DEVICES THAT INCLUDE ETHYLENE-VINYL ACETATE COPOLYMERS AND METHODS OF MAKING AND USING SAME

RELATED APPLICATION

[0001] This application claims priority to the provisional application U. S. S.N. 61/046,182 filed April 18, 2008, hereby incorporated by reference in its entirety.

FIELD

[0002] This disclosure is directed in part to an ethylene- vinyl acetate copolymer having substantially reduced monomeric vinyl acetate content.

BACKGROUND

[0003] Ethylene vinyl acetate (EVA) is a copolymer of ethylene and vinyl acetate, with a typical weight percent of vinyl acetate in the polymer varying from about 10 to about 40% with the remainder being ethylene. EVA typically has substantial softness and flexibility properties and may be processed like other thermoplastics.

[0004] EVA copolymers are often contemplated for use in medical applications, for example, for use in stents, vaginal rings, and medical use tubing. For example, EVA can be used in vaginal rings as polymeric drug delivery devices usually designed to provide controlled release of drugs in vagina over extended periods of time.

[0005] However, when formed into e.g., a vaginal ring, such as a vaginal ring having a therapeutic agent(s), such polymers may leach monomers such as vinyl acetate to a patient. Such monomers have increased toxicity and therefore it would be desirable to minimize the amount of monomer present in the polymer, for example, when the polymer is used in a patient.

SUMMARY

[0006] This disclosure is generally directed, in part, to EVA copolymers having minimal amounts of monomeric vinyl acetate and methods of making and using such purified polymers.

[0007] In an embodiment, a method of reducing the amount of vinyl acetate monomer released over time in an polymer comprising ethylene- vinyl acetate co-polymer is provided, wherein the method comprises a) washing the polymer with water, e.g, with water at about 50° to 55 ⁰ C; and b) repeating step a). In some embodiments, step a) is repeated between about two times and about 10 times, e.g., about 2, 3, 4, 5 or more times. Such disclosed methods may further comprise drying the polymer, for example, in a vacuum oven.

[0008] Also provided herein is a polymer comprising an ethylene- vinyl acetate co-polymer, wherein the polymer releases less than about 200 μg/50mL of vinyl acetate monomer per day for at least two days when about 1.5 to about 1.9 grams of the polymer is placed in a buffer solution comprising phosphate. For example, the ethylene-vinyl acetate copolymer is a random co-polymer. The ethylene-vinyl acetate copolymer may comprise about 38 to 41 percent by weight vinyl acetate.

[0009] In some embodiments a polymer comprising an ethylene-vinyl acetate co-polymer, when placed in a buffer solution comprising phosphate (and optionally an alcohol, e.g. ethanol), releases less than about 100 μg/50mL of vinyl acetate monomer per day on or after the second day of placement. Disclosed polymers, in some embodiments, may, when placed in a buffer solution comprising phosphate, release substantially no vinyl acetate monomer on or after the third day of placement.

[0010] Also disclosed herein are medical devices, for example, vaginal rings, that comprise a disclosed polymer. For example, a vaginal ring is disclosed that comprises a disclosed polymer, wherein when the ring is placed in a patient, said ring releases fewer vinyl acetate monomers as compared to a ring comprising a ethylene vinyl acetate copolymer that releases 300 μg/50mL or more of vinyl acetate monomers for at least one day when placed in a buffer solution comprising phosphate.

[0011] Also disclosed herein is a vaginal ring comprising a polymer produced by the disclosed methods, wherein when the ring is placed in a patient, said ring releases fewer vinyl acetate

monomers as compared to a ring comprising a ethylene vinyl acetate copolymer that releases 300 mg/50mL or more of vinyl acetate monomers for at least one day when placed in a buffer solution comprising phosphate.

[0012] These and other aspects and advantages of the invention will become apparent upon consideration of the following detailed description and claims.

DETAILED DESCRIPTION

[0013] This disclosed relates, in part, to ethylene-vinyl acetate (EVA) copolymers with reduced monomelic vinyl acetate.

