Pharmaceutical composition comprising local anesthetic

Abstract

The present disclosure relates to pharmaceutical compositions comprising a local anesthetic. Specifically, the invention relates to a suspension injection of a local anesthetic, which comprises active ingredient particles, a stabilizer and a liquid medium. The suspension injection can be better applied to clinic.

Description

Technical Field

[0001] The present disclosure belongs to the field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition containing a local anesthetic and a preparation method thereof. Background Art

[0002] Postoperative pain is acute tissue-damaging pain that occurs immediately after surgery and generally lasts 3-7 days. If postoperative pain is poorly controlled, it can cause a range of physiological and psychological effects on patients, such as insomnia, anxiety, irritability, elevated blood pressure, increased heart rate, and decreased gastrointestinal motility, severely hindering disease treatment and improving quality of life. Therefore, effective analgesic measures can not only alleviate postoperative pain but also reduce the occurrence of perioperative adverse reactions and shorten hospital stays.

[0003] Local anesthetics are a class of drugs that can reversibly block the generation and transmission of sensory nerve impulses in the area of ​​administration. They can reversibly cause the disappearance of local tissue pain while maintaining consciousness. Representative drugs include bupivacaine and ropivacaine. Among them, ropivacaine has good tolerance and is an ideal drug for postoperative analgesia. However, the duration of action of ropivacaine is only 4-6 hours. Currently, most clinical preparations are ordinary injections. The injection dose required for a single administration is large and the duration of action is short. Repeated administration not only leads to poor patient compliance, but also causes peak and trough effects in blood drug concentration, resulting in toxic side effects. Therefore, the development of long-acting ropivacaine preparations is of great clinical significance.

[0004] WO2020259670 discloses a sustained-release lipid composition containing ropivacaine, which exerts a sustained-release effect by forming liposomes. However, it is difficult to control the encapsulation rate of liposomes, and the drug loading in liposomes is low (such as 10-20%). Therefore, more lipid excipients need to be given at the same time during administration, which may increase toxic side effects. The risk of storage stability of liposomes also poses challenges to drug development. Summary of the Invention

[0005] In one aspect, the present disclosure provides a suspension injection of a local anesthetic, which comprises active ingredient particles, a stabilizer, and a liquid medium, wherein:

[0006] The local anesthetic comprises at least one selected from ropivacaine and a pharmaceutically acceptable salt of ropivacaine, the stabilizer comprises phospholipid, and the suspension injection does not contain a lipid vesicle structure.

[0007] The term "not containing lipid vesicle structures" as used herein may mean that no lipid vesicle structures can be observed in an optical microscope image or a scanning electron microscope image of the suspension injection. In some embodiments, the suspension injection is not a liposome.

[0008] As used herein, "phospholipids" refer to hydrophobic molecules containing at least one phosphate group, which may be natural or synthetic. For example, a phospholipid may comprise a phosphorus-containing group and a saturated or unsaturated alkyl group optionally substituted with OH, COOH, oxo, amine, or substituted or unsubstituted aryl groups. Phospholipids differ from one another in the length and degree of unsaturation of their alkyl chains.

