Pharmaceutical composition containing bupivacaine as well as preparation method and application thereof

Abstract

The invention discloses a bupivacaine-containing pharmaceutical composition and a preparation method and application thereof.The pharmaceutical composition comprises bupivacaine, sucrose acetate isobutyrate, benzyl alcohol and a stabilizer.The bupivacaine preparation has good stability and a long-acting analgesic effect, the preparation process is simple, and the preparation method is suitable for industrial production. The method is suitable for large-scale production.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical preparations, and in particular relates to a pharmaceutical composition containing bupivacaine, a method for preparing the composition, and its application. Background Technology

[0002] Bupivacaine (CAS No.: 38396-39-3) is a long-acting amide-type local anesthetic, first synthesized by the Swedish company Astra in 1957 and first used clinically in 1963. The development of bupivacaine stemmed from the persistent need for long-acting, potent local anesthetics. Its chemical structure is similar to the earlier local anesthetic mepivacaine, but through optimization of the molecular structure (introducing a butyl substituent onto the nitrogen atom of the piperidine ring), its duration of action and anesthetic efficacy were significantly prolonged.

[0003] Bupivacaine formulations have excellent anesthetic and analgesic properties. A single dose can maintain a nerve block effect for 4-8 hours, and at low concentrations, it can achieve sensory-motor blockade separation, making it an ideal choice for epidural analgesia during labor and postoperative analgesia.

[0004] Posimir, a long-acting sustained-release formulation developed by Durect, was approved by the FDA on February 2, 2021, for use in arthroscopically directed application to the subacromial space for pain relief up to 72 hours after arthroscopic subacromial decompression surgery.

[0005] Durect's patent CN101035562B discloses an injection solution composed of bupivacaine, sucrose isobutyrate, and benzyl alcohol, designed to prolong the duration of anesthetic action and enhance its long-lasting properties.

[0006] Another patent from Durect, CN115666621A, discloses a sustained-release drug delivery system and related methods that reduce impurities. Bupivacaine injection prepared by this method can ensure that the content of impurity 2,6-dimethylaniline is less than 500 ppm, the content of bupivacaine N-oxide is not more than 1%, and the metal content is less than 5 ppm, thereby improving the safety and stability of the drug. Summary of the Invention

[0007] To address the technical problems existing in the prior art, this application provides a pharmaceutical composition with better sustained-release performance, better stability, and ease of industrial production, comprising bupivacaine, sucrose isobutyrate, benzyl alcohol, and a stabilizer, wherein the stabilizer is selected from one or more of tributyl phosphate, butylated hydroxytoluene, DL-α-tocopherol, ascorbyl palmitate, palmitic acid, medium-chain triglycerides, or tricaprylic acid glycerides.

[0008] Furthermore, the stabilizer is selected from one or more of palmitic acid, medium-chain triglycerides, or trioctanoic acid glycerides.

[0009] Further, based on the total mass of the pharmaceutical composition (100%), the amount of the stabilizer is 0.01% to 5% (w / w), preferably 0.03% to 1% (w / w), and more preferably 0.1% to 0.6% (w / w).

[0010] Furthermore, the stabilizer is a combination of two or three of palmitic acid, medium-chain triglycerides, or tricaprylic acid glycerides.

[0011] Furthermore, when the stabilizer is a combination of two of palmitic acid, medium-chain triglycerides or tricaprylic acid glycerides, the mass ratio of the two stabilizers is (1-5):(1-3), preferably the mass ratio is (1-3):(1-3).

[0012] Furthermore, the stabilizer is a combination of medium-chain triglycerides and tricaprylic acid glycerides, preferably, the mass ratio of medium-chain triglycerides to tricaprylic acid glycerides is (1-3):(1-3).

[0013] Furthermore, when the stabilizer is a combination of palmitic acid, medium-chain triglycerides and trioctanoic acid glycerides, the mass ratio of the three stabilizers is 1:1:1.

[0014] Further, based on the total mass of the pharmaceutical composition, the pharmaceutical composition comprises 10-15% (w / w) bupivacaine, 60-70% (w / w) sucrose isobutyrate acetate, 20-25% (w / w) benzyl alcohol and 0.01-5% (w / w) stabilizer.