[0014] An EVA co-polymer can be, for example, a random co-polymer comprising chains of ethylene hydrocarbons with acetate groups randomly distributed throughout the chains. EVA may be formed as for example, a resin, oleo-resin, granules, beads or emulsion.

[0015] EVA, as contemplated herein, can include copolymers with other polymeric components, e.g., a ter-polymer. In certain embodiments, EVA copolymers have different subunits and/or other monomeric units that are incorporated into the polymer. In certain instances, the polymers are random copolymers, in which the different subunits and/or other monomeric units are distributed randomly throughout the polymer chain.

[0016] In part, the term "random" is intended to refer to the situation in which the particular distribution or incorporation of monomeric units in a polymer that has more than one type of monomeric units is not directed or controlled directly by the synthetic protocol, but instead results from features inherent to the polymer system, such as the reactivity, amounts of subunits and other characteristics of the synthetic reaction or other methods of manufacture, processing or treatment.

[0017] The ratio of different subunits, e.g. ethylene and vinyl acetate, in an EVA copolymer may vary. For example, copolymers can be effectively composed of two different subunits e.g. ethylene and vinyl acetate, in which the ratio of the subunits may vary from less than 1:99 to

more than 99:1, or alternatively 10:90, 15:85, 25:75, 40:60, 50:50, 60:40, 75:25, 85:15, 90:10 or the like.

[0018] For example, EVA copolymers can include about 10% to about 50% vinyl acetate, or about 15% to about 45%, e.g., 18% or about 35% to about 42% or about 38% to about 41% vinyl acetate, e.g. about 40% vinyl acetate.

[0019] Ethylene and vinyl acetate may be radically copolymerized in any desired proportions. EVA copolymers with low vinyl acetate content (up to 50% by weight of vinyl acetate) may be prepared by high pressure polymerization method. In addition to ethylene and vinyl acetate, other monomers or polymers may be added during polymerization process.

[0020] EVA copolymers may also include one or more chain terminating groups. Examples of such chain terminating groups include alcohols and amines, or other organic or inorganic moieties.

[0021] Untreated EVA copolymers may contain residual vinyl acetate monomers distributed randomly throughout the polymeric matrix. For example, EVA copolymers used in manufacturing a vaginal ring may contain a significant amount of residual vinyl acetate monomer, for example, up to about 0.3% by weight. For example, an EVA copolymer with about 40% vinyl acetate by weight, may contain about 0.1-0.3% of un-reacted (residual) vinyl acetate monomer. For example, a vaginal ring of 1.8 gram by weight made with such a polymer may thus include about 2 to 6 mg of vinyl acetate monomer in the ring. Such monomers can potentially leach into human body upon long exposure and may cause serious health problems.

[0022] This disclosure provides for ethylene- vinyl acetate monomers having minimal amounts of vinyl acetate monomer. For example, the disclosure provides for a polymer that releases less than about 200 μg/50mL, less than about 180 μg/50mL, for example about 150 μg/50mL to about 200 μg/50mL of vinyl acetate monomer per day for at least two days when about 1.5 to about 1.9 grams, e.g., about 1.7 grams of the polymer is placed in a buffer solution comprising phosphate. Such a buffer solution can be analogous to placement in-vivo.

[0023] In some embodiments, the disclosed polymer, when 1.5 to about 1.9 grams, e.g., about 1.7 grams of the polymer is placed in a buffer solution comprising phosphate, releases less than

about 100 μg/50mL, less than about 75 μg/50mL, or even less than about 50 μg/50mL of vinyl acetate monomer per day on or after the second day of placement. Disclosed polymers may, when about 1.5 to about 1.9 grams, e.g. about 1.7 grams of the polymer, is placed in a solution comprising phosphate, releases substantially no or minimal vinyl acetate monomer on or after the third day of placement.

[0024] In one embodiment, the present disclosure provides a method of reducing the level of monomeric vinyl acetate in EVA copolymer that includes washing the copolymer with water. The method includes EVA copolymers in any physical form including but not limited to powder, amorphous, bead, granule, or resin.