[0009] In some embodiments, the phospholipids include one or more of phosphatidylcholine, fatty acylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidic acid, and phosphatidylinositol. The term "phosphatidylcholine" refers to phosphatidylcholine and its derivatives. Examples of phospholipids suitable for use in the present disclosure include dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), 1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphatidylcholine (PLPC), dioleoylphosphatidylcholine (DOPC), dieucoylphosphatidylcholine (DEPC), egg yolk phosphatidylcholine (EPC), soybean phosphatidylcholine (SPC), dilauroylphosphatidylcholine (DLPC), hydrogenated palmitate, ... Soybean phosphatidylcholine (HSPC), l-myristoyl-2-palmitoylphosphatidylcholine (MPPC), l-palmitoyl-2-myristoylphosphatidylcholine (PMPC), l-palmitoyl-2-stearoylphosphatidylcholine (PSPC), l-stearoyl-2-palmitoylphosphatidylcholine (SPPC), palmitoyloleoylphosphatidylcholine (POPC), lysophosphatidylcholine, dilinoleoylphosphatidylcholine, distearoylphosphatidylethanolamine (DSPE), dimyristoylphosphatidylethanolamine (DPPE), dioleoylphosphatidylglycerol (DOPG), dimyristoylphosphatidylglycerol (DMPG), distearoylphosphatidylglycerol (DSPG), dipalmitoylglycerophosphoglycerol (DPPG), dipalmitoylphosphatidylserine (DPPS), 1,2-dioleoyl-sn-glycero-3-phosphatidylserine (DOPS), dimyristoylphosphatidylserine (DMPS), distearoylphosphatidylserine (DSPG), dipalmitoylglycerophosphoglycerol (DPPG), dipalmitoylphosphatidylserine (DPPS), 1,2-dioleoyl-sn-glycero-3-phosphatidylserine (DOPS), dimyristoylphosphatidylserine (DMPS), distearoylphosphatidylserine One or more of 1,2-dioleoyl-sn-glycero-3-phosphatidic acid (DSPS), dipalmitoylphosphatidic acid (DPPA), 1,2-dioleoyl-sn-glycero-3-phosphatidic acid (DOPA), dimyristoylphosphatidic acid (DMPA), distearoylphosphatidic acid (DSPA), dipalmitoylphosphatidylinositol (DPPI), 1,2-dioleoyl-sn-glycero-3-phosphatidylinositol (DOPI), dimyristoylphosphatidylinositol (DMPI), and distearoylphosphatidylinositol (DSPI).

[0010] In some embodiments, the phospholipids described in the present disclosure are selected from one or more of egg yolk phosphatidylcholine (EPC), soybean phosphatidylcholine (SPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dierucoylphosphatidylcholine (DEPC), dilauroylphosphatidylcholine (DLPC) and dimyristoylphosphatidylcholine (DMPC). In some embodiments, the phospholipid is dimyristoylphosphatidylcholine.

[0011] In some embodiments, the weight volume percentage of the phospholipids is 0.001%-1%, including but not limited to 0.001%, 0.005%, 0.01%, 0.015%, 0.02%, 0.025%, 0.03%, 0.035%, 0.04%, 0.045%, 0.05%, 0.055%, 0.06%, 0.065%, 0.07%, 0.075%, 0.08%, 0.085%, 0.09%, 0.095%, 0.1%, 0.12%, 0.14%, 0.15%, 0.16%, 0.18% , 0.2%, 0.22%, 0.24%, 0.25%, 0.26%, 0.28%, 0.3%, 0.32%, 0.34%, 0.35%, 0.36%, 0.38%, 0.4%, 0.42%, 0.44%, 0.45%, 0.46%, 0.48%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1% or any value between any two values, for example, it can be 0.01%-0.5%, or 0.01%-0.45%.

[0012] In some embodiments, the concentration of the phospholipid is selected from 0.01-10 mg / mL, which can be 0.01 mg / mL, 0.05 mg / mL, 0.10 mg / mL, 0.15 mg / mL, 0.20 mg / mL, 0.25 mg / mL, 0.30 mg / mL,

[0013] 0.35mg / mL, 0.40mg / mL, 0.45mg / mL, 0.50mg / mL, 0.55mg / mL, 0.60mg / mL,

[0014] 0.65 mg / mL, 0.70 mg / mL, 0.75 mg / mL, 0.80 mg / mL, 0.85 mg / mL, 0.90 mg / mL, 0.95 mg / mL, 1 mg / mL, 1.5 mg / mL, 2 mg / mL, 2.5 mg / mL, 3 mg / mL, 3.5 mg / mL, 4 mg / mL, 4.5 mg / mL, 5 mg / mL, 5.5 mg / mL, 6 mg / mL, 6.5 mg / mL, 7 mg / mL, 7.5 mg / mL, 8 mg / mL, 8.5 mg / mL, 9 mg / mL, 9.5 mg / mL, 10 mg / mL or any value between any two values, for example, 0.01-4.5 mg / mL.

