Buffered lidocaine injectable preparation and preparation method thereof

Abstract

A stable liquid formulation for parenteral administration comprising lidocaine or a pharmaceutically acceptable salt thereof. The formulation comprises a low concentration of a sodium bicarbonate buffer in an aqueous solution having a pH of about 6.5 to about 7.2, sodium chloride, and optionally a pH adjusting agent. The liquid formulation is a stable formulation, supplied as a ready-to-use or finished product in a container or vial rich in carbon dioxide in the headspace.

Description

Technical Field

[0001] The present invention relates to a stable buffered liquid formulation comprising lidocaine as an active ingredient, and more particularly to an injectable liquid formulation comprising lidocaine and a buffering agent, which is stable when stored for a long period of time in a pharmaceutically acceptable container. Background Art

[0002] Lidocaine (chemically known as 2-diethylamino-N-(2,6-dimethylphenyl)acetamide) is used as a local anesthetic, often with a small amount of adrenaline (epinephrine) to prolong its effect. Lidocaine free base is poorly soluble in water, and preparations with a pH elevated above physiological pH experience precipitation. Therefore, lidocaine stability is affected by pH, and adjusting the pH of lidocaine solutions to between 3.3 and 6.5 is known to minimize precipitation and extend shelf life. However, lidocaine solutions with a pH of 3.3 to 6.5 are also known to increase subjective pain at the injection site and delay anesthetic effects.

[0003] To address these issues, health authorities have recommended lidocaine formulations with sodium bicarbonate. However, aqueous solutions containing lidocaine and sodium bicarbonate are known to have unstable pH values ​​well above 7 upon formation and may experience a rise in pH over time when stored in vials, which can lead to undesirable precipitation of lidocaine.

[0004] Currently, lidocaine hydrochloride without epinephrine is available as an injectable solution or single-dose solution in plastic ampoules at 1%, 1.5% and 2%. The solutions contain methylparaben as an antimicrobial preservative and the pH is adjusted to a range of 5.0 to 7.0.

[0005] There remains a need for ready-to-use injectable formulations of lidocaine that provide long-term storage stability without the need for preservatives and also prevent precipitation at pH values ​​near 7.0. The present invention provides stable liquid formulations of lidocaine or a salt thereof for injectable administration that minimize precipitation and exhibit enhanced storage stability. Summary of the Invention

[0006] Described herein is a stable injectable liquid formulation of lidocaine or a salt thereof comprising a sodium bicarbonate buffer, sodium chloride, a carrier (e.g., water for injection), and a carbon dioxide gas purge as a pH adjuster and / or in the headspace of a container containing the formulation. The formulation comprises about 1% by weight or about 2% by weight of lidocaine or a salt thereof. The formulation has an acidic to neutral pH ranging from about 6.5 to about 7.4, and preferably from about 6.5 to about 7.3 or less than 7.2. The carbon dioxide purge of the injectable liquid formulation or the bulk liquid formulation for providing the injectable liquid formulation can be the only step for adjusting the pH without the need to add one or more additional pH adjusters to the formulation. As demonstrated in the present disclosure, the formulation exhibits stability under long-term and accelerated storage conditions, for example, such that one or more of the following characteristics are exhibited: the injectable liquid formulation has no more than 600 particles with an average diameter greater than 25 μm, no more than 100 particles with an average diameter greater than 25 μm, no more than 75 particles with an average diameter greater than 25 μm, no more than 50 particles with an average diameter greater than 25 μm, no more than 25 particles with an average diameter greater than 25 μm, no more than 20 particles with an average diameter greater than 25 μm, or no more than 15 particles with an average diameter greater than 25 μm after storage for 3 months at 40°C / 75 RH; and the injectable liquid formulation has no more than 0.2 wt % of ammonia, based on the total weight of the formulation, after storage for 3 months at 40°C / 75 RH. , no more than 0.1 weight % or no more than 0.06 weight % total impurities, excluding the baseline total impurity measurement when the formulation is formed; the injectable liquid formulation retains about 95% or more, about 96% or more, about 98% or more, or about 99% or more of the initial concentration of lidocaine or a pharmaceutically acceptable salt thereof after storage at 40°C / 75RH for 3 months; the injectable liquid formulation retains about 95% or more of the sodium bicarbonate buffer after storage at 40°C / 75RH for 3 months; and the injectable liquid formulation has no more than 600 particles with an average diameter greater than 10 μm, no more than 400 particles with an average diameter greater than 10 μm, no more than 200 particles with an average diameter greater than 10 μm, or no more than 175 particles with an average diameter greater than 10 μm after storage at 40°C / 75RH for 3 months.

[0007] In a first aspect, an injectable liquid formulation in a container is disclosed, the formulation comprising lidocaine or a pharmaceutically acceptable salt thereof as the sole pharmaceutically active agent present at a concentration of about 5 to about 10 mg / mL, about 7.5 to about 10 mg / mL, or 15 to 20 mg / mL; a sodium bicarbonate buffer present at a concentration of about 4 to about 17 mg / mL or about 6 to about 12 mg / mL; and a carrier, e.g., an aqueous carrier or water for injection, present in greater than 90% by weight of the injectable liquid formulation, wherein the injectable liquid formulation has a pH of about 6.5 to about 7.2 and the container includes a gas headspace comprising greater than 30%, 40%, or 50% by weight carbon dioxide.

[0008] In an example of aspect 1, the injectable liquid formulation exhibits no more than 600 particles having an average diameter greater than 10 μm after storage in the container at 40° C. for 3 months.

[0009] In an example of aspect 1, lidocaine or a pharmaceutically acceptable salt thereof is lidocaine hydrochloride, lidocaine hydrobromide, lidocaine oxalate, lidocaine fumarate, lidocaine adipate, lidocaine maleate, lidocaine malonate, or lidocaine tosylate.

[0010] In another example of aspect 1, lidocaine hydrochloride is present in the injectable liquid formulation at a concentration of about 5 mg / mL, about 9 mg / mL, or 18 mg / mL.

[0011] In another example of aspect 1, the weight ratio of sodium bicarbonate buffer to lidocaine or a pharmaceutically acceptable salt thereof is in the range of about 0.3:1 to about 1.4:1, about 0.4:1 to about 1.3:1, about 0.5:1 to about 1.2:1, about 0.6:1 to about 1.1:1, or about 0.7:1 to about 0.9:1 or about 1:1 or 0.8:1.

[0012] In another example of Aspect 1, the weight ratio of sodium bicarbonate buffer to lidocaine hydrochloride is in a range from about 0.8:1 to about 0.9:1 or about 0.84:1.

[0013] In another example of aspect 1, sodium bicarbonate is the only buffer in the injectable liquid formulation, or the buffer consists of sodium bicarbonate.

[0014] In another example of aspect 1, the container has a sealed internal volume, and the sealed internal volume consists of the injectable liquid formulation and a gas headspace. The sealed internal volume of the container can be formed by a vial sealed with a stopper.

[0015] In another example of aspect 1, the gas headspace comprises greater than 70% carbon dioxide.

[0016] In another example of aspect 1, the container has a sealed interior volume, and the gas headspace is 10% to 50% by volume of the sealed interior volume of the container. For example, a vial sealed with a stopper has a sealed interior volume occupied by the injectable liquid formulation and the remaining gas headspace.

[0017] In another example of Aspect 1, the formulation further comprises sodium chloride present at a concentration of about 1 to about 8 mg / mL.

[0018] In another example of aspect 1, the formulation further comprises one or more pH adjusters. In addition to adjusting the pH of the injectable liquid formulation with carbon dioxide gas purging, one or more pH adjusters may be added.

[0019] In another example of aspect 1, the pH of the injectable liquid formulation is about 6.5 to about 7.2, about 6.7 to about 7, or less than or equal to 7.

[0020] In another example of aspect 1, the pH of the injectable liquid formulation in the container is maintained within about 5% of the initial pH when the injectable liquid formulation is formed, compared to the pH of the injectable liquid formulation measured after storage at 40° C. in the container for 3 months.

[0021] In another example of aspect 1, the injectable liquid formulation exhibits no more than 6,000 particles having an average diameter greater than 10 μm after storage at 40° C. for 3 months.

[0022] In another example of aspect 1, the injectable liquid formulation has no more than 0.2 wt% of total impurities after storage at 40°C for 3 months.

[0023] In another example of aspect 1, the injectable liquid formulation retains more than about 95% of the initial concentration of lidocaine or a pharmaceutically acceptable salt thereof after storage at 40°C for 3 months.

[0024] In another example of aspect 1, the injectable liquid formulation retains more than about 95% of the sodium bicarbonate buffer after storage at 40°C for 3 months.

[0025] In another example of aspect 1, the injectable liquid formulation is a ready-to-use formulation or an immediate-administration formulation.

[0026] In another example of aspect 1, the container is a glass vial.

[0027] In another example of aspect 1, the container has a sulfur-treated surface that contacts the injectable liquid formulation. The sulfur-treated surface is a cavity surface of the vial and includes the interior volume of the vial.

[0028] In another example of aspect 1, the injectable liquid preparation does not contain one or more components selected from the group consisting of chelating agents, saccharides, calcium salts, sulfates, sulfides, sugars, and sugar alcohols. For example, the injectable liquid preparation does not contain chelating agents, saccharides, calcium salt compounds, sulfates, sulfides, sugars, and sugar alcohols.

[0029] In another example of aspect 1, the injectable liquid formulation contains no more than 1000 particles with an average diameter greater than 10 μm after three consecutive freeze-thaw cycles or no more than 100 particles with an average diameter greater than 25 μm after three consecutive freeze-thaw cycles, wherein each freeze-thaw cycle consists of storing the injectable liquid formulation in a vial at -20°C for 2 days and at 40°C, 75% relative humidity for 2 days.

[0030] In another example of aspect 1, the injectable liquid formulation is subjected to a pH adjustment step using carbon dioxide before being filled into a container. For example, before a portion of a bulk solution having the same composition as the injectable liquid formulation is filled into the container to form the injectable liquid formulation of aspect 1, the bulk solution is purged with carbon dioxide.

