Composition of ropivacaine or pharmaceutically acceptable salt of ropivacaine, and use of composition

Abstract

Provided are a composition of ropivacaine or a pharmaceutically acceptable salt of ropivacaine, and a use of a composition. A suspension and a solid composition can ensure a sterility level by means of sterilization and filtration, and the obtained composition has good stability and controllable product quality, is easily administered, causes little irritation, and has good medication safety and tolerance.

Description

Composition of ropivacaine or its pharmaceutically acceptable salt and use thereof

[0001] This application requires the following:

[0002] Priority to the prior application with patent application number 202310933637.5, entitled “Compositions of ropivacaine or pharmaceutically acceptable salts thereof and uses thereof”, filed with the State Intellectual Property Office of China on July 27, 2023; the full text of the prior application is incorporated into this application by reference. Technical Field

[0003] The present invention belongs to the field of pharmaceutical preparations, and specifically relates to a composition of ropivacaine or a pharmaceutically acceptable salt thereof, in particular to a suspension or solid composition of a long-acting ropivacaine or a pharmaceutically acceptable salt thereof. Background Art

[0004] Postoperative pain is acute, moderate to severe pain that occurs immediately after surgery and typically lasts no more than seven days. Reports indicate that approximately 75% of surgical patients experience postoperative pain, and over 50% experience inadequate pain relief. Inadequate postoperative pain control can lead to adverse physiological reactions and increase the risk of chronic pain.

[0005] To address the aforementioned risks of postoperative pain, patients are often prescribed analgesics. These medications primarily include opioid analgesics such as morphine, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, and local anesthetics such as bupivacaine. Currently, opioid analgesics account for the majority of the analgesic market. Despite their potent analgesic effects, they can also cause systemic adverse reactions. According to the U.S. Centers for Disease Control and Prevention, as of 2017, approximately 15 out of every 100,000 deaths in the United States were related to opioid overdose.

[0006] The consensus in clinical postoperative management in China is to reduce the use of opioids and use multimodal analgesia to treat surgical pain, but there are still shortcomings. For example, the use of local anesthetics to treat postoperative pain can avoid the adverse reactions of opioids, but the duration of action of currently used local anesthetics is usually short, and the effect can only last for a few hours after a single dose, which cannot meet the treatment cycle requirements of postoperative pain. Therefore, the clinical demand for long-acting non-opioid drugs for the treatment of postoperative pain has not been met. Prolonging the effective analgesic time of local anesthetics and reducing the use of opioids are current research hotspots.

[0007] Currently, the long-acting local anesthetics available in foreign countries all use bupivacaine or its salts as active ingredients, and are administered by liposomes. collagen implants Polyorthoester polymer and sucrose acetate isobutyrate As a sustained-release platform, these technologies suffer from complex production processes, insufficient analgesic duration, or excipient safety issues. Furthermore, bupivacaine's central nervous system and cardiovascular toxicity significantly restrict its dosage.

[0008] Compared with bupivacaine, ropivacaine (Ropivacaine) shown in the following formula has advantages such as lower toxicity, higher safety, and higher tolerable dose. Therefore, it has been developed as a long-acting local anesthetic that is expected to replace bupivacaine.

[0009] Currently available long-acting ropivacaine preparations mainly include oil-based sustained-release systems, lipid-based sustained-release systems, polymer-based sustained-release systems, and suspension-based sustained-release systems. However, these systems still have the following drawbacks:

[0010] The drug release process of oil-based sustained-release formulations involves the dissolution of drug molecules from the oily formulation into the aqueous interstitial fluid, where they are subsequently absorbed into the bloodstream. Therefore, the sustained-release effect of the drug is closely related to the time it takes for the drug to be released from the formulation. Achieving sustained-release for three days or longer is difficult with oil-based formulations.

[0011] The preparation processes for lipid-based sustained-release systems and polymer-based microsphere sustained-release systems are often complex, making commercial production difficult and subject to quality control challenges. Polymer-based sustained-release formulations can also face the problem of long in vivo polymer degradation cycles, leading to localized accumulation. Furthermore, the degradation products of PLGA-based sustained-release systems include glycolic acid and lactic acid. These acidic degradation products can cause inflammatory side effects at the site of administration, compromising treatment.

[0012] Suspension systems are currently prepared using a "top-down" method, where larger drug particles are mechanically crushed to the desired particle size. Common top-down methods include wet and airflow milling, high-speed shearing, and high-pressure homogenization. However, these methods require sterile raw materials and a sterile environment, which carries high sterility assurance risks, making the production process more difficult and costly.

[0013] Therefore, there is an urgent need to develop a long-acting ropivacaine formulation suitable for injection that has good stability, safety, and / or tolerability. It is desirable that the long-acting ropivacaine formulation also has advantages such as ease of large-scale production and controllable quality.

[0014] Summary of the Invention

[0015] To address these deficiencies, the present invention provides a suspension and solid composition of ropivacaine or a pharmaceutically acceptable salt thereof, as described below, as well as methods for preparing and using the same. The present invention also provides a method for preparing a solid composition suitable for ropivacaine and other pharmaceutically active ingredients, and the solid composition obtained by the preparation method.

[0016] The present invention provides a suspension of ropivacaine or a pharmaceutically acceptable salt thereof, wherein the suspension comprises:

[0017] a) ropivacaine or a pharmaceutically acceptable salt thereof;

[0018] Wherein, the ropivacaine or pharmaceutically acceptable salt thereof in the suspension exists in the form of particles, for example, in the form of crystals, preferably in the form of regular crystals, such as rod-shaped crystals or block-shaped crystals.

[0019] According to an embodiment of the present invention, the D90 particle size of ropivacaine or a pharmaceutically acceptable salt thereof in the suspension is less than or equal to 200 μm, or less than or equal to 150 μm, or less than or equal to 120 μm, or less than or equal to 100 μm. Preferably, the D90 particle size of ropivacaine or a pharmaceutically acceptable salt thereof in the suspension is 10 to 90 μm, for example, 10 to 80 μm, preferably 10 to 70 μm, more preferably 10 to 60 μm. As an example, the D90 particle size of ropivacaine or a pharmaceutically acceptable salt thereof in the suspension can be 10 μm, 15 μm, 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm, 50 μm, 55 μm or 60 μm.

[0020] According to an embodiment of the present invention, the pharmaceutically acceptable salt of ropivacaine is an acid salt of ropivacaine, i.e., an addition salt of ropivacaine with a pharmaceutically acceptable acid. For example, the acid salt of ropivacaine includes, but is not limited to, one or more of the following salts of ropivacaine: acetate, benzoate, benzenesulfonate, hydrobromide, camphorsulfonate, hydrochloride, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hydroiodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, methanesulfonate, naphthoate, naphthoate, nitrate, stearate, palmitate, myristate, laurate, oleate, oxalate, pamoate, phosphate, polygalacturonate, succinate, sulfate, sulfosalicylate, tartrate, toluenesulfonate, and trifluoroacetate.