[0015] On the other hand, the present invention provides a method for preparing the above-mentioned pharmaceutical composition, comprising the following steps: dissolving a stabilizer, bupivacaine, and sucrose isobutyrate in benzyl alcohol, filtering, and filling to obtain the pharmaceutical composition. Thirdly, the present invention provides the application of the above-mentioned pharmaceutical composition in the treatment of postoperative pain.

[0016] Compared with the prior art, the pharmaceutical composition provided by the present invention exhibits significant advantages in terms of stability and release performance.

[0017] First, the pharmaceutical compositions containing bupivacaine have low impurity content and good stability.

[0018] Secondly, this composition enables moderate drug release in the initial stage of administration, avoiding burst release, followed by a sustained and stable release of the active ingredient, thus providing adequate analgesia in the early postoperative period while maintaining effective analgesia for a long time. Furthermore, this formulation has advantages such as simple process, good reproducibility, and ease of control, making it more suitable for large-scale industrial production and quality control, and possessing promising clinical application prospects and industrialization value. Attached Figure Description

[0019] Figure 1 This is a comparison chart of the release rates of the original formulation F1, formulation F8 with palmitic acid as the stabilizer, formulation F10 with medium-chain triglycerides (MCT) as the stabilizer, and formulation F12 with caprylic acid glyceride as the stabilizer.

[0020] Figure 2 This is a comparison chart of the release rates of the original formulation F1, formulation F20 (stabilizers are palmitic acid and medium-chain triglycerides), formulation F21 (stabilizers are palmitic acid and tricaprylic acid glyceride), formulation F14 (stabilizers are medium-chain triglycerides and tricaprylic acid glyceride), and formulation F22 (stabilizers are palmitic acid, medium-chain triglycerides and tricaprylic acid glyceride).

[0021] Figure 3 This is a comparison chart showing the release rate of different amounts of stabilizers when the stabilizers are a combination of medium-chain triglycerides (MCT) and caprylic acid glyceride.

[0022] Figure 4 This is a comparison chart showing the release rates of the two stabilizers at different ratios when the stabilizers are a combination of medium-chain triglycerides (MCT) and caprylic acid glyceride. Detailed Implementation

[0023] The technical solutions of the embodiments of this application will be clearly described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of this application. All other embodiments obtained by those skilled in the art based on the embodiments of this application are within the scope of protection of this application.

[0024] The terms "first," "second," etc., used in the specification and claims of this application are used to distinguish similar objects and not to describe a specific order or sequence. It should be understood that such use of data can be interchanged where appropriate so that embodiments of this application can be implemented in orders other than those illustrated or described herein, and the objects distinguished by "first," "second," etc., are generally of the same class and the number of objects is not limited; for example, a first object can be one or more. Furthermore, in the specification and claims, "and / or" indicates at least one of the connected objects, and the character " / " generally indicates that the preceding and following objects are in an "or" relationship.

[0025] All publications, patents, and patent applications cited in this article, whether mentioned above or below, are incorporated herein by reference in their entirety.

[0026] Unless otherwise specified, the experimental methods used in the following examples are conventional methods; unless otherwise specified, the reagents and materials used in the following examples are commercially available.

[0027] Existing bupivacaine formulations still have significant limitations: their duration of action is insufficient to meet the needs of ultra-long-term (e.g., more than 24 hours) analgesia; accidental intravascular injection or overdose may cause serious cardiotoxicity; traditional aqueous solutions lack sustained-release properties and require repeated administration; and there is a risk of neurotoxicity when used at high concentrations.

[0028] These shortcomings have prompted researchers to develop novel drug delivery systems (such as liposomes and microspheres) to prolong drug action time, reduce toxicity, and improve safety, thereby better meeting the urgent clinical need for long-acting, safe local anesthetics.

[0029] While Posimir and its related patented technologies are dedicated to providing long-acting and stable bupivacaine extended-release formulations, there is still room for improvement in product stability and effective analgesic duration in practical applications.

[0030] <First Aspect>

[0031] In a first aspect, the pharmaceutical composition provided by the present invention comprises bupivacaine, sucrose isobutyrate, benzyl alcohol, and a stabilizer, wherein the stabilizer is selected from one or more of tributyl phosphate, butylated hydroxytoluene, DL-α-tocopherol, ascorbyl palmitate, palmitic acid, medium-chain triglycerides, or tricaprylic acid glycerides.