[0031] In another example of aspect 1, the bulk solution used to fill the container with the injectable liquid formulation is purged with carbon dioxide before filling the container to adjust the pH of the bulk solution to below 7.5, below 7.4, below 7.3, below 7.2, below 7.1, or below 7.0. The initial pH of the injectable liquid formulation filled into the container from the bulk solution is in the range of 6.7 to 7.3.

[0032] In another example of aspect 1, the only method for adjusting the pH of the bulk solution used to fill the container with the injectable liquid formulation is to subject the bulk solution to carbon dioxide. For example, after the bulk solution is formed, the pH of the bulk solution is not adjusted with a pH adjusting agent (e.g., hydrogen chloride or sodium hydroxide).

[0033] In another example of aspect 1, after filling with a bulk solution that has been subjected to carbon dioxide (e.g., carbon dioxide purging) to adjust its pH, the headspace in the container containing the injectable liquid formulation is not purged with carbon dioxide gas before sealing the container and its headspace. Alternatively, the headspace in the container containing the injectable liquid formulation is purged with carbon dioxide to produce a headspace with a carbon dioxide content of 20% by volume or more, 30% by volume or more, 40% by volume or more, 50% by volume or more, 60% by volume or more, 70% by volume or more, or 80% by volume or more.

[0034] In another example of aspect 1, before the container is filled with a portion of a bulk solution having the same composition as the injectable liquid preparation to form the injectable liquid preparation of aspect 1, the bulk solution is not purged with carbon dioxide, but after filling with the bulk solution, the head space in the container containing the injectable liquid preparation is purged with carbon dioxide to produce a head space with a carbon dioxide content of 20% by volume or more, 30% by volume or more, 40% by volume or more, 50% by volume or more, 60% by volume or more, 70% by volume or more, or 80% by volume or more.

[0035] In a second aspect, a ready-to-use injectable liquid formulation in a container is disclosed, the formulation comprising lidocaine hydrochloride present at a concentration of about 9 to about 10 mg / mL or 18 to 20 mg / mL, a sodium bicarbonate buffer present at a concentration of about 4 to about 17 mg / mL or about 6 to about 12 mg / mL, and water for injection, wherein, prior to sealing the container, the container has a gas headspace purged with carbon dioxide, the gas headspace of the sealed container having greater than 70% by weight carbon dioxide, wherein the injectable liquid formulation has an initial pH of about 6.5 to about 7 when formed, and the initial pH remains within about 5% of its value after storage at 40°C for 3 months in the container, and wherein the injectable liquid formulation exhibits no more than 500 particles having an average diameter greater than 10 μm after storage at 40°C for 3 months in the container.

[0036] In an example of aspect 2, the injectable liquid formulation further exhibits at least one of the following properties after storage at 40° C. for 3 months: no more than 600 particles with an average diameter greater than 25 μm, no more than 0.2% by weight of total impurities, an initial concentration of lidocaine hydrochloride greater than about 95%, and a sodium bicarbonate buffer greater than about 95%.

[0037] In another example of aspect 2, the injectable liquid formulation is a stable ready-to-use formulation or an immediate-administration formulation.

[0038] In another example of aspect 2, the container is a vial having a volume for containing the injectable liquid formulation, the volume having a sulfur-treated surface in contact with the injectable liquid formulation.

[0039] In another example of aspect 2, the container has a sealed interior volume, and the gas headspace is 10% to 60%, 30% to 60%, or 30% to 50% by volume of the sealed interior volume of the container.

[0040] In another example of Aspect 2, lidocaine hydrochloride is present as the only pharmaceutically active agent in the injectable liquid formulation.

[0041] In a third aspect, a method of preparing an injectable liquid formulation is disclosed, the method comprising providing a bulk liquid formulation comprising lidocaine hydrochloride as the sole pharmaceutically active agent present at a concentration of about 7.5 to about 20 mg / mL, a sodium bicarbonate buffer present at a concentration of about 4 to about 17 mg / mL or about 6 to about 12 mg / mL, and water for injection present at more than 90% by weight of the injectable liquid formulation, wherein the pH of the bulk liquid formulation is greater than 7.2; filling a portion of the bulk liquid formulation into a container under a blanket of carbon dioxide; and then sealing the container to provide an airtight enclosure having a gas headspace having greater than 50% carbon dioxide.

[0042] In one example of aspect 3, the portion of the bulk liquid formulation filled into the container is 10 mL or 20 mL.

[0043] In another example of aspect 3, the pH of the bulk liquid formulation is greater than 7.2, and the method includes the step of purging the bulk liquid formulation with carbon dioxide for a sufficient time to reduce the pH of the bulk liquid to below 7.0, for example, to 6.5 to 6.8, before filling the portion of the bulk liquid formulation into the container.

[0044] In another example of aspect 3, when used to fill the portion of the bulk liquid formulation into the container, the bulk liquid formulation does not contain a pH adjuster, and the formulation in the sealed container does not contain a pH adjuster so that the only pH adjustment of the liquid injectable formulation in the sealed container is the step of purging the bulk liquid formulation with carbon dioxide gas.

[0045] In another example of aspect 3, the pH of the bulk liquid formulation is in the range of 6.5 to 6.9 after purging with carbon dioxide gas and before filling the portion of the bulk liquid formulation into the container under the carbon dioxide-rich blanket.

[0046] In another example of aspect 3, the gas headspace of the container has greater than 70% carbon dioxide.

[0047] In another example of aspect 3, the container has a sealed interior volume, and the gas headspace portion of the sealed interior volume is 10% to 60% of the sealed interior volume of the container.

[0048] In another example of aspect 3, the container has a sulfur-treated surface that contacts the injectable liquid stored in the container.

[0049] In another example of aspect 3, the container is a glass vial sealed with a stopper (eg, a rubber stopper).

[0050] In another example of aspect 3, the pH of the injectable liquid formulation in the sealed container is less than 7.

[0051] In another example of aspect 3, the injectable liquid formulation is a ready-to-use formulation or an immediate-administration formulation.

[0052] In another example of aspect 3, the injectable liquid formulation in the sealed container has an initial pH of about 6.5 to about 7 after filling, and the initial pH remains below 7 after the container is stored at 40°C for 3 months.

[0053] In another example of Aspect 3, the initial pH is in the range of 6.5 to 6.8, and after storage in the container at 40°C for 3 months, the initial pH is below 6.8.

[0054] In another example of aspect 3, the bulk liquid formulation further comprises a pH adjuster, and sodium bicarbonate is the only buffering agent in the bulk liquid formulation.

[0055] In a fourth aspect, a ready-to-use injectable liquid formulation in a container is disclosed, comprising lidocaine or an acceptable salt thereof (e.g., lidocaine hydrochloride) present at a concentration of about 10, a sodium bicarbonate buffer present at a concentration of about 8 to about 9 mg / mL, water for injection, and optionally sodium chloride at a concentration of about 0.5 to about 2 mg / mL, wherein, before the container is sealed, the container has a gas headspace purged with carbon dioxide, the gas headspace of the sealed container has greater than 40% by weight carbon dioxide, wherein the initial pH of the injectable liquid formulation when formed is about 6.5 to about 7.3, and after storage in the container at 40°C / 75RH for 3 months, the initial pH remains within about 5% of its value, and wherein, after storage in the container at 40°C / 75RH for 3 months, the injectable liquid formulation exhibits no more than 200 particles with an average diameter greater than 10 μm or no more than 20 particles with an average diameter greater than 25 μm.

[0056] In another example of aspect 4, the injectable liquid formulation further exhibits at least one of the following properties after storage at 40°C / 75RH for 3 months: no more than 0.05% by weight of total impurities, an initial concentration of lidocaine hydrochloride greater than about 98%, and / or a sodium bicarbonate buffer greater than about 98%.

[0057] Any of the above aspects (or instances of these aspects) may be provided alone or in combination with any one or more instances of that aspect discussed above; for example, the first aspect may be provided alone or in combination with any one or more instances of the first aspect discussed above; and the second aspect may be provided alone or in combination with any one or more instances of the second aspect discussed above; and so on.

[0058] Additional features and advantages will be set forth in the following detailed description, and in part will be apparent to those skilled in the art from that description or learned by practicing the embodiments as described herein (including the following detailed description, and the claims). It should be understood that both the foregoing general description and the following detailed description are merely exemplary and are intended to provide an overview or framework for understanding the nature and character of the claims. DETAILED DESCRIPTION

[0059] Herein, ranges may be expressed as from "about" one particular value and / or to "about" another particular value. When such a range is expressed, another embodiment includes the from the one particular value and / or to the other particular value. Similarly, when a value is expressed as an approximation by using the prefix "about," it will be understood that the particular value forms another embodiment.

[0060] Herein, when a range such as 5-25 (or 5 to 25) is given, this means preferably at least 5 or greater than 5, and separately and independently, preferably not more than 25 or less than 25. In examples, such ranges are independently defined as being above 5, and separately and independently defined as being below 25.

[0061] The present disclosure relates to a stable, liquid aqueous formulation for use as a pharmaceutical preparation. The formulation is intended for administration by injection and comprises lidocaine or a pharmaceutically acceptable salt thereof, a sodium bicarbonate buffer, and a carrier, such as an aqueous carrier or water for injection. The formulation may optionally comprise sodium chloride and one or more pH adjusters in aqueous solution. The pH of the formulation is within the range of about 6.5 to about 7.2. The formulation is stable upon storage, and pH excursions outside the range of 6.5 to 7.2 are controlled.

[0062] Lidocaine preparation is for the instant preparation or instant administration type preparation of injection, and can be used without mixing extra composition before administration.Instant preparation or instant administration type preparation are aseptic liquid injectable preparations, and it can not need such as to mix with another active ingredient or buffer before use, and this makes preparation can be directly administered, or further dilutes if existing with concentrated solution.For example, instant administration type preparation can comprise required concentration and volume in final container such as syringe (syringe), bottle, ampoule or injection device (injector).The administration of preparation can be carried out by subcutaneous injection, intramuscular injection, percutaneous injection, intradermal injection or intravenous injection by syringe (optionally, pen-shaped syringe).Carrier or diluent (if used) can comprise the fluid such as water for injection or sodium chloride solution that are such as suitable for parenteral administration.