[0025] For example, a large quantity of water may be mixed with EVA copolymer, and the mixture may be stirred by mechanical stirrer or shaker to wash the copolymer material. Washing may be carried out using hot water, for example, at a temperature of about 40 ⁰ C to about 60 ⁰ C, or 50 ⁰ C to about 55 ⁰ C. In other embodiments, cold water or room temperature water may be used.

[0026] A disclosed method may include washing a mixture of EVA copolymer and water by stirring a mixture including both for about 5 minutes to about day. For example, stirring may be carried out for about 10 minutes to an hour or about 20 minutes to 40 minutes. After thorough washing, water is removed. Water removal may be carried out by any suitable water removal method including but not limited to filtration methods. For example, a 1700 micron sieve may be used for water draining process. Residual water may also be drained using other known methods such as mechanical extraction of water by a centrifuge machine.

[0027] In another embodiment, a cycle of washing and filtration may be repeated multiple times. The number of cycles used in practice can be optimized so that vinyl acetate monomer content in EVA copolymer can be reduced to a desired level. For example, washing and filtration cycles may be repeated from about 1 to 20 times, or about 5 to 10 times. After each cycle, wash water obtained from filtration may be collected and reused with or without further processing.

[0028] The disclosure also provides for a method of reducing the level of monomeric vinyl acetate in EVA copolymer that includes washing the copolymer with water and drying the washed copolymer e.g. by vacuum drying, e.g. in a vacuum oven. For example, the oven may supply heat by direct contact with the polymeric material, or alternatively supply radiative heat with water vapor generated in the drying process removed by the vacuum system. Such a vacuum oven may have a temperature of about 5° C to 200° C and/or supply a vacuum of about 1 torr to an ultra-high vacuum of less than about 10 ^~8 torr. For example, drying may be carried out under medium range vacuum pressure of about 10 ^~3 torr. Such a heat treating under vacuum may prevent surface reactions on the polymer, such as oxidation, and may further remove traces of volatile monomeric vinyl acetate and other volatile contaminating substances. Such vacuum drying may be carried out for about 1 to 10 days, for example, about 2 to 4 days. Any drying step may alternatively be carried out by other commonly employed methods such as by evaporation. In case of evaporation based drying, a gas stream, e.g., air, may apply heat by convection and carry away vapor generated from volatile substance and water.

EXEMPLIFICATION

Example 1 : Washing and filtration of EVA copolymer

[0029] 150.0 g of a EVA polymer (with 40% vinyl acetate content) (Evatane 40-55®, manufactured by Arkema) was weighed into a weighing pan. Next, 1 L of de-ionized water was placed in a 2-L beaker and was stirred water by Arrow Engineering Mixer using setting of 2.5. The polymer was charged into batch while mixing. The copolymeric beads were stirred in water for 20 minutes. After stirring, the material was filtered and collected. Evatane ® beads were washed 9 times by repeating the cycle of washing and filtration. Following wash-filter cycle, collected wash-filtered beads were further drained by passing the copolymeric material through a 1700-microns sieve. Finally, polymeric material, along with the sieve, was placed in a vacuum oven for 48 hours.

Example 2: Comparison of Vinyl Acetate Monomer Release Profile of Vaginal Rings

[0030] The release profile of vinyl acetate monomers from vaginal rings, made of EVA copolymer that was treated according to Example 1, was investigated. Results were also compared with monomeric vinyl acetate release profile from vaginal ring made of untreated EVA copolymer and commercially available Nuvaring. Vaginal rings were prepared using a bench-top injection molding machine at 90 ⁰ C using treated and untreated EVA copolymer.

Dimension of the ring was 55 mm with 4 mm in thickness. For each vaginal ring, duplicate samples were placed in 150-mL bottles containing 50 mL of phosphate buffer solution. The bottles were placed in a shaking incubator at 37 ⁰ C, shaking at 100 rpm. Medium solutions were sampled and replaced with fresh phosphate buffer solution according the schedule in Table 1. The first two samples obtained on day 1 and 2 provide estimates of vinyl acetate monomer release in each of those two consecutive days. However, samples obtained on day 4, 6, 8, 11, and 14 provide a cumulative estimate of the release of the monomer. In this study, two different media were used: phosphate buffer solution with pH 4.5, and a blend solution of 30% ethanol with 70% phosphate buffer solution. For Nuvaring, due to limited supply of the material, a single sample was used.

