Comparison of segmented polyether urethane with polyethylene IUDs in rabbits

CONTRACEPTION

COMPARISON OF SEGMENTED POLYETHER URETHANE WITH POLYETHYLENE IUDs IN RABBITS

Sidney J. Stolzenberg University of California School of Medicine Department of Pharmacology San Francisco, California 94143

Norman Fishman* Chemical Industries Center SRI International Menlo Park, California 94025

Daniel P. Sasmore Life Sciences Division SRI International Menlo Park, California

94025

ABSTRACT

A segmented polyether urethane IUD was compared with a polyethylene IUD The contraceptive efficacy of urethane IUDs was excellent. in rabbits. Moreover, the purulent slippery deposit present with the polyethylene Our studies indicate (I) was absent. IUDs and observed by Davis --I et al that the polyether urethane IUDs have a high degree of antifertility activity in rabbits and these IUDs have reduced inflammatory response, based It is on leucocytic infiltration and tissue debris in the uterine lumen. suggested that polyether urethane IUDs not requiring copper or other medication can be designed for high contraceptive efficacy, intrauterine compatibility and with the necessary rigidity for proper uterine retention in humans.

Accepted

for publication

*Send reprint

AUGUST

requests

July

5,

1979

to N. Fishman.

1979 VOL. 20 NO. 2

91

CONTRACEPTION

INTRODUCTION

Segmented polyurethanes were introduced in 1967 for use in surgically implanted prosthetic devices (1). Segmented polyurethanes have been used for many applications particularly those requiring superior flex endurance, Some polyurethanes are presently wear resistance and blood compatibility. as components used clinically as catheters, intra-aortic balloons,and (2, 3, 4, 5). The of other surgically implanted prosthetic devices polyurethanes developed at SRI International have been designed for tissue They permit normal tissue cell compatibility, particularly with blood. growth and cause little or no erythrocyte adhesiveness or platelet aggregation and appear free from immunological reaction. Physiologically compatible IDDs must have a hydrophilic outer coat, Generally, the more hydroyet be rigid enough for uterine retention. philic the polyurethane is, the less rigid it will be. Therefore, two possible approaches in the production of materials suitable for IUDs are: \a) an entire device constructed of one material with a suitable degree of hydrophilicity, or (b) a device with an inner core of predominantly hydrophobic material for necessary rigidity and an outer coating for biocompatibility and antifertility activities. In this report, we present data comparing our first prototype pf an elastomeric swellable polyurethane with nonswellable polyethylene devices on contraceptive efficacy and interactions with the uterus in rabbits.

METHODS

AND PROCEDURES

A segmented polyether urethane system used in these experiments is based on prepolymer formed by the reaction of a polyether glycol with a diisocyanate and then chain-extended in solution with various coupling agents, usually primary diamines, to yield high molecular weight polymers. These polymers are formed in solution under controlled conditions, and linear polymers having reproducible structures are obtained.

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CONTRACEPTION

The synthesis

is a two-step process

(y + 1) OCN-R-NC0

R

+ y HO(R'O)xF

OCN R-NW-O(R'0)

t

as fellows:

$@-c+

NC0 Y

I t H NR"NH 2

Y

n

The ability to vary the values of x and y and the identity of R, R', and R" within fairly wide limits, lends great. versatility to the system. Thus, materials of the above structure can have the properties of (a) tough, materials, snappy elastomers, (b) stiff, hard, pseudoelastomeric (c) highly swollen hydrophilic materials, or (d) polymers with nearly a For the more hydrophobic continuous range of properties in between. elastomeric materials, the glycol HO(RO),H is usually polyoxypropylene glycol (P4G); for hydroglycol (PPG), but can be polyoxytetramethylene The number philic polyurethanes, polyoxyethylene glycol (PEG) is used. of polyether segments per prepolymer, y, is usually one of two, but it can be higher. For both types of polyurethanes, the diisocyanate is generally methylene bis(4-phenyl isocyanate) (MDI), although hexamethylene have also been diisocyanate and methylene bis(4-cyclohexyl isocyanate) used. For all segmented polyether urethanes, a diamine coupling agent, ethylene diamine or m-xylylene diamine, has been used. Polyurethane prepared for this work contained a polyol consisting This of 80% by weight polypropylene glycol and 20% polyethylene glycol. polyol was end-capped with methylene bis (4-phenyl isocyanate) in DMSO solvent, then chain-extended with ethylene diemine to a high molecular weight polymer. The polymer was isolated from the DMSO solution by precipitating in water and drying at least 24 hours -__ in vacua at 60" C. Elastomeric swellable polyurethanes or nonswellable polyethylene devices sterilized with ethylene oxide, were anchored by means of a single Controls 3-O silk suture in one of the two uterine horns of mature rabbits. Each device, received sham surgery and an identical single silk suture. measuring 3 mm in diameter and 38 mm in length, was anchored 1 to 2 cm above the cervix. These dimensions were the same as those used by Davis et aA. (1) which were based on meticulous uterine measurements in mature rabbits. The contralateral horn in each rabbit served as a control and received no treatment. Approximately 20 days following surgery, each rabbit on experiment was double mated with two bucks of proven fertility. This was followed by a 50 I.U. injection of HCG to ensure ovulation. followed by an autopsy about 10 days later when embryo counts in each The polyurethane horn and corpora lutea counts in each ovary were made. or polyethylene device in each rabbit was weighed on an analytical balance before insertion and after removal from the uterus.

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CONTRACEPTION

Upon termination of a study, all animals received a complete postmortem examination, with emphasis on the pelvic organs and abdominal viscera. The nature, location, and extent of all lesions were recorded. Target organs (reproductive tract), and all lesions were fixed in buffered formalin. CELCh female genital tract was affixed by stapling to a card; the treated and untreated horns were identified, and the location of the device indicated by pencil marks. Tissues were processed to hematoxylin-eosin slides for histopathologic evaluation. Evaluation criteria were (a) cellular reaction in endometrium and/or stroma; (b) infection in lumen, endometrium, and/or stroma; (c) endometrial hyperplasia; (d) endometrial metaplasia; (e) tumors; and (f) lesions. Correlation with irritation or reaction to a device was made whenever possible. The pathologist (DPS) was uninformed of the treatment of each animal when examining the slides.

RESULTS

The results of the two separate experiments are shown in Table 1. In the first experiment, two of four rabbits with polyethylene devices had no embryos in the treated horn whereas all four had embryos in the In contrast, none of the polyurethane IUDcontralateral control horn. containing horns had embryos and only two of the contralateral horns contained embryos. Thus, two animals in the polyurethane group were not pregnant. Two of three in the sham operated rabbits were pregnant and The results of the second experiment had embryos in both uterine horns. were similar to the first. Two of six rabbits with polyethylene IUDs had embryos in the treated horns but only four of the six in the group Of the two nonwere pregnant or had embryos in the contralateral horn. pregnant rabbits in the polyethylene IUD group, one had corpora lutea in an advanced stage of regression, which was confirmed histologically. None of the horns in the five rabbits containing a polyurethane IUD had embryos. A sixth rabbit expelled the polyurethane IUD from the uterine horn at an unknown time and is therefore not included in the data of Table I. This rabbit had embryos in both uterine horns at necropsy. Both non-pregnant polyurethane IUD-bearing animals had regressing corpora lutea which was histologically confirmed. Luteal regression caused by an IUD had been previously observed in ewes (6, 7). The silk suture in the uteri of controls without IUDs did not impair In the second pregnancy in the sham operated horn in both experiments. experiment, there was an unexplainable decrease of ovulation rate, based on corpus luteum count, in the uterine horns containing the polyethylene (P < 0.05) or polyurethane (P < 0.01) rods compared with the control, sham operated group.