[0063] In one or more embodiments, the formulation of lidocaine is a ready-to-use formulation that can be mixed with another solution or active agent prior to administration. For example, if desired, the ready-to-use formulation of lidocaine can be mixed with epinephrine to form a mixture of the two active ingredients. Epinephrine is a catecholamine (a sympathomimetic monoamine derived from the amino acids phenylalanine and tyrosine) and is a known vasoconstrictor that has beneficial effects when used in combination with lidocaine.

[0064] The preparation can be administered for local or regional anesthesia, for example, by injection and intravenous administration. Regional anesthesia can include peripheral nerve block applications (e.g., brachial plexus and intercostal) and central nervous system applications that can include lumbar and caudal epidural blocks. The preparation of the present disclosure is suitable, for example, for administration by injection to a mammal to initiate local or regional anesthesia. Preferably, the mammal is a human.

[0065] The lidocaine liquid injectable formulations of the present disclosure are stable or exhibit stability (e.g., active agent determination, impurity spectrum, precipitation of particles) when stored. Storage of the formulation in a sealed container may cause stability problems, including formulation characteristics that may be affected by storage conditions, such as, active ingredient specifications or concentrations, impurities (e.g., single components and total impurities), visual appearance characteristics (e.g., color, clarity, turbidity, haze, precipitation, etc.) and pH drift that may cause precipitation, concentration loss, and impurity formation. Storage conditions that may affect stability may include, for example, storage temperature, humidity (e.g., relative humidity), and storage time period.

[0066] In one or more embodiments, stability can be measured by, for example, subtracting the amount of total impurities (including degradation products) formed in the container after forming the lidocaine formulation for a specified period of time from the amount of total impurities (including degradation products) formed under specified storage conditions (e.g., temperature, humidity) minus the initial total impurities measured as an initial measurement after formation. In one or more embodiments, the liquid injectable lidocaine formulation includes a formulation that retains about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 98.5% or more, or about 99% or more of the initial concentration of lidocaine or a pharmaceutically acceptable salt thereof in the formulation after storage (1 month, 2 months, 3 months) under standard conditions (e.g., 25°C) or accelerated conditions (e.g., 2-8°C, 40°C, 50°C) at a relative humidity in the range of 60% to 75%. Stability can also be measured by maintaining a desired concentration of sodium bicarbonate buffer present in the formulation. In one or more embodiments, liquid injectable lidocaine formulations include formulations that retain about 95% or greater, about 96% or greater, about 97% or greater, about 98% or greater, about 98.5% or greater, or about 99% or greater of the initial concentration of sodium bicarbonate buffer in the formulation after storage (1 month, 2 months, 3 months) under standard conditions (e.g., 25°C) or accelerated conditions (e.g., 2-8°C, 40°C, 50°C) at a relative humidity ranging from 60% to 75%.

[0067] The stability of the lidocaine formulation is measured over time after an initial time point, which is measured shortly after the formulation is formed. The initial measurement is performed within 24 hours of the formulation being filled into a sealed pharmaceutically acceptable container (e.g., a vial) for storage. In one or more embodiments, a stable lidocaine formulation includes a formulation comprising less than about 0.15%, less than about 0.2%, less than about 0.25%, less than about 0.3%, or less than about 0.5% of a single impurity (e.g., a degradation impurity or a degradation impurity associated with lidocaine) that is formed after the formulation is formed and is present after storage under standard or accelerated conditions (e.g., about 25° C., about 2-8° C., and about 40° C. or 50° C., all at a relative humidity in the range of 60% to 75%) for about 1 month, about 2 months, about 3 months, or more. Any single impurity measured for the purpose of measuring the stability of the formulations herein does not include any impurities present in any component prior to forming the lidocaine formulation. That is, as used herein, one or more impurities in a formulation of the present invention refers to any impurities (including degradation products) formed after the formulation is formed (e.g., after the formed formulation is stored in a pharmaceutically acceptable container such as an airtight glass vial).

[0068] In one or more embodiments, the formulation can contain ropivacaine as an impurity at a concentration that does not exceed that measured at a predetermined temperature and time period. For example, the formulation can contain no more than 0.1% ropivacaine, no more than about 0.05% ropivacaine, or no more than about 0.01% ropivacaine as measured after storing the formulation at about 2-8°C, 25°C, 40°C, or 50°C for a period of 1 month, 2 months, or 3 months. The relative humidity of the storage conditions can range from 60% to a maximum of 75%.

[0069] In one or more embodiments, the stable lidocaine formulations include formulations that contain about 0.15% or less, about 0.2% or less, about 0.25% or less, about 0.3% or less, about 0.5% or less, or about 1% or less of total impurities or lidocaine degradation products present after storage under standard conditions or accelerated conditions. Impurities and degradation products (whether single or total) can be measured by conventional methods such as liquid chromatography (HPLC). In an example, the stable lidocaine formulation contains about 0.5% or less, about 0.3% or less, about 0.2% or less, or about 0.15% or less of total impurities after the formulation is stored at about 25°C for a period of 3 months. In another example, the stable lidocaine formulation contains about 0.5% or less, about 0.3% or less, about 0.2% or less, or about 0.15% or less of total impurities after the formulation is stored at about 40°C for a period of 3 months.

[0070] In one or more embodiments, the liquid injectable lidocaine formulations include formulations that are stable for about 3 months or more, about 6 months or more when stored at an accelerated temperature of about 25° C. or 40° C. In one or more embodiments, the liquid injectable lidocaine formulations include formulations that are stable for about 6 months or more, or about 12 months or more when stored at about room temperature (i.e., 25° C.).

[0071] In other embodiments, the liquid injectable lidocaine formulation comprises a particle count that is below the industry standard. For example, after storage in a container at 25° C. or 40° C. and at a relative humidity in the range of 60% to 75% for 1, 3, or 6 months, the liquid injectable formulation of the present invention may have less than 6,000, less than 5,000, less than 4,000, less than 3,000, less than 2,000, less than 1,000, less than 800, less than 500, less than 400, less than 300, or less than 200 subvisible particles per stored formulation (e.g., a ready-to-use formulation in a container), wherein the size of the particles is greater than 10 μm. The number of particles may be determined according to USP 27. <788> Particulate matter in injections is determined by a light obscuration particle counting test. In another example, after storage for 1 or 3 months in a container at 25°C or 40°C and at a relative humidity in the range of 60% to 75%, the liquid injectable formulation may have less than 600, less than 500, less than 400, less than 300, less than 200, less than 100, less than 70, less than 50, less than 40, or less than 30 particles larger than 25 μm. The measured particles may be defined as having an average diameter. In other embodiments, the number of particles larger than 10 μm increases from the initial concentration of the particles when the formulation is formed to the concentration of the formulation after storage for 3 months in a container at 25°C and 40°C, and the increase is less than 70%, less than 50%, or less than 40%, and less than 125%, less than 100%, or less than 90% of the initial concentration of the particles, respectively. In yet other embodiments, the number of particles having a size greater than 25 μm increases from the initial concentration of the particles when the formulation is formed to the concentration after storage of the formulation in a container at 25° C. and 40° C. for 3 months, and the increase is less than 70%, less than 60%, or less than 50%, and less than 50%, less than 40%, or less than 30%, respectively, of the initial concentration of the particles.

[0072] In other embodiments, the injectable liquid formulation exhibits stability as measured by having a particle count below the industry standard. For example, after at least three consecutive freeze-thaw cycles (such that each freeze-thaw cycle consists of storing the injectable liquid formulation at -20°C for 2 days and then storing it at 40°C, 75% relative humidity for 2 days), each stored formulation of the liquid injectable formulation of the present invention (e.g., a ready-to-use formulation in a container) can have less than 6,000, less than 5,000, less than 4,000, less than 3,000, less than 2,000, less than 1,000, less than 800, less than 500, less than 400, less than 300, or less than 200 subvisible particles, wherein the size of the particles is greater than 10 μm. The number of particles can be determined according to USP 43, <788> Particulate matter in injections is determined by a light obscuration particle counting test. In another example, after at least three consecutive freeze-thaw cycles (such that each freeze-thaw cycle consists of storing the injectable liquid formulation at -20°C for 2 days and at 40°C, 75% relative humidity for 2 days), the liquid injectable formulation may have less than 600, less than 500, less than 400, less than 300, less than 200, less than 100, less than 70, less than 50, less than 40 or less than 30 particles with a size greater than 25 μm. The measured particles can be defined as having an average diameter.

[0073] Preparations of the present disclosure include lidocaine or any pharmaceutically acceptable salt thereof as active ingredient. In some embodiments, the preparation preferably includes lidocaine or any pharmaceutically acceptable salt thereof as sole active ingredient, characterized in that other active ingredients such as epinephrine, heparin or acetylcysteine ​​are not present or detected in the preparation. In one example, the preparation includes lidocaine hydrochloride or lidocaine hydrochloride. Other suitable salts of lidocaine include, for example, lidocaine hydrobromide, lidocaine oxalate, lidocaine fumarate, lidocaine adipate, lidocaine maleate, lidocaine malonate or lidocaine toluenesulfonate. Lidocaine or its salt, such as lidocaine hydrochloride, can be present in the preparation at a concentration of more than about 7 mg / mL (milligrams per milliliter), more than about 8 mg / mL, more than about 9 mg / mL or less than about 11 mg / mL or less than about 10 mg / mL. In some embodiments, the liquid injectable formulation comprises lidocaine or a pharmaceutically acceptable salt thereof at a concentration of about 5 mg / mL, about 7.5 mg / mL, about 8 mg / mL, about 8.5 mg / mL, about 9 mg / mL, about 9.1 mg / mL, or about 9.5 mg / mL. In one or more embodiments, the liquid lidocaine formulation comprises about 5 mg, about 6 mg, about 7 mg, about 7.5 mg, about 7.9 mg, about 8 mg, about 9 mg, or about 10 mg of lidocaine or a pharmaceutically acceptable salt thereof per storage container (e.g., vial).

