Alkali-resistant halogenated plastics for medical devices

Abstract

A medical device having an alkali-resistant halogenated polymer includes a halogenated polymer incorporating one or more polymer stabilizers, polymer plasticizers, or free radical inhibitors, or combinations thereof, and can be used to administer high pH formulations to a patient in need thereof by administering the formulation through contact with the alkali-resistant halogenated polymer.

Description

Technical Field

[0001] The present disclosure generally relates to halogenated plastics for medical devices, and more particularly to halogenated plastics for contact with high-pH formulations such as tubes for the administration of medical fluids by infusion.

Background Art

[0002] Plastic materials are widely used in the medical field, particularly for patient diagnosis and treatment procedures. Polyvinyl chloride (PVC) is among the most widely used of such plastics and is commonly used in intravenous infusion devices for administering pharmaceutical solutions. Many pharmaceutical solutions have a pH ranging from acidic to nearly neutral, for example, a pH of about 4 to about 7.4.

[0003] However, some drugs delivered by infusion medical devices can have extreme pH conditions. For example, low-pH formulations containing drugs such as cefepime, chlorpromazine, metoclopramide, and high-pH formulations containing drugs such as floran, allopurinol, ganciclovir, and methohexitol, these formulations have a pH ranging from 2 to 12 in the formulation of their excipients. Such extreme pH fluids can potentially have an adverse effect on the plastics they contact.

[0004] Furthermore, plastics used for injecting pharmaceutical solutions are typically sterilized by routes such as gamma rays, electron beams, and ethylene oxide (EtO). Other sterilization techniques include ultraviolet radiation, NO2 gas, moist heat / steam, etc. Such sterilization methods can also potentially have an adverse effect on the plastics used for the administration of pharmaceutical solutions.

[0005] For example, PVC is known to decompose (degrade) at high temperatures, exhibiting discoloration and loss of physical and mechanical properties. The thermal decomposition of PVC occurs through an autocatalytic dehydrochlorination reaction in which conjugated double bonds are subsequently formed during heat-related processes such as compounding and extrusion / injection molding. Therefore, stabilizers are used with PVC to improve its thermal stability. [Overview of the project] [Problems that the invention aims to solve]

[0006] However, there is a continuing need to stabilize plastics used in medical devices, particularly halogenated plastics that are exposed to high pH conditions and / or harsh sterilization conditions. [Means for solving the problem]

[0007] Embodiments of this technology relate to a method for administering a highly alkaline pharmaceutical formulation having a pH greater than 7. Such an alkaline pharmaceutical formulation may have a pH of 9 or higher, for example, in the range of about 7 to about 14, or in the range of about 8 or about 9 to about 12 or about 14. This method involves administering a pharmaceutical formulation having a predetermined pH by contact with an alkali-resistant halogenated polymer.

[0008] Such formulations can be administered by direct contact with alkali-resistant halogenated polymers, and the duration of administration can be extended. For example, highly alkaline formulations can be in contact with alkali-resistant halogenated polymers for periods exceeding one hour, for example, more than four hours, or even several days.

[0009] Alkali-resistant halogenated polymers can be advantageously resistant to the harmful effects of highly alkaline formulations by incorporating one or more polymer stabilizers, polymer plasticizers, or free radical inhibitors, or combinations thereof with the halogenated polymer.

[0010] In some embodiments, the alkali-resistant halogenated polymer may be in the form of a tube or drip chamber. In other embodiments, the alkali-resistant halogenated polymer may include a chlorinated polymer, such as PVC. In further embodiments, the alkali-resistant halogenated polymer is sterilized by radiation before contact with a highly alkaline pharmaceutical formulation.

[0011] The embodiments include one or more of the following features individually or in combination: For example, the polymer stabilizer may include one or more ion exchange resins or ionomers; the polymer plasticizer may include one or more aliphatic polyesters or one or more aliphatic polyesters; the free radical inhibitor may include one or more hydroquinones or derivatives thereof; and furthermore, the alkali-resistant halogenated polymer may include a non-dialkyl ester-based plasticizer.

