RUBBER BALLOON FOR AMBULATORY INFUSION

Abstract: The present invention provides a composition for a medical infusor balloon. The composition includes: (1) a polyisoprene rubber, (2) an organic peroxide catalyst from 0.5-3.0 parts per hundred parts by weight of the rubber, (3) a filler and (4) an antioxidant from 0.6-3.0 parts per hundred parts by weight of the rubber.

Description: RUBBER B LLOON FOR AMBULATORY INFUSION DESCRIPTION Technical Field The present invention relates generally to an infusor balloon and more specifically to a burst resistant rubber balloon for infusion of a therapeutic agent in a liquid form. Background Prior Art In the medical field therapeutic agents are often administered over time using medical infusor devices. Medical infusors often include a balloon for containing a dosage amount of a therapeutic agent and for supplying the therapeutic agent under pressure to the vascular system of a patient. It is critical that the balloon resist any material failure such as cracking or bursting that will compromise the delivery of the dosage amount. A prior attempt at providing a balloon for an infusor devices is disclosed in U.S. Patent Nos. 4,201,207, and 4,938,751. The '207 Patent discloses an infusor bladder of a vulcanized synthetic polyisoprene having 90-98% cis linkages that has been vulcanized with an organic peroxide such as dicumyl peroxide at a concentration of 5.5 x 10 "3 to 7.5 x 10' 3 moles of peroxide per 100 grams of polyisoprene. The '751 Patent discloses a method for preparing an infusor bladder. The process includes the steps of blending polyisoprene having 90-98% of its monomeric units joined in cis- 1,4 orientation, with carbon black or silicon dioxide or a mixture of the two. A blend of these components are vulcanized by adding a vulcanizing agent such as dicumyl peroxide and subjecting the blend to vulcanization conditions. (Col.2, line 63-col. 3, line 6). The step of vulcanizing is taken during the step of forming the mixture into tubular bodies (col. 3, lines 7-21). After the mixture is formed into a tubular body, the body is extracted with a solvent to remove the unreacted vulcanizing agents and the degradation products of the vulcanizing agent (col. 3, lines 22-25). After the extraction process an antioxidant is imbibed into the bodies by placing them in contact with a solution of the antioxidant (col. 3, lines 34-36). After the imbibing step the bodies are dried to remove the solvent from the imbibing step (col. 4, lines 2-4). This process has at least the following areas for improvement. First, the imbibing process is a time consuming and expensive process. Second, during the manufacturing process, all of the steps taken prior to the imbibing steps subject the bodies to high heat and shear without the presence of a sufficient amount of antioxidant to protect the components from oxidative and thermal degradation. While there is a trace amount of antioxidant present in the rubber when purchased it is not sufficient to provide a significant amount of protection. It was commonly believed when using a peroxide catalyst that an antioxidant should not be incorporated into the component blends prior to vulcanization as the antioxidant would react with the peroxide so that the peroxide would not be available for the curing of the rubber. Summary of the Invention The present invention provides a composition for a medical infusor balloon. The composition includes: (1) a polyisoprene rubber, (2) an organic peroxide catalyst from 0.5-3.0 parts per hundred parts by weight of the rubber, (3) a filler and (4) an antioxidant from 0.6-3.0 parts per hundred parts by weight of the rubber. In a preferred form of the invention the rubber is polyisoprene, the catalyst is dicumyl peroxide, the antioxidant is l,3,5-trimethyl-2,4,6-tris(3,5- di-t-butyl-4-hydroxybenzyl)-benzene or octadecyl 3-(3,5-di-t-butyl-4 hydroxyphenyl) propio- nate. Also the infusor balloon of the present invention should have an increased resistance to burst over prior infusor balloons. The present invention also provides a method for fabricating a medical infusor balloon. The method comprises the steps of: (1) providing a polyisoprene rubber, (2) providing an organic peroxide catalyst in an amount from about 0.5 to about 3.0 parts per one hundred parts rubber, (3) providing a filler, (4) providing an antioxidant selected from the group consisting of hindered phenols and hindered polyphenols and in an amount from about 0.6 to about 3.0 parts per one hundred parts of rubber, (5) mixing the rubber, the catalyst, the filler and the antioxidant to define a blend; (6) vulcanizing the blend and (7) extruding the blend into a balloon having an average resistance to burst for 40 balloons filled with water of greater than 3 days when stored at 90 °C at greater than 80% relative humidity for a balloon in the uninflated state having a