[0021] It should be understood that, in the context of this specification, the molar ratio of ropivacaine to the anion of the pharmaceutically acceptable acid is a ratio that renders the pharmaceutically acceptable salt of ropivacaine electrically neutral. For example, when the pharmaceutically acceptable acid is a monobasic acid, the molar ratio of the pharmaceutically acceptable acid to ropivacaine is 1:1; when the pharmaceutically acceptable acid is a dibasic acid, the molar ratio of the pharmaceutically acceptable acid to ropivacaine is 1:2.

[0022] According to an embodiment of the present invention, the suspension optionally further comprises:

[0023] b) a pharmaceutically acceptable stabilizer.

[0024] According to an embodiment of the present invention, the pharmaceutically acceptable stabilizer is selected from higher alcohols (such as C 18 ~C 30 Higher carbon alcohols), C 18 ~C 30 One or more acids or their salts.

[0025] According to an embodiment of the present invention, the pharmaceutically acceptable stabilizer is selected from one or more of cholesterol, octadecanol, cholic acid or its salts, deoxycholic acid or its salts, taurodeoxycholic acid or its salts, ursodeoxycholic acid or its salts, chenodeoxycholic acid or its salts, and glycocholic acid or its salts.

[0026] According to an embodiment of the present invention, the pharmaceutically acceptable stabilizer is selected from one or more of cholesterol, octadecanol, cholic acid, deoxycholic acid, taurodeoxycholic acid, ursodeoxycholic acid, chenodeoxycholic acid, glycocholic acid, sodium cholate, sodium deoxycholate, sodium taurodeoxycholate, sodium ursodeoxycholate, sodium chenodeoxycholate, and sodium glycocholate.

[0027] According to an embodiment of the present invention, the molar ratio of ropivacaine or a pharmaceutically acceptable salt thereof to the stabilizer is 0.5:1 to 30:1, preferably 1:1 to 15:1, preferably 1:1 to 10:1, more preferably 1:1 to 7:1, more preferably 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.

[0028] According to an embodiment of the present invention, the suspension optionally further comprises:

[0029] c) a pharmaceutically acceptable dispersant.

[0030] According to an embodiment of the present invention, the pharmaceutically acceptable dispersant is selected from one or more of polysorbate (Tween), poloxamer, polyoxyethylene fatty acid esters, polyoxyethylene fatty acid ethers, sucrose fatty acid esters, sodium lauryl sulfate, polyethylene glycol-15 hydroxystearate (HS-15), and phospholipids.

[0031] According to an embodiment of the present invention, the polysorbate is selected from one or more of polysorbate 80 (Tween 80) and polysorbate 20 (Tween 20).

[0032] According to an embodiment of the present invention, the phospholipid is selected from one or more of DMPC (dimyristoylphosphatidylcholine), DPPC (dipalmitoylphosphatidylcholine), DLPC (dilauroylphosphatidylcholine), SPC soy phosphatidylcholine (soy lecithin), EPC (egg yolk phospholipids), DEPC (dierucoyl phosphatidylcholine), DOPC (dioleoyl phosphatidylcholine), POPC (palmitoyl oleoyl phosphatidylcholine).

[0033] According to an embodiment of the present invention, the molar ratio of ropivacaine or a pharmaceutically acceptable salt thereof to the pharmaceutically acceptable dispersant is 50:1 to 1:1, preferably 40:1 to 2:1, more preferably 30:1 to 2:1, more preferably 20:1 to 2:1, more preferably 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1.

[0034] According to an embodiment of the present invention, the suspension optionally further comprises:

[0035] d) a clinically acceptable diluent.

[0036] According to an embodiment of the present invention, clinically acceptable diluents include but are not limited to one or more of water for injection, sodium chloride injection, glucose injection, lactated Ringer's solution, sucrose aqueous solution, xylitol aqueous solution, and pH buffer solution.

[0037] According to an embodiment of the present invention, the sodium chloride injection includes but is not limited to 0.9% sodium chloride injection.

[0038] According to an embodiment of the present invention, the glucose injection includes but is not limited to 5% glucose injection.

[0039] According to an embodiment of the present invention, the pH buffer is a buffer with a pH of 5.0 to 7.4, including but not limited to one or more of phosphate buffer, glycine buffer, histidine buffer, citrate buffer, and acetate buffer.

[0040] According to an embodiment of the present invention, the suspension is a suspension injection.

[0041] According to an embodiment of the present invention, the concentration of ropivacaine or a pharmaceutically acceptable salt thereof in the suspension is about 0.1 mg / mL to about 300 mg / mL, preferably about 1 mg / mL to about 50 mg / mL, and more preferably about 2.5 mg / mL to about 40 mg / mL. As an example, the concentration of ropivacaine or a pharmaceutically acceptable salt thereof in the suspension is about 0.1 mg / mL, 0.5 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. / mL, 9 mg / mL, 9.5 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, or 100 mg / mL.

[0042] According to an embodiment of the present invention, the suspension optionally further comprises:

[0043] e) pharmaceutically acceptable inorganic salts.

[0044] According to an embodiment of the present invention, the pharmaceutically acceptable inorganic salt has a water solubility of greater than 10 g / 100 mL at 20°C.

[0045] According to an embodiment of the present invention, the pharmaceutically acceptable inorganic salt is selected from one or more of sodium chloride, sodium sulfate, potassium chloride, potassium sulfate, potassium phosphate, ammonium sulfate, ammonium chloride, magnesium chloride, magnesium sulfate, calcium chloride, and barium chloride; preferably one or more of sodium chloride, potassium sulfate, magnesium chloride, magnesium sulfate, potassium chloride, and calcium chloride.

[0046] According to an embodiment of the present invention, the molar ratio of ropivacaine or a pharmaceutically acceptable salt thereof to the pharmaceutically acceptable inorganic salt is ≥1:0.02, preferably 1:0.02 to 1:2.0, examples of which are 1:0.02, 1:0.05, 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.7, 1:1.8, 1:1.9 or 1:2.0.

[0047] According to an embodiment of the present invention, the suspension optionally further comprises:

[0048] f) a pharmaceutically acceptable pH adjusting agent.

[0049] According to an embodiment of the present invention, the pH adjuster is selected from alkaline pH adjusters and acidic pH adjusters.

[0050] According to an embodiment of the present invention, the alkaline pH regulator is selected from one or more of meglumine, tromethamine, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, magnesium hydroxide, calcium hydroxide, sodium phosphate, disodium hydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, sodium citrate, sodium acetate, potassium acetate, ammonium acetate, triethylamine, ethanolamine, and diethanolamine; preferably one or more of sodium hydroxide, potassium hydroxide, magnesium hydroxide, sodium bicarbonate, and calcium hydroxide.

[0051] According to an embodiment of the present invention, the acidic pH regulator is selected from one or more of citric acid, tartaric acid, maleic acid, malic acid, fumaric acid, succinic acid, succinic acid, hydrochloric acid, phosphoric acid, ascorbic acid, lactic acid, acetic acid, methanesulfonic acid, oxalic acid, sulfuric acid, glycine, sodium dihydrogen phosphate, and potassium dihydrogen phosphate; preferably one or more of citric acid, tartaric acid, maleic acid, malic acid, fumaric acid, succinic acid, succinic acid, hydrochloric acid, phosphoric acid, lactic acid, and acetic acid.

