e r s o f a methyl v i n y l ether and maleic anhydride copolymer (9., _10, 11 ) . OCH I fCH -CH-CH I COOH Q 3

0

2

CH} | n COOR

These polymers have a c h a r a c t e r i s t i c narrow pH range above which they are s o l u b l e and below which they a r e i n s o l u b l e , and t h i s pH range v a r i e s with the s i z e o f the R-group i n the e s t e r p o r t i o n o f the copolymer. T h i s e f f e c t i s shown i n F i g u r e 3 (J2). T h i s behavior can be r e a d i l y understood by c o n s i d e r i n g the number o f i o n i z e d carboxyls that are necessary t o drag the polymer chain i n t o s o l u t i o n . With r e l a t i v e l y small e s t e r groups, only a low degree o f i o n i z a t i o n i s needed t o s o l u b i l i z e the polymer, and hence the d i s s o l u t i o n pH i s low. As the s i z e of the a l k y l group i n c r e a s e s , so does the hydrophobicity, and p r o g r e s s i v e l y more i o n i z a t i o n i s necessary t o s o l u b i l i z e the polymer r e s u l t i n g i n i n c r e a s i n g l y high d i s s o l u t i o n pH. The same argument holds f o r polymers having the same e s t e r grouping but d i f f e r e n t degrees o f e s t e r i f i c a t i o n . The higher the degree o f e s t e r i f i c a t i o n , the more hydrophobic the polymer and consequently the higher the d i s s o l u t i o n pH.



Figure 3. Relationship between pH of dissolution and size of ester group in half-esters of methyl vinyl ether-maleic anhydride copolymers. (Reprinted with permission from Ref. 12. Copyright 1980, John Wiley & Sons, Inc.)



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Even though p a r t i a l l y e s t e r i f i e d copolymers of methyl v i n y l ether-maleic anhydride copolymers were o r i g n a l l y designed to d i s s o l v e abruptly with an increase i n e x t e r n a l pH, i n a constant pH environment they undergo a c o n t r o l l e d d i s s o l u t i o n process and are t h e r e f o r e u s e f u l m a t e r i a l s f o r the c o n t r o l l e d r e l e a s e of therapeutic agents dispersed w i t h i n them (12). Figure 4 shows polymer d i s s o l u t i o n r a t e and the rate o f hydrocortisone r e l e a s e f o r an η-butyl h a l f - e s t e r of a methyl v i n y l ether-maleic anhydride copolymer f i l m c o n t a i n i n g the dispersed drug. Each p a i r of p o i n t s represents a separate device i n which the amount of drug released by the device i n t o the wash s o l u t i o n was determined by uv measurements and the amount of polymer d i s s o l v e d was c a l c u l a t e d from the t o t a l weight l o s s of the device. The e x c e l l e n t l i n e a r i t y of both polymer e r o s i o n and drug r e l e a s e over the l i f e t i m e of the device provides strong evidence f o r a s u r f a c e - e r o s i o n mechanism and f o r n e g l i g i b l e d i f f u s i o n a l r e l e a s e of the drug. The l a t t e r r e s u l t was independently v e r i f i e d by p l a c i n g a drug-containing f i l m i n water at a pH low enough that no d i s s o l u t i o n of the matrix took place and p e r i o d i c a l l y a n a l y z i n g the aqueous s o l u t i o n f o r hydrocortisone. None was found over s e v e r a l days. Type I I I E r o s i o n Polymers undergoing Type I I I e r o s i o n have found a p p l i c a t i o n s i n (a) absorbable s u r g i c a l sutures, (b) s u r g i c a l adhesives, (c) contraception, and (d) c o n t r o l l e d drug r e l e a s e . Absorbable S u r g i c a l Sutures. The search f o r an optimum absorbable s u r g i c a l suture evolved through various forms o f c o l l a g e n to the modern day catgut (13)· Although catgut i s a strong and e f f e c t i v e suture, i t s u f f e r s from v a r i o u s disadvantages, such as batch-to-batch v a r i a t i o n ; s t i f f n e s s , which r e q u i r e s the use of a c o n d i t i o n i n g storage f l u i d ; and o c c a s i o n a l intense t i s s u e r e a c t i v i t y . For these reasons i t was d e s i r a b l e to develop a s y n t h e t i c m a t e r i a l that could be t a i l o r e d to meet i d e a l suture requirements. The f i r s t s y n t h e t i c absorbable suture that reached commercial production i s Dexon, manufactured by American Cyanamid Co. I t i s p o l y ( g l y c o l i c acid) prepared by the polymerization of g l y c o l i d e (14). Another absorbable 0 II

0

II

iCH -C-0} η 2



27.