[0032] The term "bupivacaine" as used in this invention refers to bupivacaine or its pharmaceutically acceptable salt forms, including any one or a combination of at least two of bupivacaine base, bupivacaine hydrochloride, bupivacaine dihydroxynaphthyl acid, and levobupivacaine, more preferably bupivacaine base, hereinafter referred to as "API".

[0033] The "sucrose isobutyrate acetate" (SAIB) described in this invention is a non-polymerized, water-insoluble, high-viscosity liquid carrier material that has a viscosity of at least 5,000 cP at 37°C and does not undergo ordered crystallization under ambient or physiological conditions.

[0034] The "benzyl alcohol" described in this invention is a solvent that can effectively dissolve SAIB and other raw and auxiliary materials. At the same time, benzyl alcohol itself has a mild local anesthetic effect (by blocking sodium channels) and can produce a synergistic analgesic effect with bupivacaine, especially for superficial pain (such as pain at the subcutaneous injection site).

[0035] The "stabilizer" described in this invention is not an active ingredient with a clearly defined efficacy, but exists only as an auxiliary excipient in the formulation and does not have any educational significance in directly exerting pharmacological or functional effects.

[0036] Further, the stabilizer is selected from one or more of tributyl phosphate, butylated hydroxytoluene, DL-α-tocopherol, ascorbyl palmitate, palmitic acid, medium-chain triglycerides, or tricaprylic acid esters. Preferably, it is selected from one or more of tributyl phosphate, butylated hydroxytoluene, palmitic acid, medium-chain triglycerides, or tricaprylic acid esters; more preferably, it is selected from one or more of butylated hydroxytoluene, palmitic acid, medium-chain triglycerides, or tricaprylic acid esters; and even more preferably, it is selected from one or more of palmitic acid, medium-chain triglycerides, or tricaprylic acid esters.

[0037] In one specific embodiment, the stabilizer is a combination of two or three of palmitic acid, medium-chain triglycerides, or caprylic acid esters; for example, the stabilizer is a combination of palmitic acid and medium-chain triglycerides, a combination of palmitic acid and caprylic acid esters, a combination of medium-chain triglycerides and caprylic acid esters, or a combination of palmitic acid, medium-chain triglycerides, and caprylic acid esters, preferably a combination of medium-chain triglycerides and caprylic acid esters. The term "combination" refers to their combined use.

[0038] In one specific embodiment, when the stabilizer is a combination of two, the mass ratio of the two is (1-5):(1-3), for example 1:1, 1:2, 1:3, 2:1, 2:3, 3:1, 3:2, 4:1, 4:3, 5:1, 5:2 or 5:3, preferably (1-3):(1-3), further preferably 1:(1-3), more preferably 1:1, but not limited to the listed values, other unlisted values ​​within this range are also applicable.

[0039] In one specific embodiment, the stabilizer is a combination of medium-chain triglycerides and tricaprylic acid glycerides, and / or the mass ratio of medium-chain triglycerides to tricaprylic acid glycerides is (1-3):(1-3), more preferably 1:(1-3), and even more preferably 1:1, but is not limited to the listed values, other unlisted values ​​within this range are also applicable.

[0040] In one specific embodiment, when the stabilizer is a combination of three substances, the mass ratio of the three substances is 1:1:1.

[0041] In one specific embodiment, the total mass of the pharmaceutical composition is 100%.

[0042] The pharmaceutical composition comprises 10-15% (w / w) bupivacaine, 60-70% (w / w) sucrose isobutyrate acetate, 20-25% (w / w) benzyl alcohol, and 0.01-5% (w / w) stabilizer;

[0043] Preferably, the pharmaceutical composition comprises 10-15% (w / w) bupivacaine, 60-70% (w / w) sucrose isobutyrate acetate, 20-25% (w / w) benzyl alcohol and 0.01-1% (w / w) stabilizer;

[0044] Preferably, the pharmaceutical composition comprises 10-15% (w / w) bupivacaine, 60-70% (w / w) sucrose isobutyrate acetate, 20-25% (w / w) benzyl alcohol, and 0.01-0.8% (w / w) stabilizer;