[0052] According to an embodiment of the present invention, the pH value of the suspension is 6.0-9.0, preferably 6.0-8.5, preferably 6.0-8.0, more preferably 6.0-7.5, more preferably 6.2, 6.4, 6.6, 6.8, 7.0, 7.2, 7.4.

[0053] According to an embodiment of the present invention, the ropivacaine in the suspension can also be prepared in situ, for example, by reacting a pharmaceutically acceptable salt of ropivacaine with a base, preferably by reacting a pharmaceutically acceptable salt of ropivacaine with an alkaline pH regulator. The pharmaceutically acceptable salt of ropivacaine has the definition described above.

[0054] According to an embodiment of the present invention, when ropivacaine is prepared in situ as described above, the molar ratio of the pharmaceutically acceptable salt of ropivacaine to the alkaline pH adjusting agent may be 1:0.5 to 1:2.0, preferably 1:0.8 to 1:1.5, and preferably 1:1.0 to 1:1.2. As an example, the molar ratio of the pharmaceutically acceptable salt of ropivacaine to the alkaline pH adjusting agent is 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9 or 1:2.0.

[0055] According to an embodiment of the present invention, the suspension optionally further comprises:

[0056] g) a pharmaceutically acceptable osmotic pressure regulating agent.

[0057] According to an embodiment of the present invention, the osmotic pressure regulator is selected from one or more of sodium chloride, mannitol, lactose, glucose, sorbitol, sorbitol and glycerol, preferably one or more of sodium chloride, glucose, sorbitol and mannitol.

[0058] According to an embodiment of the present invention, the osmotic pressure of the suspension injection is equivalent to the physiological osmotic pressure.

[0059] According to an embodiment of the present invention, the suspension optionally further comprises:

[0060] h) a pharmaceutically acceptable lyoprotectant.

[0061] According to an embodiment of the present invention, the pharmaceutically acceptable lyoprotectant is selected from one or more of mannitol, lactose, trehalose, sucrose, maltose, dextrin, stachyose, gelatin, pectin, sugar alcohol, sorbitol, proline, histidine, lysine, arginine, polyethylene glycol or polyvinyl pyrrolidine, preferably one or more of mannitol, lactose, trehalose, sucrose and polyvinyl pyrrolidine.

[0062] According to an embodiment of the present invention, the suspension optionally does not contain a pharmaceutically acceptable suspending agent. The suspending agent is preferably a water-soluble polymer compound, including but not limited to one or more of carboxymethyl cellulose or its sodium salt, hydroxypropyl cellulose or its sodium salt, hypromellose or its sodium salt, methyl cellulose or its sodium salt, hydroxyethyl cellulose or its sodium salt, sodium hyaluronate and polyvinyl pyrrolidone.

[0063] The present invention also provides a single-dose form or a multiple-dose form of the suspension, wherein each dosage unit of the single-dose form or the multiple-dose form contains 5 mg to 1200 mg of ropivacaine or a pharmaceutically acceptable salt thereof equivalent to ropivacaine free base, preferably 20 mg to 1200 mg, more preferably 40 mg to 1200 mg. Preferably, each dosage unit of the single-dose form or the multiple-dose form is contained in a separate container.

[0064] The present invention also provides a solid composition of ropivacaine or a pharmaceutically acceptable salt thereof, characterized in that the solid composition comprises:

[0065] i) ropivacaine or a pharmaceutically acceptable salt thereof;

[0066] Wherein, the ropivacaine or pharmaceutically acceptable salt thereof in the solid composition exists in the form of particles, for example, in the form of crystals, preferably in the form of regular crystals, such as rod-shaped or block-shaped crystals.

[0067] According to an embodiment of the present invention, in the solid composition, the D90 particle size of ropivacaine or a pharmaceutically acceptable salt thereof is less than or equal to 200 μm, or less than or equal to 150 μm, or less than or equal to 120 μm, or less than or equal to 100 μm. Preferably, the D90 particle size of ropivacaine or a pharmaceutically acceptable salt thereof in the suspension is 10 to 90 μm, for example, 10 to 80 μm, preferably 10 to 70 μm, and more preferably 10 to 60 μm. As an example, the D90 particle size of ropivacaine or a pharmaceutically acceptable salt thereof in the suspension can be 10 μm, 15 μm, 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm, 50 μm, 55 μm or 60 μm.

[0068] According to an embodiment of the present invention, the pharmaceutically acceptable salt of ropivacaine is an acid salt of ropivacaine, i.e., an addition salt of ropivacaine with a pharmaceutically acceptable acid. For example, the acid salt of ropivacaine includes, but is not limited to, one or more of the following salts of ropivacaine: acetate, benzoate, benzenesulfonate, hydrobromide, camphorsulfonate, hydrochloride, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hydroiodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, methanesulfonate, naphthoate, naphthate, nitrate, stearate, palmitate, myristate, laurate, oleate, oxalate, pamoate, phosphate, polygalacturonate, succinate, sulfate, sulfosalicylate, tartrate, toluenesulfonate, trifluoroacetate.

[0069] According to an embodiment of the present invention, the solid composition optionally further comprises:

[0070] ii) a pharmaceutically acceptable stabilizer.

[0071] According to an embodiment of the present invention, the pharmaceutically acceptable stabilizer is selected from high carbonic acid (such as C 18 ~C 30 Higher carbon alcohols), C 18 ~C 30 One or more acids or their salts.

[0072] According to an embodiment of the present invention, the pharmaceutically acceptable stabilizer is selected from one or more of cholesterol, octadecanol, cholic acid or its salts, deoxycholic acid or its salts, taurodeoxycholic acid or its salts, ursodeoxycholic acid or its salts, chenodeoxycholic acid or its salts, and glycocholic acid or its salts.

[0073] According to an embodiment of the present invention, the pharmaceutically acceptable stabilizer is selected from one or more of cholesterol, octadecanol, cholic acid, deoxycholic acid, ursodeoxycholic acid, chenodeoxycholic acid, glycocholic acid, sodium cholate, sodium deoxycholate, and sodium taurodeoxycholate.

[0074] According to an embodiment of the present invention, the molar ratio of ropivacaine or a pharmaceutically acceptable salt thereof to the stabilizer is 0.5:1 to 30:1, preferably 1:1 to 15:1, preferably 1:1 to 10:1, more preferably 1:1 to 7:1, more preferably 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.

[0075] According to an embodiment of the present invention, the solid composition optionally further comprises:

[0076] iii) a pharmaceutically acceptable dispersant.

[0077] According to an embodiment of the present invention, the pharmaceutically acceptable dispersant is selected from one or more of polysorbate (Tween), poloxamer, polyoxyethylene fatty acid esters, polyoxyethylene fatty acid ethers, sucrose fatty acid esters, sodium lauryl sulfate, polyethylene glycol-15 hydroxystearate (HS-15), and phospholipids.