[0074] In other embodiments, lidocaine or its salt, such as lidocaine hydrochloride, can be present in the formulation at a concentration of about 14 mg / mL (milligrams per milliliter) or more, about 16 mg / mL or more, about 18 mg / mL or more, or about 22 mg / mL or less, or about 20 mg / mL or less. In some embodiments, the liquid injectable formulation comprises lidocaine or its pharmaceutically acceptable salt at a concentration of about 15 mg / mL, about 16 mg / mL, about 17 mg / mL, about 18 mg / mL, about 18.2 mg / mL, or about 19 mg / mL. In one or more embodiments, each storage container (e.g., vial) of the liquid lidocaine formulation comprises about 10 mg, about 12 mg, about 14 mg, about 15 mg, about 15.8 mg, about 16 mg, about 18 mg, or about 20 mg of lidocaine or its pharmaceutically acceptable salt.

[0075] In one or more embodiments, the preparation volume (for example, the amount of liquid in the storage container) is about 1 mL or more, about 2 mL or more, about 3 mL or more, about 4 mL or more, about 5 mL or more, about 6 mL or more, about 7 mL or more, or about 8 mL or more. In one or more embodiments, the preparation volume is about 25 mL or less, about 22 mL or less, about 20 mL or less, about 18 mL or less, about 15 mL or less, or about 11 mL or less. For example, the preparation volume can be about 5 mL to about 15 mL, about 8 mL to about 12 mL, about 9 mL to about 11 mL, or about 10 mL. In another example, the preparation volume can be about 30 mL to about 25 mL, about 22 mL to about 21 mL, about 20 mL to about 19 mL, or about 18 mL. A container of suitable size for storing the preparation volume can be determined by one of ordinary skill in the art. In one or more embodiments, the preparation volume can account for more than 40%, more than 45%, more than 50%, more than 60%, more than 70%, more than 80%, or more than 90% of the total volume of the container. In other embodiments, the formulation volume can be less than 90%, less than 80%, less than 70%, less than 60%, less than 55%, or less than 50% of the total volume of the container. In an example, the formulation volume can be 5 mL and stored in a 10 mL vial or can be 10 mL and stored in a 20 mL vial such that the formulation volume is 50% of the total volume of the container, with the remaining container volume being the headspace (5 mL, 10 mL) which can have a selected carbon dioxide content as described herein.

[0076] The preparation for administration by injection can be stored in any suitable container or supplied with in any suitable container.For example, preparation can be in the container including but not limited to bottle (for example, single dose or multi-dose bottle), ampoule, bottle or syringe (for example, the assembly of pre-filled syringe or automatic syringe (auto-injector)).Container can be made of any suitable material such as glass, plastics or rubber, but glass is preferred.Container (for example, bottle) can have any suitable volume for storing preparation, and for example, the volume of container can be 5mL, 10mL, 15mL, 20mL, 25mL, 30mL, 35mL or 40mL.

[0077] Before filling the preparation in the container, the container can be sterile and has been sterilized before filling with the sterile preparation of the present invention. For example, a lid, cap, closure and stopper etc. are used to seal the container as is customary in the industry. The container can also be coated or processed with one or more components to reduce the degradation of the preparation ingredients and to react with the preparation ingredients and to prevent pH drift. For example, a glass container can have a sulfur-treated surface for contacting the preparation to reduce or prevent the pH change of the preparation during storage. In another example, the container surface in contact with the preparation can be coated with silicon or a vial with a treated inner surface for storing the preparation can be used. Optionally, in order to prevent the preparation from being exposed to light, the container can optionally be opaque or painted, and is preferably stored in a box for transport or storage. For example, amber or flint-colored vials are suitable containers.

[0078] The preparation further comprises sodium chloride (NaCl) as an inorganic salt. A solution of 0.9% sodium chloride is called normal saline. Saline can help maintain osmotic pressure, play a role in acid-base balance at the local pain site, and also prevent dehydration. Sodium chloride can be present in the liquid injectable preparation at a concentration of about 0.5 mg / mL (milligrams / milliliter) or more, about 0.75 mg / mL or more, about 1 mg / mL or more, about 1.5 mg / mL or more, about 2 mg / mL or more, about 3 mg / mL or more, about 4 mg / mL or more, about 5 mg / mL or more, about 6 mg / mL or more, or about 12 mg / mL or less, about 10 mg / mL or less, about 8 mg / mL or less, about 7 mg / mL or less, about 6 mg / mL or less, about 5 mg / mL or less, about 4 mg / mL or less, or about 3 mg / mL or less. In some embodiments, the sodium chloride concentration included in the liquid injectable formulation is about 6 mg / mL, about 6.1 mg / mL, about 6.2 mg / mL, about 6.3 mg / mL, about 6.4 mg / mL or about 6.5 mg / mL. In some embodiments, the sodium chloride concentration included in the liquid injectable formulation is about 0.8 mg / mL, about 0.9 mg / mL, about 1.0 mg / mL, about 1.1 mg / mL or about 1.2 mg / mL. In one or more embodiments, each storage container (e.g., vial) of the liquid lidocaine formulation includes about 4 mg to 100 mg, about 5 mg to about 80 mg, about 6 mg to about 70 mg, about 6.2 mg to about 68 mg, about 6.3 mg to about 65 mg, or about 6.5 mg to about 63 or 64 mg of sodium chloride. In one or more embodiments, the liquid lidocaine formulation comprises about 0.1 mg to 10 mg, about 0.5 mg to about 5 mg, about 0.6 mg to about 4 mg, about 0.7 mg to about 4 mg, about 0.8 mg to about 2 mg, about 0.9 mg to about 1.5 mg, or about 1.0 mg to about 1.1 or 1.2 mg of sodium chloride per storage container (e.g., vial).

[0079] The preparation further comprises sodium bicarbonate (sodium bicarbonate) (NaHCO 3 ) or sodium hydrogen carbonate. Sodium bicarbonate can be present in the preparation at a suitable concentration to provide pH stability for the liquid preparation. For example, sodium bicarbonate can be present at a concentration of about 3 mg / mL (milligrams per milliliter) or more, about 4 mg / mL or more, about 5 mg / mL or more, about 7 mg / mL or more, about 8 mg / mL or more, or about 17 mg / mL or less, about 12 mg / mL or less, about 10 mg / mL or less, about 9 mg / mL or less, or about 8 mg / mL or less. In other embodiments, sodium bicarbonate can be present at a concentration of about 12 mg / mL (milligrams per milliliter) or more, about 14 mg / mL or more, about 16 mg / mL or more, or about 20 mg / mL or less, about 18 mg / mL or less, or about 17 mg / mL or less. In some embodiments, the sodium bicarbonate concentration included in the liquid injectable formulation is about 4 mg / mL, about 6 mg / mL, about 7 mg / mL, about 7.5 mg / mL, about 7.6 mg / mL, about 7.7 mg / mL, or about 8 mg / mL. In some embodiments, the sodium bicarbonate concentration included in the liquid injectable formulation is about 8.1 mg / mL, about 8.2 mg / mL, about 8.3 mg / mL, about 8.4 mg / mL, about 8.5 mg / mL, or about 8.6 mg / mL. In one or more embodiments, each storage container (e.g., vial) of the liquid lidocaine formulation contains about 4 mg to about 100 mg, about 5 mg to about 90 mg, about 6 mg to about 80 mg, about 7 mg to about 79 mg, about 7.5 mg to about 78 mg, about 7.6 mg to 77 mg, about 7.7 mg to about 76 mg, or about 8 mg or 76.5 mg of sodium bicarbonate. In some embodiments, the liquid injectable formulation comprises sodium bicarbonate at a concentration of about 12 mg / mL, about 14 mg / mL, about 15 mg / mL, about 15.2 mg / mL, about 15.4 mg / mL, or about 16 mg / mL. In some embodiments, the liquid injectable formulation comprises sodium bicarbonate at a concentration of about 16.2 mg / mL, about 16.4 mg / mL, about 16.6 mg / mL, about 16.8 mg / mL, about 17.0 mg / mL, or about 17.2 mg / mL.

[0080] In the aqueous solution of liquid injectable preparation, bicarbonate ion is in equilibrium state in closed system (for example in container).Bicarbonate ion can produce carbon dioxide, and if reaction causes excessive carbon dioxide to be released into the head space of container, then the concentration of bicarbonate radical may reduce.In this case, the concentration of carbonate ion may increase, and because carbonate ion is more alkaline than bicarbonate ion, the pH of solution may drift and rise over time during storage and cause undesirable instability.Lidocaine may precipitate under the long-term storage condition of pH greater than 7.5 due to its low alkaline solubility (pKa is 7.9), for example, as confirmed in table 8,9 and 14 of embodiment.The concentration of sodium bicarbonate buffer is adjusted to above-mentioned amount, to provide the amount of carbon dioxide (for example, the carbon dioxide released by the aqueous solution of sodium bicarbonate) in the head space of stable pH and control storage container.

[0081] The formulation may further optionally include one or more pH adjusters, for example, a single pH adjuster or a combination of two pH adjusters. The pH adjuster is used to assist in adjusting the pH of the aqueous formulation and selectively solubilize lidocaine or any salt thereof in the liquid formulation. The pH adjuster is used in an amount to adjust the aqueous suspension of the poorly soluble drug to a pH of about 6 to 7.5, and preferably about 7. The acid or base used depends on the pH of the injectable formulation of the present invention. When the injectable formulation is to be adjusted to a lower pH, an acidic pH adjuster such as hydrochloric acid, sulfuric acid, nitric acid, or acetic acid can be used. Hydrochloric acid is preferably used. When the injectable formulation needs to be adjusted to a higher pH, an alkaline pH adjuster such as sodium hydroxide, potassium hydroxide, calcium carbonate, magnesium oxide, or magnesium hydroxide can be used. Sodium hydroxide is preferably used. Such pH adjusters can be used alone or in combination of two or more.

[0082] In one or more embodiments, the pH adjusting agent is sodium hydroxide, hydrochloric acid, or a combination thereof. The pH adjusting agent (e.g., NaOH, HCl) may be present in the formulation at a desired concentration to shift the pH of the initially formed liquid injectable formulation to a pH range.

[0083] Before fill and sealing in container, the pH of preparation can be regulated with alternative methods, and described method is separately as unique pH regulating or with pH adjusting agent (if used) combination as above.Can be for example as the preparation of the bulk liquid solution for being filled in container with carbon dioxide purge before fill, so that the pH of bulk liquid preparation is reduced to for fill in container and subsequently by container sealing ideal pH.The pH of bulk liquid preparation can be higher than 7.2, for example, in the scope of 7.3 to 8.3,7.4 to 8.0 or 7.5 to 7.8.In order to obtain pH lower than 7.2 and preferably lower than 7.0 bulk liquid preparation, purge carbon dioxide and blast into bulk liquid preparation to reduce pH before fill.By regulating the liquid injectable preparation in container or the pH of the bulk liquid preparation for forming liquid injectable preparation with carbon dioxide purge can be for pH regulating or reach the unique step of the final pH of the preparation being filled in container. When the pH of the formulation is adjusted by purging with carbon dioxide gas, the liquid injectable formulation may not contain a pH adjuster component as described above, and thus carbon dioxide purging may eliminate the need for an additional pH adjuster component.

[0084] Liquid injectable formulations such as those stored in sealed containers can have a suitable pH in the range of about 6.5 to about 7.2 or less than 7.2. In an example, the pH of the formulation can be about 6.5 or more, about 6.6 or more, about 6.7 or more, about 6.8 or more, about 6.9 or more, or about 7.0 or more. In another example, the pH of the formulation can be about 7.2 or less, about 7.1 or less, about 7.0 or less, about 6.9 or less, about 6.8 or less, about 6.7 or less, or about 6.6 or less.

[0085] In one or more embodiments, the pH of the formulation may range from about 6.5 to about 7.2, from about 6.6 to about 7.1, from about 6.7 to about 7.0, or from about 6.8 to about 7.0.

[0086] Liquid injectable lidocaine formulations comprising sodium bicarbonate buffer may be free of chelating agents (e.g., EDTA) such that the chelating agent is absent or undetectable in the formulation. Chelating agents may be used to achieve stability, but the present invention does not rely on the use of chelating agents or stabilizers. Liquid injectable lidocaine formulations comprising sodium bicarbonate buffer may also be free of other components, such as carbohydrates (e.g., polysaccharides, heparin, hyaluronic acid), preservatives (e.g., parabens, methylparaben), glycols (e.g., propylene glycol, polyethylene glycol), calcium compounds or salts thereof (e.g., calcium acetate, calcium sulfate, calcium chloride, etc.), sulfates, sulfites (e.g., sodium metabisulfite), sulfides, sugars (e.g., glucose), and sugar alcohols.

[0087] In an exemplary liquid injectable formulation, the formulation can include lidocaine or a salt thereof in an amount of 7.8 mg / mL to 9.1 mg / mL, sodium bicarbonate as a buffer in an amount of about 7 to about 8 mg / mL, sodium chloride as an isotonicity agent in an amount of about 6 to about 9 mg / mL, sodium hydroxide and / or hydrochloric acid as a pH adjuster in an amount required to adjust the pH to a range of about 6.5 to about 7.2 or about 6.5 to about 7.0, and a carrier (e.g., water for injection).

[0088] Another object of the present disclosure is to prevent lidocaine from precipitating from a liquid formulation in a container over time during storage. Ideally, the pH of the liquid formulation should not drift above 7.2 during storage and is preferably maintained within a range of 6.5 to 7.2. To prevent pH drift, the formulation can be filled into the container under a blanket of carbon dioxide-rich gas, thereby controlling the headspace gas in the container when sealed, for example, with a stopper. The increase in carbon dioxide gas in the container's headspace limits the dissociation of sodium bicarbonate and the release of carbon dioxide into the container's headspace, thereby preventing a rise in pH over time.

[0089] The headspace in the container of storage liquid preparation can comprise the carbon dioxide more than at least 50%, and the remainder of gas headspace is preferably inert gas such as argon or nitrogen and ambient air.The headspace can be included in the carbon dioxide in the scope of about 20 volume % to about 95 volume %, about 30 volume % to about 90 volume %, about 40 volume % to about 90 volume %, 50 volume % to about 85 volume %, about 60 volume % to about 75 volume % or about 65 volume %, about 70 volume % or about 75 volume %.In other examples, the headspace of container can comprise the carbon dioxide more than 20 volume %, more than 30 volume %, more than 40 volume %, more than 50 volume %, more than 55 volume %, more than 60 volume %, more than 65 volume %, more than 70 volume %, more than 80 volume % or more than 87 volume %.

[0090] Adjusting the pH of the formulation to below 7.2 or within the range of 6.5 to 7.0 before filling into containers and controlling the amount of carbon dioxide in the headspace of the sealed container in which the formulation is stored ensures a stable pH range that does not increase significantly over time. Preventing a rise in pH reduces the likelihood that lidocaine will precipitate out of the formulation and form undesirable particles.

[0091] In order to demonstrate the practice of the present invention, the following examples were prepared and tested. However, the examples should not be considered to limit the scope of the present invention. The claims will be used to define the present invention.

[0092] Example

[0093] Example 1

[0094] This embodiment demonstrates the stability of an exemplary formulation comprising lidocaine hydrochloride, sodium bicarbonate, sodium chloride, a pH regulator, and water. A bulk solution for sample preparation was prepared by adding 900 g of water for injection (WFI) as 90% of a batch. Sodium chloride was added to the WFI and resulted in a pH of 5.9. Sodium bicarbonate was further added to the solution, resulting in a solution with a pH of 8.31. Lidocaine hydrochloride was then added to the solution to form a bulk solution with a pH of 7.50. The bulk solution was purged with carbon dioxide to reduce the pH to 6.74, with dissolved oxygen (DO) = 1.7 ppm. WFI was added to the bulk solution to increase the volume to 1 L, resulting in a pH of 6.83. The bulk solution was filtered under carbon dioxide with a 0.22 μm PVDF membrane to obtain a final bulk solution with a pH of 6.75.

[0095] Separate samples of bulk solutions containing the formulations of Table 1 below were prepared by filling approximately 10 mL of the bulk solution into 10 mL glass vials (Tube Type 1 (Standard)) at 60% by volume of carbon dioxide (8.4% as measured using an oxygen sensor). The vials were stoppered with rubber stoppers (Flurotec supplied by West). The sample vials were not autoclaved.

[0096] Table 1

[0097] Element concentration Lidocaine hydrochloride 9.09 mg / mL Sodium bicarbonate 7.64 mg / mL Sodium chloride 6.36 mg / mL pH adjustment using carbon dioxide purge Adjust pH to 6.8 WFI Dilute to 1 mL <![CDATA[Top space CO2]]> 60% by volume

[0098] Samples of the formulations were stored at 2-8°C, 25°C / 60% RH, 40°C / 75% RH, and 50°C / 75% RH. At the set storage time periods, the samples were analyzed by HPLC, and measurements of the formulations were performed as shown in Table 2 below. The HPLC conditions were as follows:

[0099] Column: ACE C18 (250 × 4.6 mm), 5 μm; Mobile phase A: 50 mL of glacial acetic acid and 930 mL of deionized water, pH adjusted to 3.4 with 1N NaOH; Mobile phase B: Acetonitrile (HPLC grade); Column temperature: 30°C; Flow rate: 1.5 mL / min; Injection volume: 20 μL; Injector temperature: 10°C; Separation mode: Gradient; Gradient program:

[0100] Time (minutes) % Mobile phase A % mobile phase B 0 85 15 9 85 15 25 70 30 26 85 15 30 85 15

[0101] Table 2

[0102]

[0103] As can be seen from Table 2, the formulation retained 100% of the initial concentration of lidocaine hydrochloride after storage at 25°C and 40°C for 3 and 6 months. The formulation further demonstrated retention of 100% of the initial concentration of sodium bicarbonate after storage at 25°C and 40°C for 3 and 6 months. It was also demonstrated that no single impurity or degradation product was present at levels greater than approximately 0.05% or 0.03% after storage at 25°C and 40°C for 3 and 6 months. Total impurities in the formulation remained below 0.15% after storage at 25°C and 40°C for 2, 3, and 6 months. As shown by HPLC analysis of individual and total impurities and lidocaine, the formulation was stable over time under accelerated storage conditions within a pH range of 6.8 to 7.2.

[0104] The samples were also tested to determine the particle counts present at threshold diameters of 10 μm and 25 μm. The measured particle data is shown in Table 3 below.

[0105] Table 3

[0106]

[0107] As can be seen from Table 3, the formulation exhibited pharmaceutically acceptable amounts of both 10 μm and 25 μm particle counts after 3 and 6 months of storage at 25°C and 40°C. For example, the formulation exhibited no more than 30 and no more than 25 or 15 particles with an average diameter greater than 25 μm after 3 and 6 months of storage at 25°C and 40°C, respectively. The formulation also exhibited no more than 300 and no more than 400 particles with an average diameter greater than 10 μm after 3 months of storage at 25°C and 40°C, respectively, and no more than 500 and no more than 400 particles with an average diameter greater than 10 μm after 6 months of storage at 25°C and 40°C, respectively. The results for all particles in Table 3 demonstrate that the formulation is stable over time under accelerated storage conditions within a pH range of 6.8 to 7.2.

[0108] Example 2

[0109] This example demonstrates the stability of an exemplary formulation comprising lidocaine hydrochloride, sodium bicarbonate, sodium chloride, a pH regulator, and water. Individual samples of the formulations of Table 4 below were prepared in aqueous solution at specified concentrations. A bulk solution for sample preparation was formed by adding 900 g of water for injection (WFI) as 90% of the batch. Sodium chloride was added to the WFI and mixed for 10 minutes, resulting in a pH of 5.81 at 20.6°C. Sodium bicarbonate was further added to the solution and mixed for 10 minutes, which resulted in a pH of 8.31 at 19.7°C. Lidocaine hydrochloride was then added to the solution and mixed to form a bulk solution, which had a pH of 7.50 at 19.4°C and dissolved oxygen (DO) = 7.43 ppm. The bulk solution was purged with carbon dioxide to reduce the pH to 6.63, DO = 0.16 ppm. WFI was added to the bulk solution to increase the volume to 1 L, which resulted in a pH of 6.7 at 20°C. The bulk solution was purged with carbon dioxide again to maintain the pH at 6.63 and D0 = 0.00 ppm. The bulk solution was concentrated in a glove box with 0.22 μm Membrane filtration was performed to obtain a final bulk solution with a pH of 6.63 at 20° C. The bulk solution was divided into two batches, each with a final pH of 6.7.