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Polymers

T I M E (hours)

Figure 4. Rate of polymer dissolution and hydrocortisone release from n-butyl half-ester of methyl vinyl ether-maleic anhydride copolymer containing 10 wt% drug. (Reprinted with permission from Ref. 12. Copyright 1980, John Wiley & Sons, Inc.)


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INITIATION OF POLYMERIZATION

suture i s V i c r y l , manufactured by E t h i c o n Company. V i c r y l i s the 10/90 c o p o l y m e r r p o l y ( l a c t i d e - c o - g l y c o l i d e ) and i s prepared by the copolymerization o f 9 parts L(-) l a c t i d e and 1 part g l y c o l i d e (15). Both polymers degrade by a simple h y d r o l y s i s r e a c t i o n , and no c e l l u l a r or enzyme a c t i v i t y i s necessary f o r suture absorption (16, 17)* S u r g i c a l Adhesives. I n many procedures i t i s d i f f i c u l t t o use conventional s u t u r i n g techniques. Consequently, procedures whereby i n c i s i o n s or cut ends o f a r t e r i e s can be joined by means of an adhesive would represent a s i g n i f i c a n t s u r g i c a l advance

Q8). Because α-cyanoacrylates contain a double bond s u b s t i t u t e d by two electron-withdrawing s u b s t i t u e n t s , they are h i g h l y s u s c e p t i b l e t o a n i o n i c i n i t i a t i o n , and water i s b a s i c enough t o i n i t i a t e very r a p i d polymerization. Therefore, because moisture can i n i t i a t e polymerization and because the formed polymer i s able t o f i r m l y adhere t o moist surfaces, i t has evoked considerable medical i n t e r e s t as a t i s s u e adhesive 0 9 , 20). However, i t has been observed that methyl α-cyanoacrylate i n these a p p l i c a t i o n s leads t o t i s s u e i n f l a m a t i o n and c e l l n e c r o s i s , and f u r t h e r research has shown that the polymer undergoes a degradation r e a c t i o n that occurs both _in v i v o and i n v i t r o . Because poly(alky1 α-cyanoacrylates) are s t r u c t u r a l l y s i m i l a r t o p o l y ( v i n y l i d e n e cyanide), which has been postulated to degrade by a reverse Knoevenagel r e a c t i o n with e v o l u t i o n o f formaldehyde (21), the f o l l o w i n g degradation mechanism f o r p o l y ( a l k y l cyanoacrylates), which a l s o degrade with e v o l u t i o n o f formaldehyde, has been suggested (22, 23): CN

CN

^CH -C-CH -C^ 0

2

CN CN I l ^H -C-CH 0H + 0 C ^ ι \ C00R C00R

OlP

+

9

C00R

o

1

2 ,

J

C00R

CN

1

CN

+ I C00R

QC^>

H 0 o

1

»

HC^ + 0H^ \ C00R

CN

CN

M]H -C-CH 0H + O l F z

I

z

COOR

o

* 2

OH

-C0 + [CHj I I COOR OH 2

0 - H 0 + H-C-H o

2



27.

