SE452711B - ELASTOMES BLADE FOR USE IN A MEDICAL INFUSION DEVICE AND SET FOR THE PREPARATION OF THE BLADE - Google Patents

Description

According to the invention, there is provided an elastomeric bladder for use in a medical infusion device, consisting of a tubular body formed of a vulcanized homogeneous mixture of synthetic polyisoprene having about 90% to about 98% cis-1,4 bonds, which bubble has improved resistance to rupture, when filled, and which is characterized in that it contains from 3 to ppb particulate silica or particulate carbon black with a nominal average diameter in the range from about 1 x 10-5 to about 5 x 10_3 mm, and from about 0.2 11111 about 2 ppb of a non-toxic, substantially non-leachable antioxidant, the amounts of silica or carbon black and antioxidant being sufficient for the half-life of a population of blisters at 40 ° C to be at least 10 times longer than the half-life of a comparable population of blisters, made from the vulcanized synthetic polyisoprene but without the silica or carbon black and the antioxidant.

The invention also relates to a process for the manufacture of an elastomeric bladder for use in a medical infusion device with improved resistance to rupture when filled, homogeneously mixing a synthetic polyisoprene with about 90% to about 98% cis-1,4 bonds. with from 3 to 10 pph of a particulate silica or particulate carbon black having a nominal average diameter in the range of about 1 x 10-5 to about 5 x 10-3 mm to substantially inhibit spontaneous rupture of the bladder due to stress in the bladder wall caused by filling the bladder, and an amount of vulcanizing agent sufficient to vulcanize the mixture and vulcanize the mixture, which is characterized by exposing the mixture to vulcanization conditions while at the same time a) forming the mixture into a tubular body, b) solvent extracting unreacted vulcanizing agent and degradation products of the vulcanizing agent from the body and c) disperses a non-toxic , substantially non-leachable antioxidant in the body by contacting the body with a liquid solution of antioxidant, the amount of antioxidant dispersed into the body being sufficient to substantially inhibit oxidative degradation of the body.

The term "ppb" refers to parts per 100 parts of synthetic polyisoprene. Best Mode for Carrying Out the Invention The synthetic polyisoprene used to make the blisters has about 90% to about 98% of its monomeric units joined in the cis-1,4 orientation. It is preferably of the type made using Ziegler catalysts, and is characterized in that it has about 96 to about 98% cis-1,4 bonds. This polyisoprene is homogeneously mixed with particulate silica or particulate carbon black or mixtures thereof having the above particle size. Indicated silicon dioxide is preferred. Such silicon dioxide is produced by hydrolysis of silicone tetrachloride vapor in a flame of hydrogen and oxygen at temperatures above the melting point of silica (about 1710 ° C). In this combustion process, molten spheres of silica are formed, which on cooling fuse with each other and form branched three-dimensional chain-like aggregates. The final product usually has a surface area in the range of about 150 to about 450 m2 / g measured by the BET method. Such vaporized silicas are provided by Cabot Corporation, Boston, Mass. under the trade name Cab-O-Sil. Carbon black usually has a surface area in the range of about 50 to about 250 m2 / g measured by the BET method. The amount of silica or carbon black mixed with the polyisoprene must be sufficient to substantially prevent spontaneous rupture of the bladder due to the stresses which occur in the bladder walls when the bladder is filled with medical fluid. About 3 to about 10 pph, preferably 3 to 7 pph of silica or carbon black are normally mixed with the synthetic polyisoprene. Smaller amounts do not give a significant increase in resistance to rupture. More than 10 pph can be added, but such amounts do not correspondingly provide greater reinforcement of the resistance to rupture and can adversely affect the constant pressure performance of the bladder.

The polyisoprene silica / carbon black mixture is vulcanized to produce carbon to carbon or monothio crosslinks in the 1- and 4-positions of the isoprene unit. To achieve such vulcanization, a vulcanizing agent is added to the mixture, and the mixture is subjected to vulcanizing conditions. Vulcanizing agents and methods that can be used are described in U.S. Patent 4,201,207, second column line 54 to third column line 13 and in U.S. Patent 3,993,069 column 8 line 50 to column 10 line 25, which publications are hereby incorporated by reference. incorporated as the reference Dicumyl peroxide is added in amounts in the range of about 1 to 2 pph as a preferred vulcanizing agent. The vulcanization is usually carried out during the manufacturing process used to make the tubular bodies of the mixture. One such method involves rolling the polyisoprene silica / carbon black mixture into a sheet and placing a sheet-shaped segment of the sheet in an injection mold which forms the sheet into hollow cylindrical tubes of desired geometry. Conventional injection molding procedures can also be used to shape the body.

Shape temperature, pressure and time are such that the desired vulcanization (crosslinking) of the polyisoprene is achieved. The geometry of the tubular bodies is the same as that described in USP 3,993,069 column 4 lines 26 to 41, which is hereby incorporated by reference.

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

After extraction, the antioxidant is absorbed into the bodies by placing them in contact with a solution of the antioxidant. The antioxidant penetrates the bodies, which are usually multiple swollen with solvents, by diffusion. Accordingly, the amount of antioxidant absorbed in a body depends on the body's diffusion coefficient of the antioxidant, the concentration of the antioxidant in the solution, the solubility of the antioxidant in the body, the thickness of the body, the swelling volume at equilibrium characteristic of the elastomer-solvent combination. during which the contact is made.

Preferably, the same pure solvent is used for the extraction and absorption of the antioxidant. The amount of antioxidant absorbed in the body should be sufficient so that oxidative degradation of the bladder (and thus rupture) is usually inhibited for a period of at least about 1 year. The amount required to achieve such inhibition depends on the particular antioxidant used. For the hindered phenolic antioxidants described below, about 0.2 to about 2 pph is preferably absorbed, preferably about 1 pph. Antioxidants which are not toxic, such as those approved in accordance with the provisions of § 21 of the Code of Federal Regulations for use in plastics, which are used in conjunction with medicinal products or foodstuffs, and which are essentially not leachable with the medicinal liquid, with which the bladder is to be filled can be used. The term "substantially non-leachable" means that the antioxidant meter is soluble to less than 0.1% by weight in the medicinal liquid.

Non-toxic hindered polyphenol antioxidants such as tetrakis [methylene-3- (3 ', 5'-di-t-butyl-4'-hydroxyphenyl) -propionate] -methane and 1,3,5-trimethyl-2,4,6 -tris (3,5-di-t-butyl-4-hydroxybenzyl) -benzene are preferred antioxidants for use in the invention.

After the desired amount of the antioxidant has diffused into the body, the body is taken from the solution, and the solvent is removed from the body, e.g. by drying at temperatures up to SOOC.

At this stage, the bladder is ready to be incorporated into the infusion device.

The incorporation of the silica or carbon black and the antioxidant into the bladder together substantially reduces the likelihood that the bladder will rupture spontaneously when filled. This reduction (or increase in deficiency resistance) can be quantified relative to synthetic polyisoprene blisters, which do not contain silica or carbon black and antioxidants by comparing the half-lives of populations of the respective blisters under the same filling conditions. The half-life is the period of time from filling until 50% of the blisters in the population rupture. A population of at least 10 blisters is desirable to ensure that the results are statistically significant. Such tests performed at 40 ° C show that the half-life of the blisters according to the invention is at least times and usually more than 100 times longer than the half-life of blisters which do not contain silica or carbon black and antioxidants.

The following examples describe an embodiment of the invention. This example does not limit the invention but is given by way of example only.

Preparation of mixture 100 parts of synthetic polyisoprene (Natsyn 2200, 96% to 98% cis -1.4 bonds) was added to a Farrell Laboratory mill (15.24 cm x 33.02 cm rolls) at 54.4 in 5, 6 ° C, and the gap between the rollers was adjusted to 2,032-2,286 mm. After about 3 minutes of grinding, 5.0 pph of steamed silica (Cab-O-Sil M5, 200 l 25 m2 / g surface area, 1.4 x 10-5 mm nominal average diameter) was added to the mill over a one-minute period. One and a half pph dicumyl peroxide (Di Cup R) was then added to the polyisoprene silica mixture in four equal portions. Grinding was continued until at least 18 minutes had elapsed from the time the polyisoprene was added to the mill.

Vulcanization and injection molding The mixture above was charged into an injection mold with four mold spaces, maintained at a temperature of 162.8-165.6 ° C and with a locking force of 000 kg. The mold cavities and mandrels were designed for the manufacture of hollow cylindrical blisters 75.6 mm long with an outer diameter of 6.63 mm and an inner diameter of 5.16 mm in diameter and an integral circular flange at each end 1.587 mm wide and 12.7 mm in diameter. The curing time was 20 minutes.

Extraction Blisters shaped and vulcanized as above were placed vertically in the extraction vessel of a Soxhlet extractor, equipped with a 100 ml flask. Sufficient ethyl acetate was added to fill the Soxhlet apparatus and so that 250 ml of ethyl acetate was present in the flask. The flask was heated and extraction of the blisters with the ethyl acetate was performed for 4 hours.

Absorption of Antioxidant 1.1% by weight solution of 1,3,5-trimethyl-2,4,6-tris (3,4-di-t-butyl-4-hydroxybenzyl) -benzene in ethyl acetate was placed in a piston. Newly extracted blisters were placed in the solution and kept there at room temperature for 4 hours. Previous experiments had shown that the correlation between the weight percent of this antioxidant absorbed in the blisters was linear, with 0.45% being absorbed at a 1% concentration and 0.68% being absorbed at a 1.5% concentration ( 4 hours absorption time). Consequently, about 0.5 pph of antioxidant was absorbed into the vesicles. 452 711 Half-life test Half-life tests were performed on blisters, prepared as above except that 1.2 pph of tetrakis [methylene-3- (3 ', 5'-di-t-butyl-4'-hydroxyphenyl) -propionate] -methane was absorbed in the blisters from an acetone / toluene solution instead of the antioxidant described above. A population of 24 of these blisters filled with 60 ml of water and kept in air at 40 ° C had a half-life of about 14 months. Similar tests with populations of synthetic polyisoprene blisters manufactured in essentially the same way but without silica or antioxidants show that such blisters have a half-life of about 1-2 days.