[0078] According to an embodiment of the present invention, the polysorbate is selected from one or more of polysorbate 80 (Tween 80) and polysorbate 20 (Tween 20).

[0079] According to an embodiment of the present invention, the phospholipid is selected from one or more of DMPC (dimyristoylphosphatidylcholine), DPPC (dipalmitoylphosphatidylcholine), DLPC (dilauroylphosphatidylcholine), SPC soy phosphatidylcholine (soy lecithin), EPC (egg yolk phospholipids), DEPC (dierucoyl phosphatidylcholine), DOPC (dioleoyl phosphatidylcholine), POPC (palmitoyl oleoyl phosphatidylcholine).

[0080] According to an embodiment of the present invention, the molar ratio of ropivacaine or a pharmaceutically acceptable salt thereof to the pharmaceutically acceptable dispersant is 50:1 to 1:1, preferably 40:1 to 2:1, more preferably 30:1 to 2:1, more preferably 20:1 to 2:1, more preferably 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, and 2:1.

[0081] According to an embodiment of the present invention, the solid composition optionally further comprises:

[0082] iv) pharmaceutically acceptable inorganic salts.

[0083] According to an embodiment of the present invention, the solubility of the pharmaceutically acceptable inorganic salt in water at 20° C. is greater than 10 g / 100 mL.

[0084] According to an embodiment of the present invention, the solid composition optionally comprises: an inorganic salt selected from one or more of sodium chloride, sodium sulfate, potassium chloride, potassium sulfate, potassium phosphate, ammonium sulfate, ammonium chloride, magnesium chloride, magnesium sulfate, calcium chloride, and barium chloride; preferably one or more of sodium chloride, potassium sulfate, magnesium chloride, magnesium sulfate, potassium chloride, and calcium chloride.

[0085] According to an embodiment of the present invention, the molar ratio of ropivacaine or a pharmaceutically acceptable salt thereof to a pharmaceutically acceptable inorganic salt is ≥1:0.02, preferably 1:0.02 to 1:2.0, more preferably 1:0.02, 1:0.05, 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.7, 1:1.8, 1:1.9, 1:2.0.

[0086] According to an embodiment of the present invention, the solid composition optionally further comprises:

[0087] v) a pharmaceutically acceptable pH adjusting agent.

[0088] According to an embodiment of the present invention, the pH adjuster is selected from alkaline pH adjusters and acidic pH adjusters.

[0089] According to an embodiment of the present invention, the alkaline pH regulator is selected from one or more of meglumine, tromethamine, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, magnesium hydroxide, calcium hydroxide, sodium phosphate, disodium hydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, sodium citrate, sodium acetate, potassium acetate, ammonium acetate, triethylamine, ethanolamine, and diethanolamine; preferably one or more of sodium hydroxide, potassium hydroxide, magnesium hydroxide, sodium bicarbonate, and calcium hydroxide.

[0090] According to an embodiment of the present invention, the acidic pH regulator is selected from one or more of citric acid, tartaric acid, maleic acid, malic acid, fumaric acid, succinic acid, succinic acid, hydrochloric acid, phosphoric acid, ascorbic acid, lactic acid, acetic acid, methanesulfonic acid, oxalic acid, sulfuric acid, glycine, sodium dihydrogen phosphate, and potassium dihydrogen phosphate; preferably one or more of citric acid, tartaric acid, maleic acid, malic acid, fumaric acid, succinic acid, succinic acid, hydrochloric acid, phosphoric acid, lactic acid, and acetic acid.

[0091] According to an embodiment of the present invention, the solid composition forms a suspension after reconstitution.

[0092] According to an embodiment of the present invention, the pH value of the suspension is 6.0-9.0, preferably 6.0-8.5, preferably 6.0-8.0, more preferably 6.0-7.5, more preferably 6.2, 6.4, 6.6, 6.8, 7.0, 7.2, 7.4.

[0093] According to an embodiment of the present invention, the solid composition optionally further comprises:

[0094] vi) a pharmaceutically acceptable osmotic pressure regulating agent.

[0095] According to an embodiment of the present invention, the pharmaceutically acceptable osmotic pressure regulator is selected from one or more of sodium chloride, mannitol, lactose, glucose, sorbitol, sorbitol and glycerol, preferably one or more of sodium chloride, glucose, sorbitol and mannitol.

[0096] According to an embodiment of the present invention, the solid composition optionally further comprises:

[0097] vii) a pharmaceutically acceptable lyoprotectant.

[0098] According to an embodiment of the present invention, the pharmaceutically acceptable lyoprotectant is selected from one or more of mannitol, lactose, trehalose, sucrose, maltose, dextrin, stachyose, gelatin, pectin, sugar alcohol, sorbitol, proline, histidine, lysine, arginine, polyethylene glycol or polyvinyl pyrrolidine, preferably one or more of mannitol, lactose, trehalose, sucrose and polyvinyl pyrrolidine.

[0099] According to an embodiment of the present invention, the solid composition optionally does not contain a pharmaceutically acceptable suspending agent, and the suspending agent is preferably a water-soluble polymer compound, including but not limited to one or more of carboxymethyl cellulose or its sodium salt, hydroxypropyl cellulose or its sodium salt, hydroxypropyl methylcellulose or its sodium salt, methyl cellulose or its sodium salt, hydroxyethyl cellulose or its sodium salt, sodium hyaluronate and polyvinyl pyrrolidone.

[0100] The present invention also provides a method for preparing a solid pharmaceutical composition, which comprises: drying a solution containing active pharmaceutical ingredients to obtain the solid composition.

[0101] According to an embodiment of the present invention, in the solid pharmaceutical composition obtained after drying, the pharmaceutically active ingredient exists in the form of particles, for example, in the form of crystals, preferably in the form of regular crystals, such as rod-shaped crystals or block-shaped crystals.

[0102] According to an embodiment of the present invention, the preparation method comprises: sterilizing, filtering, and drying a solution containing a pharmaceutically active ingredient to obtain the solid pharmaceutical composition.

[0103] According to an embodiment of the present invention, in the solid pharmaceutical composition obtained after drying, the D90 particle size of the active pharmaceutical ingredient is less than or equal to 200 μm, or less than or equal to 150 μm, or less than or equal to 120 μm, or less than or equal to 100 μm. Preferably, the D90 particle size of the active pharmaceutical ingredient is 10 to 90 μm, for example, 10 to 80 μm, preferably 10 to 70 μm, and more preferably 10 to 60 μm. As an example, the D90 particle size of the active pharmaceutical ingredient can be 10 μm, 15 μm, 20 μm, 25 μm, 30 μm, 35 μm, 40 μm, 45 μm, 50 μm, 55 μm or 60 μm.

[0104] According to an embodiment of the present invention, the drying method includes evaporative drying, freeze drying, spray drying, preferably freeze drying.

[0105] According to an embodiment of the present invention, the freeze-drying includes a pre-freezing process and a drying process.