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Polymers

381

The r a t e o f degradation depends on the s i z e o f the e s t e r group, and, as shown i n Figure 5, the r a t e o f degradation as measured by formaldehyde e v o l u t i o n o f the methyl e s t e r a t pH 7.0 i s considerably f a s t e r than the r a t e o f degradation o f the higher e s t e r s . A dependence o f degradation r a t e on polymer molecular weight has a l s o been reported (24). Because poly(methyl α-cyanoacrylate) degrades r e l a t i v e l y r a p i d l y t o methyl α-cyanoacrylate, which i s an i n t e n s e l y n e c r o t i z i n g and pyogenic compound (25, _26), polymerization o f t h i s compound i s c l e a r l y not a v i a b l e s u r g i c a l procedure. However, higher α-cyanoacrylate e s t e r s are considerably l e s s t o x i c , and polymer degradation occurs a t a much lower r a t e so that these m a t e r i a l s may have p o t e n t i a l as s u r g i c a l l y u s e f u l m a t e r i a l s (27, 28, 29). Contraception. The r a p i d polymerization o f methyl a cyanoacrylate and i t s e f f e c t on l i v i n g t i s s u e has been u t i l i z e d i n female s t e r i l i z a t i o n by oviduct blockage (30)* In t h i s procedure methyl α-cyanoacrylate i s i n s t i l l e d i n t o the oviduct where i t r a p i d l y polymerizes i n t o a s o l i d . Subsequent degradation o f the polymer leads t o formation o f scar t i s s u e , which e v e n t u a l l y permanently blocks the oviduct. The o v e r a l l process i s shown i n F i g u r e 6 (31). Major advantage o f t h i s method i s that the methyl cyanoacrylate can be i n s t i l l e d by a s p e c i a l l y - d e s i g n e d t r a n s c e r v i c a l d e l i v e r y device (31) by t r a i n e d paramedical personnel and does not r e q u i r e a s u r g i c a l procedure. Thus, t h i s method may be a t t r a c t i v e t o developing c o u n t r i e s with serious population problems. C o n t r o l l e d Drug Release—Because the degradation products o f Type I I I b i o e r o s i o n are small, water s o l u b l e molecules, the p r i n c i p a l a p p l i c a t i o n o f polymers undergoing such degradation i s f o r the systemic a d m i n i s t r a t i o n o f therapeutic agents from subcutaneous, intramuscular or i n t r a p e r i t o n e a l implantation s i t e s . A p p l i c a t i o n o f Type I I I b i o e r o s i o n to c o n t r o l l e d drug r e l e a s e was f i r s t described i n 1970 (32) and has since then been e x t e n s i v e l y i n v e s t i g a t e d . The v a r i o u s types o f devices c u r r e n t l y under development can be c l a s s i f i e d i n t o (a) d i f f u s i o n a l and (b) monolithic (7.). D i f f u s i o n a l Devices. In these systems a drug-containing core i s surrounded by a b i o e r o d i b l e r a t e - c o n t r o l l i n g membrane. Thus, these devices combine the a t t r i b u t e s o f a r a t e - c o n t r o l l i n g polymer membrane, which provides a constant r a t e o f drug r e l e a s e from a r e s e r v o i r - t y p e device, with e r o d i b i l i t y , which r e s u l t s i n b i o e r o s i o n and makes s u r g i c a l removal o f the drug-depleted device unnecessary. Because constancy o f drug release demands that the b i o e r o d i b l e polymer membrane remain e s s e n t i a l l y unchanged during the d e l i v e r y regime, s i g n i f i c a n t b i o e r o s i o n must not occur u n t i l a f t e r drug d e l i v e r y has been completed. Thus polymer capsules w i l l remain i n the t i s s u e f o r varying lengths o f time a f t e r completion o f therapy.


INITIATION OF

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382

Figure 5. Homogeneous degradation of α-cyanoacrylate polymers in aqueous acetonitrile. (Reprinted with permission from Ref. 22. Copyright 1966, John Wiley & Sons, Inc.)



27.

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383

Polymers

ACTION O F M C A W I T H I N OVIDUCT

APPROXIMATE TIME AFTER MCA EJECTION ο few sec

ACTION LIQUID MCA ENTERS OVIDUCT

sec. to minutes

LIOUID MCA—^ SOLID POLY (MCA)

OVIDUCT

/

ν ν

ν

severol days

POLY(MCA) DEGRADES TO SMALL MOLECULES

\

(

•·

INFLAMMATORY RESPONSE COLLAGEN TISSUE DEPOSITED. BLOCKING TUBE

severe I months

Permonent lu bo I blockoge with person's own fibrous tissue; no troces of poly MCA Figure 6. Schematic of the action of methyl cyanoacrylate within an oviduct. (Reprinted from Ref. 31. Copyright 1981, American Chemical Society.)