length of about 3 inches, a wall thickness of about 0.038 inches, an inner diameter of about 0.158 inches and the balloon is cured to the extent that when filled with 60 mL of water the water has a pressure of about 10 psi. The present invention also provides a medical infusor balloon fabricated from the formulation set forth above and by the method set forth above. Brief Description of the Drawings Figure 1 shows a infusor balloon of the present invention. Detailed Description While this invention is susceptible of embodiments in many different forms, and will herein be described in detail, preferred embodiments of the invention are disclosed with the under- standing that the present disclosure is to be considered as exemplifications of the principles of the invention and are not intended to limit the broad aspects of the invention to the embodiments illustrated. Figure 1 shows a medical infusor balloon 10 of the present invention. The balloon has a monolayer sidewall 12 defining an internal reservoir 14 for containing a dosage amount of a therapeutic agent such as a drug for delivery under pressure to the vascular system of a patient. In a preferred form of the invention, the reservoir 14 in the uninflated state has a wall thickness from about 0.033 inches to about 0.043 inches, an inner diameter of from about 0.151 to about 0.165 inches and when inflated with about 60 mL of water, the water is under pressure from about 9.0-11.0 psi and more preferably from about 9.5 psi to about 10.0 psi. The balloon is fabricated from a blend of a rubber, a filler, a catalyst and an antioxidant. Unlike the prior art compositions for infusor balloons, the present composition includes the antioxidant together with an organic peroxide catalyst in the blend prior to vulcanizing or curing the blend and processing the blend into a balloon. In a preferred form of the invention, the blend has about 100 parts of the rubber, from about 0.5-3.0 parts and more preferably from about 1.0-2.0 parts of the catalyst, from about 0.6-3.0 parts of the antioxidant, and from about 3-10 parts of the filler. The rubber should be selected from any suitable polyisoprene rubber that provides adequate strength after processing to form a medical infusor balloon. In a preferred form of the invention the rubber is polyisoprene sold by Goodyear Tire and Rubber Company under the product designation NATSYN 2205. The catalyst should be an organic peroxide and in a preferred form of the invention is a dicumyl peroxide. In a preferred form of the invention the catalyst is sold by Hercules Chemical Company under the trade name Di Cup-R. The antioxidant should be an additive that is capable of minimizing the degradation of the blend components during processing and preferably is a hindered phenol or a hindered polyphenol. Suitable antioxidants include, but are not limited to, tetrakis [methylene 3-(3',5'-di- t-butyl-4'-hydroxyphenyl) propionate] methane, l,3,5-trimethyl-2,4,6-tris(3,5-di-t-butyl-4- hydroxybenzyl)-benzene, 2,6-di-t-butyl-4-methylphenol and octadecyl 3-(3,5-di-t-butyl-4 hydroxyphenyl) propionate. In the most preferred form of the invention the antioxidant is 1,3,5- trimethyl-2,4,6-tris(3,5-di-t-butyl-4-hydroxybenzyl)-benzene sold by Albemarle under the product designation ETHANOX 330 or an octadecyl 3-(3,5-di-t-butyl-4 hydroxyphenyl) propionate sold by Seiba-Geigy under the trade name IRGANOX 1076. The filler preferably adds strength to the blend and preferably is selected from the group consisting of fumed silicon dioxides. In a preferred form of the invention the filler is sold by DeGusse under the product designation AEROSIL 200. In a preferred form of the invention the balloon will have the following physical properties: (1) a 100% modulus of preferably less than about 300 psi, more preferably less than about 250 psi, and most preferably less than 200 psi; (2) an average stress at break of greater than about 500 psi (3); a percent strain at break of preferably greater than about 400%, more preferably greater than about 450% and most preferably greater than about 500%; (4) an antioxidant content of from 0.7-1.0% by weight of the composition, and (5) has an average resistance to burst for 40 balloons filled with water of greater than 3 days when stored at 90 °C at greater than 80% relative humidity for a balloon in the uninflated state having a length of about 3 inches, a wall thickness of about 0.038 inches, an inner diameter of about 0.158 inches and the balloon is cured to the extent that when filled with 60 mL of water the water has a pressure of about 10 psi. The method for fabricating the blend into an infusor balloon requires the following steps. First, the blend components are blended in a high intensity blender such as a Banbury mixer, a twin screw mixer or a continuous high intensity mixer. After the components are adequately blended the blend