Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~ 3~ ARC-756
- ELASTOMERIC BLADDERS FOR MEDICAL INFUSERS
Description
s
Technical Field
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The invention relates to synthetic polyi~oprene bladder~
~or medioal infusers which have improved reslstance to ~pon-
taneous rupture.
Background Art
Medical devices that infuse liquids into patients are
called infusers. One type of infuser uses an elastomeric bladder
as its power so~rce. Such infusers and bladders are described
in U.S. Patents NQS. 3,993,069 and 4,201,207. These infusers
consist of a housing, an elastomeric bladder contained within
the housing that is inflated with the liquid to be infused,
and a conduit that leads from the bladder to the infusion site.
The rate at which the liquid is infused from the infuser depends
upon the pressure exerted on the liquid by the bladder, the
~isc03ity of the liquid, and the ~low restriction characteristics
of the conduit. The above cited patents describe bladders
that are capable of maintaining the pressure on the liquid
3ubstantially constant over discharge o~ a large proportion of
the liquid. The bladder~ de3cribed in these patents are made
from vulcanized synthetic polyisoprene that has a low frequency
hy~teresis less thar about 1~% and a stress relaxation less
than about 10~. Such hysteresi~ and stress relaxation charac-
teristics were considered as key factors in realizing substan-
tially constant pressure performance.
In making large numbers of such bladders from synthetic
polyisoprene it was found that a small but significant number
of them ruptured when inflated- particularly after prolonged
storage in an inflated state. Even though only a small portion
of the bladdes 30 ruptured it was desirable to decrease the
incidence o~ rupture in order to provide a greater margin of
safety against rupture in the marketplace~ The above patent~
say nothing about reducing the incidence of bladder rupture.
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The present invention seeks to provide synthetic polyisoprene bladders
that have a reduced incidence of rupture and acceptable pressure conskancy per-
formance.
One aspect of the invention is an elastomeric bladder for use in a
medical infuser that has improved resistance to rupture when :inflated, the b:lad-
der being a tubular body
(a) made from a vulcanized homogeneous mixture of synthetic polyisoprene
having about 90% to about 98% cis-1,4 linkages and particulate silicon dioxide
or particulate carbon black which have a nominal average diameter in the range
of about 1 x 10 5 to about 5 x 10 3 mm and
(b) into which a nontoxic substantially nonleachable antioxidant has been
diffused, the amounts of silicon dioxide or carbon black and antioxidant being
sufficient to make the half-life of a population of the bladders at least about
ten times longer than the half-life of a comparable ~opulation of bladders made
from said vulcanized synthetic polyisoprene that do not include the silicon di-
oxide or carbon black and do not include the antioxidant.
Another aspect of the invention is a process for making an elastomeric
bladder ~or use in a medical infuser and having an improved resistance to rup-
ture when inflated comprising:
(a) mixing homogeneously a synthetic polyisoprene having about 90% to about
95 % cis~-1,4 linkages, about 3 to about 10phr particulate silicon dioxide or
particulate carbon black which have a nominal average diameter in the range of
about 1 x 10 5 to about 5 x 10 3 mm, and an amount of vulcanizing agent suffi-
cient to vulcanize the mixture,
(b) subjecting the mixture to vulcanizing conditions while simultaneously
(c) forming the mixture into a tubular body;
(d) solvent extracting the degradation products of the vulcanizing agent
from the body; and
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(e) diffusing about 0.2 ta about 2 phr of a nontoxic substantially non-
leachable antioxidant into the body by contacting the body with a liquid solu-
tion of the antioxidant.
As used herein the designation "phr" means parts per hundred parts of
synthetic polyisoprene.