[0045] Preferably, the pharmaceutical composition comprises 10-15% (w / w) bupivacaine, 60-70% (w / w) sucrose isobutyrate acetate, 20-25% (w / w) benzyl alcohol, and 0.01-0.6% (w / w) stabilizer;

[0046] Preferably, the pharmaceutical composition comprises 10-15% (w / w) bupivacaine, 65-70% (w / w) sucrose isobutyrate acetate, 20-22% (w / w) benzyl alcohol and 0.1-1% (w / w) stabilizer;

[0047] More preferably, the pharmaceutical composition comprises 10-15% (w / w) bupivacaine, 65-70% (w / w) sucrose isobutyrate acetate, 20-22% (w / w) benzyl alcohol, and 0.1-0.8% (w / w) stabilizer;

[0048] More preferably, the pharmaceutical composition comprises 10-15% (w / w) bupivacaine, 65-70% (w / w) sucrose isobutyrate acetate, 20-22% (w / w) benzyl alcohol, and 0.1-0.6% (w / w) stabilizer;

[0049] More preferably, the pharmaceutical composition comprises 12 (w / w) bupivacaine, 66% (w / w) sucrose isobutyrate, 20%–22% (w / w) benzyl alcohol, and 0.1–0.6% (w / w) stabilizer.

[0050] The amount of stabilizer can be 0.01-5% (w / w), preferably 0.03%-1% (w / w), more preferably 0.1%-0.8% (w / w), and even more preferably 0.1%-0.6% (w / w), for example 0.1%, 0.2%, 0.3%, 0.4%, 0.5% or 0.6%, but is not limited to the listed values. Other unlisted values ​​within this range are also applicable, for example, 0.1%-0.5% (w / w), 0.1%-0.4% (w / w), 0.1%-0.3% (w / w), or 0.1%-0.2% (w / w).

[0051] In one embodiment of the present invention, when kept in contact with a dissolution medium at pH 7.4 ± 0.05, the bupivacaine formulation obtained by the present invention is consistent with the following release curves: less than or equal to 30% bupivacaine is released from the formulation at 2 hours, 45-75% bupivacaine is released from the formulation at 8 hours, and more than 70% bupivacaine is released from the formulation at 16 hours.

[0052] As a more preferred release standard of the present invention, in one embodiment of the present invention, when kept in contact with a dissolution medium at pH 7.4 ± 0.05, the bupivacaine formulation obtained by the present invention is consistent with the following release curves: 10% to 20% bupivacaine is released from the formulation at 2 hours, 50% to 70% bupivacaine is released from the formulation at 8 hours, and more than 80% bupivacaine is released from the formulation at 16 hours.

[0053] The bupivacaine long-acting injection of the present invention aims to achieve a stable and sustained drug release. Ideally, the formulation should avoid burst release in the initial stage (e.g., the first 2 hours), releasing as little drug as possible while meeting basic analgesic needs, in order to facilitate stable release over a longer period, thereby maintaining a sustained analgesic effect, resulting in more stable blood drug concentrations, reducing peak-trough effects, and minimizing later adverse reactions.

[0054] <Second aspect>

[0055] In a second aspect, the present invention provides a method for preparing a pharmaceutical composition, comprising the following steps:

[0056] The stabilizer, bupivacaine, and sucrose isobutyrate are dissolved in benzyl alcohol, filtered, and filled to obtain the pharmaceutical composition.

[0057] In one specific embodiment, the stabilizer, bupivacaine, and sucrose isobutyrate are dissolved in benzyl alcohol, stirred and dissolved, filtered, filled into packaging containers according to specifications, sterilized, and capped to obtain bupivacaine injection solution.

[0058] In one specific embodiment, the pharmaceutical composition is prepared by heating benzyl alcohol and then mixing it with sucrose isobutyrate acetate, a stabilizer, and bupivacaine, stirring until dissolved. The mixture is then filled into a packaging container and sealed with a rubber stopper and an aluminum cap.