Modification of the blisters described above, which is obvious to the person skilled in the art in connection with the invention, is also covered by the following requirements.

Claims (14)

10 15 20 25 30 35 452 711 Patent claims An elastomer bladder for use in a medical infusion device. consisting of a tubular body. formed from a vulcanized homogeneous mixture of synthetic polyisoprene with about 90 h to about 98 2 cis-1,4 bonds. which bladder has improved resistance to rupture. when refilled, and is characterized in that it contains from 3 to 10 pph particulate silica or particulate carbon black with a nominal average diameter in the range from about 1 x 1o'5: 111 about sx 1o'3 ma, and from about 0.2 now about 2 pph of a non-toxic, substantially non-leachable antioxidant. wherein the amounts of silica or carbon black and antioxidants are sufficient for the half-life of a population of blisters at 40 ° C to be at least 10 times longer than the half-life of a comparable population of blisters, made of the vulcanized synthetic polyisoprene but without the silica or carbon black and the antioxidant. Elastones blowing according to claim 1, characterized in that the particulate silica is vaporized silica. Elastomer bladder according to claim 1 or 2, characterized in that the synthetic polyisoprene has about 96 2 to 98 2 cis-1.4 bonds. 4. An elastomeric bladder according to claim 1, 2 or 3, characterized in that the vulcanized synthetic polyisoprene has carbon-to-carbon crosslinks. 5. S. Elastomer bladder according to claim 1, 3 or 4, characterized in that it contains about 3 to about 7 pph of steamed silica and has a surface area in the range from about 150 to about 450 m2 / g. 10 15 20 25 30 35 452 711 Elastomer bladder according to claim 5, in that the surface area is 200 ¿20 m2 / g. k ä n n e t e c k n a d Elastomer bladder according to claim 1. 2, 3, 4, 5 or 6, characterized in that the antioxidant is a substituted polyphenol. Elastone bladder according to claim 7, characterized in that the substituted polyphenol is tetrakis [methylene-3- (3 ', 5' - di-t-butyl-4'-hydroxyphenyl) -propionate] -methane or 1,3.5 -trinethyl-2,4,6-tris (3,5-di-t-butyl-4-hydroxybenzyl) -benzene. Blastone bladder according to claim 8, characterized in that it is vulcanized down about 1.5 pph dicunyl peroxide and contains about 1 pph 1,3,5-trinethyl-2,4,6-tris (3,5-di-t-butyl-4- hydroxybenzyl) -benzene. 10. Methods of making an elastomeric bladder for use in a medical infusion device down improved notch note rupture when refilled. honogenically mixing a synthetic polyisoprene with about 90 8 to about 98 2 cis-1.4 bonds, down from 3 to 10 pph of a particulate silica or particulate carbon black, son having a noninal particle diameter in the range of about 1 x 10-5 to about 5 x 10-3 nn to substantially inhibit spontaneous rupture of the bladder due to stress in the bladder wall caused by the filling of the bladder, and a tightened vulcanizing needle sufficient to vulcanize the mixture truly vulcanizes the mixture. n n e t e c k n a t that nan exposes the mixture to vulcanization conditions below nan in a timely manner: (a) shapes the mixture into a tubular body. (b) solution extract extracts unsaturated vulcanizing agent and degradation products from the vulcanizing agent from the body and (c) disperses a non-toxic. mainly non-leachable antioxidant in the body by bringing the body into contact with a liquid solution of antioxidant. whereby the amount of antioxidant, which is spread into the body. is sufficient to substantially inhibit the oxidative degradation of the body. 11. ll. A method according to claim 10, characterized in that the synthetic polyisoprene is mixed with vaporized silica. 12. A method according to claim 11. know that the amount of vaporized silica is about 3 to about 10 pph. wherein the antioxidant is a substituted polyphenol, and the amount of antioxidant is about 0.5 to about 2 pph. 13. A method according to claim 12, characterized in that the vaporized silica has a surface area of 200 ¿20 m2 / g, the amount of vaporized silica is 5 pph, the vulcanizing agent is dicumyl peroxide. the amount of vulcanizing agent is 1.5 pph. the antioxidant is tetrakis [ethylene-3- (3'.S'-di-t-butyl-4'-hydroxyphenyl) -propionate] -methane or 1,3,5-trimethyl-2,4,6-tris- (3,5-di-t-butyl-4-hydroxybenzyl) -benzene and the amount of antioxidant is about 0.2 to about 2 ppb. 14. A method according to claim 13, characterized in that the antioxidant is 1,3,5-trimethyl-2,4,6-tris (3,5-di-t-butyl-4-hydroxybenzyl) -benzene, the amount of antioxidant is 1 pph, the solvent is ethyl acetate and the antioxidant is dissolved in ethyl acetate.