NL8200218A - ELASTOMERIC BLADES FOR MEDICAL INFUSION DEVICES. - Google Patents

Description

V * IT.o. 30,765

Elastomeric bladders for medical infusion devices.

The present invention relates to synthetic polyisoprene bladders for medical infusion devices that have improved spontaneous rupture resistance.

Medical devices that add fluids to 5 patients by infusion are called infusion devices. One type of infusion device uses an elastomeric bladder as the power source. Such infusion devices and bladders are described in U.S. Pat. Nos. 3,999,669 and 4,201,207. These infusion devices consist of a housing, an elastomeric bladder, which is present in the housing, which is filled with the liquid to be infused and a conduit leading from the bladder to the infusion site. The rate at which the fluid from the infusion device is added depends on the pressure exerted on the fluid by the bladder, the viscosity of the fluid and the flow limiting properties of the line.

The aforementioned patents disclose bladders capable of keeping the pressure on the fluid substantially constant during the discharge of a large amount of the fluid. The bladders described in these patents are made from vulcanized synthetic polyisoprene, which has a low frequency hysteresis less than about 10% and a stress relaxation less than about 10%. Such hysteresis and stress relaxation properties were considered key factors in achieving a substantially constant pressure behavior.

In the manufacture of large numbers of such blisters from synthetic polyisoprene, it has been found that a small, but substantial, number of them broke upon filling, especially after continued storage in a filled state. Even though only a small portion of the bladders thus broke, it was desirable to reduce the occurrence of breakage to provide a greater margin of safety against breakage at the site of use. The aforementioned patents do not mention anything about reducing the incidence of bladder rupture.

A primary object of the present invention is to provide synthetic polyisoprene bladders that have a reduced fracture appearance and an acceptable constant pressure behavior.

8200218

• V

One aspect of the invention is an elastomeric bladder for use in a medical infusion device, which has improved resistance to breakage upon filling, which is a tubular body 5 (a) made from a vulcanized homogeneous mixture. of synthetic polyisoprene with about 90% to about 98% cis-1.4 bonds and particulate silica or particulate carbon black, which has a nominal mean diameter in the range -5-3 from about 1x10 to about 5-10 m and 10 (b) in which a nontoxic, substantially non-washable antioxidant has diffused, wherein the amounts of silica or carbon black and antioxidant are sufficient to make the half life of a number of blisters at least about ten times longer than the half life of a comparable number of bubbles made from the vulcanized synthetic polyisoprene, which does not contain the silica or carbon black and the antioxidant.

Another aspect of the invention is a method of manufacturing an elastomeric bladder for use in a medical infusion device and with an improved resistance to breakage at filling comprising: (a) homogeneously mixing a synthetic polyisoprene with about 90 % to about 98% cis-1.4 bonds, about 3 to about 10% particulate silica or particulate carbon black, which have a nominal average diameter in the range -5-3 from about 1 x 10 J to about 5 x 10 mm and an amount of vulcanizing agent sufficient to vulcanize the mixture, (b) subjecting the mixture to vulcanizing conditions, while at the same time (c) molding the mixture into a tubular body; (d) the degradation products of the vulcanizing agent from the body are extracted with solvent and (e) about 0.2 to about 2% of a non-toxic, substantially non-washable antioxidant in the body is diffused through the body into contact with a liquid solution of the antioxidant.

As used herein, the term means percent parts per hundred parts synthetic polyisoprene.

Preferred embodiment of the invention.

The synthetic polyisoprene used for the 8200218% -3 manufacture of the bladders has united about 90% to about 98% of the monomer units in requirement 1.4 orientation. It is preferably of the type, as manufactured using Ziegler catalysts, which is characterized by about 96% to about 98% cis-1,4 bonds. This polyisoprene is homogeneously mixed with particulate silicon dioxide or particulate gaseous or mixtures thereof having the particle size indicated above. Smoked silica is preferred. Such silica is prepared by hydrolysis of silicon tetrachloride in a flame of hydrogen and oxygen at temperatures above the melting temperature of silica (about 1710 ° C). In this combustion process, molten silica spheres are formed, which bake together on cooling to form branched, three-dimensional, chain-like aggregate holes. The final product usually has a specific surface area in the range of from about 150 to about 450 m / gram as measured by the BET method. Such smoked silicon dioxides are sold by Cabot Corporation, Boston, Mass, under the tradename Cab-O-Sil. The carbon black will usually have a specific surface area in the range from about 50 to about 250 m / gram as measured by the BET method. The amount of silicon dioxide or carbon black mixed with the polyisoprene should be sufficient to prevent substantially spontaneous rupture of the bladder due to stresses occurring in the bladder walls when the bladder is filled with medicated fluid.