[0012] Further advantages of this technology will be readily apparent to those skilled in the art from the following detailed description, where only specific embodiments of the technology are shown and described by illustration only. It should be understood that other different configurations of the technology are possible, and some of its details can be modified in various other ways without departing in any way from the technology. Therefore, the drawings and description should be considered illustrative and not restrictive. [Modes for carrying out the invention]

[0013] The detailed description below illustrates various configurations of the Art and is not intended to represent only one configuration in which the Art can be implemented. The detailed description includes certain details for the purpose of providing a complete understanding of the Art. Accordingly, dimensions are provided for certain embodiments as non-limiting examples. However, it will be apparent to those skilled in the art that the Art can be implemented without these specific details. In some cases, well-known structures and components are shown in block diagram form to avoid obscuring the concepts of the Art.

[0014] It should be understood that this disclosure includes examples of the technology and does not limit the scope of the appended claims. Herein, various aspects of the technology are disclosed according to certain non-limiting examples. The various embodiments described herein may be performed in different ways and variations depending on the desired use or implementation.

[0015] Embodiments of this technology relate to medical devices that may come into contact with high-pH pharmaceutical formulations. Such devices include, for example, medical tubing, drip chambers, and the like. Medical treatment often involves infusing a patient with a drug solution (e.g., saline solution or other liquid formulation) using an intravenous (IV) catheter connected to a drug solution source, such as an IV bag, via an arrangement of flexible tubing and fittings commonly referred to as an "IV set." Such medical tubing and other devices in the infusion assembly may be formed from halogenated polymers such as polyvinyl chloride.

[0016] Such medical devices are typically sterilized using pathways such as gamma rays, electron beams, and ethylene oxide (EtO). Other sterilization methods include ultraviolet radiation, NO2 gas, and moist heat / steam. These sterilization methods can have adverse effects on the use of plastics for administering medications. It has been found that administering highly alkaline pharmaceutical formulations can cause precipitation of substances from plasticized PVC tubes.

[0017] Development studies of formulations have shown that several factors affect the alkali resistance of PVC tubing. Among these factors, the ratio of stabilizers, their loading concentrations, and the type and loading level of plasticizers are sensitive factors that affect the high pH resistance of PVC. However, optimizing the PVC formulation using conventional stabilizers and plasticizers could not completely eliminate particulate matter. Furthermore, a large amount of particulate matter was observed in gamma-ray or electron beam radiation sterilization compared to unsterilized PVC.

[0018] To improve the alkali resistance of halogenated polymers used in medical devices, one or more polymer components or free radical stabilizers can be incorporated into the halogenated polymer. Accordingly, one aspect of this technology relates to alkali-resistant halogenated polymers containing one or more polymer stabilizers, polymer plasticizers, or free radical inhibitors. Such alkali-resistant halogenated polymers can be used to administer highly alkaline pharmaceutical formulations with a pH greater than 7, for example, 8 or higher, for example, about 9 or higher, for example, in the range of about 7 to about 14 or about 9 to about 12, to patients requiring such formulations. Such formulations can be administered over extended administration times by direct contact with the alkali-resistant halogenated polymer. For example, highly alkaline formulations can be in contact with the alkali-resistant halogenated polymer for more than one hour, for example, more than four hours, or even for several days.

[0019] Examples of halogenated polymers that can be compounded with one or more polymer stabilizers, polymer plasticizers, or free radical inhibitors to form alkali-resistant halogenated polymers include chlorinated polymers such as polyvinyl chloride (PVC) and poly(vinylidene chloride), fluorinated polymers such as poly(vinylidene fluoride) and poly(tetrafluoroethylene), and mixed halogenated polymers such as poly(chlorotrifluoroethylene).

[0020] One aspect of the present disclosure includes medical tubing and drip chambers comprising polyvinyl chloride as a halogenated polymer incorporating one or more polymer stabilizers, polymer plasticizers, or free radical inhibitors to improve resistance to high pH alkaline extraction for use after radiation sterilization.