The synthetic polyisoprene that is used to make the bladders has about
90% to about 98% of its monomeric units jained in cis~ orientation. lt is
preferably of the type made using Ziegler catalysts which is characterized by
having about g6% to about 98% cis~ linkages. This polyisoprene is mixed homo-
geneously with particulate silicon dioxide or particulate carbon black or mix-
tures thereof which have the above indicated particle size. Fumed silicon di-
oxide is preferred. Such silicon dioxide is produced by the hydrolysis of sili-
con tetrachloride vapor in a flame of hydrogen and oxygen at temperatures above
the fusion temperature of silica (ca 1710 C). In this combustion process molten
spheres of silica are formed that on cooling fuse with one another to form
branched, three-dimensional, chain-like aggregates. The final product typically
has a surface area in the range of about 150 to about 450 m2/gram as measured by
the BET method. Such fumed silicon dioxides are sold by Cabot Corporation,
Boston, Mass. under the trademark Cab-0-Sil ~ . The carbon black will typically
have a surface area in the range of about 50 to about 250 m2/gram as measured by
the BET method. The amount of silicon dioxide or carbon black that is mixed with
the polyisoprene should be sufficient to substantially inhibit spontaneous rup-
ture of the bladder due to the stresses that occur in the bladder walls when the
bladder is inflated with medical fluid. About 3 to about 10 phr, preferably 3
to 7 phr, of the silicon dioxide or carbon black will normally be mixed with the
synthetic polyisoprene. Lesser amounts will not give a significant increase in
rupture resistance. More ~han 10 phr may be added, but such amounts do not pro-
duce correspondingly greater enhancement of rupture resistance and may affect
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the pressure constancy performance of the bladder adversely.
The polyisoprene-silicon dioxide/carbon black mixture is vulcanized
to form carbon-to-carbon or monothio crosslinks at the 1 and ~ positions of the
isoprene unit. To achieve such vulcanization a vulcanizing agent is added to
the mixture and the mixture is subjected to vulcanizat:ion conditions. Vulcan-
izing agents and procedures that may be used are disclosed in United States
Patent No. 4,201,207 at column 2, line 54 to column 3, line 13 and in United
States Patent No. 3,993,069 at column 8, line 50 to column 10, line 25.
Dicumyl peroxide added in amounts in the range of about 1 to 2 phr is a pre-
ferred vulcanizing agent. The vulcanization will typically be effected during
the forming process that is used to make the tubular bod:ies from the mixture.
One such process involves calendering the polyisoprene-silicon dioxide/carbon
black-vulcanizing agent mixture into a sheet and placing a disc-shaped segment
of the sheet into a transfer mold that forms the sheet into hollow cylindrical
tubes of the desired geometry. Conventional injection molding techni~ues may
also be used to form the body. The molding temperature, pressure, and time are
such as to achieve the desired vulcanization (crosslinking) of the polyisoprene.
The geome~ry of the tubular bodies is the same as that disclosed in United
States Patent No. 3,993,069 at column 4, lines 26 to 41.
After the mixture is formed into tubular bodies, the bodies are ex-
tracted with a solvent that removes substantially all unreacted vulcanizing
agent and the degradation products of the vulcanizing agent from the body. The
solvent should have no lasting deleterious effects on the body and should not
leave a toxic residue in or on the body. The particular solvent used and the
extraction time and temperatwre will depend upon the vulcanizing agent that
was used. The purpose of the extraction is to prevent contamination of the
medical fluid that is ultimately charged to the bladder with the vulcanizing
agent or its degradation products.
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v v ARC-756
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After the extraction, the antioxidant is imbibed into the
bodies by placing them into contact with a solution of the
antioxidant. The antioxidant enters the bodies9 whlch ar~
usually swollen several fold with solvent~ by diffusion. The
amount of antioxidant imbibed into a body will, accordingly~
depend upon the diffusion coefficient of the body with re~pect
to the antioxidant, the concentration of the antioxidant ln
the solution, the solubility of the antioxidant in the body,
the thickness of the body5 the equilibrium swelling volume
that is characteristic of ~he elastomeric-solvent combination,
and the conditions (time and temperature) under which the
contact is made. Preferably the same pure solvent is used for
the extraction and antioxidant imbibition. The amount of
antioxidant imbibed into the body should be sufficient to
1S inhibit oxidative degradation (and thus rupture) of the bladder,
usually over a period of at least about one year. The quantity
required to achieye such inhibition will depend on the particular
antioxidant that is used.- In the case of the hindered phenol
antioxidants described below, about 0.2 to about 2 phr,
pre~erably about 1 phr, will usually be imbibed. Antioxidants
2~ that are nontoxic, such as those approved and under the provi
sions of Title 21 of the Code of Federal Regulations for use
in plastics that are used in association with drugs or food,
and whieh are substantially nonleachable by the medical fluid
with which the bladder is to be inflated may be used. The
term "substantially nonleachable" means that the antioxidant
is less than Q.1% by weight soluble in the medical fluid.