384

INITIATION OF

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Two types of e r o d i b l e d i f f u s i o n a l devices are under development: (1) rod-shaped i n s e r t and (2) microcapsules. Each of these types of devices has c e r t a i n advantages and c e r t a i n disadvantages. Subdermal placement o f rod-shaped devices r e q u i r e s a minor s u r g i c a l procedure, and the device remains v i s i b l e as a small lump. However, because i t can be r e a d i l y removed should t e r m i n a t i o n o f therapy become d e s i r a b l e or necessary, therapy l a s t i n g many months i s p o s s i b l e . On the other hand, microcapsules can be r e a d i l y i n j e c t e d through an 18gauge hypodermic needle, but r e t r i e v a l of microcapsules i s not p o s s i b l e without an extensive s u r g i c a l i n t e r v e n t i o n . For t h i s reason i t has been suggested that the capsules be designed f o r r e l a t i v e l y short-term r e l e a s e , such as three months (33)* Major emphasis f o r the development o f these e r o d i b l e d i f f u s i o n a l systems have been devices that r e l e a s e c o n t r a c e p t i v e s t e r o i d s or n a r c o t i c a n t a g o n i s t s . The polymer systems most e x t e n s i v e l y i n v e s t i g a t e d f o r use as a subdermal capsule f o r the r e l e a s e of l e v o n o r g e s t r e l were v a r i o u s a l i p h a t i c p o l y e s t e r s and, i n p a r t i c u l a r , poly(u)-caprolactone). The r e l e a s e r a t e of l e v o n o r g e s t r e l from such a device, developed by the Research T r i a n g l e I n s t i t u t e and named Capronor, i s shown i n F i g u r e 7 (34). C l e a r l y , e x c e l l e n t constant d a i l y r e l e a s e over many months has been achieved, and those devices are about to undergo Phase I I c l i n i c a l t e s t i n g (35). The polymer most a c t i v e l y i n v e s t i g a t e d f o r use i n a microcapsular d e l i v e r y system i s p o l y ( D L - l a c t i c a c i d ) , and r e l e a s e of norethindrone measured as blood plasma l e v e l from such microcapsules i s shown i n F i g u r e 8 (36). These data show reasonably constant blood l e v e l s and demonstrate that f o r a f i x e d t o t a l weight o f microcapsules, r a t e of drug r e l e a s e and d u r a t i o n o f therapy can be regulated by capsule s i z e . Furthermore, because each capsule f u n c t i o n s as an independent drug d e l i v e r y system, the r a t e of drug d e l i v e r y can a l s o be regulated by v a r i a t i o n i n the t o t a l number of i n j e c t e d microcapsules. M o n o l i t h i c D e v i c e s — I n these systems the drug i s homogeneously dispersed w i t h i n a b i o e r o d i b l e polymer matrix, and r e l e a s e of the drug can be c o n t r o l l e d e i t h e r by d i f f u s i o n or by polymer e r o s i o n . I f e r o s i o n of the matrix i s very much slower than drug d i f f u s i o n , then r e l e a s e k i n e t i c s f o l l o w the Higuchi model (37) and drug r e l e a s e r a t e decreases e x p o n e n t i a l l y with time, f o l l o w i n g t ~ ' ' dependence over a major p o r t i o n of the release rate. I f e r o s i o n i s r e l a t i v e l y f a s t and the drug i s w e l l immobilized i n the s o l i d matrix so that d i f f u s i o n a l r e l e a s e i s minimal, matrix e r o s i o n determines r a t e of drug r e l e a s e . However, i t i s important to d i s t i n g u i s h two types of h y d r o l y t i c e r o s i o n of a s o l i d , hydrophobic polymer. In one, r e f e r r e d to as homogeneous e r o s i o n , the h y d r o l y s i s occurs at a uniform r a t e throughout the matrix. In the other, c a l l e d heterogeneous 2



RELEAS

- I t *

-

Ι

160

ι

170

190

200

210

220

230 DAY

1 . . . I . . . I. . . I . ι . I . i

180

ι ι I t ι ι

"

240

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260

270

280

ANIMAL SACRIFICED JUNE 23. 1977 (DAY 292)

290

Figure 7. Daily rate of release of norgestrel from poly(u-caprolactone) capsule implanted in rat after 32 days in vitro. (Reprinted with permission from Ref. 4. Copyright 1980, Academic Press, Inc.)