[0021] Useful polymer stabilizers include one or more ion exchange resins, such as cation exchange resins, and / or one or more ionomers. The cation exchange resins may have submicro to nanoscale particle size structures as HCl scavengers. Ion exchange resins are generally formed from methacrylic acid, sulfonated styrene, and divinylbenzene (DVB), and their general structures are shown in Scheme 1 and Scheme 2 below, respectively. [ka]

[0022] Such ion exchange resins typically contain metal cations, such as sodium cations. The ion exchange resin can be immobilized in a crosslinked 3D network, and its diffusion is significantly restricted within the localized halogenated polymer matrix, thus minimizing the diffusion of the resin into aqueous formulations. The ability of ion exchange resins, such as cation exchange resins, to stabilize halogenated polymers such as PVC depends in part on the resin's acid absorption capacity in the halogenated polymer, the resin's particle size / surface area, and the resin's loading level. In one aspect of this disclosure, metal cations of the ion exchange resin include Li, Na, K and other elements from Group 1 of the periodic table, or Mg, Ca and other elements from Group 2 of the periodic table, as well as other transition metals such as Zn, Cd, and Ni. One example is Dow's Dowex brand.

[0023] Alternatively, the polymer heat stabilizer that can be incorporated into the halogenated polymer to form an alkali-resistant halogenated polymer can be a metal salt of an organic polymer, such as an ionomer. In one embodiment, the ionomer is a metal salt from an acrylic acid-containing polymer or a metal salt from sulfonated polystyrene. The metal cation of the ionomer can be, for example, one or more of a lithium cation, a sodium cation, a potassium cation, a calcium cation, a barium cation, and a zinc cation. Additional ionomers useful for inclusion in the alkali-resistant halogenated polymers of the present disclosure can be found in U.S. Patent No. 5,328,948, which is incorporated herein by reference.

[0024] In addition to, or alternatively to, the low molecular weight plasticizer, the alkali-resistant halogenated polymers of the present disclosure can include one or more polymeric plasticizers. Useful polymeric plasticizers that can be used in the alkali-resistant halogenated polymers of the present disclosure include one or more of aliphatic polyesters such as polyadipate and bio-based polymeric plasticizers such as plasticizers based on vegetable oils such as castor oil. Table 1 below lists some polymeric plasticizers that can be incorporated into the halogenated polymer to form the alkali-resistant halogenated polymers of the present disclosure.

[0025] As shown in the following table, polyadipate is an aliphatic polyester with medium to ultra-high molecular weight formed from polyalcohol and adipic acid by polycondensation. These linear or slightly branched polyester polyols have low melting and glass transition temperatures and excellent solvent resistance and flame retardancy, but relatively poor hydrolysis stability due to their inherent ester functional groups. However, due to their high molecular weight, it is expected that even partially decomposed fragments will have slow mobility. For example, high molecular weight polyesters have a very low potential for migration into lipophilic substances. In a recent study measuring the extraction of di(2-ethylhexyl)phthalate (DEHP) and polyadipate by juices and nutritional solutions from PVC nasogastric tubes, it was found that the leaching of polyadipate was 10 times lower than that of DEHP in the nutritional solution group and 100 times lower than that in the gastric juice (digestive fluid) group. See Van Vliet ED et al., "A review of alternatives to di(2-ethylhexyl)phthalate-containing medical devices in the neonatal intensive care unit", J. Perinatol, August 2011, 31(8):551-560.

Table 1

[0026] Three common polymeric adipates are polyethylene adipate, polypropylene adipate and polybutylene adipate, which can be exemplified by Scheme 3 below. For example, a commercially available polyadipate is Palamoll® (a polymeric plasticizer obtained from BASF).

Chem.