is optionally milled in a two-roll mill. The blended components are then cut into strips. These strips are put into a first extruder with a fine screen pack to remove particulate matter that may cause bursting of the balloon. After the screening step, the screened strips are placed in a second extruder and are extruded into tubes. The tubes exiting the extruder are passed through a salt bath of sodium nitrate and potassium nitrate to cure the tubes and the tubes are cut to size. After the salt curing step the tube segments are placed in an oven to volatilize the unwanted residues. The following are non-limiting examples of the invention and should not be used to limit the scope of the claims set forth below. Example 1 Two groups of infusor balloons were fabricated. The first group of samples denoted as Control were fabricated from a composition that did not include an antioxidant during the steps of processing the composition into tubes. An antioxidant was added in a separate imbibing step after processing. This process is consistent with the disclosure of U.S. Patent No. 4,938,751. In particular the following components were blended in a Banbury mixer: 100 parts NATSYN 2205 (polyisoprene), 5 parts AEROSIL 200 (filler), 1.5 parts Di-Cup R (catalyst). The blend was milled in a 2-roll mill. The milled blend was extruded through a screen pack to eliminate particulate matter. The screened composition was then extruded into tubes and cured in a salt bath of sodium nitrate and potassium nitrate. The tubes were cut into 3 inch lengths and filled with 60 mL of water and were found to have a water pressure of about 10 psi. The tubes were then subjected to an imbibing process where the tubes were submerged in Ethanox 330 dissolved in ethyl acetate. The tubes were allowed to reside in this solution for a 24 hour period. The tubes were allowed to dry by evaporation of the solvent. The second group of balloons, denoted as Example, were fabricated in a process subject of the present invention where the antioxidant was added during the initial blending step. The process included the steps of blending in a Banbury mixer 100 parts Natsyn 2205 (polyisoprene), 5 parts Aerosil 200 (filler), 1.73 parts Di-Cup R (catalyst), and 0.969 parts Ethanox 330 (antioxidant) and milling the components in a 2-roll mill. The milled blend was extruded through a screen pack to eliminate particulate matter. The screened composition was then extruded into tubes and cured in a salt bath of sodium nitrate and potassium nitrate. The tubes were cut into 3 inch lengths and filled with about 60 mL of water and were found to have a water pressure of about 10 psi. The tubes were then placed in an oven at 180° C for 14 hours to volatilize unwanted residues. The balloons from the Control and the Example were compared for burst strength. The burst strength test was conducted using the following procedure: (1) fill the balloons with 60 mL deionized water, (2) hang the filled reservoirs vertically inside a plastic container, (3) fill the plastic container with water to a point below the reservoirs, (4) cap the container as tight as possible to maintain high humidity inside the container, (5) place the container with reservoirs in a air circulating oven set at 90 °C, and (6) record the time it takes for the reservoirs to burst. These data points are set forth below in Table 1. Table- 1 Burst Time of Filled Reservoir at 90 Degree C These data show that the average burst resistance for the Example balloons where the antioxidant is added prior to blending is greater than 4 days while the burst strength of the balloon made by the process where the antioxidant is added after processing is less than 3 days. Example 2: Infusor balloon were fabricated from a formulation having 100 parts polyisoprene, 5 parts filler, 1.5 parts catalyst and 0.5 parts antioxidant. The formulation components were mixed in a high intensity mixer, then milled in a two-roll mill, the milled formulation was then cut into strips. The strips were extruded with a fine screen pack and then extruded a second time into tubes. The tubes were passed through a salt bath of sodium nitrate and potassium nitrate to cure the rubber. The cured tubes were placed in an oven to volatilize unwanted residues. The resulting infusor balloons readily stuck to one another and to themselves. These infusor balloons are unsuitable for use in the infusor device shown in Figure 1 as they would adhere to the sidewalls of the device which in turn would lead to an unacceptably high burst rate. It will be understood that the invention may be embodied in other specific forms without departing from the spirit or central characteristics thereof. The present examples and embodiments, therefore, are to be considered in all respects as illustrative and not restrictive, and the invention is not to be limited to the details given herein.