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1979VOL.20N0.2

2

rabbits

.05 .Ol rabbit

in

in

group

Rroup

I”D*§

IUD

not

not

pregnant;

pregnant; no

embryos

found found

at at

autopsy

autopsy

315

315 416

:!6

2/4

O/L

415

213 414

?I4

embryos in

in

Number vith Embryos Number in Croup

‘!3

no

Number with Embryos Number Treated

IIJO

horn.

horn.

2 0.0.

0.0

either

either

f 1.0

f 1.0

0.0

3.0

f

3.3

0.0

2 0.0 ? 1.4

2.0

with IUD

4.0

“or”

t

+ 0.6

? 0.9

3.0

2.7

1.5

* 1.0

3.7

6.0

? 1.2

5.0

0.5

f

5.5

Control “or”

Embryo Count nean ? S.E.

MD

i

3.3

2

f

3.3

7.0

f

0.x:+

0.1**

0.7

1.1

0.7 5.8

? 2.1 t

5.0

IUD

Lutea

5.3

5.0

5.8

7.0

5.0

7.7

0.9

I

:

:

:

7.9

j.2

!.9

0.6

1 1.3

I

Over-Control Horn

of Corpora in Each Ovary Mea” f S.E.

6.0

Over-Treated “or”

Number

expelled from uterine horn of one rabbit i-hich had 6 embryos in the treated horn, 4 in the contralateral horn. These data are not included in results. Two “onpregnant rabbits had corpora lutea in advanced stages of regression; not included in calculati”R mean “umber corpora lutea. One “onpregnant rabbit had corpora lucea in advanced stages of regression; not included in calculatinR mea” “umber corpora lucea. Uterine horns without embryos or ovaries with regressing corpora lutea are excluded from the means.

P ( P c One I‘ve

Polyecher

IUD

urethane

operated*

Polvethyle”e’6

Sham

Experiment

Polyether

1

urethane

operated*

Polyethylene

Sham

Experiment

HOI-”

containing

I

ANTIFERTILITY ACTIVITIES OF POLYETHYLENE POLYLXETHANE DEVICES IN THE RABBIT

Table

CONTRACEPTION Pathological evaluations were performed on uterine sections taken from the site where the endometrium had been in direct contact with an Combining IUD or at a similar location in the sham operated animals. the results of both experiments, no inflammatory response, as evidenced by leukocytic infiltration, was observed in the endometrium adjacent to Two rabbits showed a polyurethane device in any of the nine rabbits. In contrast, six of small amounts of cell debris in the uterine lumen. ten animals with polyethylene devices showed leukocytic infiltration in Of the the stroma and eight of ten showed cellular debris in the lumen. six animals with leukocytic infiltration, two had lipomatous polyps. In agreement with the observations of Davis et &. (1) all polyethylene rods were surrounded by a "purulent slippery-like material" when In contrast, the polyurethane rods were free of removed at necropsy. the slippery material but had a rubbery-gelatinous consistency upon removal. The polyurethane devices used in these experiments had a mean water uptake of 21.7% compared with 0.2% forthepolyethylene devices (P < O.Ol), based on weight differences before insertion of the IUDs and following It is possible to vary the water uptake and removal during necropsy. strength of the polyurethanes by variation in ratios of starting materials and bonding between polymer chains.

DISCUSSION

With the increasing numbers of IUD users, a search for new polymers that would increase safety, contraceptive effectiveness, life span of IUDs, and would also diminishunwanted side effects, appears appropriate at this time. The preliminary results of these experiments indicate better contraceptive action and a diminished inflammatory response for a polyether urethane compared with polyethylene in rabbits. The increased contraceptive efficacy may be the result of a different mechanism of action compared with polyethylene polymers presently in use. The hydrophilic nature of this prototype may contribute to the high degree of contraceptive efficacy observed in our first studies with rabbits. The rubbery-gelatinous consistency, its swellability after one month of residence in the rabbit uterus, and the lack of accumulation of slippery, purulent material which often accumulates around IUDs should result in better uterine retention. Davis et -- al. (1) also observed improved uterine tolerance of copper bearing hydrogel IUDs compared with polyethylene. They also observed an accumulation of slippery purulent material around polyethylene IUDs but not around hydrogel IUDs.