[0015] In some embodiments, the suspension injection described in the present disclosure may also contain other neutral lipids, cationic lipids and / or anionic lipids. Examples of other neutral lipids that can be used in the present disclosure include: steroids such as cholesterol and its derivatives. In some embodiments, the suspension injection does not contain cholesterol.

[0016] In some embodiments, the suspension injection does not contain lipids other than phospholipids.

[0017] In some embodiments, the weight volume percentage of the local anesthetic is 0.01%-20%, including but not limited to 0.01%, 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, or any value between any two values, for example, it can be 0.1%-5%.

[0018] In some embodiments, the concentration of the local anesthetic is selected from 0.01-100 mg / mL, which can be 0.01 mg / mL, 0.05 mg / mL, 0.10 mg / mL, 0.15 mg / mL, 0.20 mg / mL, 0.25 mg / mL,

[0019] 0.30mg / mL, 0.35mg / mL, 0.40mg / mL, 0.45mg / mL, 0.50mg / mL, 0.55mg / mL,

[0020] 0.60mg / mL, 0.65mg / mL, 0.70mg / mL, 0.75mg / mL, 0.80mg / mL, 0.85mg / mL,

[0021] The dosage form can include any of the following: 0.90 mg / mL, 0.95 mg / mL, 1 mg / mL, 2 mg / mL, 3 mg / mL, 4 mg / mL, 5 mg / mL, 6 mg / mL, 7 mg / mL, 8 mg / mL, 9 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, 80 mg / mL, 85 mg / mL, 90 mg / mL, 95 mg / mL, 100 mg / mL or any value between any two values, for example, 0.05-70 mg / mL.

[0022] In some embodiments, the local anesthetic is a combination of ropivacaine and a pharmaceutically acceptable salt of ropivacaine, such as a combination of ropivacaine and ropivacaine hydrochloride.

[0023] In some embodiments, the molar ratio of ropivacaine to the pharmaceutically acceptable salt of ropivacaine is selected from 0.01:1-100:1, including but not limited to 0.01:1, 0.05:1, 0.1:1, 0.15:1, 0.2:1, 0.25:1, 0.3:1, 0.35:1, 0.4:1, 0.45:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, 5:1, 5.5:1, 6:1, 6.5:1, 7:1, 7.5:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1 :1, 8.5:1, 9:1, 9.5:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 35:1, 40:1, 45:1, 50:1, 55:1, 60:1, 65:1, 70:1, 75:1, 80:1, 85:1, 90:1, 95:1, 100:1 or any value between any two values, for example, it can be 1:1-20:1.

[0024] In some embodiments, the active ingredient particles of the present disclosure are ropivacaine particles. In some embodiments, the active ingredient particles are crystalline particles of ropivacaine.

[0025] In some embodiments, the particle size D(10) of the ropivacaine crystal particles in the suspension is greater than 0.5 μm, such as greater than 1 μm, or 1-20 μm. In some embodiments, the particle size D(50) of the ropivacaine crystal particles in the suspension is greater than 1 μm, such as greater than 5 μm, such as greater than 10 μm, or 5-50 μm. In some embodiments, the particle size D(90) of the ropivacaine crystal particles in the suspension is greater than 10 μm, such as greater than 15 μm, such as greater than 20 μm, or 15-90 μm.