About 3 to about 10%, preferably 3 to 7%, of the silica or carbon black will usually be mixed with the synthetic polyisoprene. Smaller amounts will not significantly increase fracture resistance. More than 10% can be added, but such amounts do not give a correspondingly greater increase in fracture resistance and can adversely affect the bladder pressure consistency behavior.

The polyisoprene-silica / carbon black mixture is vulcanized to form carbon-carbon or monothio cross bonds at positions 1 and 4 of the isoprene unit. To achieve such vulcanization, a vulcanizing agent is added to the mixture and the mixture is subjected to vulcanization conditions. Tulcanizing agents and methods which can be used are described in U.S. Patent No. 4 * 201,207, column 2, line 54 to column 3, 8200218 * * -4 line 13, and in U.S. Patent 3,995,069> column 8, line 50 to column 10, line 25. Dicumyl peroxide, added in amounts in the range of about 1 to 2%, is a preferred vulcanizing agent. Vulcanization will usually be carried out during the molding process used to manufacture the tubular bodies from the mixture. Such a method involves calendering the polyisoprene-silica / carbon black vulcanizing agent mixture into a layer and placing a disc-shaped segment of the layer 10 into a transfer form, which forms the layer into hollow cylindrical tubes of the desired geometry. Conventional injection molding techniques can also be used to form the body. The forming temperature, pressure and time are such that the desired vulcanization (cross-linking) of the polyisoprene is achieved. The geometry of the tubular bodies is the same as described in U.S. Patent 3,993.0é9 column 4, lines 26 to 41

After the mixture is formed into tubular bodies, the bodies are extracted with a solvent which removes substantially all unreacted vulcanizing agents and the degradation products of the vulcanizing agent from the body. The solvent should not have any lasting harmful effects on the body and should not leave any toxic residue or on the body. The particular solvent used and the extraction time and temperature will depend on the vulcanizing agent used. The purpose of the extraction is to prevent contamination of the medicinal liquid, which is finally added to the bladder with the vulcanizing agent or its breakdown products.

After the extraction, the antioxidant is absorbed into the bodies by. contacting it with a solution of the antioxidant. The antioxidant enters the bodies, which are usually multi-swollen with solvent by diffusion. The amount of antioxidant incorporated into a body will therefore depend on the diffusion coefficient of the body with respect to the antioxidant, the concentration of the antioxidant in the solution, the solubility of the antioxidant in the body. , the thickness of the body, the equilibrium sz-w & 'volume characteristic of the elastomer-solvent combination and the conditions (time and temperature) under which the contact was made. Preferably, the same pure solvent is used for the extraction and uptake of antioxidant. The amount of antioxidant absorbed into the body should be sufficient to inhibit oxidative breakdown (and therefore rupture) of the bladder, usually; for a period of at least about 1 year. The amount required to achieve such inhibition will depend on the particular antioxidant used. In the case of the hindered phenol antioxidants as described below, usually about 0.2 to about 2%, preferably about 1%, would be included. Anti-oxidants, which are non-toxic, such as those authorized under the provisions of Chapter 21 of the Code of Federal Regulations for use in plastics, which are used in conjunction with 15 drugs or nutrients, and which are substantially non-washable by the medicated fluid used to fill the bladder can be used. The term "substantially non-washable" means that the antioxidant is less than 0.1% by weight soluble in the medicinal liquid. Non-toxic hindered polyphenol antioxidants such as teirakis [methylene 3- (3 5'-di-tert-butyl-4'-hydroxyphenyl) propionate, methane and 1,5,5-trimethyl-2,4'-tris (3,5- (2'-1'-1'-1'-yl) -7-) 4-4-hydroxy-benzyl) benzene are preferred antioxidants for use in the invention After the desired amount of antioxidant has diffused into the body, the body is taken out of solution and the solvent is removed from the solution. removed from the body such as by drying at temperatures up to 50 ° C.