[0027] Other useful plasticizers that can be incorporated into halogenated polymers to form the alkali-resistant halogenated polymers of this disclosure include non-dialkyl ester-based plasticizers. Such non-dialkyl ester-based plasticizers can enhance the hydrolytic stability of halogenated polymers in contact with high-pH formulations. Thus, in addition to or as an alternative to low molecular weight plasticizers, the alkali-resistant halogenated polymers of this disclosure may contain one or more non-dialkyl ester-based plasticizers. An example of such a non-dialkyl ester-based plasticizer is epoxidized cardanol diethyl phosphate, which can be prepared from cardanol, as illustrated in Scheme 4 below. See the short review by Puyou Jia, Haoyu Xia et al., “Plasticizers derived from biomass resources,” Polymers 2018, 10, 1303. Such non-dialkyl ester-based plasticizers can enhance the thermal stability of, for example, PVC. [ka]

[0028] Other non-dialkylester-based plasticizers that can be incorporated into halogenated polymers to form the alkali-resistant halogenated polymers of this disclosure include alkylsulfonic acid phenyl esters (ASEs), sulfonamides, such as N-ethyltoluenesulfonamide, N-(2-hydroxypropyl)benzenesulfonamide, and N-(n-butyl)benzenesulfonamide.

[0029] The alkali-resistant halogenated polymers of this disclosure may contain one or more free radical inhibitors. Free radical inhibitors are not typically incorporated into halogenated polymers such as PVC. However, it has been found that the use of free radical inhibitors can improve the alkali resistance of halogenated polymers that have been sterilized, such as by radiation sterilization.

[0030] During radiation sterilization, the molecular skeleton or any of the susceptible atoms may dissociate, generating radicals, which can propagate and continue reacting until they are quenched by recombination or reaction termination. To minimize this process, radical inhibitors can be added to halogenated polymers to halt free radicals. Common free radical inhibitors include phenolic compounds such as hydroquinone (HQ), 4-methoxyphenol (MEHQ), and their derivatives. Scheme 5 below shows the structure of MEHQ. [ka]

[0031] Such free radical inhibitors can be incorporated into halogenated polymers, such as PVC, at concentrations ranging from approximately 1 part (phr) to 0.01 phr per 100 parts of resin, for example, less than 0.1 phr, to prevent radiation damage at the molecular level by mitigating the propagation of free radicals. [Examples]

[0032] Examples Commercially available PVC tubing, which can be used with IV infusion sets, was tested by extracting the tubing with sodium hydroxide in pH 11 phosphate buffer for up to 7 days. The PVC tubing was plasticized with di(2-ethylhexyl) azipart (DEHA), di-2-ethylhexyl phthalate (DEHP), and tris(2-ethylhexyl) trimelitate (TOTM), with hardness ranging from 70 Shore A to 90 Shore A, and contained zinc and calcium carboxylate stabilizers. White microparticles were observed to form during the extraction process. Chemical analysis studies of DEHA-plasticized PVC showed that these microparticles consisted of the plasticizer DEHA and its fragment 2-ethyl-hexanol, as well as stearic acid and palmitic acid. A summary of the main components of the microparticles is shown in Table 2 below. [Table 2]

[0033] As shown in the table above, exposure of commercially available PVC tubing to a highly alkaline solution leads to the decomposition (degradation) of low molecular weight stabilizers, and their fragments are observed. Fragments from palmitic acid and stearic acid stabilizers are also observed. Zinc carboxylate and calcium carboxylate stabilizers in PVC tubing are thought to have some mobility and diffuse onto the surface of the tubing when the tubing comes into contact with a metal die during extrusion formation and when the tubing is exposed to radiation sterilization. The corresponding carboxylates (having 8-18 carbon chains) of zinc carboxylate and calcium carboxylate stabilizers may dissociate from the tubing surface to form immiscible aggregates of solid precipitate. Under harsh processing conditions, low molecular weight ester plasticizers are susceptible to hydrolysis under high pH conditions, forming surfactant structures with polar heads and non-polar tails. As summarized in the table above, chemical analytical studies show that the white precipitate consists of stearic acid and palmitic acid from the stabilizers, as well as 2-ethyl-1-hexanol from the DEHA plasticizer.

[0034] Adding free radical inhibitors to PVC-based resins is not common practice. However, including one or more free radical inhibitors in halogenated polymers such as PVC is thought to reduce their degradation (degradation) when the halogenated polymer is exposed to heat during the formation of medical devices using the material and / or during sterilization. When halogenated polymers are sterilized and exposed to heat in this way, they become more susceptible to degradation when in contact with high-pH fluids.