[0026] The liquid medium disclosed herein can be water, an isotonic solution or a buffer. The isotonic solution has a solution with substantially the same osmotic pressure as human blood, which can be prepared by an isotonic agent and water. The isotonic agent includes sodium chloride, potassium chloride, magnesium chloride, calcium chloride, glucose, xylitol, and sorbitol. The buffer refers to a buffered solution that prevents pH changes by the action of its acid-base conjugate components. In some embodiments, the pH range of the buffer disclosed herein is from about 4.5 to about 8.5. Examples of buffers that can control pH to within this range include acetates (e.g., sodium acetate), succinates (e.g., sodium succinate), gluconates, histidine, citrates, carbonates, PBS, HEPES, or other organic acid buffers.

[0027] In some embodiments, the local anesthetic comprises ropivacaine, and optionally a pharmaceutically acceptable salt of ropivacaine. In some embodiments, the local anesthetic is ropivacaine, and optionally ropivacaine hydrochloride.

[0028] In some embodiments, the local anesthetic is a combination of ropivacaine and ropivacaine hydrochloride, the molar ratio of ropivacaine to the pharmaceutically acceptable salt of ropivacaine is 1:1-20:1, the phospholipid is selected from one or more of egg yolk phosphatidylcholine, soybean phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, dioleoyl phosphatidylcholine, dierucoyl phosphatidylcholine, dilauroyl phosphatidylcholine and dimyristoyl phosphatidylcholine, and the mass volume percentage of the phospholipid is 0.01%-0.45%.

[0029] The present disclosure also provides a method for preparing the suspension injection described in the present disclosure, comprising the steps of mixing a local anesthetic with a stabilizer and a dispersing liquid to form a pre-lyophilized solution, freeze-drying the pre-solution to form a lyophilized composition, and adding a liquid medium to redissolve the lyophilized composition.

[0030] Available dispersions include, but are not limited to, water, organic solvents, and water / organic solvent co-solvent systems. The organic solvents include, but are not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, acetone, acetonitrile, dichloromethane, dimethyl sulfoxide, and the like. In some embodiments, the dispersion can be water, ethanol, isopropanol, tert-butanol, water / ethanol, water / isopropanol, water / tert-butanol, and the like. In some embodiments, the dispersion is selected from ethanol, isopropanol, tert-butanol, water / ethanol, water / isopropanol, and water / tert-butanol. The volume ratio of water to organic solvent can be 1000:1-1:1000, such as 9:1-1:1000, or 1:4-1:1000, such as 1:5, 1:6, 1:7, 1:8, 1:9, and the like.

[0031] The present disclosure also provides a freeze-dried composition, which is reconstituted in a liquid medium to obtain the aforementioned suspension injection.

[0032] The ropivacaine suspension injection disclosed herein has excellent stability, rapid onset of action, and long-term analgesic effects, making it suitable for clinical application. Conventional liposomes, emulsions, and hydrogels typically have low drug loading due to drug encapsulation or carrier loading. The advantage of suspension injections is that they do not require the addition of additional carriers, allowing for 100% drug loading.

[0033] The “mass volume percentage” (w / v) described in the present disclosure refers to the mass (in g) of the component contained in every 100 mL of liquid system, that is, g / 100 mL.

[0034] The contents (including percentages) of the various substances described in the present disclosure and their ratios to each other are allowed to have an error of ±5%. For example, "the content of ropivacaine in the composition is 5 to 20 mg / mL" means that the content of ropivacaine in the composition is 4.75 to 21 mg / mL, all of which are within the scope of the present disclosure; "the weight ratio of the ropivacaine to the phospholipid is selected from 1:1 to 1:100" means that the weight ratio of the ropivacaine to the phospholipid is selected from 1:0.95 to 1:105, all of which are within the scope of the present disclosure.

[0035] "Optionally" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs and where it does not.

[0036] The terms "mixed" and "mixed" in the present disclosure do not limit the order in which the components are added. For example, mixing A into B can mean either adding A to B or adding B to A. Mixing A and B can mean either adding A to B or adding B to A.

