Agricultural and Synthetic Polymers - American Chemical Society

Chapter 15

Bioabsorbable Fibers of p-Dioxanone Copolymers R. S. Bezwada, S. W. Shalaby, and H. D. Newman, Jr.

Downloaded by FUDAN UNIV on January 23, 2017 | http://pubs.acs.org Publication Date: July 13, 1990 | doi: 10.1021/bk-1990-0433.ch015

Ethicon, Inc., Somerville, NJ 08876-0151

Growing interest in synthetic, absorbable copolymers and their use in the production of fibers, including sutures, and drug delivery systems has been addressed in the patent and technical literature over the past fifteen years . However, most investigators have focused their attention on copolymers which are derived primarily from -hydroxy acids , anhydrides or oxalate esters . The preparation of high molecular weight poly(p-dioxanone) , a polyether-ester, and its conversion to a useful absorbable suture with unique properties has now led to the interest in exploring the potential of poly(p-dioxanone) containing other comonomeric units in the chain. . Hence, the studies which form the basis of this report were conducted to determine the effect of incorporating different quantities of glycolyl moieties into the poly(p-dioxanone) chains on the physical and biological properties of drawn monofilaments. 1-11

3-6

9-11

12

13,14

EXPERIMENTAL Materials and Major Characterization Methods. Polymerization grade p-dioxanone and glycolide monomers were obtained as described in early reports . Varian XL-300 H and C NMR, DuPont DSC, Waters-Model 150C GPC, and X-ray diffractometers were used in the characterization of the copolymers prior to processing. Inherent viscosities (I.V.) were obtained in hexafluoroisopropanol (HFlP) at 25°C and 0.1 d1/g concentration using a Ubbehlohde viscometer. Melt rheological studies and polymer extrusion were conducted using an Instron Model 3211 A stock solution of stannous octoate of known concentration (e.g., 0.33 M) in toluene was prepared under anhydrous conditions. The tensile properties of the fibers were determined using an Instron Tensile Tester, Model 1130 (strain rate - 2"/min. and gauge length = 2"). 3,12

1

13

0097-6156/90AM33-0167$06.00A) © 1990 American Chemical Society

Glass and Swift; Agricultural and Synthetic Polymers ACS Symposium Series; American Chemical Society: Washington, DC, 1990.

7,8


168

AGRICULTURAL AND

SYNTHETIC POLYMERS

Polymerization Scheme and Typical Examples. General Polymerization Scheme and Preparation of Copolymer I. A copolymer of p-dioxanone and glycolide at 95/5 by weight was prepared by charging 95g (0.9306 mole) of p-dioxanone, 0.266 ml of 1-dodecanol, and 0.0984 ml of a toluene solution of stannous octoate (0.33 molar) into a 250 ml, round bottom, two-neck flask. The contents of the reaction flask were held under high vacuum at room temperature for about 16 hours. The flask was fitted with a mechanical stirrer and an adaptor with a hose connection. The reactor was purged with nitrogen before being vented with nitrogen. The reaction mixture was heated to 110°C, and maintained there for 5 hours while stirring. A small sample of this polymer was removed for analysis (Inherent Viscosity = 1.21 dl/g), and 5.0g (0.04308 mole) of glycolide was added to the reaction mixture. The temperature was raised to 140°C, and maintained for 1 hour. The temperature was then lowered to 90°C, and maintained for 65 hours at 90°C. The copolymer was isolated, ground, and dried about 48 hours/80°C/0.1 mm Hg to remove any unreacted monomer. A weight loss of 13.7% was observed. Preparation of Copolymers II and III. Using the above general copolymerization scheme, two more copolymers of p-dioxanone/glycolide at 90/10 and 80/20 i n i t i a l weight composition were prepared. The following amounts of reactants and catalysts were used. Copolymer II PDO/glycolide, i n i t i a l weight r a t i o 90/10 p-dioxanone (PDO) 90 g(0.8816 mole) 1-dodecanol 0.26 ml Sn(oct)2(0.33 molar) 0.098 ml glycolide 10 g(0.0862 mole)

Copolymer ITI 80/20 80g(0./836 mole) 0.217 ml 0.048 ml 20g(0.1723 mole)

Conversion of copolymers to fibers and pertinent t e n s i l e date. Copolymers I-III described i n Table I were melt extruded, and the extrudates were oriented by drawing and then annealed. The t e n s i l e properties of the unannealed and annealed fibers are summarized i n Table II and I I I , respectively. E f f e c t of i n i t i a t o r type on copolymer properties. Copolymer IV of p-dioxanone/glycolide at 90/10 weight composition was prepared using diethylene g l y c o l (DEG) as the i n i t i a t o r . Fiber properties of the r e s u l t i n g copolymer were determined and compared with those of Copolymer I I , which was made using 1-dodecanol as an i n i t i a t o r (as shown i n Table IV). In-Vivo Absorption and breaking strength retention studies. For comparing PDS monofilament in-vivo properties with copolymeric f i b e r s , a second 90/10 PDO/glycolide copolymer (II-A) was prepared and processed following s i m i l a r schemes to those used f o r copolymer II.


