WO2025015011A1 - Bupivacaine compositions and methods - Google Patents

Abstract

A sterile and ready-to-use bupivacaine solution is contained in a polymeric bag and is substantially free of any buffer, excipient, and preservative. Advantageously, the solution and the polymeric material allow for autoclaving to sterility without a significant pH drift towards lower pH values and for maintaining active ingredient in solution.

Description

Attny Dkt No. 104297.0035PCT Client Ref. NVK046 BUPIVACAINE COMPOSITIONS AND METHODS [0001] This application claims priority to our copending US provisional patent application with the serial number 63/512,736, which was filed 7/10/2023, and which is incorporated by reference herein. Field of the Invention [0002] The field of the invention is pharmaceutical compositions comprising bupivacaine, and especially as it relates to ready-to-use containers comprising a bupivacaine composition that is substantially buffer free and has no preservatives, and that can be autoclaved with low or no pH drift. Background of the Invention [0003] The background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art. [0004] All publications and patent applications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply. [0005] Bupivacaine (1-alkyl-N-(2,6-dimethylphenyl)-2-piperidinecaboxamide) is a commonly used anesthetic with relatively long-lasting activity and is frequently used for nerve blocks to reduce or alleviate pain. For example, bupivacaine is often used for local infiltration, peripheral nerve block, sympathetic nerve block, epidural and caudal blocks. Bupivacaine is chemically stable and can be stored in a variety of containers, including glass and polymeric containers. While storage in glass containers appears not to affect the pH, a significant pH drift (decrease by 1-2 pH units) was reported where the bupivacaine was autoclaved in a polypropylene container as described in US 6,284,805. To solve the problem of pH drift, the inventor of the ‘805 patent included a buffering agent (such as citrate or lactate) to maintain the pH in a range Attny Dkt No. 104297.0035PCT Client Ref. NVK046 of between 3-6. Unfortunately, where bupivacaine is used for longer term epidural anesthesia at significant volumes (e.g., more than 50 mL), infusion of a buffer at such acidic pH is undesirable. [0006] Thus, even though various compositions and methods of preparing and storing sterile bupivacaine formulations are known in the art, all or almost all of them suffer from several drawbacks. Therefore, there remains a need for improved polymeric containers for storing bupivacaine formulations, and especially ready-to-use bupivacaine formulations in polymeric containers that exhibit low or no pH drift and product loss upon autoclaving in compositions that do not contain appreciable quantities of a buffer. Summary of The Invention [0007] The inventive subject matter is directed to bupivacaine compositions and polymeric containers that contain such compositions, wherein the composition is substantially free of buffers and preservatives, and wherein the composition exhibits low or no pH drift and low or no product loss upon autoclaving in the polymeric container. [0008] In one aspect of the inventive subject matter, the inventors contemplate a pharmaceutical product that comprises a polymeric container containing a sterile ready-to-use bupivacaine solution. Preferably, the ready-to-use bupivacaine solution comprises an aqueous solvent containing dissolved bupivacaine or a pharmaceutically acceptable salt thereof at a ready-to-use concentration and further comprises a tonicity agent in an amount sufficient to render the ready-to-use bupivacaine solution isotonic. It is still further preferred that the ready- to-use bupivacaine solution is free of a buffer. The polymeric container in contemplated products preferably comprises a multi-layer polymeric bag that contains at least one layer comprising a cyclic olefin copolymer, and it is especially preferred that the multi-layer polymeric bag has a composition such that (a) the pH differential of the ready-to-use bupivacaine solution before and after autoclaving in the polymeric container is no more than 0.4 pH units, and/or (b) a product loss of the ready-to-use bupivacaine solution before and after autoclaving in the polymeric container is no more than 0.4%. [0009] For example, suitable ready-to-use concentrations of the bupivacaine or a pharmaceutically acceptable salt thereof will be equal or less than 0.80% w/v, or equal or less than 0.50% w/v, or equal or less than 0.150% w/v, such as 0.0625% w/v or 0.125% w/v. It is further contemplated that the pharmaceutically acceptable salt of bupivacaine is racemic Attny Dkt No. 104297.0035PCT Client Ref. NVK046 bupivacaine HCl, that the aqueous solvent is water for injection, and/or that the tonicity agent is sodium chloride, sucrose, or glycerol (e.g., such that the isotonic bupivacaine solution has an osmolality of between 285 and 300 mOsm). Most typically, the ready-to-use bupivacaine solution is substantially free of a preservative. [0010] In further contemplated embodiments, the ready-to-use bupivacaine solution has - before autoclaving - a pH of between 6.0 and 5.4, and/or the pH differential before and after autoclaving is no more than 0.3 pH units, or no more than 0.2 pH units. In additional embodiments, the pH differential between immediate post-autoclaving and storage for one month after sterilization is no more than 0.3 pH units, or no more than 0.2 pH units. Most typically, autoclaving is performed at 121 °C for 15-30 min, and/or the container contains 100 mL or 250 mL of the ready-to-use bupivacaine solution. In some embodiments, the layer comprising the cyclic olefin polymer (COP) or cyclic olefin copolymer (COC) is an innermost layer in the multi-layer polymeric bag, while in other embodiments the layer comprising the cyclic olefin polymer or cyclic olefin copolymer is an intermediate layer in the multi-layer polymeric bag. [0011] Therefore, and viewed from a different perspective, the inventors contemplate a pharmaceutical product that comprises a polymeric container containing a sterile ready-to-use bupivacaine solution. In such product, the ready-to-use bupivacaine solution consists (or essentially consists) of an aqueous solvent containing dissolved bupivacaine HCl at a ready- to-use concentration of 1.25mg/mL or 0.625 mg/mL and sodium chloride dissolved at a concentration of 8.8 mg/mL or 9 mg/mL, respectively. Moreover, it is contemplated that the polymeric container comprises a multi-layer polymeric bag that contains at least one layer comprising a cyclic olefin polymer (COC) or cyclic olefin copolymer (COP), wherein the polymeric container maintains a pH differential of the ready-to-use bupivacaine solution before and after autoclaving in the polymeric container within 0.4 pH units and a product loss of the ready-to-use bupivacaine solution before and after autoclaving in the polymeric container within 0.4%. [0012] Viewed from a different perspective, the inventors therefore also contemplate a method of preparing a sterile ready-to-use bupivacaine solution in a container that includes a step of dissolving in an aqueous solvent (a) bupivacaine or a pharmaceutically acceptable salt thereof at a ready-to-use concentration, and (b) a tonicity agent in an amount sufficient to render the ready-to-use bupivacaine solution isotonic, thereby forming the ready-to-use bupivacaine Attny Dkt No. 104297.0035PCT Client Ref. NVK046 solution. In another step, the pH of the ready-to-use bupivacaine solution is adjusted to a pH between 6.0 and 5.4, and the isotonic ready-to-use bupivacaine solution is filled into a multi- layer polymeric bag that contains at least one layer comprising a cyclic olefin polymer or cyclic olefin copolymer. In still another step, the isotonic ready-to-use bupivacaine solution is autoclaved in the multi-layer polymeric bag to sterility. In such methods, the multi-layer polymeric bag has a composition such that a pH differential of the ready-to-use bupivacaine solution before and after autoclaving in the polymeric container is no more than 0.4 pH units, and/or such that a product loss of the ready-to-use bupivacaine solution before and after autoclaving in the polymeric container is no more than 0.4%, or no more than 0.2%, or has no apparent product loss. [0013] Most typically, the ready-to-use concentration of the bupivacaine or the pharmaceutically acceptable salt thereof is 0.0625% w/v or 0.125% w/v, and the sterile ready- to-use bupivacaine solution is substantially free of a buffer and/or a preservative. [0014] Various objects, features, aspects, and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments. Detailed Description [0015] The inventors have discovered that ready-to-use bupivacaine solutions can be prepared in a simple and effective manner that avoids significant pH deviations and product loss upon autoclaving. Most advantageously, contemplated solutions are substantially free of buffers, and preservatives, and exhibit only low or even no pH drift and/or product loss upon autoclaving. In addition, once autoclaved, the solutions contemplated herein have a stable pH over extended periods of time. [0016] With respect to the active ingredient bupivacaine, it is contemplated that all forms are deemed suitable for use herein, including the free base, and various addition salt such as the HCl or HBr salt. The structure of rac-bupivacaine (1-alkyl-N-(2,6-dimethylphenyl)-2- piperidine-caboxamide) is shown in Formula I below. Moreover, contemplated compositions may also comprise isolated stereoisomers (and especially levo-bupivacaine) or may be compositions that are enriched in a single stereoisomer. Attny Dkt No. 104297.0035PCT Client Ref. NVK046

Formula I [0017] As will be further readily appreciated, contemplated formulations may also include a second active ingredient, and particularly contemplated second active ingredients include various analgesics, including various natural and synthetic opioids (e.g., morphine, hydromorphone, alfentanil, fentanyl, sufentanil, etorphine, etc.), sedatives (e.g., barbiturates, benzodiazepines, etc.), hypnotics (e.g., quinazolinones, zopiclone, etc.), and clonidine. [0018] Moreover, it is generally preferred that the solution that contains bupivacaine is an aqueous solution that contains at least 70 vol%, or at least 80 vol%, or at least 90 vol%, or at least 95 vol%, or at least 98 vol% water as the primary solvent. Where co-solvents are employed, it is typically preferred that the cosolvent is water miscible and a pharmaceutically acceptable cosolvent. Therefore, contemplated cosolvents include methanol, ethanol, propylene glycol, polyethylene glycol, glycerol, dimethylsulfoxide, dimethylformamide, etc. Most typically, the pH of the bupivacaine solution will be adjusted to an initial pH (before autoclaving) of between 4.0 to 6.5, or between 4.5 and 6.5, or between 5.0 and 6.5, or between 4.5 and 6.0, or between 5.0 and 6.0, or between 5.2 and 6.0, or between 5.4 and 6.0, or between 5.5 and 6.2, or between 5.6 and 6.0, typically using HCl or NaOH as needed. For example, the pH of the bupivacaine solution will be adjusted to an initial pH (before autoclaving) of 5.2 +/- 0.2, or 5.4 +/- 0.2, or 5.6 +/- 0.2, or 5.8 +/- 0.2, or 6.0 +/- 0.2. [0019] In still further aspects of the inventive subject matter, contemplated formulations will include one or more tonicity agents to render the formulation substantially isotonic (i.e., to have an osmolality of between 285-300 mOsm). While there are numerous tonicity agents known in the art, various pharmaceutically acceptable salts (and especially inorganic salts such as NaCl) are particularly preferred. Without wishing to be bound by any specific theory or hypothesis, the inventors contemplate that the anion component provided by the tonicity agent (particularly in conjunction with the relatively low bupivacaine concentrations used) may act as sufficient counter ions for acidification during autoclaving of the formulation in the polymeric container. Attny Dkt No. 104297.0035PCT Client Ref. NVK046 However, and in addition to (or as replacement of) various salts, non-salt tonicity agents are also deemed suitable for use herein. For example, acceptable tonicity agents include sucrose, lactose, dextrose, mannitol, trehalose, raffinose, glycerol, thioglycerol, etc. and all reasonable combinations thereof. [0020] While generally not preferred, one or more additional excipients and preservatives (e.g., methylparaben, propylparaben) are also contemplated. In addition, in at least some embodiments, at least some of the tonicity agent may also have a buffer function, and contemplated tonicity agents with buffer function include histidine, aspartic and glutamic acid, gluconic acid, tartaric acid, fumarate, α-ketoglutarate, malate, succinate. However, in at least some embodiments, the sterile ready-to-use bupivacaine solution will be buffer free (i.e., any buffer no more than 5 mM, or no more than 3 mM, or no more than 1 mM), and/or will be free of preservative. [0021] With respect to suitable containers, it is preferred that the containers will be polymeric bags having a volume sufficient to hold at least 50 mL, or at least 100 mL, or at least 250 mL of the bupivacaine compositions contemplated herein, and that such containers are fabricated from a material that will withstand autoclaving conditions (e.g., temperature of at least 110 °C, or at least 115 °C, or at least 120 °C, etc. for a duration of at least 10 minutes, or at least 15 minutes, or at least 20 minutes, or at least 30 minutes, and even longer). In addition, it is further preferred that he container with the bupivacaine compositions contemplated herein may be disposed in a (typically polymeric) overwrap, and that the autoclaving of the bupivacaine composition will be performed while the composition is enclosed in the container and the overwrap. However, in further embodiments, the formulation is autoclaved in the container without overwrap. [0022] Suitable polymeric bags may be manufactured from a variety of materials, including polyethylene, polypropylene, polyvinyl chloride, polycarbonate, and any mixtures thereof. Furthermore, and as described in more detail below, especially preferred polymeric containers will include multi-layer polymeric bags in which at least one layer is manufactured from or comprises a cyclic olefin copolymer (COC) or cyclic olefin polymer (COP), and examples for such materials for multi-layer polymeric bags will include the COC/COP containing layer as the innermost layer contacting the ready-to-use bupivacaine solution or as an intermediate layer sandwiched between, for example, polyethylene or polypropylene containing layers. Without wishing to be bound by any theory or hypothesis, it is contemplated that such multi-layer bags Attny Dkt No. 104297.0035PCT Client Ref. NVK046 exhibit a lower leachable content, which may contribute to the unexpectedly low product loss (as measured in Assay% shown below) and pH differential between before and post- autoclaving (typically as measured within 4 hours of autoclaving). [0023] Most notably, when using a multi-layer polymeric bag with a COC/COP containing layer, the pH differential between before (typically no more than 4 hours or no more than 2 hours, or no more than 1 hour) autoclaving and after (typically no more than 4 hours or no more than 2 hours, or no more than 1 hour) autoclaving was unexpectedly low and was typically equal or less than 0.4 pH units, or equal or less than 0.35 pH units, or equal or less than 0.3 pH units, or equal or less than 0.25 pH units, or equal or less than 0.2 pH units, or equal or less than 0.15 pH units, or even less. Thus, the pH differential between before and after autoclaving will typically be between 0.2-0.4 pH units, or between 0.15-0.35 pH units, or between 0.1 and 0.3 pH units. Similarly, the change in pH between immediately after autoclaving (e.g., within less than 2 hours, or within less than 1 hour) and one month after autoclaving (at 25 °C and 40% relative humidity, or at 40 °C and no more than 25% relative humidity or at 60 °C and no more than 40% relative humidity storage conditions) was also surprisingly low such as equal or less than 0.4 pH units, or equal or less than 0.35 pH units, or equal or less than 0.3 pH units, or equal or less than 0.25 pH units, or equal or less than 0.2 pH units, or equal or less than 0.15 pH units, or even less. Thus, the pH differential after one month will typically be between 0.2- 0.4 pH units, or between 0.15-0.35 pH units, or between 0.1 and 0.3 pH units. [0024] Similarly, when using a multi-layer polymeric bag with a COC/COP containing layer, the product loss as measured by Assay% as shown below was also unexpectedly reduced and was in some examples equal or less than 0.4%, or equal or less than 0.35%, or equal or less than 0.3%, or equal or less than 0.25%, or equal or less than 0.2%, equal or less than 0.15%, or even lower. Thus, in addition to the benefits of reducing a pH decrease during autoclaving provided by the formulations and packaging presented herein as shown in more detail below, the inventors also observed that the product loss was significantly reduced and that the pH remained stable over extended periods after autoclaving (also shown in more detail below). Examples [0025] In the following example, various experimental conditions are given that demonstrate that a decrease in pH of a bupivacaine formulation can be significantly reduced as compared to an otherwise expected drop in pH value between 1.0-2.0 pH units as was shown in US Attny Dkt No. 104297.0035PCT Client Ref. NVK046 6,284,805. Moreover, it should be appreciated that the formulations as shown in the examples below had the least amount of ingredients and so avoided use of buffers and preservatives that are frequently used. Such simple composition is particularly beneficial where the composition is to be used for epidural administration in late stages of pregnancy and delivery or Caesarian section. [0026] Container Materials: The following autoclaving examples use different container materials and were performed with a ready-to-use bupivacaine solution with a composition as listed in Table 1. Here, a weighed quantity of Milliq water was taken in a glass compounding vessel. Weighed quantity of sodium chloride was added to the glass vessel. The solution was mixed with a PTFE stir bar for 10 minutes. Weighed quantity of Bupivacaine hydrochloride was added to the glass vessel. The solution was mixed for 15 minutes. The pH of the solution was checked and adjusted to pH 6.0 using sodium hydroxide and/or hydrochloric acid. Volume of the solution was made up with Milliq water and the solution was mixed until homogenous solution was obtained. The product was filled in various container closures. The product was terminally sterilized at 121 °C for 30 minutes. The drug product was tested pre-sterilization in the container closure and post completion of terminal sterilization. Table 1

[0027] Tables 2-4 provide exemplary results for the various container materials where RRT denotes Relative Retention Time, CCS denotes Clear colorless solution, and where NR denotes Not Reported (<0.05%). Notably, as can be seen from the results above, a significant pH drop was not observed in glass and polymeric multilayer bags with a COP layer. All other tested bag films did not prevent a pH drop post terminal sterilization. Similarly, product loss was minimal with glass containers and polymeric multilayer bags with a COP layer, but evident in all other polymeric bags. Attny Dkt No. 104297.0035PCT Client Ref. NVK046 Table 2

Table 3

Attny Dkt No. 104297.0035PCT Client Ref. NVK046 Table 4

[0028] In further experiments, the inventors used different polypropylene polymeric containers with an overwrap for autoclaving at 0.0625% concentration, with Table 5 showing the formulation details (here, the overwrap was added post sterilization). Table 5

[0029] Exemplary results and conditions are shown in Table 6 that demonstrate an extended stability during storage. of the drug product (Bupivacaine Hydrochloride – 0.0625%) stored in polypropylene bags. Here, RRT denotes Relative Retention Time, CCS denotes Clear colorless solution, and where NR denotes Not Reported (<0.05%). Attny Dkt No. 104297.0035PCT Client Ref. NVK046 [0030] As can be readily seen from the data in Table 6, a pH drop was observed post terminal sterilization in polypropylene bags. This also corresponded with about 1% loss in bupivacaine assay post terminal sterilization. [0031] To determine stability of the Bupivacaine Hydrochloride drug product in PP/COP bags, composition described in Table 7 was prepared as follows: Table 7

[0032] A weighed quantity of Milliq water was taken in a stainless steel compounding vessel. Weighed quantity of sodium chloride was added to the stainless steel vessel. The solution was mixed for 10 minutes using an overhead stirrer. Weighed quantity of Bupivacaine hydrochloride was added to the glass vessel. The solution was mixed for 15 minutes. The pH of the solution was checked and adjusted to pH 6.0 using sodium hydroxide and/or hydrochloric acid. Volume of the solution was made up with Milliq water and the solution was mixed until a homogenous solution was obtained. The drug product was filtered through a 0.22 micron filter. The product was filled in PP/COP bags. The product was terminally sterilized at 121 °C for 30 minutes. The drug product was tested pre-sterilization in the container closure and post completion of terminal sterilization. The bags were packaged in clear overwrap and placed on stability at 25 °C/40% RH and 40 °C/NMT 25% RH. Samples were collected at various time points and tested. Data is presented in Table 8. As can be readily seen from the data, the polymeric multilayer bag with a COP layer performed significantly better than the other bag materials. Table 8

Attny Dkt No. 104297.0035PCT Client Ref. NVK046

[0033] In some embodiments, the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” As used herein, the terms "about" and "approximately", when referring to a specified, measurable value (such as a parameter, an amount, a temporal duration, and the like), is meant to encompass the specified value and variations of and from the specified value, such as variations of +/-10% or less, alternatively +/-5% or less, alternatively +/-1% or less, alternatively +/-0.1% or less of and from the specified value, insofar as such variations are appropriate to perform in the disclosed embodiments. Thus, the value to which the modifier "about" or "approximately" refers is itself also specifically disclosed. The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. [0034] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention. The terms “ready- to-use” and “ready-to-administer” when used in conjunction with a pharmaceutical composition are used interchangeable herein and refer to a pharmaceutical composition that can be administered, and most typically be injected, to a subject without further manipulation such as dilution and/or transfer into a device for administration (such as a syringe). Attny Dkt No. 104297.0035PCT Client Ref. NVK046 [0035] As used in the description herein and throughout the claims that follow, the meaning of “a,” “an,” and “the” includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of “in” includes “in” and “on” unless the context clearly dictates otherwise. As also used herein, and unless the context dictates otherwise, the term "coupled to" is intended to include both direct coupling (in which two elements that are coupled to each other contact each other) and indirect coupling (in which at least one additional element is located between the two elements). Therefore, the terms "coupled to" and "coupled with" are used synonymously. [0036] It should be apparent to those skilled in the art that many more modifications besides those already described are possible without departing from the inventive concepts herein. The inventive subject matter, therefore, is not to be restricted except in the scope of the appended claims. Moreover, in interpreting both the specification and the claims, all terms should be interpreted in the broadest possible manner consistent with the context. In particular, the terms “comprises” and “comprising” should be interpreted as referring to elements, components, or steps in a non-exclusive manner, indicating that the referenced elements, components, or steps may be present, or utilized, or combined with other elements, components, or steps that are not expressly referenced. Where the specification or claims refer to at least one of something selected from the group consisting of A, B, C …. and N, the text should be interpreted as requiring only one element from the group, not A plus N, or B plus N, etc.

Claims

Attny Dkt No. 104297.0035PCT Client Ref. NVK046 CLAIMS What is claimed is: 1. A pharmaceutical product, comprising: a polymeric container containing a sterile ready-to-use bupivacaine solution; wherein the ready-to-use bupivacaine solution comprises an aqueous solvent containing dissolved bupivacaine or a pharmaceutically acceptable salt thereof at a ready-to-use concentration; a tonicity agent in an amount sufficient to render the ready-to-use bupivacaine solution isotonic; wherein the ready-to-use bupivacaine solution is free of a buffer; wherein the polymeric container comprises a multi-layer polymeric bag that contains at least one layer comprising a cyclic olefin copolymer; wherein the multi-layer polymeric bag has a composition such that a pH differential of the ready-to-use bupivacaine solution before and after autoclaving in the polymeric container is no more than 0.4 pH units; and wherein the multi-layer polymeric bag has a composition such that a product loss of the ready-to-use bupivacaine solution before and after autoclaving in the polymeric container is no more than 0.4%. 2. The polymeric container of claim 1, wherein the ready-to-use concentration of the bupivacaine or a pharmaceutically acceptable salt thereof is equal or less than 0.8% w/v. 3. The polymeric container of claim 1, wherein the ready-to-use concentration of the bupivacaine or a pharmaceutically acceptable salt thereof is 0.0625% w/v or 0.125% w/v. 4. The polymeric container of claim 1, wherein the pharmaceutically acceptable salt of bupivacaine is racemic bupivacaine HCl. 5. The polymeric container of claim 1, wherein the aqueous solvent is water for injection. 6. The polymeric container of claim 1, wherein the tonicity agent is NaCl, sucrose, mannitol or glycerol. Attny Dkt No. 104297.0035PCT Client Ref. NVK046 7. The polymeric container of claim 1, wherein the isotonic bupivacaine solution has an osmolality of between 260 and 325 mOsm. 8. The polymeric container of claim 1, wherein the ready-to-use bupivacaine solution before autoclaving has a pH of between 6.0 and 4.0. 9. The polymeric container of claim 1, wherein the pH differential before and after autoclaving is no more than 0.3 pH units. 10. The polymeric container of claim 1, wherein the pH differential before and after autoclaving is no more than 0.2 pH units. 11. The polymeric container of claim 1, wherein a pH differential between immediate post- autoclaving and storage for one month after sterilization is no more than 0.3 pH units. 12. The polymeric container of claim 1, wherein a pH differential between immediate post- autoclaving and storage for one month after sterilization is no more than 0.2 pH units. 13. The polymeric container of claim 1, wherein autoclaving is performed at 121 °C for at least 15min. 14. The polymeric container of claim 1, wherein the layer comprising the cyclic olefin copolymer is an innermost layer in the multi-layer polymeric bag. 15. The polymeric container of claim 1, wherein the layer comprising the cyclic olefin copolymer is an intermediate layer in the multi-layer polymeric bag. 16. The polymeric container of claim 1, wherein the container contains 100 mL or 250 mL of the ready-to-use bupivacaine solution. 17. The polymeric container of claim 1, wherein the ready-to-use bupivacaine solution is substantially free of a preservative. 18. A method of preparing a sterile ready-to-use bupivacaine solution in a container, comprising: dissolving in an aqueous solvent (a) bupivacaine or a pharmaceutically acceptable salt thereof at a ready-to-use concentration, and (b) a tonicity agent in an amount Attny Dkt No. 104297.0035PCT Client Ref. NVK046 sufficient to render the ready-to-use bupivacaine solution isotonic, thereby forming the ready-to-use bupivacaine solution; adjusting a pH of the ready-to-use bupivacaine solution to a pH between 6.0 and 5.4; filling the isotonic ready-to-use bupivacaine solution into a multi-layer polymeric bag that contains at least one layer comprising a cyclic olefin copolymer; and autoclaving the isotonic ready-to-use bupivacaine solution in the multi-layer polymeric bag to sterility; wherein the multi-layer polymeric bag has a composition such that a pH differential of the ready-to-use bupivacaine solution before and after autoclaving in the polymeric container is no more than 0.4 pH units; and wherein the multi-layer polymeric bag has a composition such that a product loss of the ready-to-use bupivacaine solution before and after autoclaving in the polymeric container is no more than 0.4%. 19. The method of claim 18, wherein the ready-to-use concentration of the bupivacaine or a pharmaceutically acceptable salt thereof is 0.0625% w/v or 0.125% w/v, and wherein the sterile ready-to-use bupivacaine solution is substantially free of an excipient and/or a preservative. 20. A pharmaceutical product, comprising: a polymeric container containing a sterile ready-to-use bupivacaine solution; wherein the ready-to-use bupivacaine solution consist of an aqueous solvent containing dissolved bupivacaine HCl at a ready-to-use concentration of 1.25mg/mL or 0.625 mg/mL and sodium chloride dissolved at a concentration of 9 mg/mL; and wherein the polymeric container comprises a multi-layer polymeric bag that contains at least one layer comprising a cyclic olefin copolymer; and wherein the polymeric container maintains a pH differential of the ready-to-use bupivacaine solution before and after autoclaving in the polymeric container within 0.4 pH units and a product loss of the ready-to-use bupivacaine solution before and after autoclaving in the polymeric container within 0.4%.