[0037] The term "particle size distribution" or "PSD" refers to the particle size distribution determined by dynamic light scattering techniques well known to those skilled in the art, such as using a Malvern Mastersizer TM The particle size distribution of the composition measured at 3000 is as follows. "D(10)" as used in this disclosure refers to the particle size corresponding to the 10% cumulative particle size distribution percentage of a sample. "D(50)" refers to the particle size corresponding to the 50% cumulative particle size distribution percentage of a sample. "D(90)" refers to the particle size corresponding to the 90% cumulative particle size distribution percentage of a sample. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 This is a microscopic image of the suspension injection of composition 3 in Example 1;

[0039] Figure 2 This is a cryo-scanning electron micrograph of ropivacaine liposomes according to Example 2;

[0040] Figure 3 This is the in vitro release rate diagram of the suspension injection of composition 3 in Example 1;

[0041] Figure 4 This is the plasma PK curve of the suspension injection of composition 3 in Example 1;

[0042] Figure 5 Dispersion of lyophilized powder reconstitution solutions prepared with different stabilizers;

[0043] Figure 6 Microscopic images of lyophilized powder reconstitution solutions prepared with different stabilizers;

[0044] Figure 7 Dispersion of lyophilized powder reconstituted solutions prepared at different drug ratios;

[0045] Figure 8 Microscopic images of lyophilized powder reconstitution solutions prepared at different drug ratios. DETAILED DESCRIPTION

[0046] The present disclosure is further described in detail by the following examples. These examples are for illustrative purposes only and are not intended to limit the scope of the present disclosure.

[0047] Example 1

[0048] Pour an appropriate amount of tert-butyl alcohol and water for injection into a container successively, turn on a stirrer and stir until evenly mixed to obtain a tert-butyl alcohol solution. The tert-butyl alcohol solution in the container is transferred to a preparation tank. Turn on stirring and control the water bath temperature. According to the proportioning of Table 1, ropivacaine, ropivacaine hydrochloride, and DMPC are dropped into a preparation tank, stirred until the visual inspection solution is free of insoluble particles, and then constant to volume with the tert-butyl alcohol solution. After sterile filtration, the mixture is loaded into a cillin bottle and placed in a freeze dryer for freeze drying to obtain a lyophilized powder.

[0049] The lyophilized powder was reconstituted with 10 ml of normal saline and mixed evenly to obtain a suspension injection.

[0050] Table 1

[0051]

[0052] The appearance, reconstitution, and microscopic morphology of the freeze-dried product and the suspension injection of each composition were examined. The results are shown in Table 2.

[0053] Table 2

[0054]

[0055] Example 2

[0056] According to the proportions in Table 3, phospholipids, cholesterol, ropivacaine free base, and ropivacaine hydrochloride were weighed, dissolved with an appropriate amount of tert-butyl alcohol-water mixed solvent, dispensed into vials, and placed in a freeze dryer for freeze drying. The lyophilized product was redissolved with 10 ml of normal saline and mixed to obtain a reconstituted solution. Cryo-scanning electron microscopy images showed the presence of lipid vesicles such as multilamellar liposomes, indicating a liposome preparation.

[0057] Table 3

[0058] Material Name Dosage Ropivacaine hydrochloride 32.3mg Ropivacaine free base 161.5mg DMPC 242.8mg cholesterol 46.2mg

[0059] Example 3

[0060] The lyophilized powder of Composition 3 in Example 1 and the lyophilized powder of Example 2 were added to physiological saline, and the reconstitution time of the lyophilized powders was tested, as shown in the table below. The results show that the lyophilized powder of Composition 3 reconstitutes rapidly, which is beneficial for clinical convenience and reduces the impact of different personnel and different operations on the quality of the reconstitution solution.

[0061] Table 4

[0062] sample Reconstitution time Composition 3 <15s Example 2 1.5min

[0063] Example 4 Ropivacaine suspension injection in vitro release

[0064] 1. Cleaning of dialysis bags:

[0065] Weigh 10g of sodium bicarbonate and 0.168g of EDTA·2Na into 500ml of water and mix thoroughly. Cut the dialysis bag into 10cm segments. Boil the bag with washing solution in a 1L beaker for 10 minutes. Rinse the bag 10 times with 200ml of purified water. Add 500ml of purified water and boil for 10 minutes. If the bag is not used for an extended period, store it in 10% ethanol and rinse it 10 times with 200ml of purified water before use.