At this stage, the bladder is ready for admission into the infusion device.

Inclusion of the silica or carbon black and the antioxidant in the bladder together greatly reduces the likelihood that the bladder will spontaneously break when filled. This reduction (or increase in resistance to fracture) can be measured with respect to synthetic polyisoprene bladders, which do not contain silica or carbon black and antioxidant by comparing the half-life times of numbers of the respective bladders under the same recording conditions, Be half-value time is the time period from inflation to fracture of 50%> of the bladders in the total number.

40 A number of at least 10 bladders is desired to ensure that the results are statistically significant. Such comparisons, conducted at 40 ° C> show that the half-life of the blisters of the invention is at least 10 times and usually more than 100 times longer than the half-life of 5 blisters, which do not contain silica or carbon black and antioxidant .

Preparation of a mixture.

One hundred parts of synthetic polyisoprene (ïTatsyn 2200, 96% to 98% cis-1,4 bonds) were added to a Farrell laboratory 10 mill (rollers 15 cm x 34 cm) at 54 + 5 ° C and the gap between the rollers was set to 20-2.3mm .Ha about 5 minutes grinding, 5% fumed silica (Cab-0-Sil M5, 2-5 200 + 25m / gram specific surface, 1.4 x ΙΟ- '' mm nominal mean diameter) to the roller in 5 minutes. 1.5% di-15 cumyl peroxide (Di Cup R) were then added to the polyisoprene-silica mixture in four equal proportions.

Grinding was continued until at least 18 minutes elapsed from the time the polyisoprene was added to the roller.

20 Vulcanizing and Shaping.

The foregoing mixture was fed into a four-cavity transfer mold maintained at a temperature of 163 DEG to 166 DEG C. and a clamping force of 25,000 kg. The mold cavities and mandrels were designed to produce hollow cylindrical bladders of 75-6 mm in length, with an outer diameter of 6.63 mm and an inner diameter of 5.16 mm and with an inner round flange at each end with a width of 1,587 mm and a diameter of 12.7 mm. The curing time was 20 minutes.

Extraction.

Bladders, formed and vulcanized as before, were placed vertically in an extraction pot of a Soxhlet extractor equipped with a 1000 ml flask. Sufficient ethyl acetate was added to fill the Soxhlet apparatus with 250 ml of ethyl acetate in the flask. The flask 55 was heated and extraction of the bladders with ethyl acetate was performed for 4 hours.

Intake of antioxidant.

A 1.1 wt% solution of 1,3,5-trimethyl-2,4'-6-tris (3,4-di-tert-butyl-4-hydroxybenzyl) benzene in ethyl acetate was placed in a flask. Freshly extracted bladders were placed in the solution 8200218 z * -7- and kept there at ambient temperature for 4 hours. Previous tests had shown that the relationship between the weight percent of this antioxidant incorporated into the bladders was linear with 0.45% included at a concentration of 1% and 5 0.68% included at a concentration of 1.5 % (recording time 4 hours).

As a result, about 0.5% antioxidant was incorporated into the bladders.

Dry over the half-life.

Half-lives were carried out on blowing, prepared as described above, except that 1.2% tetrakis [methylene 3- (3 ', 5'-di-tert-butyl-4-hydroxyphenyl) propionate] methane in the bladders were taken up from an acetone / toluene solution in place of the above-described antioxidant. Some 24 of these bladders filled with 60 ml of water and kept in air at 40 ° C had a half-life of about 14 months. Similar tests on numbers of synthetic polyisoprene bladders, manufactured in substantially the same manner, but without silica or antioxidant, have shown that such bubbles have a half-life of about 1 to 2 days.

Modifications of the above-described bladders, which are obvious to those skilled in the art, are also within the scope of the present claims.