[0059] In one specific embodiment, the pharmaceutical composition is prepared by heating benzyl alcohol and stirring it with sucrose isobutyrate until dissolved. Then, a stabilizer and bupivacaine are added and stirred until dissolved. The mixture is then filled into a packaging container and sealed with a rubber stopper and an aluminum cap.

[0060] In one specific embodiment, the method for preparing the pharmaceutical composition includes the following steps:

[0061] (1) Add benzyl alcohol to the mixing tank and heat it to above 40°C.

[0062] (2) Add the pre-weighed SAIB and mix well.

[0063] (3) Cool the preparation obtained in step (2) to room temperature, then add the stabilizer and the prescribed amount of bupivacaine, stir to dissolve and filter, fill into packaging containers according to specifications, sterilize and cap to obtain bupivacaine injection solution.

[0064] The packaging container material of the present invention may be one of the following: soda-lime glass, medium borosilicate glass, high borosilicate glass, low-density polyethylene infusion bottle, polypropylene infusion bottle, three-layer co-extruded infusion film or bag, five-layer co-extruded infusion film or bag, or multi-layer co-extruded infusion film or bag.

[0065] Preferably, the packaging container is made of borosilicate glass ampoules or borosilicate glass tubular bottles.

[0066] <Third aspect>

[0067] In a third aspect, the present invention provides the use of the pharmaceutical composition, the method of which relates to using the composition as a local anesthetic treatment for postoperative incision pain. Such use of the composition eliminates or at least alleviates the need for adjunctive treatment, such as administering general analgesia to manage the postoperative pain. Therefore, the composition can be used to manage postoperative pain accompanying various types of medical procedures, such as major surgeries (e.g., thoracotomy, aortic repair, bowel resection, etc.), medium-sized surgeries (e.g., cesarean section, hysterectomy, and appendectomy), and minor surgeries (laparoscopy, arthroscopy, and biopsy procedures), which may be debilitating and may require 3–5 days of postoperative pain management.

[0068] In preferred embodiments, the compositions of this application are particularly suitable for wound treatment. The non-polymer carrier system allows for the easy application of one or more anesthetics to the wound (directly into the wound and / or near the wound) using very simple application techniques, such as dripping, spraying, smearing, spreading, shaping, or otherwise manually manipulating a composition of liquid, spray, cream, lotion, ointment, gel, serum, oil, emulsion, microemulsion, soft solid or hard ointment, film, granules, microparticles, or powder, by dripping, spraying, smearing, spreading, shaping, or otherwise manually manipulating it. Therefore, the composition can be used for wounds of any size or shape and will provide uniform distribution of one or more anesthetics over the entire area of ​​the wound for better retention and effectiveness. Wounds that can be treated using such methods can range from the most superficial to the deepest, from the surface to the incision, and from surgical (or other considerations) to the extent of the accident. If the composition is to be injected, it can be applied to the subcutaneous space along the side or outer boundary of the wound using trailing injection. Combined methods can also be used, such as placing the composition both directly into the wound, for example before surgical closure, and additionally along the wound. In a particularly preferred embodiment, the method of this application relates to using the composition of the invention as a local anesthetic for treating postoperative incision pain. Using the composition of the invention in this manner can avoid or at least reduce the need for adjunctive treatment, such as the administration of general anesthetic analgesics to treat such postoperative pain, as described in patents CN101035562B and CN115666621A, the entire contents of which are incorporated herein by reference.

[0069] Preferably, the composition is administered as a liquid by injection, or as an aerosol, paste, or emulsion. When used as an aerosol, any solvent present in the aerosol solution typically evaporates upon application, thereby allowing the composition to form as a film. Alternatively, the aerosol or emulsion can be prepared without a solvent. In this case, an aerosol propellant can also be used as a solvent. The formation of the aerosol or emulsion can be achieved using techniques known to those skilled in the art. See, for example, Ansel, HC, et al., Pharmaceutical Dose Formation and Drug Delivery Systems, 6th Edition (1995).

[0070] In addition to the uses described above, the compositions of the present invention can be administered via an osmotic pump. In one case, the device is designed to be implanted in the tissue of a subject and is designed to achieve continuous release over time.

[0071] The composition can also be applied using porous or non-porous tubes, ideally made from extruded biodegradable polymers. Tubes with varying degrees of porosity can be prepared depending on the properties of the composition and the desired release characteristics.