Table 1 Sampling Schedule for Drug Release Media

Example 3: Analytical Quantification of Released Vinyl Acetate Monomer

[0031] The amount of released monomeric vinyl acetate from EVA copolymer can be estimated using an analytical assay. In this study, High Performance Liquid Chromatography (HPLC) method was used to determine the dissolved monomeric vinyl acetate in the sampled solutions. Limit of detection (LOD) and limit of quantitation (LOQ) in the HPLC method used in the study is shown in Table 2. Table 2 shows that when a solution had minimum vinyl acetate concentration of 0.2 μg/mL, HPLC assay could quantitatively determine the presence of vinyl acetate in the solution.

Table 2 LOD and LOQ of HPLC Assay Method for Vinyl Acetate Aqueous Samples

[0032] Results from HPLC assay showed that the Nuvaring® released substantially more monomeric vinyl acetate in buffer medium compared to vaginal ring made of treated EVA copolymer. Table 3 shows the amount of monomeric vinyl acetate released by vaginal rings made of treated EVA copolymers and Nuvaring in both phosphate buffer solution (PBS) and blend medium (30% ethanol/80% PBS) at 37 ⁰ C. Results indicate that in day 1, the amount of vinyl acetate released in phosphate buffer solution from vaginal ring made of treated EVA copolymer (about 163 μg/ 50 mL) is almost 55% less compared to the amount released from Nuvaring (361 μg/ 50 mL). Similarly, in blend solution, vaginal ring made of treated EVA copolymer released about 50% less vinyl acetate compared to Nuvaring. In day 2, the amount of released vinyl acetate from vaginal ring made of treated EVA copolymer is almost half of the amount released from Nuvaring. Beyond day 2, treated vaginal ring made of treated EVA copolymer, when placed in a phosphate buffer solution, released less than about 100 μg/50mL of vinyl acetate monomer per day on or after the second day of placement.

Table 3 Amount of Vinyl Acetate Released from Vaginal Rings Made of Treated EVA Copolymer and Nuvaring at 37 ⁰ C

[0033] The study also indicated that the amount of vinyl acetate released from vaginal rings made of treated EVA copolymer was substantially less compared to rings made of unwashed EVA copolymers. Table 4 shows a comparative vinyl acetate release profile of the two types of vaginal rings. Vaginal rings made of unwashed EVA copolymers released 212 μg of vinyl acetate per 50 mL in day 1. In subsequent days, unwashed EVA copolymers released 2541 and 1812 μg of vinyl acetate per 50 mL which was substantially higher compared of the amount released by treated EVA copolymer. These results clearly indicate that vaginal rings made of treated EVA copolymer have significantly lower amount of leachable vinyl acetate.

Table 4 Amount of Vinyl Acetate Monomer Released from Vaginal Rings Made of Unwashed EVA Copolymer at 37 ⁰ C

Amount VA Released, μg/ 50 mL

Sample

Sample ID Description Medium Wt, g 3,4&56,7&89,10&l l 12,13&14

UW-3 PBS 1.6901 212.82541 1812 103.2

Unwashed

UW-4 EVA PBS 1.6900 201.42876 1812

Example 4 Quantification of monomelic vinyl acetate remained in EVA beads.

[0034] The presence of residual (unreacted) monomeric vinyl acetate present in EVA beads was determined using head-space gas chromatography (HS-GC). EVA beads were washed with de-ionized water ten times, according to the procedure described in Example 1, and then drained. The washed beads were dried by placing in them in a vacuum oven for 72 hours. The remaining vinyl acetate monomer of both untreated (raw) and treated EVA beads were determined. Table 5 shows the results of analyses.

Table 5

REFERENCES

[0035] All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

EQUIVALENTS

[0036] While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

[0037] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention.

[0038] What is claimed is: