JPS6351702B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is a medical infusion user.
Synthetic polyisoprene bladders with improved resistance to spontaneous rupture for use in infusers.

A medical device that injects fluid into a patient is called an infuser. One type of infuser uses an elastomeric bladder as its power source. Such infuser and pouches are described in US Pat. No. 3,993,069 and US Pat. No. 4,201,207. These infusers consist of a jacket, an elastomeric bladder contained within the jacket and inflated by the liquid to be injected, and a conduit leading from the bladder to the injection site. The rate at which fluid is injected from the infuser depends on the pressure exerted on the fluid by the bladder, the viscosity of the fluid, and the flow restriction characteristics of the conduit. The patent describes a bladder capable of maintaining the pressure exerted on a liquid substantially constant until the bulk of the liquid has been expelled. The bags described in these patent specifications have low frequency hysteresis of less than about 10% and about
Made from vulcanized synthetic polyisoprene with less than 10% stress relaxation. Such hysteresis and stress relaxation characteristics were considered fundamental factors in achieving substantially constant pressure performance.

In making a number of such pouches from synthetic polyisoprene, it has been found that a small but significant number of the pouches burst when inflated, especially after long-term storage in the inflated state. It was. It was desired to reduce the rate of rupture to provide a greater margin of safety against rupture in the marketplace, even if only a small number of such bags ruptured. The patent specification does not mention anything about reducing the rupture rate of pouches.

The primary objective of the present invention is to provide a synthetic polyisoprene bag with reduced burst rate and acceptable pressure stability performance.

The present invention is an elastomeric pouch for use in medical infuser users having improved resistance to rupture when inflated;
The bag comprises (a) synthetic polyisoprene having about 90% to about 98% cis-1,4 bonds and about 1 x 10 ^-5 mm to about 5 x
made from a vulcanized homogeneous mixture of finely divided silicon dioxide or finely divided carbon black having a nominal average diameter in the range of 10 ^-3 mm, and (b) non-toxic, substantially non-leaching oxidation The amount of silicon dioxide or carbon black and antioxidant in which the inhibitor is diffused determines the half-life of the population of the bag. At least about
That's enough to make it ten times longer.

The present invention provides (a) a synthetic polyisoprene having about 90% to about 98% cis-1,4 bonds and about 1 x 10 ^-5 mm to about 5 x
~3 phr ~ with a nominal average diameter in the range of 10 ^-3 mm
(b) homogeneously mixing about 10 phr of finely divided silicon dioxide or finely divided carbon black with an amount of vulcanizing agent sufficient to vulcanize the resulting mixture; forming the mixture into a tube, (d) solvent extracting the decomposition products of the vulcanizing agent from the tube, and (e) coating the tube with a non-toxic, substantially non-leachable antioxidant. About 0.2 phr to about 2 phr of antioxidant is diffused into the tubular body by contacting with the liquid solution.

The present invention also relates to a method of making an elastomeric pouch for use in a medical infuser having improved resistance to rupture when inflated.

As used herein, the designation "phr" means parts per 100 parts of synthetic polyisoprene.

The synthetic polyisoprene used to make the pouches contains from about 90% to about 98% of its monomer units bonded in the cis-1,4 orientation. Ziegler
A type made using a catalyst is preferred;
It is characterized by having about 96% to about 98% cis-1,4 bonds. The polyisoprene is homogeneously mixed with finely divided silicon dioxide or finely divided carbon black or mixtures thereof having the above particle size. Fumed silicon dioxide is preferred. Such silicon dioxide is produced by hydrolysis of silicon tetrachloride in a hydrogen and oxygen flame at temperatures above the melting temperature of silica (approximately 1710°C). This combustion process forms molten spheres of silica that, upon cooling, fuse together to form branched, three-dimensional chain-like aggregates. This final product is typically BET
It has a surface area ranging from about 150 m ² /g to about 450 m ² /g, as measured by the method. Such fume silicon dioxide is manufactured by Cabot, Mass., Boston.
Corporation) is Cab-O-Sil (Cab-O-
It is commercially available under the trade name Sil. Carbon black is typically around 50 when measured using the BET method.
It will have a surface area ranging from m ² /g to about 250 m ² /g. The amount of silicon dioxide or carbon black mixed with the polyisoprene is sufficient to substantially inhibit spontaneous rupture of the bag due to stresses created in its walls when the bag is inflated by the medical fluid. It should be a reasonable amount. Usually about
3 phr to 10 phr, preferably 3 to 7 phr of silicon dioxide or carbon black is mixed with the synthetic polyisoprene. Lower amounts do not result in a significant increase in burst resistance. Although it can be added in amounts greater than 10 phr, such amounts do not produce a correspondingly greater improvement in burst resistance, while they may adversely affect the pressure constancy performance of the bladder.