[0072] Table 1 shows the sources of raw materials and auxiliary materials involved in the experimental examples.

[0073]

[0074]

[0075] Experimental Example 1: Screening of Stabilizer Types

[0076] Table 2. Formulation composition of different preparations

[0077] Raw materials % F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 API 12 12 12 12 12 12 12 12 12 12 12 12 SAIB 66 61.5 66 65.97 66 66 66 66 66 66 66 66 benzyl alcohol 22 20.5 21 22 21 21 21.9 21.8 21.9 21.8 21.9 21.8 bitter / 6 / / / / / / / / / / Tributyl phosphate / / 1 / / / / / / / / / Butylated hydroxytoluene / / / 0.03 / / / / / / / / DL-α-tocopherol / / / / 1 / / / / / / / Ascorbyl palmitate / / / / / 1 / / / / / / Palmitic acid / / / / / / 0.1 0.2 / / / / medium-chain triglycerides / / / / / / / / 0.1 0.2 / / Trioctyl glyceride / / / / / / / / / / 0.1 0.2

[0078] The preparation method is as follows:

[0079] Dissolve the stabilizer, bupivacaine, and sucrose isobutyrate in benzyl alcohol, filter, fill into borosilicate glass according to the predetermined specifications, and seal with rubber stoppers and aluminum caps.

[0080] To investigate the stability of the formulation

[0081] Determined according to the high performance liquid chromatography method in the Chinese Pharmacopoeia (Appendix 0512).

[0082] For the test solution, take an appropriate amount of this product (approximately equivalent to 20 mg of bupivacaine), accurately weigh it, place it in a 20 ml volumetric flask, add 12 ml of ethanol, then dilute with water to the mark, shake well, filter, and collect the filtrate.

[0083] Reference solution: Weigh an appropriate amount of bupivacaine accurately, dissolve and dilute it with an appropriate amount of ethanol-water (60:40) to prepare a solution containing approximately 10 μg of bupivacaine per 1 ml.

[0084] Chromatographic conditions using octadecylsilane-bonded silica gel as the stationary phase (Waters XBridge C18).

[0085] A 4.6 mm × 250 mm, 5 μm or equivalent column was used. The mobile phase A was 0.05 mol / L phosphate buffer (6.8 g potassium dihydrogen phosphate and 1.87 g sodium hydroxide were weighed, added to 1000 ml of water, and the pH was adjusted to 8.0) - acetonitrile (65:35); the mobile phase B was acetonitrile, and elution was performed according to the table below. The detection wavelength was 240 nm; the column temperature was 30 °C; the flow rate was 1.0 ml per minute; and the injection volume was 50 μl.

[0086]

[0087] Note: In accordance with the provisions of ICH guidelines and the "Guidelines for the Analysis of Drug Impurities in Chinese Pharmacopoeia 9102" and the dosage and characteristics of the bupivacaine injection of this invention, this application performs quantitative analysis on all detected impurities.

[0088] Table 3 Impurity content of different formulations

[0089]

[0090] Note 1: Specific impurities refer to impurities for which specific limits are defined and controlled separately in the quality standards formulated in accordance with ICH guidelines and the provisions of the Chinese Pharmacopoeia. Impurities with an RRT of 0.28 are impurities whose structures are not identified but can be reproducibly detected.

[0091] 2: RRT stands for Relative Retention Time.

[0092] The stability of formulations F1 to F12 was investigated in this invention. Formulation F1, obtained according to the formulation and process of the prior art (Example 4 of CN101035562B and Formulation A of Example 1 of CN115666621A), had high levels of specific impurities and total impurities with an RRT of 0.28. In contrast, the impurity level of formulation F2, which contained caprylic acid, was close to that of formulation F1. This indicates that caprylic acid has no effect on the impurity control of bupivacaine injection.