[0035] In summary, alkali-resistant halogenated polymers, comprising one or more halogenated polymers incorporating one or more polymer stabilizers, polymer plasticizers, or free radical inhibitors, minimize degradation and diffusion during heating and radiation sterilization, and enable the material to have resistance to degradation, such as the formation of precipitates, when in prolonged contact with highly alkaline pharmaceutical formulations.

[0036] Any particular order or hierarchy of blocks in the disclosed process method is to be understood as an example of an illustrative approach. It is understood that the specific order or hierarchy of blocks in the process may be rearranged based on design or implementation preferences, or that all illustrated blocks may be executed. In some implementations, any of the blocks may be executed simultaneously.

[0037] This disclosure is provided to enable any person skilled in the art to implement the various embodiments described herein. This disclosure provides various examples of the art, and the art is not limited to these examples. Various modifications to these embodiments will be readily apparent to a person skilled in the art, and the general principles defined herein may be applied to other embodiments.

[0038] References to singular elements are intended to mean "one or more" rather than "unique" unless otherwise specified. Unless otherwise specified, the term "several" ("some," "some") refers to one or more. Masculine pronouns (e.g., his) include feminine and neuter forms (e.g., her, its), and vice versa. Headings and subheadings, if any, are used for convenience only and do not limit the invention.

[0039] The term “exemplary” is used herein to mean “serving as an example or illustration.” Any embodiment or design described herein as “exemplary” should not necessarily be construed as being preferable or advantageous to other embodiments or designs. In one embodiment, various alternative configurations and operations described herein may be considered at least equivalent.

[0040] When used herein, the phrase “at least one” preceding a set of items, along with the term “or” separating any of the items, modifies the entire list, rather than each individual item in the list. The phrase “at least one” does not require the selection of at least one item. Rather, it allows for meanings that include at least one of any of the items, and / or at least one of any combination of the items, and / or at least one of each of the items. For example, the phrase “at least one A, B, or C” may refer to A only, B only, or C only, or any combination of A, B, and C.

[0041] The terms "aspect" and similar phrases do not mean that such aspects are essential to the Art, or that such aspects apply to all configurations of the Art. Disclosure relating to a particular aspect may apply to all configurations or one or more configurations. A particular aspect may provide one or more examples. The terms "aspect" and similar phrases may refer to one or more aspects, and vice versa. The terms "embodiment" and similar phrases do not mean that such embodiments are essential to the Art, or that such embodiments apply to all configurations of the Art. Disclosure relating to a particular embodiment may apply to all embodiments or one or more embodiments. A particular embodiment may provide one or more examples. The terms "embodiment" and similar phrases may refer to one or more embodiments, and vice versa. The terms "configuration" and similar phrases do not mean that such configurations are essential to the Art, or that such configurations apply to all configurations of the Art. Disclosure relating to a particular configuration may apply to all configurations or one or more configurations. A particular configuration may provide one or more examples. The term "such configuration" may refer to one or more configurations, and vice versa.

[0042] In one embodiment, unless otherwise stated, all measurements, values, evaluations, locations, sizes, dimensions, and other specifications described herein, including in subsequent claims, are approximate and not precise. In one embodiment, they are intended to have a reasonable range consistent with the functions to which they relate and with those commonly used in the art in which they pertain.

[0043] It should be understood that any specific order or hierarchy of disclosed steps, operations, or processes is illustrative of a typical approach. It should be understood that any specific order or hierarchy of steps, operations, or processes may be rearranged based on design preferences. Some steps, operations, or processes may be executed simultaneously. Some or all of the steps, operations, or processes may be executed automatically without user intervention. The accompanying method claims present various elements of steps, operations, or processes, if any, in a sample order and are not intended to be limited to any specific order or hierarchy presented.