8200218

Claims (15)

1. Elastomeric bladder for use with a medical infusion device. . containing a tubular body formed from a vulcanized homogeneous mixture of synthetic polyisopene having from about 90% to about 98% cis-1,4 bonds, which bladder has improved filling resistance and is characterized by the presence of particulate silicon dioxide or particulate carbon black with a nominal average diameter in the range of from about 1x10 to about 5x10 mm and a non-toxic, substantially non-washable antioxidant, the amounts of silica or carbon black and antioxidant being sufficient to make the half-life of some of the blisters at 40 ° C at least about 10 times greater than the half-life of a comparable number of blisters made from the vulcanized synthetic polyisoprene, but without the silica or carbon black and the antioxidant . Bladder according to claim 1, characterized in that the particulate silicon dioxide is fumed silicon dioxide and is present in amounts of 5 to 10%, Bladder according to claim 1 or 2, characterized in that the synthetic polyisoprene has about 9% to 98% cis-1,4 bonds. Bladder according to claims 1 to 5? characterized in that the vulcanized synthetic polyisoprene carbon has 25. carbon cross-links. Bladder according to Claims 1 to 4, characterized in that about 0.2 to about 2% of the non-toxic, substantially non-washable antioxidant is present. 6. Bladder according to claims 1, 3, 4 or 5, characterized in that about 3 to about 7% of smoked silica with a specific surface area are present in the range of from about 150 to about 450 m / gram. Bladder according to claim 6, characterized in that the specific surface area is 200 + 20 m / gram. 8. Blow according to claims 1 to 7> not characterized in that the antioxidant is a hindered polyphenol. Bladder according to claim 8, characterized in that the hindered polyphenol tetrakis [methylene 3- (3 *, 51> di-tert. 8200218 -9- Λ -ς-butyl-41-hydroxyphenyl) propionate methane or 1,3 5-trimethyl-2,4,6-tris (3,5-dl-tert-butyl-4-hydroxybenzyl) benzene. Bladder according to claim 9, characterized in that the bladder is vulcanized with about 1.5% dicumyl peroxide 5 and about 1% 1} 5} 5-frimethyl-2,4 »6-tris (5,5- contains i-tert-butyl-4-hydroxybenzyl) benzene. 11. A method of manufacturing an elastomeric bladder for use in a medical infusion device with improved filling fracture resistance, characterized in that a synthetic polyisoprene having from about 90% to about 98% cis-1 is used. .4 bonds, a sufficient amount of particulate silicon dioxide or particulate carbon black, which has a nominal mean diameter in the range of about 1 × 10 to about 5 × 10 mm for substantially spontaneous rupture of the bladder due to stress. the bladder wall caused by inhibiting bladder filling and an amount of vulcanizing agent sufficient to vulcanize the mixture homogeneously mixes the mixture vulcanizes by subjecting the mixture to vulcanization conditions, at the same time: (a) turning the mixture into a tubular body (b) unreacted vulcanizing agent and the breakdown products of the vulcanizing agent from the body by solvent are extracted and (c) a non-toxic, substantially non-washable antioxidant, is diffused into the body by contacting the body with a liquid solution of the antioxidant, the amount of the antioxidant diffused in the body is sufficient to substantially inhibit the oxidative degradation of the body., 12. Process according to claim 11, characterized in that the synthetic polyisoprene is mixed with fumed silica. Process according to claim 12, characterized in that an amount of fumed silica 55 is used from about 3 to about 10%, the antioxidant being a hindered polyphenol and the amount of antioxidant being about 0.5 to about 2% amounts. 14. Process according to claim 13, characterized in that a smoked silicon dioxide with a specific surface area of 200 + 20 m / gram is used, wherein the amount of 8200218 VV * -10- smoked silica is 5%, the vulcanizing agent dicumyl- peroxide, the amount of vulcanizing agent is 1.5%, the antioxidant tetrakis [methylene 3- (3% 5% di-tert-butyl-4'-hydroxy-phenyl) propionate] methane or 1,3-trimethyl-2 4,6-tris (3,5- <ii -tert. 5 butyl-4-hydroxybenzyl) benzene and the amount of anti-oxidant is about 0.2 to about 2%. Process according to claim 14, characterized in that the antioxidant used is 1,3,5-trimethyl-2,4,6-tris (3,5 "ii" tert-butyl-4-hydroxybenzyl) benzene wherein the amount of the antioxidant is 1%, the solvent is ethyl acetate, and the antioxidant is dissolved in ethyl acetate. --- 000O000 --- 8200218