[0066] 2. Release medium configuration:

[0067] Weigh 2.3g of potassium dihydrogen phosphate, 7.6g of dipotassium hydrogen phosphate trihydrate, and 5.6g of sodium chloride into a 1000ml volumetric flask, add water to make up to volume, and mix well.

[0068] 3. Release sample placement and sampling measurement:

[0069] Accurately pipette 0.5 ml of the suspension of Composition 3 from Example 1 to be tested into a 10 cm dialysis bag. Add 0.5 ml of release medium. Clamp both ends of the bag with clips and place in a 150 ml tall beaker containing 99.5 ml of release medium. Incubate the sample on a shaker at 37°C and 10 rpm. At designated time points, sample 1 ml of the solution for analysis by HPLC.

[0070] The test results are as follows Figure 3 The results showed that the initial release of ropivacaine suspension injection was rapid, which facilitated the rapid analgesic effect of local analgesics; and the sustained release lasted up to 96 hours, which facilitated the long-term maintenance of analgesic effect.

[0071] Example 5 Pharmacokinetics of Ropivacaine Suspension Injection in Rats

[0072] 1. Test drug

[0073] The ropivacaine suspension prepared from composition 3 of Example 1 had the following particle size parameters: D(10) of 3.47 μm; D(50) of 14.5 μm; and D(90) of 44.4 μm.

[0074] 2. Experimental Animals

[0075] SD rats (SPF grade), male, about 6-8 weeks old.

[0076] 3. Experimental steps

[0077] Eight SD rats, half male and half female, weighing approximately 210-270 g, were used. A suspension sample was obtained. After a single subcutaneous injection of 100 mg / kg of the preparation, 0.2 mL of blood was collected from the retroorbital venous plexus before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 24, 48, and 72 h after administration. The plasma concentration of ropivacaine was determined by liquid chromatography-tandem mass spectrometry (LC-MS / MS). The pharmacokinetic parameters were calculated and the drug-dose curve was plotted. The results are shown in the following table and Figure 4 shown.

[0078] Table 5

[0079]

[0080] *:T max Parameters are medians (ranges).

[0081] The results showed that ropivacaine suspension injection can not only take effect quickly but also maintain a sustained-release effect for a long time, which is beneficial to improving patient compliance.

[0082] Example 6 Stability Test of Ropivacaine Suspension Injection

[0083] The ropivacaine suspension sample prepared from Composition 3 of Example 1 was placed in a vial and placed at room temperature to test its stability. The results are shown in the table below.

[0084] Table 6

[0085]

[0086] Example 7

[0087] According to the method of Example 1, DMPC was replaced with other stabilizers to prepare lyophilized powders and reconstituted solutions. The composition of the compositions is shown in Table 7. The reconstitution of each composition and the microscopic morphology of the suspension injection were investigated, and the results are shown in Table 8.

[0088] Table 7

[0089]

[0090] Table 8 Investigation of the state of the reconstituted solution

[0091]

[0092] Screening different stabilizers revealed that compositions prepared using conventional stabilizers, such as PVP or CMC-Na, exhibited poor dispersion after reconstitution. The PVP-treated lyophilized powder reconstituted solution was nearly impossible to disperse, with a large amount of lyophilized powder floating on the upper surface and a significant amount of precipitate clinging to the bottom. Similarly, the CMC-Na-treated lyophilized powder reconstituted solution was difficult to disperse, with unwetted lyophilized powder clinging to the bottle walls. The Tween-80 and Poloxamer-188-treated solutions still exhibited clinging to the bottom and walls of the bottle, making complete dispersion difficult.