Nontoxie hindered polyphenol antioxidants) such as tetrakis
emethylen~ 3-(3',5'~di-t-butyl-4'-hydroxyphenyl) propionate~
methane and 1,3,5-trimethyl-2,456-tris(395-di-t-butyl-4-4-
hydroxybenzyl~ benzene, are pre~erred antioxidants for use inthe invention. After the desired amount of antioxidant has
di~fused into th0 body, the body is taken from the solution
and the solvent is removed from the body9 such as by drying at
tempera~ures up to 50 C. At this stage, the bladder is ready
for incorporation lnto the infuser.
~ 3~7
ARC-756
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The incluslon of the silicon dioxide or carbon black and
the antioxidant in the bladder together substantially reduce
the likelihood that the bladder will rupture spontaneously
when it is in~lated. T~is reduction (or increase in rupture
re~istance) may be quantified relative to ~ynthetic polyisoprene
bladders that do not contain silicon dioxide or carbon black
and antioxidant by comparing the half-lives of populations of
the respective bladders under the same inflation conditions.
The half-life is the time period from inflation to rupture of
50~ of the bladders in the population. A population of at
least ten bladders is desired to ensure that the results are
statistically significant. Such comparisons carried out at
40 C indicate that the half life of the invention bladders i3
at lea~t 10 times, and typically more than 100 times, longer
than the half-life of bladders that do not contain silicon
dioxide or carbon black and antioxidant.
The ~ollowing example illustrates one embodiment of the
invention. This example is not intended to limit the invention
and is of~ered only by way of exemplificationO
2~ Preparation of Mixture
One hundred parts of synthetic polyisoprene (Natsyn 2200 ,
96% to 98% cis-1,4 linkages) were added to a Farrell Laboratory
Mill (6 in. x 13 in. roll~) at 130 + 10 F and the gap between
rolls was adjusted to 0.08~0.09 in. After about 3 minuteq of
milling, 5.0 phr fumed silicon dioxide (Cab-O-Sil~ M5, 200 +
25 m2/gram surface area, 1.4 x 10-5 mm nominal average diameter)
were added to the mill over a 5 min. period. One and one-half
phr o~ dicumyl peroxide (Di Cup R~ were then added to the
polyisoprene-silicon dioxide mix in four equal portions.
Milling was continued until at least 18 min. had elapsed from
the time the polyisoprene was added to the mill.
Vulcanization and Mold ng
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The above mixture was charged to a four-cavity transfer
mold maintained at 325-330 F and having 25,000 kg of clamping
force. The mold cavities and mandrels were designed to make
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Trademark
~L2~
ARC-756
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hollow cylindrical bladders 75.6 mm long with a 6.63 mm outer
diameter and 5.16 mm inner diameter having diameter and having
an integral circular flange at each end 1.587 mm wide and 12.7 mm
in diameter. The curing time was 20 min~
Extraction
Bladders ~ormed and vulcanized as above were placed
vertically in the extraction pot of a Soxhlet exkraction
apparatus fitked to a 1000 ml flask. Enough ethyl acetate was
added to fill the Soxhlet apparatus and have 250 ml of ethyl
acetate in the ~lask. The flask was heated and extraction of
the bladders with the ethyl acetate was carried out for four
hours.
Imbibition of Antioxidant
A 1.1% by weight solution of 1,3,5-trimethyl-2,4,6-tris(3,4-
di-t-butyl-4-hydr~xybenzyl) benzene in ethyl acetate was placed
in a ~lask. Freshly extracted bladders were placed into-the
solution and kept there at a~bient temperature for four hours.
Previous tests had shown that the relationship between the wt.
~ % oY this antioxidant imbibed into the bladders was linear
with 0.45% imbibed at a 1% concentration, and 0.68% imbibed at
1.5% concentration (~our hours imbibition time). Accordingly
about 0.5 phr antioxidant was imbibed into the b]adders.
~5 Half~ e Tests
.
Half li~e test~ were carried out on bladders prepared as
above except that 1.2 phr o~ tetrakis Lmethylene 3-(3',5'-di~
t-butyl-4'-hydroxyphenyl) propionate~ methane was imbibed into
the bladders ~rom an acetone/toluene solution instead of the
above described antioxidant. A population of 24 o~ these blad-
ders inflated with 60 ml water and kept in air at 40 C had a
hal~ life of approximately 14 months. Similar tests on popula-
tions of synthetic polyisoprene bladd~r~ made in substantially
the same manner but without silicon dioxide or antioxidant
indieate such bladders have a half-life of about 1 to 2 days.
Modification of the above-described bladders that are
obvious to those o~ ordinary skill in the arts related to the
invention are intended to be within ~he scope of the following
claims.