The polyisoprene-silicon dioxide/carbon black mixture is vulcanized to form carbon-carbon or monothio bridges at the 1 and 4 positions of the isoprene units. To achieve such vulcanization,
A crosslinking agent is added to the mixture and the mixture is subjected to vulcanization conditions. Vulcanizing agents and operations that can be used are described in U.S. Pat. No. 4,201,207, column 2, line 54.
Column 3, line 13 and U.S. Patent No. 3,993,069, column 8, line 50 to column 10, line 25, the disclosures of which are hereby incorporated by reference. Diquimyl peroxide, added in an amount ranging from about 1 to 2 phr, is a preferred vulcanizing agent. Vulcanization typically occurs during the molding process used to make tubular bodies from polyisoprene mixtures. One such method involves forming a polyisoprene-silicon dioxide/carbon black-vulcanizing agent mixture into a sheet by calendering, and forming the sheet into a hollow cylindrical tube of the desired geometry using a transfer mold. including placing disc-shaped segments of the sheet into a shape. Conventional injection molding techniques can also be used to form the tubular body. Molding temperature, pressure and time are such values that achieve the desired vulcanization (crosslinking) for the polyisoprene. The geometry of the tubular body is the same as disclosed in U.S. Pat. No. 3,993,069, column 4, lines 26-41, which disclosure is incorporated herein by reference.

After the polyisoprene mixture is formed into a tube, the tube is extracted with a solvent that removes substantially all of the unreacted vulcanizing agent and bulking agent decomposition products from the tube. The solvent should not have a permanent adverse effect on the tubing and should not leave toxic residues in or on the tubing. The particular solvent used and extraction time and temperature will depend on the vulcanizing agent used. The purpose of the extraction is to prevent contamination of the medical fluid that is finally added to the pouch with the vulcanizing agent or its decomposition products.

After extraction, the antioxidant is absorbed into the tubular body by placing the tubular body in contact with a solution of the antioxidant. The antioxidant enters the tubular body by diffusion;
The tubular body is usually swollen several times by the solvent.
The amount of antioxidant absorbed into the tubing is therefore dependent on the diffusion coefficient of the tubing for the antioxidant, the concentration of the antioxidant in solution, the solubility of the antioxidant in the tubing, the thickness of the tubing, and the elastomer-solvent. The equilibrium swelling volume, which is a combination of properties, will depend on the conditions (time and temperature) under which the contact is carried out. Preferably, the same pure solvent is used for extraction and absorption of the antioxidant. The amount of antioxidant absorbed into the tubing should be sufficient to inhibit oxidative deterioration (and eventual rupture) of the pouch over a period of time, usually at least about one year. The amount required to achieve such inhibition will vary depending on the particular antioxidant used. For the hindered phenolic antioxidants described below, approximately
0.2 phr to about 2 phr, preferably about 1 phr is usually absorbed. Code of Federal Regulations for use in plastics used in connection with medicine or food.
Antioxidants may be used that are non-toxic and that are not substantially leached by the medical fluid in which the bag is to be inflated, such as those permitted by the provisions of Title 21 of the Regulations. . The term "substantially non-leachable" means that the antioxidant dissolves less than 0.1% by weight in the medical fluid. 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)propionate
Non-toxic hindered polyphenyl antioxidants such as (butyl-4-hydroxybenzyl)benzene are preferred antioxidants for use in the present invention. Once the desired amount of antioxidant has diffused into the tubing, the tubing is removed from the solution and the solvent is removed from the tubing, for example by drying at a temperature of up to 50°C. At this step, the bag can be installed into the infuser.