5

10

15

40,


300

1

00 LO

ni

to


386


0

12

24

36

48

60

72

84

96

108

120

132

144

156

168

TIME, days Figure 8. Baboon peripheral serum levels of immune-reactive norethisterone after intramuscular injection of 300 mg of poly(DL-lactic acid) microcapsules containing 75 mg of drug. Size of capsules: A, 10-240 μτη; Β, 65-124 μηι; C, 10-40 μτη. (Reprinted with permission from Ref. 36, p. 75. Copyright 1980.)


180

27.

HELLER

Synthesis of Biodegradable Polymers

387

e r o s i o n , the process i s confined t o the surface o f the device and i s , f o r that reason, commonly r e f e r r e d t o as surface e r o s i o n


(38)· Drug r e l e a s e rate f o r matrices undergoing bulk erosion i s nonlinear and d i f f i c u l t t o p r e d i c t because i t i s determined by a combination o f d i f f u s i o n and e r o s i o n . However, drug r e l e a s e from devices undergoing surface e r o s i o n i s p r e d i c t a b l e and can lead t o zero o r d e r - k i n e t i c s provided d i f f u s i o n a l r e l e a s e o f the drug i s minimal and the o v e r a l l surface area o f the device remains e s s e n t i a l l y constant. Many s t u d i e s on drug r e l e a s e from b i o e r o d i b l e monolithic devices have been performed and the majority o f these s t u d i e s used p o l y ( l a c t i c acid) or copolymers o f l a c t i c and g l y c o l i c a c i d s (J_, 7.). Because these polymers undergo a bulk degradation process, drug r e l e a s e i s nonlinear and not amenable t o a d e t a i l e d mechanistic i n t e r p r e t a t i o n . Nevertheless, s e v e r a l systems having p o t e n t i a l f o r the prolonged released o f v a r i o u s therapeutic agents such as c o n t r a c e p t i v e s t e r o i d s , n a r c o t i c antagonists, a n t i c a n c e r agents, and a n t i m a l a r i a l agents have been demonstrated (J29, 40, 41). Because surface e r o s i o n r e s u l t s i n constant and p r e d i c t a b l e r a t e o f drug r e l e a s e , t h i s type o f e r o s i o n i s c l e a r l y p r e f e r r a b l e t o bulk e r o s i o n . However, t o achieve surface e r o d i b i l i t y , a system must be devised i n which the r a t e o f polymer degradation a t the surface o f a device i s very much f a s t e r than the r a t e o f degradation i n the i n t e r i o r . One approach t o surface e r o d i b i l i t y i s t o prepare a polymer that contains linkages that are s t a b l e i n base but are very l a b i l e i n a c i d . Because one such linkage i s an ortho e s t e r , p o l y ( o r t h o e s t e r s ) are c u r r e n t l y under i n t e n s i v e development as monolithic devices f o r zero order drug r e l e a s e (7). Poly(ortho e s t e r s ) were f i r s t d i s c l o s e d i n a s e r i e s o f patents assigned t o the A l z a Corporation (42-45) and were prepared by a t r a n s e s t e r i f i c a t i o n r e a c t i o n as f o l l o w s :