Claims: CLAIMS We claim: 1. A composition for a medical infusor balloon prior to vulcanization comprising: a polyisoprene rubber; an organic peroxide catalyst from 0.5-3.0 parts per hundred parts by weight of the rubber; a filler; and an antioxidant from 0.6-3.0 parts per hundred parts by weight of the rubber. 2. The composition of claim 1 wherein the filler is present in an amount from about 3-10 parts per hundred by weight of the rubber. 3. The composition of claim 2 wherein the filler is a fumed silicon dioxide. 4. The composition of claim 3 wherein the catalyst is dicumyl peroxide. 5. The composition of claim 4 wherein the antioxidant is selected from the group consisting of hindered phenols and hindered polyphenols. 6. The composition of claim 5 wherein the antioxidant is selected from the group consisting of tetrakis [methylene 3-(3',5'-di-t-butyl-4'-hydroxyphenyl) propionate] methane, 1,3,5-trimethyl- 2,4,6-tris(3,5-di-t-butyl-4-hydroxybenzyl)-benzene, 2,6-di-t-butyl-4-methylphenol and octadecyl 3-(3,5-di-t-butyl-4 hydroxyphenyl) propionate. 7. The composition of claim 6 wherein the rubber is polyisoprene, the catalyst is dicumyl peroxide, the antioxidant is l,3,5-trimethyl-2,4,6-tris(3,5-di-t-butyl-4-hydroxybenzyl)-benzene or octadecyl 3-(3,5-di-t-butyl-4 hydroxyphenyl) propionate, and the filler is fumed silicon dioxide. 8. A composition for a medical infusor balloon comprising: a polyisoprene rubber; an organic peroxide catalyst from 0.5-3.0 parts per hundred parts by weight of the rubber; a filler; an antioxidant from 0.6-3.0 parts per hundred parts by weight of the rubber; and wherein the antioxidant is added to the composition prior to vulcanization and an infusor balloon fabricated from this composition has an average resistance to burst for 40 balloons filled with water of greater than 3 days when stored at 90 °C at greater than 80% relative humidity for a balloon in the uninflated state having a length of about 3 inches, a wall thickness of about 0.038 inches, an inner diameter of about 0.158 inches and the balloon is cured to the extent that when filled with 60 mL of water the water has a pressure of about 10 psi. 9. The composition of claim 8 wherein the filler resin is present in an amount from about 3 to about 10 parts per hundred by weight of the rubber. 10. The composition of claim 9 wherein the catalyst is dicumyl peroxide. 11. The composition of claim 10 wherein the antioxidant is selected from the group consisting of hindered phenols and hindered polyphenols. 12. The composition of claim 11 wherein the antioxidant is selected from the group consisting of tetrakis [methylene 3-(3',5'-di-t-butyl-4'-hydroxyphenyl) propionate] methane, 1,3,5-trimethyl- 2,4,6-tris(3,5-di-t-butyl-4-hydroxybenzyl)-benzene, 2,6-di-t-butyl-4-methylphenol and octadecyl 3-(3,5-di-t-butyl-4 hydroxyphenyl) propionate. 13. The composition of claim 12 wherein the filler is filmed silicon dioxide. 14. The composition of claim 13 wherein the rubber is polyisoprene, the catalyst is dicumyl peroxide, the antioxidant is l,3,5-trimethyl-2,4,6-tris(3,5-di-t-butyl-4-hydroxybenzyl)-benzene or octadecyl 3-(3,5-di-t-butyl-4 hydroxyphenyl) propionate., and the filler is fumed silicon dioxide. 