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1979 VOL. 20 NO. 2

CONTRACEPTION

Our experience indicates that polyether urethanes can be "tailor made" These could even include polymers with for highly specific functions. permeability to ions and compounds capable of sustained and controlled However, these experiments suggest that polyether urerelease (4, 8, 9). tl%lIleS of high tissue compatibility may be useful for IUDs without the requirement of copper or other slow releasing drugs. There are two ways to obtain a completed IUD with both the required One approach is to vary the rigidity and the required hydrophilicitv. molecular weight and composition of the polyether, which imparts the A second approach is to form the inner core from a hydrophobic rigidity. polyether urethane with the appropriate rigidity and then apply an outer coat of hydrophilic polymer. The concept of using two polyethers for the synthesis of segmented polyether urethanes was proven in the development of a material for intraaortic balloons (4). This concept was extended to include the use of a polyether of two different types in making polymers for preliminary studies cited herein. Consequently, it shoulsl be possible to make a polyether urethane with the right rigidity and the desired hydrophilicitv for a particular application. Polyurethanes have been designed for highly specific purposes which As an additional goal, it seems include good compatibility with blood. reasonable to attempt to design a polymer that not only has good tissue compatibility at the region of contact with the endometrium but one that would substantially reduce undesirable side eEfects, viz. the increased bleeding, protrusion through the uterus, pain and other discomforts, inflammatory response and uterine expulsion of the IUD. Good contraceptive efficacy coupled with the lack of a requirement for drug or copper release should impart a life span of long duration to such a well designed polvurethane IUD. Considerable toxicological data of substances of the same class of polyether urethane are available and clinical testing of heart assist devices with segmented polyether urethanes have been performed (l-4). This background information should help shorten the interval between animal and clinlcal studies.

CONCLUSIONS

Swellable hydrophilic polyurethane IUDs with good tissue compatibility give promise of improved efficacy and durabilj.ty. They can be specially developed and fabricated for these characteristics and for the avoidance of undesirable side effects. Approval for human trial will depend upon demonstration of safety in a variety of pre-clinical tests.

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CONTRACEPTION

REFERENCES

1.

Davis, R. H., Scott, H., Kyriazis, G. A. and Balin, H. The antifertility effect and improved tolerance of copper hydrogel coaced intrauterine devices in rabbits. Proc. Sot. Exp. Biol. Med. 147: 407-411 (1974).

2.

Boretos, J. W. and Pierce, W. S. Segmented polyurethane: a new elastomer for biomedical application. Science 158:1481-1482 (1968).

3.

Boretos, Donachy, urethane (1975).

4.

Brauman, S. K. and Fritzinger, B. K. Transport properties of new copolyether-ester and copolyether-urethane dialysis membranes. J. Appl. Polymer Sci. 16:2439-2441 (1972).

5.

Brash, J. L., Fritzinger, B. K. and Bruck, S. D. Development of block copolyether urethane intra-aortic balloons and other medical J. Biomed. Mater. Res. 7:313-334 (1973). devices.

6.

Hawk, H. W. Physiologic responses to conception control methods domestic animals. J. Am. Vet. Med. Assn. 157:1795-1799 (1970).

7.

Warren, bearing

8.

Fritzinger, B. K., Brauman, S. K. and Lyman, D. J. Permeability J. Biomed. parameters and frictional coefficients for cuprophane. Mater. Res. 5:3-16 (1971).

9.

Brauman, dialysis

98

J. W., Pierce, W. S., Bauer, R. E., Leroy, E. F. and H. J. Surface and bulk characteristics of a polyether for artificial hearts. J. Biomed. Mater. Res. 9:327-340

Corpus luteum regression J. E.,Jr. and Hawk, H. W. ewes. J. Animal Sci. 33:270-271 (1971).

S. K. and Fritzinger, B. K. J. Biomed. Mater. membrane.

in

in IUD-

Transport properties of a new Res. Symposium 1: 31-41 (1971).

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