[0106] According to an embodiment of the present invention, freeze drying can be performed in containers such as vials.

[0107] According to an embodiment of the present invention, the pharmaceutically active ingredient may be dissolved in a solvent to form the solution containing the pharmaceutically active ingredient.

[0108] According to an embodiment of the present invention, the solvent can be selected from an inorganic solvent, an organic solvent or a mixture thereof suitable for dissolving the active pharmaceutical ingredient. For example, the solvent is water, an organic solvent or a co-solvent system comprising water and an organic solvent, preferably one or more of water, methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butanol, isobutyl alcohol, the tert-butyl alcohol, acetone, acetonitrile, methylene chloride, and dimethyl sulfoxide (DMSO), more preferably water, ethanol, isopropyl alcohol, the tert-butyl alcohol, or a co-solvent system comprising water and one or more of the following organic solvents: methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butanol, isobutyl alcohol, the tert-butyl alcohol, acetone, acetonitrile, methylene chloride, and dimethyl sulfoxide (DMSO). For example, the co-solvent system is selected from a co-solvent system comprising water and a co-solvent system selected from one of the following organic solvents: ethanol, isopropyl alcohol, the tert-butyl alcohol.

[0109] According to an embodiment of the present invention, in the co-solvent system of water and an organic solvent, the volume percentage of the organic solvent is 1% to 99%, for example 10% to 90%, preferably 50% to 90%, and examples thereof can be 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%.

[0110] For example, the co-solvent system of water and an organic solvent is selected from a co-solvent system of water and tert-butyl alcohol. In the co-solvent system, the volume percentage of tert-butyl alcohol can be 50-95%, preferably 60-90%, more preferably 65-85%, and examples thereof are 65%, 70%, 75%, 80% or 85%.

[0111] According to an embodiment of the present invention, when the solubility of the pharmaceutical active ingredient in water is lower than that in an organic solvent, the solvent is selected from a co-solvent system comprising water and the organic solvent.

[0112] According to an embodiment of the present invention, the mass volume ratio of the pharmaceutical active ingredient to the solvent is ≥1 mg / mL, preferably ≥5 mg / mL, for example ≥10 mg / mL.

[0113] According to an embodiment of the present invention, the solution containing the pharmaceutical active ingredient optionally further comprises:

[0114] 1) Pharmaceutically acceptable stabilizers.

[0115] According to an embodiment of the present invention, the pharmaceutically acceptable stabilizer is selected from high carbonic acid (such as C 18 ~C 30 Higher carbon alcohols), C 18 ~C 30 One or more acids or their salts.

[0116] According to an embodiment of the present invention, the pharmaceutically acceptable stabilizer is selected from one or more of cholesterol, octadecanol, cholic acid or its salts, deoxycholic acid or its salts, taurodeoxycholic acid or its salts, ursodeoxycholic acid or its salts, chenodeoxycholic acid or its salts, and glycocholic acid or its salts.

[0117] According to an embodiment of the present invention, the pharmaceutically acceptable stabilizer is selected from one or more of cholesterol, octadecanol, cholic acid, deoxycholic acid, ursodeoxycholic acid, chenodeoxycholic acid, glycocholic acid, sodium cholate, sodium deoxycholate, and sodium taurodeoxycholate.

[0118] According to an embodiment of the present invention, the molar ratio of the pharmaceutical active ingredient to the stabilizer is 0.5:1 to 30:1, preferably 1:1 to 15:1, preferably 1:1 to 10:1, more preferably 1:1 to 7:1, more preferably 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.

[0119] According to an embodiment of the present invention, the solution containing the pharmaceutical active ingredient optionally further comprises:

[0120] 2) Pharmaceutically acceptable dispersants.

[0121] According to an embodiment of the present invention, the pharmaceutically acceptable dispersant is selected from one or more of polysorbate (Tween), poloxamer, polyoxyethylene fatty acid esters, polyoxyethylene fatty acid ethers, sucrose fatty acid esters, sodium lauryl sulfate, polyethylene glycol-15 hydroxystearate (HS-15), and phospholipids.

[0122] According to an embodiment of the present invention, the polysorbate is selected from one or more of polysorbate 80 (Tween 80) and polysorbate 20 (Tween 20).

[0123] According to an embodiment of the present invention, the phospholipid is selected from one or more of DMPC (dimyristoylphosphatidylcholine), DPPC (dipalmitoylphosphatidylcholine), DLPC (dilauroylphosphatidylcholine), SPC soy phosphatidylcholine (soy lecithin), EPC (egg yolk phospholipids), DEPC (dierucoyl phosphatidylcholine), DOPC (dioleoyl phosphatidylcholine), and POPC (palmitoyl oleoyl phosphatidylcholine).

[0124] According to an embodiment of the present invention, the molar ratio of the pharmaceutical active ingredient to the pharmaceutically acceptable dispersant is 50:1 to 1:1, preferably 40:1 to 2:1, more preferably 30:1 to 2:1, more preferably 20:1 to 2:1, more preferably 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1.

[0125] According to an embodiment of the present invention, the solution containing the pharmaceutical active ingredient optionally further comprises:

[0126] 3) Pharmaceutically acceptable inorganic salts.

[0127] According to an embodiment of the present invention, the solubility of the pharmaceutically acceptable inorganic salt in water at 20° C. is greater than 10 g / 100 mL.

[0128] According to an embodiment of the present invention, the inorganic salt is selected from one or more of sodium chloride, sodium sulfate, potassium chloride, potassium sulfate, potassium phosphate, ammonium sulfate, ammonium chloride, magnesium chloride, magnesium sulfate, calcium chloride, and barium chloride; preferably one or more of sodium chloride, potassium sulfate, magnesium chloride, magnesium sulfate, potassium chloride, and calcium chloride.

[0129] According to an embodiment of the present invention, the molar ratio of the pharmaceutical active ingredient to the pharmaceutically acceptable inorganic salt is ≥1:0.02, preferably 1:0.02 to 1:2.0, and more preferably 1:0.02, 1:0.05, 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.7, 1:1.8, 1:1.9, 1:2.0.

[0130] According to an embodiment of the present invention, the solution containing the active pharmaceutical ingredient may further comprise:

[0131] 4) Pharmaceutically acceptable pH adjusters.

[0132] According to an embodiment of the present invention, the pH adjuster is selected from alkaline pH adjusters and acidic pH adjusters.

[0133] According to an embodiment of the present invention, the alkaline pH regulator is selected from one or more of meglumine, tromethamine, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, magnesium hydroxide, calcium hydroxide, sodium phosphate, disodium hydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, sodium citrate, sodium acetate, potassium acetate, ammonium acetate, triethylamine, ethanolamine, and diethanolamine; preferably one or more of sodium hydroxide, potassium hydroxide, magnesium hydroxide, sodium bicarbonate, and calcium hydroxide.