[0044] All structural and functional equivalents to elements of various aspects described herein, known to those skilled in the art, or to become known thereafter, are expressly incorporated herein by reference and intended to be encompassed by the claims. Furthermore, nothing disclosed herein is intended to be made generally available, regardless of whether such disclosure is expressly included in the claims. Elements described in the claims shall not be construed under 35 U.S. SC Section 112(f) unless their term is expressly described using the phrase “means for” or, in the case of a method claim, unless their element is described using the phrase “steps for.” Furthermore, to the extent that terms such as “include” and “have” are used, such terms are intended to be as comprehensive as “comprise,” so as the term “comprise” is construed when “comprise” is adopted as a transitional clause in a claim.

[0045] The Title of the Invention, Background Art, Summary of the Invention, Brief Description of the Drawings, and Abstract of the Invention in this Disclosure are incorporated herein and provided as examples of the Disclosure, not as limiting descriptions. It should be understood that these are not used to limit the scope or meaning of the claims. Furthermore, the Detailed Description of the Invention may be understood as providing examples and grouping various features into various embodiments for the purpose of simplifying the disclosure. The manner of this Disclosure should not be interpreted as reflecting an intention that the subject matter of the Invention requires more specific details than expressly stated in each claim. Rather, as reflected in the following claims, the subject matter of the Invention lies in fewer specific details than all the details of a single configuration or operation disclosed. The following claims are incorporated herein into the Detailed Description of the Invention, and each claim exists independently as subject matter claimed individually.

[0046] The claims are not intended to be limited to the embodiments described herein, but rather to be consistent with the full scope of the literal claims and to encompass all legal equivalents. Nevertheless, no claim is intended, nor should it be construed, to encompass inventive content that does not meet the requirements of 35 U.S. SC Sections 101, 102, or 103. The various aspects and embodiments that may be included in the present invention are summarized below. [1] A method for administering a highly alkaline pharmaceutical preparation having a pH greater than 7, The process involves administering the formulation via contact with an alkali-resistant halogenated polymer. A method comprising a halogenated polymer incorporating one or more polymer stabilizers, polymer plasticizers, or free radical inhibitors, which is an alkali-resistant halogenated polymer. [2] The method according to item 1, wherein the highly alkaline pharmaceutical formulation has a pH in the range of greater than 7 to 14, and the highly alkaline formulation is in contact with the alkali-resistant halogenated polymer for more than 1 hour. [3] The method according to item 1, wherein the alkali-resistant halogenated polymer is sterilized by radiation before contact with the highly alkaline pharmaceutical formulation. [4] The method according to item 3, wherein the alkali-resistant halogenated polymer includes polyvinyl chloride as the halogenated polymer. [5] The method according to item 1, comprising administering the formulation via contact with a tube containing the alkali-resistant halogenated polymer. [6] The method according to item 5, wherein the alkali-resistant halogenated polymer includes polyvinyl chloride as the halogenated polymer. [7] The method according to item 6, wherein the alkali-resistant halogenated polymer is sterilized by radiation before coming into contact with a highly alkaline pharmaceutical formulation. [8] The method according to item 1, wherein the alkali-resistant halogenated polymer includes polyvinyl chloride as the halogenated polymer. [9] The method according to item 1, wherein the halogenated polymer is a chlorinated polymer.

[10] The method according to item 1, wherein the polymer stabilizer comprises one or more ion exchange resins or ionomers.

[11] The method according to item 1, wherein the polymer plasticizer comprises one or more aliphatic polyesters.

[12] The method according to item 1, wherein the free radical inhibitor comprises one or more hydroquinones or derivatives thereof.

[13] The method according to item 1, wherein the alkali-resistant halogenated polymer comprises a non-dialkyl ester-based plasticizer.

[14] The method according to item 1, wherein the formulation is in contact with the alkali-resistant halogenated polymer for more than one hour.

[15] A medical device comprising an alkali-resistant halogenated polymer containing one or more polymer stabilizers, polymer plasticizers, or free radical inhibitors, or a combination thereof, of the halogenated polymer.

[16] The medical device according to item 15, wherein the halogenated polymer includes polyvinyl chloride.

[17] The medical device according to item 16, wherein the halogenated polymer comprises polyvinyl chloride and is in the form of a tube or drip chamber.