Including silicon dioxide or carbon black and an antioxidant together in the pouch substantially reduces the likelihood that the pouch will burst spontaneously when it is inflated. This reduction (or increase in burst resistance) reduces the half-life of each bag population for synthetic polyisoprene bags without silicon dioxide or carbon black and antioxidants under the same inflation conditions. It can be quantified by comparing. Half-life is the period of time from inflation to rupture of 50% of the sacs in the population.
A population of at least 10 pouches is desirable to ensure that the results are statistically meaningful. Such comparisons made at 40°C show that the half-life of the pouches of the present invention is at least 10 times the half-life of pouches not containing silicon dioxide or carbon black and antioxidants, typically shows that it is over 100 times longer.

The following example describes one embodiment of the invention. This example is not intended to limit the invention, but is given for illustrative purposes only.

Preparation of the Mixture 100 parts of synthetic polyisoprene (Natsyn 2200, 96-98% cis-1,4 bonds) was prepared using a Farrell Laboratory Mill.
Laboratory Mill) (6 inch x 13 inch rolls) at 130±10 mm and the gap between the rolls was adjusted to 0.08-0.09 inch. After about 3 minutes of kneading,
5.0phr fume silicon dioxide (kaboosil)
M5, surface area 200±25m ² /g, nominal average diameter 1.4×
10 ⁻⁵ mm) was added to the mill over a period of 5 minutes.
Next, 1.5 phr of diquinyl peroxide (Di Cup R) was added to the polyisoprene-silicon dioxide mixture in four equal portions. Milling was continued until at least 18 minutes had elapsed after the polyisoprene was added to the mill.

Vulcanization and molding The above mixture has a mold clamping force of 25000Kg, 325 ~
It was placed in a 4-cavity transfer mold held in a 330 mm. The mold cavity and mandrel create a hollow cylindrical bag 75.6 mm long, 6.63 mm outside diameter and 5.16 mm inside diameter with integrally molded circular flanges at each end 1.587 mm wide and 12.7 mm diameter. It was designed as such. Curing time was 20 minutes.

Extraction The pouches formed and vulcanized as described above were placed vertically into the extraction bottle of a Soxhlet extractor fitted with a 1000 ml flask. Enough ethyl acetate was added to fill the Soxhlet extractor and fill the flask with 250 ml of ethyl acetate.
The flask was heated and the bag was extracted with ethyl acetate for 4 hours.

Absorption of Antioxidant A 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 flask. The freshly extracted pouches were placed in the solution and kept at ambient temperature for 4 hours.
According to the above test, the relationship between the weight percent of this antioxidant absorbed in the sachets was determined at a concentration of 1%.
A linear relationship was shown with 0.68% absorbed (4 hour absorption time) at concentrations of 0.45% and 1.5%. Therefore, about 0.5 phr of antioxidant was absorbed into the pouch.

Half-life test 1.2 phr of tetrakis [methylene 3-(3',5'-
di-t-butyl-4'-hydroxyphenyl) propionate] pouches prepared as above except that methane was absorbed into the pouches from an acetone/toluene solution instead of the above antioxidant. A half-life test was conducted on the product. Inflate with 60ml of water,
A population of 24 of these pouches kept in air at 40°C had a half-life of approximately 14 months. A similar test on a population of synthetic polyisoprene pouches made in substantially the same manner but without silicon dioxide or antioxidants showed that such pouches
It has been shown to have a half-life of ~2 days.

Modifications of the bag described above that are obvious to those skilled in the art to which the present invention pertains also fall within the scope of the claims.