[0093] Example 8

[0094] According to the method of Example 1, the molar ratio of ropivacaine to ropivacaine hydrochloride was adjusted to prepare lyophilized powders and reconstituted solutions. The composition of the compositions is shown in Table 9. The appearance of the lyophilized product, the reconstitution, and the microscopic morphology of the suspension injection of each composition were examined, and the results are shown in Table 10.

[0095] Table 9

[0096]

[0097] Table 10

[0098]

[0099] The results showed that ropivacaine suspensions could be prepared with different ratios of ropivacaine to ropivacaine hydrochloride.

Claims

1. A suspension injection of a local anesthetic comprising active ingredient particles, a stabilizer and a liquid medium, wherein: The local anesthetic comprises at least one selected from ropivacaine and a pharmaceutically acceptable salt of ropivacaine, the stabilizer comprises phospholipid, and the suspension injection does not contain a lipid vesicle structure. The phospholipid is selected from one or more of egg yolk phosphatidylcholine, soybean phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, dioleoyl phosphatidylcholine, dierucoyl phosphatidylcholine, dilauroyl phosphatidylcholine and dimyristoyl phosphatidylcholine.

2. The suspension injection according to claim 1, wherein the mass volume percentage of the phospholipid is 0.001%-1%, preferably 0.01%-0.5%, more preferably 0.01%-0.45%.

3. The suspension injection according to claim 1 or 2, wherein the suspension injection does not contain other lipids except phospholipids.

4. The suspension injection according to any one of claims 1 to 3, wherein the mass volume percentage of the local anesthetic is 0.01% to 20%, preferably 0.1% to 5%.

5. The suspension injection according to any one of claims 1 to 4, wherein the concentration of the local anesthetic is selected from 0.01-100 mg / mL, preferably 0.05-70 mg / mL.

6. The suspension injection according to any one of claims 1 to 5, wherein the local anesthetic comprises ropivacaine, and optionally a pharmaceutically acceptable salt of ropivacaine, preferably a combination of ropivacaine and a pharmaceutically acceptable salt of ropivacaine, more preferably a combination of ropivacaine and ropivacaine hydrochloride.

7. The suspension injection according to claim 6, wherein the molar ratio of ropivacaine to the pharmaceutically acceptable salt of ropivacaine is selected from 0.01:1-100:1, preferably 1:1-20:

1.

8. The suspension injection according to any one of claims 1 to 7, wherein the liquid medium is selected from water, isotonic solution and buffer.

9. The suspension injection according to any one of claims 1 to 8, wherein the local anesthetic is a combination of ropivacaine and ropivacaine hydrochloride, the molar ratio of ropivacaine to the pharmaceutically acceptable salt of ropivacaine is 1:1-20:1, and the phospholipid is selected from one or more of egg yolk phosphatidylcholine, soybean phosphatidylcholine, dipalmitoyl phosphatidylcholine, distearoyl phosphatidylcholine, dioleoyl phosphatidylcholine, dierucoyl phosphatidylcholine, dilauroyl phosphatidylcholine and dimyristoyl phosphatidylcholine, and the mass volume percentage of the phospholipid is 0.01%-0.45%.

10. The suspension injection according to any one of claims 1 to 9, wherein the active ingredient particles are ropivacaine particles, preferably ropivacaine crystal particles. The suspension injection according to claim 10 , wherein the D(10) of the ropivacaine crystal particles is greater than 0.5 μm, preferably D(50) is greater than 1 μm, and more preferably D(90) is greater than 10 μm.

12. A freeze-dried composition, which is reconstituted in a liquid medium to obtain the suspension injection according to any one of claims 1 to 11.

13. A method for preparing the suspension injection according to any one of claims 1 to 11, the method comprising the steps of mixing a local anesthetic with a stabilizer and a dispersing liquid to form a pre-lyophilized solution, lyophilizing the pre-solution to form a lyophilized composition, and adding a liquid medium to reconstitute the lyophilized composition.

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