[0093] Further investigation was conducted on the impurity changes of other formulations under harsh conditions (placed at 60°C for 3 days), and the specific results are as follows:

[0094] Table 4. Impurities in the formulation at high temperatures

[0095]

[0096] Tables 3 and 4 show that the specific impurities and total impurities of formulation F1 (RRT = 0.28) increased somewhat at high temperatures. Formulation F3, with the addition of 1% tributyl phosphate, showed no significant change in overall impurities, effectively controlling the increase of related substances in bupivacaine formulations. Formulation F4, with the addition of 0.03% butylated hydroxytoluene (BHT), had even better impurity content than F3 at day 0 and day 3 at high temperatures, indicating that BHT has a good impurity control effect in bupivacaine formulations. However, because tributyl phosphate is a toxic substance, belonging to the moderate toxicity level, its dosage should be minimized. Considering the safety and feasibility of the formulation, further research was not conducted. While BHT, as an antioxidant, is listed in the pharmacopoeias of many countries and is permitted for use in pharmaceuticals, food, and cosmetics, it must meet the limit standards (usually 0.001%-0.1%). In liquid pharmaceutical preparations, the content of BHT is usually controlled at a low level. Considering the safety and feasibility of the formulation, BHT is not the optimal choice.

[0097] Formulation F5, which contains the commonly used antioxidant DL-α-tocopherol, initially showed a significantly lower impurity content compared to formulation F1. However, after being placed at high temperature for 3 days, its RRT = 0.28 and total impurity content were significantly too high.

[0098] In contrast, formulation F6, which uses ascorbyl palmitate (L-AP), had a lower initial impurity content compared to formulation F1. However, the impurity content and total impurity content with an RRT of 0.28 exceeded 1%, indicating that the impurity growth was too rapid.

[0099] Formulations F7 to F12, which use palmitic acid, medium-chain triglycerides, and tricaprylic acid glycerides, showed significantly lower initial and post-treatment impurity levels than formulation F1, and their effects were good at concentrations of 0.1% to 0.2%.

[0100] In summary, adding a certain amount of palmitic acid, medium-chain triglycerides, or caprylic acid glycerides to the bupivacaine injection system can improve the product's stability.

[0101] Experimental Example 2: Investigating the stability of formulations using multiple stabilizers simultaneously. The specific prescription details are shown in Table 5:

[0102] Table 5 contains formulations with multiple stabilizers.

[0103]

[0104]

[0105] The impurity content and stability of formulations containing multiple stabilizers were investigated. The detection method is as in Experiment 1, and the specific results are shown in Tables 6 and 7.

[0106] Table 6 shows the impurity content of formulations containing multiple stabilizers.

[0107]

[0108] Table 7 shows the stability and impurity status of formulations containing multiple stabilizers (after 3 days at 60°C).

[0109]

[0110] As shown in Tables 6 and 7, using one, two, or three of palmitic acid, medium-chain triglycerides, or tricaprylic acid glycerides can effectively reduce the impurity content compared to formulation F1. Furthermore, it exhibits good stability under high-temperature conditions. The impurity levels of formulations F13–F22, obtained using two or more stabilizers, are close to those of formulations using only one stabilizer (F7–F12).

[0111] Experiment Example 3: Examination of Release Effect

[0112] As a long-acting analgesic, the sustained-release effect of bupivacaine formulations is an important aspect of its efficacy. This invention employs the following method to quickly and intuitively compare the release rates of formulations.

[0113] The release rate was measured according to the second method (paddle method) of Dissolution and Release Rate in Chapter 4, General Section 0913 of the 2020 edition of the Chinese Pharmacopoeia. Approximately 0.4 ml of the drug solution was injected into 900 ml of release medium (phosphate buffer solution with pH 7.4 ± 0.05 containing 0.03% sodium dodecyl sulfate) at 40 ± 0.5 °C. The rotation speed was set to 100 rpm, and samples were taken at 0.5, 1, 2, 4, 6, 8, 12, 16, and 24 hours, filtered, and measured.

[0114] Table 8. Release status of the formulation

[0115]

[0116] Note: Table 8 and Appendix Figures 1-4 In this context, A refers to palmitic acid, B refers to medium-chain triglycerides (MCT), and C refers to caprylic / capric triglycerides.

[0117] The original formulation claimed to achieve an analgesic effect of 72 hours. To provide a more direct and rapid comparison of formulation release, this invention employs a rapid release method. (See Table 8 and Appendix...) Figures 1-4 It can be seen that, compared with the original formulation F1, the formulations using palmitic acid, medium-chain triglycerides or tricaprylic acid glycerides are significantly slower, especially reducing the initial sustained-release rate.