EtO

-fO 0-R} η

OEt * + HO-R-OH

/

0

+ EtOH

Although the A l z a poly(ortho e s t e r ) system has never been s t r u c t u r a l l y i d e n t i f i e d other than by i t s tradename Chronomer, and l a t e r Alzamer, s e v e r a l p u b l i c a t i o n s provide a general d e s c r i p t i o n o f the use o f the polymer f o r the r e l e a s e o f naltrexone (46) and c o n t r a c e p t i v e s t e r o i d s (47, 48, 49). Poly(ortho e s t e r s ) have a l s o been produced by the a d d i t i o n o f d i o l s t o diketene a c e t a l s (50)* P r i n c i p a l l y because o f ease of monomer s y n t h e s i s , polymers were prepared by the a d d i t i o n o f


388

INITIATION OF

POLYMERIZATION

various d i o l s to 3,9-bis(methylene 2,4,8,10-tetraoxaspiro[5,5] undecane), R = H or 3 , 9 - b i s ( e t h y l i d o n e 2,4,8,10-tetraoxaspiro [5,5]undecane), R = CHg. R

0-CH \

2

/

o

C=C


C=C

O-CH^

RCH

CH-0

\

/

/

\

2

CH.R

\

c

C \ O-CH,

/

N

^CH -0 2

HOR'OH

Η

2

0

2

+

CH -0

O-CH,

/ 0

R /

2

C

Η

-

CH -0 \

/

^

/

/ c N

2

!

0-R -

Because poly(ortho esters) are s t a b l e i n a l k a l i n e environments, i n i t i a l attempts to develop a surface-eroding system were based on the i n c o r p o r a t i o n o f sodium carbonate i n t o the bulk m a t e r i a l . Polymer erosion was expected to occur only at the outer surface of a s o l i d device i n which the incorporated b a s i c s a l t i s n e u t r a l i z e d by the e x t e r n a l b u f f e r (51, 52). However, i t was found that as a consequence of an osmotic imbibing o f water caused by the incorporated water-soluble s a l t , a s w e l l i n g f r o n t develops, and drug i s released from the matrix by d i f f u s i o n from the swollen polymer. Because poly(ortho esters) are s t a b l e i n base, no polymer erosion takes p l a c e . Nevertheless, as shown i n F i g u r e 9, constant drug r e l e a s e i s achieved. The use o f o s m o t i c a l l y a c t i v e n e u t r a l s a l t s such as sodium s u l f a t e , a l s o shown i n Figure 9, produces a constant rate o f drug r e l e a s e f o r about 60 days, a f t e r which drug r e l e a s e rate a c c e l e r a t e s up t o drug d e p l e t i o n (j£, 54), The number below the arrow i n d i c a t e s weight l o s s a t 160 days. C l e a r l y , polymer erosion s i g n i f i c a n t l y lags drug r e l e a s e . Furthermore, the r a t e of drug r e l e a s e observed with sodium s u l f a t e i s not that expected from a simple movement o f a s w e l l i n g f r o n t , but instead i n d i c a t e s that the a c t i v e surface area increases with time. T h i s has been v e r i f i e d by observations o f a s u b s t a n t i a l increase i n s i z e and by scanning e l e c t r o n micrograph, which revealed a foam-type i n t e r i o r and heavy surface c r a t e r i n g . Current work i s aimed at producing poly(ortho ester) systems i n which drug r e l e a s e and polymer erosion takes place concomitantly by using incorporated agents that are capable o f lowering the pH at the polymer-water i n t e r f a c e .



27.

HELLER


389

Polymers

Time - Days Figure 9. Norethindrone (NE) release from 3,9-bis(methylene 2,4,8,10-tetraoxa spiro [5,5] undecane)/1,6-hexane diol polyfortho ester), 63-mm-diameter discs at pH 7.4 and 37 °C. Key: O, 10 wt% NE, 10 wt% Na SO,„ 0.6-mm-thick disc, total drug content 2.4 mg; Δ , 10 wt% NE, 10 wt% Na C0 1.2-mm-thick disc, total drug content 4.0 mg. 2

2

3)


390


LITERATURE CITED 1. 2. 3.


4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.