[0134] According to an embodiment of the present invention, the acidic pH regulator is selected from one or more of citric acid, tartaric acid, maleic acid, malic acid, fumaric acid, succinic acid, succinic acid, hydrochloric acid, phosphoric acid, ascorbic acid, lactic acid, acetic acid, methanesulfonic acid, oxalic acid, sulfuric acid, glycine, sodium dihydrogen phosphate, and potassium dihydrogen phosphate; preferably one or more of citric acid, tartaric acid, maleic acid, malic acid, fumaric acid, succinic acid, succinic acid, hydrochloric acid, phosphoric acid, lactic acid, and acetic acid.

[0135] According to an embodiment of the present invention, the solution containing the pharmaceutical active ingredient optionally further comprises:

[0136] 5) Pharmaceutically acceptable osmotic pressure regulator.

[0137] According to an embodiment of the present invention, the osmotic pressure regulator is selected from one or more of sodium chloride, mannitol, lactose, glucose, sorbitol, sorbitol and glycerol, preferably one or more of sodium chloride, glucose, sorbitol and mannitol.

[0138] According to an embodiment of the present invention, the osmotic pressure of the suspension injection is equivalent to the physiological osmotic pressure.

[0139] According to an embodiment of the present invention, the solution containing the pharmaceutical active ingredient optionally further comprises:

[0140] 6) Pharmaceutically acceptable lyoprotectants.

[0141] According to an embodiment of the present invention, the pharmaceutically acceptable lyoprotectant is selected from one or more of mannitol, lactose, trehalose, sucrose, maltose, dextrin, stachyose, gelatin, pectin, sugar alcohol, sorbitol, proline, histidine, lysine, arginine, polyethylene glycol or polyvinyl pyrrolidine, preferably one or more of mannitol, lactose, trehalose, sucrose and polyvinyl pyrrolidine.

[0142] According to an embodiment of the present invention, the solid pharmaceutical composition may optionally not contain a pharmaceutically acceptable suspending agent, and the suspending agent is preferably a water-soluble polymer compound, including but not limited to one or more of carboxymethyl cellulose or its sodium salt, hydroxypropyl cellulose or its sodium salt, hydroxypropyl methylcellulose or its sodium salt, methyl cellulose or its sodium salt, hydroxyethyl cellulose or its sodium salt, sodium hyaluronate and polyvinyl pyrrolidone.

[0143] According to an embodiment of the present invention, the preparation method comprises: dissolving each component in a solution to obtain a solution, and drying to obtain a solid composition.

[0144] According to an embodiment of the present invention, the preparation method comprises: dissolving each component in the solution to obtain a solution, sterilizing and filtering, and drying to obtain a solid composition.

[0145] According to an embodiment of the present invention, the pharmaceutically active ingredient may be selected from ropivacaine, a pharmaceutically acceptable salt of ropivacaine, or other pharmaceutically active ingredients that can be used to treat a disease or condition.

[0146] According to an embodiment of the present invention, the solid pharmaceutical composition may be selected from a solid composition of ropivacaine or a pharmaceutically acceptable salt thereof, which may include but is not limited to the solid composition of ropivacaine or a pharmaceutically acceptable salt thereof described above and below in this specification.

[0147] According to an embodiment of the present invention, the pharmaceutically acceptable salt of ropivacaine is an acid salt of ropivacaine, i.e., an addition salt of ropivacaine with a pharmaceutically acceptable acid. For example, the acid salt of ropivacaine includes, but is not limited to, one or more of the following salts of ropivacaine: acetate, benzoate, benzenesulfonate, hydrobromide, camphorsulfonate, hydrochloride, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hydroiodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, methanesulfonate, naphthoate, naphthoate, nitrate, stearate, palmitate, myristate, laurate, oleate, oxalate, pamoate, phosphate, polygalacturonate, succinate, sulfate, sulfosalicylate, tartrate, toluenesulfonate, and trifluoroacetate.

[0148] According to an embodiment of the present invention, when the pharmaceutically active ingredient in the solution is a pharmaceutically acceptable salt, such as a pharmaceutically acceptable acid addition salt or base addition salt, it can react with a pH regulator in the solution to thereby prepare in situ the corresponding free active ingredient, such as a free alkaline active ingredient or a free acidic active ingredient.

[0149] Alternatively, when the pharmaceutically active ingredient in the solution is a free alkaline active ingredient or a free acidic active ingredient, it can react with a pH adjuster in the solution to prepare a corresponding pharmaceutically acceptable salt in situ.

[0150] For example, when the pharmaceutically active ingredient in the solution is a pharmaceutically acceptable salt of ropivacaine, ropivacaine can be prepared in situ by reacting the pharmaceutically acceptable salt of ropivacaine with an alkaline pH regulator.

[0151] According to an embodiment of the present invention, the pharmaceutically acceptable salt of ropivacaine has the definition described above.

[0152] According to an embodiment of the present invention, when the free active ingredient or pharmaceutically acceptable salt is prepared in situ as described above, the molar ratio of the pharmaceutically active ingredient as a reaction raw material to the pH adjuster can be determined by a person skilled in the art, for example, 3:1 to 1:3. For example, when the pharmaceutically active ingredient as a reaction raw material is a pharmaceutically acceptable salt of ropivacaine, the molar ratio thereof to the alkaline pH adjuster can be 1:0.5 to 1:2.0, preferably 1:0.8 to 1:1.5, and preferably 1:1.0 to 1:1.2. As an example, the molar ratio of the pharmaceutically acceptable salt of ropivacaine to the alkaline pH adjuster is 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, or 1:2.0.

[0153] The present invention also provides a solid pharmaceutical composition prepared by the above preparation method, such as a solid composition of ropivacaine or a pharmaceutically acceptable salt thereof.

[0154] The present invention also provides a method for preparing a suspension, which comprises redissolving the solid pharmaceutical composition to obtain the suspension.

[0155] According to an embodiment of the present invention, the preparation method comprises mixing the above solid pharmaceutical composition with a clinically acceptable diluent to obtain a suspension.

[0156] According to an embodiment of the present invention, the clinically acceptable diluent includes but is not limited to one or more of water for injection, sodium chloride injection, glucose injection, lactated Ringer's solution, sucrose solution, xylitol solution, and pH buffer solution.

[0157] According to an embodiment of the present invention, the sodium chloride injection includes but is not limited to 0.9% sodium chloride injection.

[0158] According to an embodiment of the present invention, the glucose injection includes but is not limited to 5% glucose injection.

[0159] According to an embodiment of the present invention, the pH buffer is selected from a buffer having a pH of 5.0 to 7.4, including but not limited to one or more of phosphate buffer, glycine buffer, histidine buffer, citrate buffer, and acetate buffer.

[0160] According to an embodiment of the present invention, the pH of the suspension is 6.0-9.0, preferably 6.0-8.5, preferably 6.0-8.0, more preferably 6.0-7.5, more preferably 6.2, 6.4, 6.6, 6.8, 7.0, 7.2, 7.4.