[0110] In the first batch, 10 mL of the bulk solution having the formulation shown in Table 4 below was filled into two different vials. The first vial was a 20 mL clear glass vial (sulfur-treated tubular type 1 supplied by Schott's Fiolax (20 mm neck)). The second vial was a 20 mL glass vial (tubular type 1 (standard)). Both sets of filled vials contained approximately 50% headspace. Both sets of vials were stoppered with rubber stoppers (Flurotec supplied by West). The sample vials were not autoclaved.

[0111] Table 4

[0112] Element concentration Lidocaine hydrochloride 9.09 mg / mL Sodium bicarbonate 7.64 mg / mL Sodium chloride 6.36 mg / mL pH adjustment using carbon dioxide purge Adjust pH to 6.8 WFI Dilute to 1 mL <![CDATA[Top space CO2]]> 75% by volume

[0113] Vial samples of the formulations were stored at 25°C / 60% RH and 40°C / 75% RH. At the set storage time periods, the samples were analyzed by HPLC, the conditions being as described above, and the measurements on the formulations were performed as shown in Table 5 below.

[0114] Table 5

[0115]

[0116] As can be seen from Table 5, the formulation in the first sulfur-treated vial retained 100% of the initial concentrations of lidocaine and sodium bicarbonate at a pH of 6.5-6.8 after storage at 25°C and 40°C for one and six months. The formulation in the first vial also demonstrated that no single ropivacaine impurity was present above approximately 0.01% after storage at 25°C and 40°C for one and six months. Total impurities in the formulation remained below 0.15% after one month at 25°C and 40°C, and below approximately 0.1% after six months at 25°C and 40°C. As shown by HPLC analysis of individual and total impurities and lidocaine, the formulation was stable over time under accelerated storage conditions within the pH range of 6.5 in the first vial. The use of the sulfur-treated vials also demonstrated a reduction in pH excursions in the formulation compared to the same formulation stored in non-sulfur-treated vials.

[0117] The formulation in the second, unsulfurized vial also retained 100% of the initial concentrations of lidocaine and sodium bicarbonate after storage at a pH of 6.6-6.7 at 25°C and 40°C for one month. It was also demonstrated that the formulation in the second vial contained no detectable amounts of single impurities or degradation products after storage at 25°C and 40°C for one month. Total impurities in the formulation remained below 0.15% after storage at 25°C and 40°C for one month. As shown by HPLC analysis of single and total impurities and lidocaine assays, the formulation was stable over time in the second vial under accelerated storage conditions within the pH range of 6.6-6.7.

[0118] Two vials of samples were also tested to determine the particle counts present at the threshold diameters of 10 μm and 25 μm. The measured particle data is shown in Table 6 below.

[0119] Table 6

[0120]

[0121]

[0122] As can be seen from Table 6, the formulation in the first sulfur-treated vial exhibited pharmaceutically acceptable amounts of both 10 μm and 25 μm particle counts after storage at 25°C and 40°C for 1 month and 6 months. For example, the formulation exhibited no more than 30 and no more than 40 particles with an average diameter greater than 25 μm after storage at 25°C and 40°C, respectively. In another example, the formulation exhibited no more than 35 and no more than 30 particles with an average diameter greater than 25 μm after storage at 25°C and 40°C, respectively, for 6 months. The formulation also exhibited no more than 400 and no more than 500 particles with an average diameter greater than 10 μm after storage at 25°C and 40°C, respectively, for 1 month. In a further example, the formulation also exhibited no more than 450 and no more than 550 particles with an average diameter greater than 10 μm after storage at 25°C and 40°C, respectively, for 6 months. The results for all particles in Table 6 demonstrate that the formulation is stable over time under accelerated storage conditions at a pH of 6.5.

[0123] The formulation in the second vial exhibited pharmaceutically acceptable counts of both 10 μm and 25 μm particles after storage for 1 month and 6 months at 25°C and 40°C. The formulation exhibited no more than 70 and no more than 100 particles with an average diameter greater than 25 μm after storage for 1 month at 25°C and 40°C, respectively. In another embodiment, the formulation exhibited no more than 40 and no more than 55 particles with an average diameter greater than 25 μm after storage for 6 months at 25°C and 40°C, respectively. The formulation also exhibited no more than 800 and no more than 900 particles with an average diameter greater than 10 μm after storage for 1 month at 25°C and 40°C, respectively. In a further embodiment, the formulation also exhibited no more than 500 and no more than 1050 particles with an average diameter greater than 10 μm after storage for 6 months at 25°C and 40°C, respectively. The results for all particles in Table 6 demonstrate that the formulation is stable over time under accelerated storage conditions at a pH within the range of 6.6-6.7.

[0124] Example 3

[0125] Samples of the bulk formulations as detailed in the table below were used to evaluate the stability of the samples after multiple freeze-thaw cycles and after storage for one month at 40°C / 75% relative humidity and 2-8°C.

[0126] Element concentration Lidocaine hydrochloride 9.09 mg / mL Sodium bicarbonate 7.64 mg / mL Sodium chloride 6.36 mg / mL pH adjustment using carbon dioxide purge Adjust pH to 7.5 WFI Dilute to 1 mL <![CDATA[Top space CO2]]> As described, 0%, 50% and 75% by volume

[0127] 11 sample batches are prepared from the bulk formulation to evaluate multiple freeze-thaw cycles and the stability of storing one month at 40°C / 75% relative humidity and 2-8°C. For each sample batch, 10 mL of the sample batch was filled into glass vials (tubular type 1 (standard type)) at 0%, 50% and 75% by volume of carbon dioxide (measured using an oxygen sensor, 20, 10, 5ppm respectively). The vials were plugged with rubber stoppers (Flurotec supplied by West). Some vials from the sample batch were subjected to autoclaving before storage, i.e., vials from sample batches 9 and 11. In order to test the vials 1a to 11a from the sample batch, a single freeze-thaw cycle was performed by storing the sample at -20°C for 2 days and then converting the vials to 40°C, 75% relative humidity for 2 days. Each vial was subjected to three separate freeze-thaw cycles. The vials were observed for clarity and were also tested to determine the particle counts present at threshold diameters of 10 μm and 25 μm. The initial measured particle and pH data for the vials are shown in Table 7 below.

[0128] Table 7

[0129]

[0130]

[0131] The particulate matter data measured for the vials after three separate freeze-thaw cycles are shown below in Table 8. As can be seen from Table 7, the samples from batches 1a, 1b, and 1c exhibited an initial pH of 7.7, which was due to the fact that no carbon dioxide purge of the bulk solution and no carbon dioxide purge of the headspace were performed.

[0132] Table 8

[0133] Sample batch vials pH Appearance Particles -> 10μm Particles -> 25μm 1a 7.7 Visible particles 1466 742 2a 6.9 clear solution 447 43 3a 6.8 clear solution 510 47 4a 6.8 clear solution 743 42 5a 6.7 clear solution 162 13 6a 6.9 clear solution 316 28 7a 7.2 clear solution 412 42 8a 6.8 clear solution 257 7 9a 6.7 clear solution 765 12 10a 6.6 clear solution 330 22 11a 6.7 clear solution 932 43

[0134] As can be seen from Table 8, the formulations of sample batch vials 2a-11a showed both 10 μm and 25 μm particle counts in pharmaceutically acceptable amounts after three consecutive freeze-thaw cycles. For example, the vial samples showed no more than 43 particles with an average diameter greater than 25 μm after three consecutive freeze-thaw cycles. Sample batch vials 2a-3a, 5a-8a, and 10a also showed no more than 600 particles with an average diameter greater than 10 μm after three consecutive freeze-thaw cycles. The results for all particles in Table 8 demonstrate that the vial formulations are stable over time after freeze-thaw cycles at a pH of 6.6-7.2. In contrast, the formulations of sample batch 1a, which did not undergo a carbon dioxide purge of the bulk solution used to fill the vials or a carbon dioxide purge of the headspace in the vials, showed visible particles. Therefore, the steps of adjusting the pH of the bulk solution before filling the container, purging the headspace of the container with carbon dioxide, or a combination thereof, result in a clear solution free of visible particles and the above-mentioned particle characteristics.

[0135] As described above, batch samples were also tested in vials to determine the particle counts at threshold diameters of 10 μm and 25 μm after storage at 40°C / 75% relative humidity (sample batch vials 1b to 11b) and 2-8°C (sample batch vials 1c to 11c) for one month and six months. The particle data for sample batch vials 1b,c to 11b,c, measured initially, within 24 hours of vial filling, and one month are shown in Table 9 below. All batch sample vials showed clear solutions when examined after one month.

[0136] Table 9

[0137]

[0138]

[0139]

[0140] As can be seen from Table 9, under accelerated aging conditions of 40°C / 75% relative humidity, when the volume percent carbon dioxide in the vial headspace was 0% and the pH was above 7.7, the formulation from sample batch vial 1b exhibited a greater than 3.5-fold increase in particles with an average diameter greater than 10 μm and a nearly 8.5-fold increase in particles with an average diameter greater than 25 μm. Similar to the formulation from sample batch vial 1a of Table 8 (which also did not undergo a carbon dioxide purge of the bulk solution used to fill the vials or a carbon dioxide purge of the vial headspace), the formulation from sample batch vial 1b exhibited visible particles after 6 months of storage at 40°C / 75% RH. Thus, the steps of adjusting the pH of the bulk solution prior to container filling, purging the container headspace with carbon dioxide, or a combination thereof, as used in the remaining sample batch vials, resulted in clear solutions free of visible particles and the particle characteristics described below, maintained at 40°C / 75% RH for at least 1 month and 6 months. After 6 months of storage at 40°C / 75% RH, the pH of the formulation in sample batch vial 1b also showed an increase to a pH of 8.1. In contrast, after 6 months of storage at 40°C / 75% RH, the pH of the formulations in the remaining sample batch vials (which had undergone at least a carbon dioxide purge of the bulk solution, a carbon dioxide purge of the headspace in the vial, or a combination thereof) remained below pH 7.6, demonstrating the result of a clear solution free of visible particles.

[0141] The remaining sample batch vials stored at 40°C / 75% relative humidity exhibited acceptable counts of both 10 μm and 25 μm particles. For example, formulations from sample batch vials 2b-11b exhibited no more than 55 particles with an average diameter greater than 25 μm after one month of storage at 40°C / 75% RH. After six months of storage at 40°C / 75% RH, formulations from sample batch vials 3b and 5b-10b exhibited no more than 115 particles with an average diameter greater than 25 μm, and optionally, formulations from sample batch vials 3b, 5b-6b, and 8b-10b exhibited no more than 75 particles with an average diameter greater than 25 μm. Formulations 2b-11b also exhibited no more than 970 particles with an average diameter greater than 10 μm after one month of storage at 40°C / 75% RH. In another example, after storage for 6 months at 40°C / 75% RH, the formulations of sample batches of vials 3b and 5b-10b exhibited no more than 800 particles having an average diameter greater than 10 μm.

[0142] After one month of refrigerated storage at 2-8°C, sample batches of vials 1c-11c exhibited no more than 76 particles with an average diameter greater than 25 μm after one month of storage at 2-8°C. The highest count of particles with an average diameter greater than 25 μm occurred in sample batch vial 7c, which had a 0% CO2 volume percentage in the vial headspace. The sample batch formulation also exhibited no more than 788 particles with an average diameter greater than 10 μm after one month of storage at 2-8°C. Similarly, the highest count of particles with an average diameter greater than 10 μm occurred in sample batch vial 7c, which had a 0% CO2 volume percentage in the vial headspace. Samples 2, 4, and 5, which had a pH range of 6.8-7.0 and a 75% CO2 vial headspace, exhibited a reduction in particles with an average diameter greater than 25 μm and 10 μm after one month of storage at 2-8°C.

[0143] Example 4

[0144] This example demonstrates the stability of an exemplary formulation comprising lidocaine hydrochloride, sodium bicarbonate, sodium chloride, a pH adjuster, and water. The bulk solution of the formulation was divided into seven different batches, and the pH was lowered using a carbon dioxide purge to form seven different batches of bulk solution for filling vials. The bulk solution of formulations 1-4 was adjusted to 7, formulation 5 to 6.8, formulation 6 to 7.3, and formulation 7 to 7.5.

[0145] Individual samples of bulk solutions containing the formulations of Table 10 below were prepared by filling approximately 10 mL of bulk solution into 20 mL glass vials (Tube Type 1 (Standard)) at 20%, 40%, 60%, or 75% by volume of carbon dioxide (measured using an oxygen sensor, 16.8%, 12.6%, 8.4%, or 5.2%). The vials were stoppered with butyl rubber stoppers (Flurotec supplied by West). The sample vials were not autoclaved.

[0146] Table 10

[0147] Element concentration Lidocaine hydrochloride 10.0 mg / mL Sodium bicarbonate 8.4 mg / mL Sodium chloride 1.0 mg / mL pH adjustment using carbon dioxide purge Adjust pH as described for Formulations 1-7 WFI Dilute to 1 mL <![CDATA[Top space CO2]]> As described, 20%, 40%, 60% and 75% by volume

[0148] Vial samples of the formulations were stored at 25°C / 60% RH and 40°C / 75% RH. At the designated storage time periods, the samples were analyzed by HPLC using the conditions described above and the formulation measurements were performed as shown in Table 11 below. During the test period, all vials were clear solutions and free of particles.

[0149] Table 11

[0150]

[0151]

[0152]

[0153] As can be seen from Table 11, the formulations retained 99-100% of the initial concentration of lidocaine hydrochloride after storage at 25°C / 60RH and 40°C / 75RH for 1 month, 2 months, and 3 months. The formulations further demonstrated retention of 99-100% of the initial concentration of sodium bicarbonate after storage at 25°C / 60RH and 40°C / 75RH for 1 month, 2 months, and 3 months. It was also demonstrated that no single impurity or degradation product was present at above 0.01% after storage at 25°C / 60RH and 40°C / 75RH for 1 month, 2 months, and 3 months at a carbon dioxide headspace of 20%, 40%, 60%, or 75% by volume and a pH range of 6.8-7.3. After storage for 1 month, 2 months, and 3 months at 25°C / 60RH and 40°C / 75RH with a carbon dioxide headspace of 20%, 40%, 60%, or 75% by volume and a pH range of 6.8-7.3, the total impurities in the formulation remained below 0.05% or below 0.06%. As shown by the results of individual and total impurities determined by HPLC and the assay for lidocaine, the formulation was stable over time under accelerated storage conditions at a pH range of 6.8 to 7.3 and a carbon dioxide headspace of 20%, 40%, 60%, or 75% by volume.

[0154] The samples were also tested to determine the particle counts present at threshold diameters of 10 μm and 25 μm. The measured particle data is shown in Table 12 below.

[0155] Table 12

[0156]

[0157]

[0158]

[0159] As can be seen from Table 12, the formulations exhibited pharmaceutically acceptable amounts of both 10 μm and 25 μm particle counts after storage for 1 month, 2 months, and 3 months at 25°C / 60 RH and 40°C / 75 RH. For example, formulations 1-5 and 7 exhibited no more than 30 particles with an average diameter greater than 25 μm after storage for 1 month and 2 months at 40°C / 75 RH with a carbon dioxide headspace of 20%, 40%, 60%, or 75% by volume, respectively. Formulations 1-5 and 7 also exhibited no more than 175 particles with an average diameter greater than 10 μm after storage for 1 month and 2 months at 40°C / 75 RH with a carbon dioxide headspace of 20%, 40%, 60%, or 75% by volume, respectively. After storage for 3 months at 40°C / 75 RH, all formulations exhibited no more than 152 particles with an average diameter greater than 10 μm and no more than 12 particles with an average diameter greater than 25 μm. The results for all granules in Table 12 demonstrate that the formulations are stable over time under accelerated storage conditions at a pH of 6.8-7.3.

[0160] Example 5

[0161] An exemplary formulation comprising lidocaine hydrochloride, sodium bicarbonate, sodium chloride, a pH adjuster, and water was formed as shown below in Table 13. The bulk solution was divided into two batches, A and B. Batch A was not purged with carbon dioxide to lower the pH, while batch B was purged with carbon dioxide to lower the pH, prior to filling vials with the bulk solution.

[0162] Vials for batches A and B were prepared by filling approximately 10 mL of the bulk solution into 20 mL glass vials (Type 1) at 0% or 75% by volume of carbon dioxide (measured using an oxygen sensor, 21% or 5.2%). The vials were stoppered with butyl rubber stoppers (Flurotec supplied by West). The sample vials were indeed sterilized by autoclaving.

[0163] Table 13

[0164] Element concentration Lidocaine hydrochloride 10.0 mg / mL Sodium bicarbonate 8.4 mg / mL Sodium chloride 7.0 mg / mL pH adjustment using carbon dioxide purge As described WFI Dilute to 1 mL <![CDATA[Top space CO2]]> As stated, 0 vol% and 75 vol%

[0165] Two vials of samples were also tested to determine the particle counts present at the threshold diameters of 10 μm and 25 μm. The measured particle data is shown in Table 14 below.

[0166] Table 14

[0167]

[0168] As can be seen in Table 14, the absence of carbon dioxide in the headspace resulted in an initial pH of approximately 7.8 and an increase in the pH of the solution over 1 month and 6 months. After 1 month of storage at 40°C and 75% relative humidity, the vials without carbon dioxide in the headspace showed visible crystalline particles (visible particles began to form after 1-2 weeks) and had more than 1500 particles with an average diameter greater than 25 μm and more than 5800 particles with an average diameter greater than 10 μm. After 6 months of storage at 40°C and 75% relative humidity, the vials without carbon dioxide in the headspace showed a large number of visible particles. The vials of Batch A showed a pH drift during storage, rising to a value of 8.1, which affected the precipitation of particles, as evidenced by the appearance of visible particles. This further demonstrates the impact of carbon dioxide sparging and / or the presence of carbon dioxide in the vial headspace on stability and particle formation in the injectable solution. In contrast, after 1 month of storage at 40°C and 75% relative humidity, the vials with 75% carbon dioxide in the headspace measured no more than 60 particles with an average diameter greater than 25 μm and no more than 623 particles with an average diameter greater than 10 μm. This represents an 89% reduction (10 μm particles) and a 96% reduction (25 μm particles) compared to the vials from Batch A. Notably, the vials from Batch B appeared as clear solutions throughout the test and storage period, and showed a reduction in particles at 6 months compared to the values ​​measured at 1 month.

[0169] Example 6

[0170] An exemplary formulation comprising lidocaine hydrochloride, sodium bicarbonate, sodium chloride, a pH adjuster, and water was formed as shown below in Table 15. The bulk solution was divided into one batch, Batch A. Batch A was not purged with carbon dioxide to lower the pH prior to filling vials with the bulk solution, but rather hydrochloric acid was used to adjust the pH.

[0171] Batch A vials were prepared by filling approximately 10 mL of the bulk solution into 10 mL glass vials (Type 1) at 0% by volume of carbon dioxide (21% as measured using an oxygen sensor). The vials were stoppered with butyl rubber stoppers (Flurotec supplied by West). The sample vials were indeed sterilized by autoclaving.

[0172] Table 15

[0173]

[0174]

[0175] The vial samples were also tested to determine the particle counts present at the threshold diameters of 10 μm and 25 μm. The measured particle data is shown in Table 16 below.

[0176] Table 16

[0177]

[0178] As can be seen in Table 16, the absence of carbon dioxide in the headspace and the failure to use carbon dioxide to adjust the initial pH of the bulk resulted in the presence of visible small particles before 1 month of storage at elevated temperatures. After 1 month of storage at 40°C and 75% relative humidity, the vials showed visible (visible particles began to form after 2 weeks) and at 6 months had over 1050 particles with an average diameter greater than 10 μm.

[0179] Example 7

[0180] An exemplary formulation comprising lidocaine hydrochloride, sodium bicarbonate, sodium chloride, a pH adjuster, and water was formed as shown in Table 17 below. The bulk solution was divided into two batches, A and B. Batch A was not purged with carbon dioxide to lower the pH prior to filling vials with the bulk solution, while Batch B was purged with carbon dioxide to lower the pH to 6.9. The bulk solution of Batch A, which did not undergo a carbon dioxide purge, exhibited particle precipitation after formation, and therefore no vials were filled for stability studies.