Heller, J. Biomaterials 1980, 1, 51-57. Tobolsky, Α. V. Nature 1967, 215, 509-510. Davis, P.; Tabor, B. E . , J. Polymer Sci.: Part A 1963, 1, 799-815. Coopes, I. H. J. Polymer Soi. Part A-1 1970, 8, 1793-1811. Robinson, I. D. J. Appl. Polymer Sci. 1964, 8, 1903-1918. Goldman, R.; Goldstein, L.; Katchalsky, E. "Biochemical Aspects of Reactions on Solid Supports"; Stark, G. R., Ed. Academic Press: New York, 1971, pp 1-78. Heller, J. "Pharmaceutical Applications of Controlled Release Drug Delivery Systems"; Langer, R. S.; Wise, D. L., Eds. CRC Press, in press. Heller, J.; Baker, R. W.; Helwing, R. F.; Tuttle, M. E. J. Biomed. Mater. Res. to be published. Lappas, L. C.; McKeehan, W. J. Pharm. Sci. 1962, 51, 808. Lappas, L. C.; McKeehan, W. J. Pharm. Sci. 1965, 54, 176181. Lappas, L. C.; McKeehan, W. J. Pharm. Sci. 1967, 56, 12571261. Heller, J.; Baker, R. W.; Gale, R. M.; Rodin, J. O. J. Appl. Polymer Sci. 1978, 22, 1991-2009. Goldenberg, I. S. Surgery 1959, 46, 908-912. Frazza, E. J.; Schmitt, E. E. J. Biomed. Mater. Res. Symposium 1971, 1, 43-58. Craig, P. H.; Williams, J. A.; Davis, K. W.; Magoun, A. D.; Levy, A. J.; Bogdansky, S.; Jones, J. P. Jr. Surg. Gynecol. Obstet. 1975, 141, 1-10. Salthouse, T. N.; Matlaga, B. F. Surg. Gynecol. Obstet. 1976, 142, 544-550. Chu, C. C. J. Biomed. Mater. Res., 1981, 15, 19-27. Nathan, H. S.; Nachlas, M. M.; Solomon, R. D.; Halpern, B. D.; Seligman, A. M. Ann. Surg. 1960, 152, 648-659. Leonard, F.; Kulkarni, R. K.; Nelson, J.; Brandes, G. J. Biomed. Mater. Res. 1967, 1, 3-9. Leonard, F.; Hodge, J. W. Jr.; Houston, S; Ousterhout, D. K. J. Biomed. Mater. Res. 1968, 2, 173-178. Gilbert, H; Miller, F. F.; Averill, S. J.; Schmidt, R. F.; Stewart, F. D.; Trumbull, H. L. J. Am. Chem. Soc. 1954, 76, 1074-1076. Leonard, F.; Kulkarni, R. K.; Brandes, G; Nelson, J.; Cameron, J. J. J. Appl. Polymer Sci. 1966, 10, 259-272. Wade, C.W.R.; Leonard, F. J. Biomed. Mater. Res. 1972, 6, 215-220. Venzin, W. R.; Florence, A. J. J. Biomed. Mater. Res. 1980, 14, 93-106.


27. HELLER 25. 26. 27. 28.


29. 30. 31.

32. 33. 34. 35. 36.

37. 38. 39.

40.

41. 42. 43.