[0118] As a long-acting analgesic, the ideal goal is to achieve a certain release level in the early stage (non-burst release), and then maintain an effective analgesic effect slowly and persistently.

[0119] When the amount of stabilizer is the same, the release of bupivacaine formulations is slower when two or three stabilizers are used in combination (e.g., F14, F20, F21, and F22 compared to F8, F10, and F12).

[0120] When two stabilizers are combined, formulation F19, with a total amount of 0.8% of medium-chain triglycerides and caprylic acid glycerides, has a release rate of 48.2% after 8 hours and only 72% after 16 hours, which is relatively low. In contrast, a stabilizer amount of 0.1% to 0.6% can achieve a better sustained-release rate (such as formulations F13 to F18).

[0121] When stabilizers are used in combination, the ratio of stabilizer dosage is also important. In particular, when the dosage of medium-chain triglycerides and caprylic acid glycerides is (1-5):(1-3) (formulations F14-F17), it has a significant effect on reducing the release rate compared to formulation F1 and formulations F8, F10, and F12 that use a single stabilizer. When the dosage ratio of the two is (1-3):(1-3) (such as formulations F14-F16), the release rate is more uniform and slower, which can exert the effective analgesic effect of bupivacaine while the release rate is sufficiently moderate, which is the ideal sustained-release rate.

[0122] Meanwhile, the combination of palmitic acid, medium-chain triglycerides and tricaprylic acid glyceride (such as formulation F22) can also achieve the desired sustained-release effect.

[0123] The embodiments of this application have been described above with reference to the accompanying drawings. However, this application is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of this application without departing from the spirit and scope of the claims, and all of these forms are within the protection scope of this application.

Claims

1. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises bupivacaine, sucrose isobutyrate, benzyl alcohol, and a stabilizer, wherein the stabilizer is selected from one or more of tributyl phosphate, butylated hydroxytoluene, DL-α-tocopherol, ascorbyl palmitate, palmitic acid, medium-chain triglycerides, or tricaprylic acid glycerides.

2. The pharmaceutical composition according to claim 1, characterized in that, The stabilizer is selected from one or more of palmitic acid, medium-chain triglycerides, or trioctanoic acid glycerides.

3. The pharmaceutical composition according to claim 1, characterized in that, The amount of stabilizer used is 0.01% to 5% (w / w) based on the total mass of the pharmaceutical composition of 100%, preferably 0.03% to 1% (w / w), and more preferably 0.1% to 0.6% (w / w).

4. The pharmaceutical composition according to claim 3, characterized in that, The stabilizer is a combination of two or three of palmitic acid, medium-chain triglycerides, or trioctanoic acid glycerides.

5. The pharmaceutical composition according to claim 4, characterized in that, When the stabilizer is a combination of two of palmitic acid, medium-chain triglycerides or tricaprylic acid glycerides, the mass ratio of the two stabilizers is (1-5):(1-3), preferably (1-3):(1-3).

6. The pharmaceutical composition according to claim 5, characterized in that, The stabilizer is a combination of medium-chain triglycerides and tricaprylic acid glycerides, preferably in a mass ratio of (1-3):(1-3).

7. The pharmaceutical composition according to claim 4, characterized in that, When the stabilizer is a combination of palmitic acid, medium-chain triglycerides and trioctanoic acid glycerides, the mass ratio of the three stabilizers is 1:1:

1.

8. The pharmaceutical composition according to any one of claims 1 to 7, characterized in that, The total mass of the pharmaceutical composition is 100%, and the pharmaceutical composition comprises 10% to 15% (w / w) bupivacaine, 60% to 70% (w / w) sucrose isobutyrate acetate, 20% to 25% (w / w) benzyl alcohol and 0.01% to 5% (w / w) stabilizer.

9. A method for preparing the pharmaceutical composition according to any one of claims 1 to 8, characterized in that, The process includes the following steps: dissolving a stabilizer, bupivacaine, and sucrose isobutyrate in benzyl alcohol, filtering, and filling to obtain the pharmaceutical composition.

10. The use of the pharmaceutical composition according to any one of claims 1 to 9 in the treatment of postoperative pain.

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