Claims (1)

Claims: 1. For use in a medical infusion comprising a tubular body formed from a vulcanized homogeneous mixture of synthetic polyisoprene having from about 90% to about 98% cis-1,4 bonds. elastomeric pouch, wherein the polyisoprene has a molecular weight of about 1 x 10 ^-5 to about 5
finely divided silicon dioxide or finely divided carbon black having a nominal average diameter in the range of ×10 ^-3 mm, and a non-toxic, substantially non-leaching antioxidant; and the silicon dioxide or carbon black and the antioxidant. The amount of half-life at 40°C of a population of said bags made from said vulcanized synthetic polyisoprene but without said silicon dioxide or carbon black and antioxidants. CLAIMS 1. An elastomeric pouch having improved resistance to rupture when inflated, the amount being sufficient to extend the half-life of a comparison population of pouches by at least about 10 times. 2. The elastomeric pouch of claim 1, wherein the particulate silicon dioxide is fumed silicon dioxide and is present in an amount of 3 to 10 phr. 3. The elastomeric pouch of claim 1 or 2, wherein the synthetic polyisoprene has about 96-98% cis-1,4 bonds. 4. The elastomeric bag according to claim 1, 2 or 3, wherein the vulcanized synthetic polyisoprene has carbon-carbon crosslinks. 5. The method of claim 1, 2, 3, or 4 containing from about 0.2 phr to about 2 phr of a non-toxic, substantially non-leachable antioxidant. Elastomeric pouch. 6 About 3 phr to about 7 phr, about 150 m ² /g to about 450
Claims 1 and 3 contain fume silicon dioxide having a surface area in the range m ² /g.
The elastomeric bag-like article according to item 1, 4 or 5. 7. The elastomeric bag according to claim 6, wherein the surface area is 200±20 m ² /g. 8 Claims 1, 2, and 3, wherein the antioxidant is a hindered polyphenol.
The elastomeric bag according to item 4, item 5, item 6 or item 7. 9 The hindered polyphenol is tetrakis[methylene 3-(3′,5′-di-t-butyl-4′-hydroxyphenyl)propionate]methane or 1,3,5-trimethyl-2,4,6- The elastomeric pouch according to claim 8, which is tris(3,5-di-t-butyl-4-hydroxybenzyl)benzene. 10 vulcanized with about 1.5 phr of dikymyl peroxide and about 1 phr of 1,3,5-trimethyl-2,4,6-tris(3,5-di-t-butyl-4-hydroxybenzyl)benzene. An elastomeric pouch according to claim 9, containing an elastomeric bag according to claim 9. 11 Synthetic polyisoprene with about 90% to about 98% cis-1,4 bonds and spontaneous rupture of the pouch due to stress in the wall of the pouch caused by expansion of the pouch. The resulting mixture is vulcanized with a sufficient amount of finely divided silicon dioxide or finely divided carbon black having a nominal average diameter in the range of about 1×10 ⁻⁵ mm to about 5×10 ⁻³ mm to substantially inhibit for use in medical infusers with improved resistance to rupture when being expanded, consisting of homogeneously mixing a sufficient amount of vulcanizing agent and vulcanizing the resulting mixture. (a) subjecting the mixture to vulcanization conditions and simultaneously forming the mixture into a tubular body; (b) removing unreacted vulcanizing agent and the vulcanized material from the tubular body; (c) treating the tubular body with a non-toxic, substantially non-leachable liquid solution of antioxidant sufficient to substantially inhibit oxidative degradation of the tubular body; A method for producing an elastomeric pouch, characterized in that an antioxidant is diffused into the tubular body by contacting the tubular body with an amount of the antioxidant diffused into the tubular body. 12. The method of claim 11, wherein the synthetic polyisoprene is mixed with fumed silicon dioxide. 13 The amount of the fume silicon dioxide is about 3 phr to about
10 phr, the antioxidant is a hindered polyphenol, and the amount of antioxidant is from about 0.5 phr to about 2 phr.
The method described in Section 2. 14 The fume silicon dioxide has a surface area of 200±20 m ² /g, the amount thereof is 5 phr, the vulcanizing agent is dikyumyl peroxide, the amount of the vulcanizing agent is 1.5 phr, and the oxidizing agent is 1.5 phr. The inhibitor is tetrakis[methylene 3-(3',5'-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 its antioxidant 14. The method of claim 13, wherein the amount of agent is from about 0.2 phr to about 2 phr. 15 The antioxidant is 1,3,5-trimethyl-2,4,6-tris(3,5-di-t-butyl-4-hydroxybenzyl)benzene, the amount is 1 phr, and the solvent is is ethyl acetate,
15. The method of claim 14, wherein the antioxidant is dissolved in the ethyl acetate.