Synthesis of Biodegradable Polymers

Cameron, J. L; Woodward, S. C.; Herrmann, J. B. Arch. Surg. 1064, 89, 546. Woodward, S. C.; Herrmann, J. B.; Leonard, F. Fed. Proc. 1964, 23, 495. Woodward, S. C.; Herrmann, J. B.; Cameron, J. L; Brandes, G.; Pulaski, E. J.; Leonard, F. Ann. Surg. 1965, 162, 113122. Lehman, R.A.W.; Hayes, G. J.; Leonard, F. Arch. Surg., 93, 441-446. Leonard, F.; Kulkarni, R. K.; Nelson, J.; Brandes, G. J. Biomed. Mater. Res., 1967, 1, 3-9. Stevenson, T. C.; Taylor, D. S. J. Obstet. Gynaecol. Brit. Comm. 1972, 79, 1028-1039. Hoffman, A. S.; Hale, T. J.; Nightingale, J.A.S.; Halbert, S. Α.; Buckles, R. G. Presented at Second World Congress of Chemical Engineering and World Chemical Exposition, Montreal, Canada, October 4-9, 1981. Yolles, S; Eldridge, J. E . ; Woodland, J.H.R., Polymer News 1970, 1, 9-15. Beck, L. R.; Pope, V. Z.; Cowsar, D. R.; Lewis, D. H.; Tice, T. R., Contracept. Deliv. Syst. 1980, 1, 79-86. Pitt, C. G.; Marks, T.A.; Schindler, A. "Controlled Release of Bioactive Materials"; Baker, R. W., Ed.; Academic Press: New York, 1980, pp. 19-43. Pitt, C. G.; Schindler, A. "Pharmaceutical Applications of Controlled Release Drug Delivery Systems"; Langer, R. S.; Wise, D. L. Eds.; CRC Press, in press. Beck, L. R.; Cowsar, D. R.; Lewis, D. H., "Biodegradables and Delivery Systems for Contraception"; Hafez, E.S.E.; van Os, W.A.A., Eds.; G. K. Hall Medical Publishers: Boston, 1980, pp 63-81. Higuchi, T. J. Pharm. Sci. 1961, 50, 874-875. Heller, J.; Baker, R. W. "Controlled Release of Bioactive Materials"; Baker, R. W., Ed; Academic Press: New York, 1980, pp. 1-17. Wise, D. L.; Schwope, A. D.; Harringan, S. E . ; McCarthy, D. A.; Howes, J. F. "Polymeric Delivery Systems"; Kostelnik, R. J., Ed.; Gordon and Breach Science Publishers: New York, 1978, pp. 75-86. Wise, D. L; Gregory, J. B.; Newberne, P. M.; Bartholow, L. C.; Stanbury, J. B. "Polymeric Delivery Systems"; Kostelnik, R. J., Ed.; Gordon and Breach Science Publishers: New York, 1978, pp. 121-136. Yolles, S; Sartori, M. F. "Drug Delivery Systems", Juliano, R. L., Ed.; Oxford university Press, New York, 1980, pp. 84-111. Choi, N. S.; Heller, J. U.S. Patent 4,093,709, June 6, 1978. Choi, N. S.; Heller, J. U.S. Patent 4,131,648, December 26, 1978.


391

392 44. 45. 46. 47.


48. 49. 50. 51. 52. 53. 54.


Choi, N. S.; Heller, J. U.S Patent 4,138,344, February 6, 1979. Choi, N. S., Heller, J. U.S. Patent 4,180,646, December 25, 1979 Capoza, R. C.; Sendelbeck, L.; Balkenhol, W. J. "Polymeric Delivery System"; Kostelnik, R. J. Ed.; Gordon and Breach Science Publishers, New York, 1978, pp. 59-70. Benagiano, G.; Gabelnick, H. L. J. of Steroid Biochem. 1979, 11, 449-455. Pharriss, B. B.; Place, V. A.; Sendelbeck, L; Schmitt, E. E. J. Reproductive Med. 1976, 1 7 , 91-97. Benagiano, G.; Schmitt, E . ; Wise, D.; Goodman, M. J. Polymer Sci.. Polym. Symp. 1979, 66, 129-148. Heller, J; Penhale, D.W.H.; Helwing, R. F. J. Polymer Sci. Polymer Lett., 1980, 18, 619-624. Heller, J.; Penhale, D.W.H.; Helwing, R. F.; Fritzinger, B. K.; Baker, R. W. Chem. Eng. Progress Symp. Series No. 206, 1981, 77, 28-36. Heller, J; Penhale, D.W.H.; Helwing, R. F.; Fritzinger, B. K. Polymer Eng. Sci. 1981, 21. 727-731. Heller, J.; Penhale, D.W.H.; Helwing, R. F.; Fritzinger, B. K. Controlled Release Delivery Systems"; Roseman, T. J.; Mansdorf, S. Z., Eds.; Marcell Dekker, New York, in press. Heller, J.; Penhale, D.W.H.; Fritzinger, B. K.; Rose, J. E.; Helwing, R. F. Contracept. Deliv. Syst. in press.

RECEIVED October 25, 1982


Initiation of Polymerization - ACS Publications - American Chemical

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