15. BEZWADA ET AL.

Bioobsorbable Fibers ofp-Dioxanone Copolymers

COPOLYMER CHARACTERIZATION Analytical data of copolymers I to III are summarized in Table I. TABLE I COPOLYMERIZATION CONDITIONS AND SOME PROPERTIES OF RESULTING COPOLYMERS II T.II Copolymer 80/20 p-oxanone/glycolide95/5 90/10 i n i t i a l weight ratio Final comp. PDS/PGA, mole %

87.3/12.7

82.7/17.3

100/0

1.63

1.44

1.64

1.8

96~100°C

100-105°C


a

I.V. dl/g M.P. (hot-stage) % Conversion

86.3 b

—

45%

c

— —

-8 97

DSC Data< >, Tg» °C Tm» °C

95~100°C

86.2

Crystallinity, %

(a) (b) (c) *

PDS* 100/0

93.6

Z5

40%

50% -10 to -15 110-115

-2 125

using NMR using X-ray diffraction second heat, using a heating rate of 20 C/min. in N2 Typical properties of poly(p-dioxanone) made according to reference #12

SOURCE: Ref.

14.

TABLE II EFFECT OF DRAWING SCHEMES ON TENSILE PROPERTIES OF MONOFILAMENT FIBERS Tensile Data Copolymer Example No. I

Drawing Conditions 4 χ at 58'C followed by 1.562 χ at 75

e

5 χ at 52 C followed by 1.3 χ at 72°C

II

5 x at 50 C followed by 1.2 χ at 71°C

III

SOURCE: Ref.

Diameter Straight (mils) KPSI

Knot KPSI

Young·s Elong. Modulus % Kpsi

7.1

88

53

49

211

7.3

87

49

61

143

7.5

65

43

94

81

14.


AGRICULTURAL AND SYNTHETIC POLYMERS

170

Ethylene oxide s t e r i l i z e d monofilaments of copolymer II-A and a poly(p-dioxanone) were compared i n terms of t h e i r in-vivo absorption and BSR (breaking strength retention) p r o f i l e s . The BSR and absorption studies were conducted i n rats according to the procedures described e l s e w h e r e * . The comparative data of these studies are given i n Table V. 1

15


DISCUSSION OP RESULTS During the melt polymerization of PDO, about 75% conversion i s attained a f t e r 5-6 hrs/110°C. Addition of g l y c o l i d e to the melt polymerized PDS f a c i l i t a t e s the copoiymerization of the unreacted PDO with g l y c o l i d e , thereby, creating a copolymer s o f t segment a t the end of the poly(p-dioxanone) chain. Incorporation of such segments provided more compliant f i b e r s as compared with those made from PDS. The copolymers of PDO/glycolide provided monofilaments with higher strength and improved absorbability and decreased propensity to r e t a i n t h e i r in-vivo breaking strength. The properties of the copolymers of p-dioxanone/glycolide at 95/5, 90/10 and 80/20 by i n i t i a l weight are summarized i n Table I. I t was observed that the increase of g l y c o l i d e content from 0 to 20% was associated with a decrease i n c r y s t a l l i n i t y from 50% to 40%. Tg of the copolymers increased with the increase of g l y c o l i d e r a t i o but only a s l i g h t increase i n the value of Tm could be observed. Copolymer I I I based on 20% glycolide displayed a Tm @ 125 C. Copolymers I-III were extruded into monofilaments and the t e n s i l e properties a f t e r drawing and annealing are shown i n Tables II and I I I . The reported data indicate that copolymeric monofilaments can be made to have equivalent or higher t e n s i l e strength as compared with those made from PDS. e

TABLE III TENSILE PROPERTIES OF DRAWN, ANNEALED MONOFILAMENTS MADE OF COPOLYMERS I TO I I I AND PDS III II Copolymer I Fiber Properties 7.5 7.3 7.5 Diameter (mils) 61 85 79 Straight Tensile Strength Kpsi 51 62 50 Knot Strength, Kpsi 55 39 34 Elongation, % 201 283 Young's Modulus, Kpsi 281 (a)

SOURCE: Ref. 14.

PDS* 8.65 75 45 28 278 β

(a) A l l f i b e r s were annealed at constant s t r a i n f o r 12 hrs. β 60 C * Typical properties of PDS made according to reference #12 Using diethylene g l y c o l (DEG) as an i n i t i a t o r , a copolymer (IV) of PDO/glycolide at 90/10 by weight was preapred and i t s properties are compared with those of a 90/10 copolymer (II) made i n the presence of 1-dodecanol (Table IV). Although the t e n s i l e properties of IV are comparable those of I I , the percent BSR of the l a t t e r i s higher. This may be associated with a difference i n the copolymeric


15. BEZWADA ET AL.

BioabsorbabU Fibers of p~Dioxanone Copolymers


chain microstructure and/or molecular weight. However, a lower modulus of IV suggest a major contribution of the microstructure to the o v e r a l l properties of the f i b e r s . A second 90/10 PDO/glycolide copolymer (II-A) made s i m i l a r l y to copolymer II was converted to drawn annealed monofilaments which displayed higher t e n s i l e properties and compliance than those of PDS. The monofilaments of the copolymer II-A exhibited faster i n vivo absorption. At four weeks the in-vivo BSR of PDS i s 69%, whereas the BSR of the copolymer i s only 12%. At 119 days, monofilaments of the copolymer absorbed (in-vivo) completely, whereas PDS monofilaments absorb i n about 180-210 days.