[0161] According to an embodiment of the present invention, the concentration of the active pharmaceutical ingredient in the suspension is about 0.1 mg / mL to about 300 mg / mL, preferably about 1 mg / mL to about 50 mg / mL, and more preferably about 2.5 mg / mL to about 40 mg / mL. As an example, the concentration of ropivacaine or a pharmaceutically acceptable salt thereof in the suspension is about 0.1 mg / mL, 0.5 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. / mL, 9 mg / mL, 9.5 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, or 100 mg / mL.

[0162] According to an embodiment of the present invention, the suspension is a suspension of ropivacaine or a pharmaceutically acceptable salt thereof, which includes but is not limited to the suspension of ropivacaine or a pharmaceutically acceptable salt thereof described above and below in this specification.

[0163] The present invention also provides a suspension prepared by the above preparation method, such as a suspension of ropivacaine or a pharmaceutically acceptable salt thereof.

[0164] The present invention also provides use of a pharmaceutically acceptable inorganic salt and / or a pharmaceutically acceptable stabilizer as a stabilizer for particles (eg, crystals) of ropivacaine or a pharmaceutically acceptable salt thereof.

[0165] The present invention also provides the use of a pharmaceutically acceptable inorganic salt and / or a pharmaceutically acceptable stabilizer as a stabilizer for ropivacaine particles or a pharmaceutically acceptable salt thereof (e.g., crystals) in the method for preparing the above-mentioned suspension of ropivacaine or a pharmaceutically acceptable salt thereof, or a solid composition of ropivacaine or a pharmaceutically acceptable salt thereof.

[0166] According to an embodiment of the present invention, the pharmaceutically acceptable inorganic salt and / or pharmaceutically acceptable stabilizer is used to promote the (stable) presence of ropivacaine or its pharmaceutically acceptable salt in a suspension or solid composition in the form of particles (e.g., crystals), preferably in the form of regular crystals, such as rod-shaped or block-shaped crystals.

[0167] According to an embodiment of the present invention, the inorganic salt is selected from pharmaceutically acceptable inorganic salts having a solubility in water greater than 10 g / 100 mL of water at 20°C.

[0168] According to an embodiment of the present invention, the inorganic salt is selected from one or more of sodium chloride, sodium sulfate, potassium chloride, potassium sulfate, potassium phosphate, ammonium sulfate, ammonium chloride, magnesium chloride, magnesium sulfate, calcium chloride, and barium chloride; preferably one or more of sodium chloride, potassium sulfate, magnesium chloride, magnesium sulfate, potassium chloride, and calcium chloride.

[0169] According to an embodiment of the present invention, the pharmaceutically acceptable stabilizer is selected from C 18 ~C 30 Higher alcohols, C 18 ~C 30 acid or its salt.

[0170] According to an embodiment of the present invention, the pharmaceutically acceptable stabilizer is selected from one or more of cholesterol, octadecanol, cholic acid, deoxycholic acid, ursodeoxycholic acid, chenodeoxycholic acid, glycocholic acid, sodium cholate, sodium deoxycholate, and sodium taurodeoxycholate.

[0171] The present invention also provides use of the above suspension or solid composition in preparing a drug for producing anesthesia or relieving pain.

[0172] The present invention also provides use of the above suspension or solid composition in preparing a medicament for treating and / or preventing pain.

[0173] The present invention also provides the above suspension or solid composition, which is used for treating and / or preventing pain.

[0174] According to an embodiment of the present invention, the suspension or solid composition is administered around a nerve or to a surgical wound.

[0175] According to an embodiment of the present invention, the pain is chronic postoperative pain or labor pain.

[0176] The present invention also provides a method for producing anesthesia, comprising administering the above suspension or solid composition to an individual.

[0177] The present invention also provides a method for treating, improving and / or preventing pain, comprising administering the above suspension or solid composition to an individual.

[0178] According to an embodiment of the present invention, the administration is parenteral administration and / or topical administration.

[0179] According to an embodiment of the present invention, parenteral administration is selected from intravenous, intramuscular, subcutaneous injection, intra-articular injection, epidural administration, subarachnoid administration, incisional perfusion administration, infiltration and nerve block, preferably intramuscular, subcutaneous injection, intra-articular injection, epidural administration, subarachnoid administration, incisional perfusion administration, infiltration and nerve block.

[0180] As used herein, the term "subject" includes mammals and humans.

[0181] According to embodiments of the present invention, the suspension or solid composition provides sustained release of the drug in an individual for not less than 12 hours. Some embodiments provide sustained release of the drug for not less than 24 hours. Some embodiments provide sustained release of the drug for not less than 36 hours. Some embodiments provide sustained release of the drug for not less than 48 hours. Some embodiments provide sustained release of the drug for not less than 60 hours. Some embodiments provide sustained release of the drug for not less than 72 hours. Some embodiments provide sustained release of the drug for not less than 120 hours. Some embodiments provide sustained release of the drug for not less than 168 hours.

[0182] According to an embodiment of the present invention, the above-mentioned suspension or solid composition can reach the peak drug concentration within about 3 hours after administration to an individual, for example, within about 2 hours, preferably within about 1.5 hours, more preferably within about 1 hour, and most preferably within about 30 minutes. Beneficial effects

[0183] The present invention provides a new solid composition of ropivacaine and a pharmaceutically acceptable salt thereof. The solid composition preparation is a freeze-dried powder injection, which forms a suspension after reconstitution. In the solid composition and the suspension, ropivacaine or a pharmaceutically acceptable salt thereof is stably present in the system in the form of particles (e.g., crystals).

[0184] The addition of an acceptable inorganic salt and / or a pharmaceutically acceptable stabilizer to the above-mentioned formulation system can significantly improve the crystal form of ropivacaine or a pharmaceutically acceptable salt thereof in the suspension or solid composition, preferably forming regular crystals of ropivacaine or a pharmaceutically acceptable salt thereof, such as rod-shaped or block-shaped crystals; after administration, the drug crystals slowly dissolve, thereby achieving a slow release effect.

[0185] The suspension (eg, suspension injection) and solid composition of the present invention have good stability, controllable product quality, are easy to administer, have low irritation, and have good medication safety and tolerability.

[0186] The sustained-release formulation system provided by the present invention enables excellent release of active pharmaceutical ingredients, reducing the possibility of burst release. It is particularly suitable for the development of pharmaceutical formulations with anesthetic and analgesic properties, offering advantages over existing technologies, such as a simple preparation process, guaranteed sterility through sterile filtration, and ease of scale-up. It also provides sustained and stable release of the analgesic active ingredient, good patient tolerance, and minimal side effects.

[0187] Terms and abbreviations

[0188] Unless otherwise indicated, all numbers used in this specification and claims to indicate content, concentration, ratio, weight, percentage, technical effect, etc. should be understood as being modified by the term "about" or "approximately" in any case. "About" represents a range of ±10% of the value it modifies.

[0189] Therefore, unless otherwise indicated, the numerical parameters listed in the following specification and the appended claims are approximate values. Unless otherwise indicated, the terms used herein have the meanings commonly understood by those skilled in the art. For those skilled in the art, it can vary depending on the desired properties and effects sought to be obtained through this disclosure, and each numerical parameter should be interpreted in accordance with the number of significant digits and conventional rounding methods or in a manner understood by those skilled in the art.