[0181] Batch B vials were prepared by filling approximately 10 mL of the bulk solution into 10 mL glass vials (Type 1) at 75% by volume of carbon dioxide (5.2% as measured using an oxygen sensor). The vials were stoppered with butyl rubber stoppers (Flurotec supplied by West). The sample vials were indeed sterilized by autoclaving.

[0182] Table 17

[0183] Element concentration Lidocaine hydrochloride 18.18 mg / mL Sodium bicarbonate 7.64 mg / mL Sodium chloride 6.40 mg / mL pH adjustment using carbon dioxide purge 6.9 WFI Dilute to 1 mL <![CDATA[Top space CO2]]> 75% by volume

[0184] Samples of Batch B vials were tested to determine the particle counts present at the threshold diameters of 10 μm and 25 μm. The measured particle data is shown in Table 18 below.

[0185] Table 18

[0186]

[0187] As can be seen in Table 18, even at lidocaine concentrations exceeding 18 mg / mL, carbon dioxide in the headspace and a pH in the range of 6.7-6.9 resulted in clear solutions after 3 months at 40°C and 75% relative humidity. After 3 months of storage at 40°C and 75% relative humidity, no more than 45 particles with an average diameter greater than 25 μm and no more than 800 particles with an average diameter greater than 10 μm were measured in the vials with 75% carbon dioxide in the headspace. Notably, the vials from Batch B exhibited clear solutions throughout the test and for over 6 months of storage.

[0188] Example 8

[0189] An exemplary formulation comprising lidocaine hydrochloride, sodium bicarbonate, sodium chloride, a pH regulator, and water was prepared as shown in Table 19 below. Before the bulk solution was filled into two batches, A and B, the bulk solution was purged with carbon dioxide to reduce the pH to 6.9. The bottles of batches A and B were prepared by filling approximately 10 mL of the bulk solution into 10 mL glass vials (type 1) at 20% or 40% by volume of carbon dioxide (measured using an oxygen sensor, 16.8% and 12.6%). The vials were plugged with butyl rubber stoppers (Flurotec supplied by West). The sample vials were sterilized under high pressure.

[0190] Table 19

[0191] Element concentration Lidocaine hydrochloride 9.09 mg / mL Sodium bicarbonate 7.64 mg / mL Sodium chloride 6.36 mg / mL pH adjustment using carbon dioxide purge 6.9 WFI Dilute to 1 mL <![CDATA[Top Space CO2]]> As mentioned, 20% and 40% by volume

[0192] Samples from two vial batches were also tested to determine the particle counts present at the threshold diameters of 10 μm and 25 μm. The measured particle data is shown in Table 20 below.

[0193] Table 20

[0194]

[0195]

[0196] As can be seen in Table 20, the lower concentration of carbon dioxide in the headspace (20%) resulted in a greater concentration of particles in the solution over 2 weeks to 6 months of storage under both storage conditions (2-8°C and 40°C and 75% relative humidity). After 2 weeks of storage at 2-8°C, the vial with 20% carbon dioxide in the headspace had 1368 particles with an average diameter greater than 10 μm, while the vial with 40% carbon dioxide in the headspace had 833 particles with an average diameter greater than 10 μm, representing a 39% reduction in particles. In another example, after storage for 6 months at 40°C and 75% relative humidity, the vials with 20% carbon dioxide in the headspace had 3063 particles with an average diameter greater than 10 μm and 108 particles with an average diameter greater than 25 μm, respectively, while the vials with 40% carbon dioxide in the headspace had 708 particles with an average diameter greater than 10 μm and 16 particles with an average diameter greater than 25 μm, respectively, representing a 77% and 85% reduction in particles.

[0197] Example 9

[0198] This example demonstrates the stability of an exemplary formulation comprising lidocaine hydrochloride, sodium bicarbonate, sodium chloride, a pH adjuster, and water. The bulk solution was purged with carbon dioxide to lower the pH to form four different batches of bulk solution for filling vials, batches A, B, C1, C2, and D. The bulk solution for batch A was adjusted to 7.4, batch B was adjusted to 7.2, batches C1 and C2 were adjusted to 7, and batch D was adjusted to 6.8.

[0199] Individual samples of bulk solution from each batch containing the formulations of Table 21 below were prepared by filling approximately 10 mL of bulk solution into 10 mL glass vials (Type 1) at 40% or 75% by volume of carbon dioxide (12.6% or 5.2% as measured using an oxygen sensor). The vials were stoppered with rubber stoppers (Omniflex plus). The sample vials were indeed sterilized by autoclaving.

[0200] Table 21

[0201] Element concentration Lidocaine hydrochloride 9.09 mg / mL Sodium bicarbonate 7.64 mg / mL Sodium chloride 6.36 mg / mL pH adjustment using carbon dioxide purge As described, 6.8-7.4 WFI Dilute to 1 mL <![CDATA[Top space CO2]]> As mentioned, 40% and 75% by volume

[0202] The samples were also tested to determine the particle counts present at threshold diameters of 10 μm and 25 μm. The measured particle data is shown in Table 22 below.

[0203] Table 22

[0204]

[0205]

[0206] All solutions listed in Table 22 were clear during the test. As can be seen from the data, adjusting the pH of the bulk solution to a range of 6.8 to 7.2 with a carbon dioxide purge prior to filling the vials and maintaining a carbon dioxide content of 40% or more in the vial headspace can control particle formation. After 3 months of storage at 40°C and 75% relative humidity, the vials filled with the bulk solution adjusted to a pH of 7.4 had the highest particle concentration (32 particles with an average diameter greater than 25 μm), which represented a 63% reduction compared to the closest amount of 12 particles in the only vial without a 75% carbon dioxide headspace. However, Batch A represents a formulation that is stable and clear over time under accelerated storage conditions when the bulk solution is adjusted to a pH of 7.4 with carbon dioxide prior to filling.

[0207] In the case of not departing from the spirit and various principles of the present disclosure in fact, many changes and modifications can be made to the above-mentioned embodiments of the present disclosure.All such modifications and changes are intended to be included in this article within the scope of the present disclosure and protected by the appended claims.

Claims

1. An injectable liquid preparation in a container, the preparation comprising: a. lidocaine or a pharmaceutically acceptable salt thereof as the sole pharmaceutically active agent at a concentration of from about 5 to about 20 mg / mL; b. sodium bicarbonate buffer present at a concentration of about 4 to about 17 mg / mL; and c. carrier, wherein the injectable liquid formulation has a pH of about 6.5 to about 7.4 and the container comprises a gas headspace comprising greater than 20% carbon dioxide.

2. The injectable liquid preparation according to claim 1, wherein the pharmaceutically acceptable salt of lidocaine is selected from the group consisting of lidocaine hydrochloride, lidocaine hydrobromide, lidocaine oxalate, lidocaine fumarate, lidocaine adipate, lidocaine maleate, lidocaine malonate and lidocaine tosylate.

3. The injectable liquid formulation of claim 2, wherein the pharmaceutically acceptable salt of lidocaine is present at a concentration of about 5 mg / mL, about 9 mg / mL, about 10 mg / mL, or about 20 mg / mL.

4. The injectable liquid preparation according to claim 1, wherein the weight ratio of the sodium bicarbonate buffer to the lidocaine or a pharmaceutically acceptable salt thereof is in the range of about 0.3:1 to about 1.4:

1.

5. The injectable liquid preparation according to claim 2, wherein the weight ratio of the sodium bicarbonate buffer to the pharmaceutically acceptable salt of lidocaine is about 0.84:

1.

6. The injectable liquid preparation according to claim 1, wherein sodium bicarbonate is the only buffering agent in the injectable liquid preparation.

7. The injectable liquid formulation of claim 1, further comprising sodium chloride present at a concentration of about 1 to about 8 mg / mL. The injectable liquid preparation according to claim 1 , further comprising a pH adjuster.

9. The injectable liquid formulation of claim 1, wherein the gas head space comprises more than 40% carbon dioxide.

10. The injectable liquid formulation of claim 9, wherein the container has a sealed interior volume and the gas headspace constitutes 10% to 60% of the sealed interior volume of the container.

11. The injectable liquid formulation of claim 1, wherein the pH of the injectable liquid formulation is about 6.7 to about 7.

2. The injectable liquid preparation according to claim 1 , wherein the pH of the injectable liquid preparation is less than 7.

13. The injectable liquid preparation according to claim 1, wherein The pH of the injectable liquid formulation in the container is maintained within about 5% of the initial pH measured within 24 hours of filling the injectable liquid formulation in the container, compared to the pH measured after storage of the injectable liquid formulation in the container at 40° C. for 3 months. The injectable liquid preparation according to claim 1 , wherein the injectable liquid preparation contains no more than 600 particles having an average diameter greater than 10 μm after storage at 40° C. for 3 months. The injectable liquid preparation according to claim 1 , wherein the injectable liquid preparation contains no more than 0.2 wt % of total impurities after storage at 40° C. for 3 months. The injectable liquid preparation according to claim 1 , wherein the injectable liquid preparation retains about 95% or more of the initial concentration of lidocaine or a pharmaceutically acceptable salt thereof after storage at 40° C. for 3 months.

17. The injectable liquid preparation according to claim 1, wherein the injectable liquid preparation retains about 98% or more of the sodium bicarbonate buffer after storage at 40°C for 3 months. The injectable liquid preparation according to claim 1 , wherein the injectable liquid preparation is a ready-to-use preparation or an immediate administration preparation. The injectable liquid preparation according to claim 1 , wherein the container is a glass vial with a volume ranging from 10 mL to 20 mL.

20. The injectable liquid preparation according to claim 1, wherein the injectable liquid preparation does not contain one or more components selected from the group consisting of chelating agents, parabens, glycols, sugars, calcium salts, sulfates, sulfites, sulfides, sugars, and sugar alcohols. The injectable liquid preparation according to claim 1 , wherein the injectable liquid preparation comprises no more than 100 particles having an average diameter greater than 25 μm after storage at 40° C. for 3 months.

22. The injectable liquid formulation of claim 1, wherein the carrier is an aqueous carrier present in more than 90% by weight of the injectable liquid formulation.

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