TABLE IV EFFECT OF INITIATOR TYPE ON FIBER PROPERTIES Copolymer II Composition of 90/10 PDO/glycolide i n i t i a l weight r a t i o I n i t i a t o r Type 1-dodecanol I.V.,

dl/g.

Fiber Properties (annealed f o r 12 hr/60°C Diameter, (mils) Straight T e n s i l e , Kpsi Knot Strength, Kpsi Elongation, % Y.M., Kpsi In-Vitro BSR, % remaining at 4 days/50°C SOURCE: Ref.

ÎY 90/10

diethylene g l y c o l

1.44

1.88

7.3 85 62 39 283

7.4 88 55 30 204

49

34

14.

CONCLUSION Melt polymerization of p-dioxanone, proceeds to about 75% conversion at 110*0. Addition of g l y c o l i d e at t h i s stage allows f o r the copolymerization of the unreacted p-dioxanone with g l y c o l i d e , to produce amorphous glycolide/p-dioxanone segments at the end of the poly(p-dioxanone) chains. Incorporation of such segments provides much more compliant monofilaments as compared with those made from poly(p-dioxanone). The copolymers of p-dioxanone/glycolide provided monofilaments with higher strength and improved absorbability and more rapid loss of in-vivo breaking strength than the homopolymer of p-dioxanone.


171

AGRICULTURAL AND SYNTHETIC POLYMERS

172

TABLE V COMPARATIVE PROPERTIES OF PDS AND COPOLYMER II-A FIBERS PDS*


Polymer I.V. Tm, °C (Hot stage microscope) Fiber Properties Diameter (mils) Straight Tensile strength, Kpsi Knot strength, Kpsi Elongation, % Y.M. Kpsi

1.80 U0-U5 C e

8.65 75

Copolymer II-A 1.82 98-102°C

7.8 86

45 28 278

53 48 221

In-Vivo BSR, % at 3 weeks 4 weeks

— 69

30 12

In-Vivo Absorption, X remaining at 91 days 119 days 180-210 days

96 — 0

23% 0

SOURCE: Ref. 14.

*Typicai properties of PDS made according to reference #12

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9.

S. W. Shalaby, Chap. 3 in "High Technology Fibers: Part A (M. Lewin & J . Preston, Eds.) Marcel Dekker, New York, 1985. S. W. Shalaby, Vol. 1, in "Encyclopedia of Pharmaceutical Technology" (J. C. Boylan & J . Swarbrick, Eds.) p. 465, Wiley, New York (1988). S. W. Shalaby & D. D. Jamiolkowski, U.S. Pat. (to ETHICON, Inc.) 4,605,730 (1986). M. N. Rosensaft and R. L. Webb, U.S. Pat. (to American Cyanamid) 4,243,775 (1981). S. W. Shalaby & D. D. Jamiolkowski, Polym. Preprints, 26 (2), 200 (1985) A. Kafrawy, D. D. Jamiolkowski & S. W. Shalaby, J . Bioact. Biocomp. Polym., 2, 305 (1987). A. J . Domb, E. Ron, & R. Langer, Macromolecules, 21, 1925-1929 (1988). A. J . Domb, & R. S. Langer, U.S. Pat. (to M.I.T.) 4,757,128 (1988). S. W. Shalaby & D. D. Jamiolkowski, U.S. Pat. (to ETHICON, Inc.) 4,205,399 (1980).


BEZWADAETAL.

Bioobsorbable Fibers of p-Dioxanone Copolymers


10.

S. W. Shalaby & D. D. Jamiolkowski, U.S. Pat. (to ETHICON, Inc.) 4,209,607 (1980). 11. S. W. Shalaby & D. D. Jamiolkowski, U.S. Pat. (to ETHICON, Inc.) 4,141,087 (1979). 12. N. Doddi, C. C. Versfelt, and D. Wasserman, U.S. Pat. (to ETHICON, Inc.) 4,052,988 (1977). 13. R. S. Bezwada, S. W. Shalaby, H. D. Newman, and A. Kafrawy, U.S. Pat. (to ETHICON, Inc.) 4,643,191 (1987). 14. R. S. Bezwada, S. W. Shalaby and H. D. Newman, U.S. Pat. (to ETHICON, Inc.) 4,653,497 (1987); J . Appl. Biomater. (in press). 15. T. N. Salthouse, Chap. 2 in "Biocompability in Clinical Practice, Vol. I. (D. F. Williams, Ed.) C.R.C. Press, Boca Raton, Fl., 1982. RECEIVED February 14, 1990


Agricultural and Synthetic Polymers - American Chemical Society

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