15. A method for fabricating a medical infusor balloon comprising the steps of: providing a polyisoprene rubber; providing an organic peroxide catalyst in an amount from about 0.5 to about 3.0 parts per one hundred parts rubber; providing a filler; providing an antioxidant selected from the group consisting of hindered phenols and hindered polyphenols and in an amount from about 0.6 to about 3.0 parts per one hundred parts of rubber; mixing the rubber, the catalyst, the filler and the antioxidant to define a blend; vulcanizing the blend; and extruding the blend into a balloon having an average resistance to burst for 40 balloons filled with water of greater than 3 days when stored at 90 °C at greater than 80% relative humidity for a balloon in the uninflated state having a length of about 3 inches, a wall thickness of about 0.038 inches, an inner diameter of about 0.158 inches and the balloon is cured to the extent that when filled with 60 mL of water the water has a pressure of about 10 psi. 16. The method of claim 15 wherein the filler is a fumed silicon dioxide. 17. The method of claim 16 wherein the antioxidant is selected from the group comprising tetrakis [methylene 3-(3',5'-di-t-butyl-4'-hydroxyphenyl) propionate] methane, 1,3,5-trimethyl- 2,4,6-tris(3,5-di-t-butyl-4-hydroxybenzyl)-benzene, 2,6-di-t-butyl-4-methylphenol and octadecyl 3-(3,5-di-t-butyl-4 hydroxyphenyl) propionate. 18. The method of claim 17 wherein the rubber is polyisoprene, the catalyst is dicumyl peroxide, the antioxidant is l,3,5-trimethyl-2,4,6-tris(3,5-di-t-butyl-4-hydroxybenzyl)-benzene or octadecyl 3-(3,5-di-t-butyl-4 hydroxyphenyl) propionate. 19. A medical infusor balloon comprising: a sidewall defining an inner chamber and having a fluid outlet, the sidewall fabricated from a composition of a polyisoprene rubber, an organic peroxide catalyst from about 0.5 to about 3.0 parts per hundred parts by weight of the rubber, a filler from about 3 to about 10 parts per hundred parts of the rubber, an antioxidant from about 0.6 to about 3.0 parts per hundred parts by weight of the rubber; and wherein the antioxidant is added to the composition prior to vulcanization and the infusor balloon has an average resistance to burst for 40 balloons filled with water of greater than 3 days when stored at 90 °C at greater than 80% relative humidity for a balloon in the uninflated state having a length of about 3 inches, a wall thickness of about 0.038 inches, an inner diameter of about 0.158 inches and the balloon is cured to the extent that when filled with 60 mL of water the water has a pressure of about 10 psi. 20. The balloon of claim 19 wherein the filler is fumed silicon dioxide. 21. The balloon of claim 19 wherein the catalyst is an organic peroxide. 22. The balloon of claim 19 wherein the antioxidant is selected from the group consisting of hindered phenols and hindered polyphenols. 23. The balloon of claim 22 wherein the antioxidant is selected from the group consisting of tetrakis [methylene 3-(3',5'-di-t-butyl-4'-hydroxyphenyl) propionate] methane, 1,3,5-trimethyl- 2,4,6-tris(3,5-di-t-butyl-4-hydroxybenzyl)-benzene, 2,6-di-t-butyl-4-methylphenol and octadecyl 3-(3,5-di-t-butyl-4 hydroxyphenyl) propionate. 24. The balloon of claim 19 wherein the rubber is polyisoprene, the catalyst is dicumyl peroxide, the antioxidant is l,3,5-trimethyl-2,4,6-tris(3,5-di-t-butyl-4-hydroxybenzyl)-benzene or octadecyl 3-(3,5-di-t-butyl-4 hydroxyphenyl) propionate, and the filler is fumed silicon dioxide.

Inventors: BUAN ANGELES LILLIAN, DING YUAN-PANG SAMUEL, JENKE DENNIS, LE TU, SHETH MIHIR, BUAN, ANGELES, LILLIAN, DING, YUAN-PANG, SAMUEL, JENKE, DENNIS, LE, TU, SHETH, MIHIR
Applicants: BAXTER INT, BAXTER INTERNATIONAL INC.
Application year: 2000
Main classification: C08K5
IPC codes: A61L29, A61M5, C08J5, C08K3, C08K5, C08L9