[18] The medical device according to item 17, wherein the alkali-resistant halogenated polymer is sterilized by radiation.

[19] The medical device according to item 15, wherein the alkali-resistant halogenated polymer is in contact with a highly alkaline pharmaceutical formulation having a pH greater than 7.

[20] The medical device according to item 15, wherein the alkali-resistant halogenated polymer is in contact with a highly alkaline pharmaceutical formulation having a pH in the range of 8 to 14.

Claims

1. A medical device comprising an alkali-resistant halogenated polymer, used for administering a highly alkaline pharmaceutical formulation having a pH greater than 7 via contact with the alkali-resistant halogenated polymer, This alkali-resistant halogenated polymer includes a halogenated polymer incorporating a free radical inhibitor, a polymer stabilizer, and a polymer plasticizer. The alkali-resistant halogenated polymer is sterilized by radiation before coming into contact with the highly alkaline pharmaceutical formulation. The polymer stabilizer comprises an ion exchange resin or an ionomer. The polymer plasticizer includes polyazipart, The free radical inhibitor is incorporated into the halogenated polymer at a concentration between 0.01 parts per 100 parts of resin and 1 part per 100 parts of resin. Medical devices.

2. The medical device according to claim 1, wherein the highly alkaline pharmaceutical formulation has a pH in the range of greater than 7 to 14, and the contact of the highly alkaline formulation with the alkali-resistant halogenated polymer lasts for more than one hour.

3. The medical device according to claim 2, wherein the alkali-resistant halogenated polymer includes polyvinyl chloride as the halogenated polymer.

4. The medical device according to claim 1, wherein the formulation is administered via contact with a tube containing the alkali-resistant halogenated polymer.

5. The medical device according to claim 4, wherein the alkali-resistant halogenated polymer includes polyvinyl chloride as the halogenated polymer.

6. The medical device according to claim 1, wherein the alkali-resistant halogenated polymer includes polyvinyl chloride as the halogenated polymer.

7. The medical device according to claim 1, wherein the halogenated polymer is a chlorinated polymer.

8. The polyadipate contained in the aforementioned polymer plasticizer is Polymers composed of hexanedioic acid, 2,2-dimethyl-1,3-propanediol and 1,2-propanediol, isononyl esters, A polymer composed of hexanediol, 1,2-propanediol, octyl ester, or A polymer composed of hexanedioic acid and 1,2-propanediol, acetate A medical device according to any one of claims 1 to 7, including the medical device described in any one of claims 1 to 7.

9. The medical device according to any one of claims 1 to 7, wherein the free radical inhibitor comprises one or more hydroquinones or derivatives thereof.

10. The medical device according to any one of claims 1 to 7, wherein the alkali-resistant halogenated polymer comprises a non-dialkyl ester-based plasticizer.

11. The medical device according to claim 1, wherein the contact between the formulation and the alkali-resistant halogenated polymer is for more than one hour.

12. A sterile medical device comprising an alkali-resistant halogenated polymer containing a halogenated polymer incorporating a free radical inhibitor, a polymer stabilizer, and a polymer plasticizer, The alkali-resistant halogenated polymer is sterilized by radiation. The polymer stabilizer comprises an ion exchange resin or an ionomer. The polymer plasticizer includes polyazipart, The free radical inhibitor is incorporated into the halogenated polymer at a concentration between 0.01 parts per 100 parts of resin and 1 part per 100 parts of resin. Sterilized medical devices.

13. The sterile medical device according to claim 12, wherein the halogenated polymer comprises polyvinyl chloride.

14. The sterile medical device according to claim 13, wherein the halogenated polymer contains polyvinyl chloride and is in the form of a tube or drip chamber.

15. The sterile medical device according to claim 12, wherein the alkali-resistant halogenated polymer is in contact with a highly alkaline pharmaceutical formulation having a pH greater than 7.

16. The sterile medical device according to claim 12, wherein the alkali-resistant halogenated polymer is in contact with a highly alkaline pharmaceutical formulation having a pH in the range of 8 to 14.

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