[0190] Although the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values ​​set forth in the specific examples are provided as precisely as possible. However, any numerical value inherently contains certain errors necessarily resulting from the standard deviation found in its respective testing measurements. Every numerical range given herein will include every narrower numerical range that falls within such broader numerical range, as if such narrower numerical ranges were expressly written herein.

[0191] Unless otherwise stated, the definitions of excipients in this specification and claims, including definitions used as examples, exemplary definitions, preferred definitions, definitions in tables, and definitions of specific excipients in examples, may be arbitrarily combined and coupled with one another. Such combinations and couplings shall fall within the scope of the excipients described in this specification.

[0192] The term "D50" used in this specification refers to the particle size at which the cumulative particle size distribution percentage of a sample reaches 50%. The term "D90" refers to the particle size at which the cumulative particle size distribution percentage of a sample reaches 90%.

[0193] The term "higher alcohol" refers to higher alkanols, also known as higher fatty alcohols, which include saturated monohydric alcohols with more than twelve carbon atoms that are waxy solids.18 ~C 30 When referring to "higher alcohol", it means C 18 ~C 30 Saturated monohydric alcohol, that is, a saturated monohydric alcohol having 18 to 30 carbon atoms. As an example, the C 18 ~C 30 The higher carbon alcohol can be selected from cholesterol and octadecyl alcohol.

[0194] The term "particle" refers to a solid geometric body with a certain shape and within a certain size range. Preferably, the particle size of the "particle" in the context of this specification is in the micrometer range.

[0195] The term "regular crystal" means a particle having a specific shape. In the context of this specification, a regular crystal can be in the form of a rod, a sphere, a block, or the like.

[0196] The term "irregular crystals" means particles that do not have a specific shape.

[0197] The osmotic pressure of the pharmaceutical composition is equivalent to the physiological osmotic pressure, and the osmotic pressure of the suspension injection is equivalent to the physiological osmotic pressure, and the meaning of equivalent is: 300±50mmol / L.

[0198] The term "freeze drying" includes a pre-freezing process and a drying process. For example, the pre-freezing process includes a cooling step 1, an annealing step, and a cooling step 2. Or, for example, the drying process includes a primary drying step and a secondary drying step.

[0199] The abbreviations used in this specification have the following definitions: TW80 is Tween 80; TW20 is Tween 20; HS-15 is polyethylene glycol-15 hydroxystearate; F68 is poloxamer 188; DMPC is dimyristoylphosphatidylcholine; DPPC is dipalmitoylphosphatidylcholine; DLPC is dilauroylphosphatidylcholine; SPC is soybean phosphatidylcholine (soy lecithin); EPC is egg yolk phospholipids; DEPC is dieucoyl phosphatidylcholine; DOPC is dioleoyl phosphatidylcholine; POPC is palmitoyl oleoyl phosphatidylcholine; HSPC is hydrogenated soybean lecithin; DSPC is distearoyl phosphatidylcholine; ROP is ropivacaine; CHO is cholesterol; TBA is tert-butyl alcohol; MgCl2·6H2O is magnesium chloride hexahydrate; NaCl is sodium chloride. BRIEF DESCRIPTION OF THE DRAWINGS

[0200] FIG1 is a microscopic morphology of ropivacaine in Example composition 6006;

[0201] FIG2 is a microscopic morphology of ropivacaine in Example compositions 6030 to 6035;

[0202] FIG3 is a microscopic morphology of ropivacaine in Example compositions 6036, 6037, 6039, 6040, 6041, 6042, 6044, and 6045;

[0203] FIG4 is a microscopic morphology of ropivacaine in Example compositions 6046 and 6049;

[0204] FIG5 is a microscopic morphology of ropivacaine in Example compositions 6010 and 6064;

[0205] FIG6 is a microscopic morphology of ropivacaine in Example compositions 6074, 6076, and 6078;

[0206] FIG7 is a microscopic morphology of ropivacaine in Example compositions 6083 and 6087;

[0207] FIG8 is a microscopic morphology of ropivacaine in Example compositions 6091, 6097, 6098, and 6104;

[0208] FIG9 is a microscopic morphology of ropivacaine after reconstitution of Example composition 6105 with purified water, sodium chloride aqueous solution, and magnesium chloride aqueous solution;

[0209] FIG10 is a microscopic morphology of ropivacaine in Example compositions 6106 and 6107;

[0210] FIG11 is an electron microscopic morphology of ropivacaine in Example composition 6106;

[0211] FIG12 is a microscopic morphology of ropivacaine in Example compositions 6106, 6126, 6127, and 6128;

[0212] FIG13 is a diagram of the crystalline morphology of ropivacaine of Example composition 6129;

[0213] FIG14 is a blood concentration curve of Example compositions 6106 and 6143 in rats;

[0214] FIG15 is a comparison of the efficacy of Example composition 6144 and EXPAREL in rats;

[0215] FIG16 is a comparison of the local safety of Example composition 6154 and Comparative Example 3. DETAILED DESCRIPTION

[0216] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0217] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0218] Unless otherwise noted, the percentages of tert-butyl alcohol (TBA) in the tert-butyl alcohol aqueous solutions in the following examples are by volume. When a percentage less than 100% is described together with TBA (including but not limited to 80% TBA, 75% TBA, etc.), it refers to an aqueous solution containing the stated percentage of tert-butyl alcohol. When a percentage of 100% is described together with TBA (i.e., 100% TBA), it refers to tert-butyl alcohol without the addition of water.

[0219] Source of experimental animals:

[0220] Beagle: Jiangsu Masi Biotechnology Co., Ltd.; male;

[0221] Rats: Zhejiang Weitonglihua Experimental Animal Technology Co., Ltd., Animal Experiment Center of Nantong University; male.

[0222] Example 1

[0223] Investigation of conventional freeze-dried compositions

[0224] (1) Compositions containing freeze-drying protective agents

[0225] Weigh the prescribed amount of ropivacaine and lyoprotectant according to Table 1-1 into a Schott flask. Add tert-butyl alcohol aqueous solution and heat and stir until completely dissolved. Pass the solution through a 0.22 μm filter and dispense into 2 mL / vial. Freeze-dry according to Table 1-3. Add 2 mL of normal saline to the lyophilized powder and shake until evenly dispersed. Observe the reconstitution and dispersibility using an Olympus CX41 microscope.

[0226] Table 1-1 Compositions containing freeze-drying protective agents

[0227] Table 1-2 Redissolution and dispersibility results

[0228] Table 1-3 Freeze-drying methods

[0229] The results showed that the composition containing only the lyoprotectant could not be dispersed after reconstitution.

[0230] (2) Compositions containing suspending agents

[0231] Weigh the prescribed amount of ropivacaine and suspending agent according to Table 1-4 into a Schott flask. Add tert-butyl alcohol aqueous solution and heat and stir until completely dissolved. Pass the solution through a 0.22 μm filter and aliquot into 2 mL bottles. Freeze-dry according to Table 1-3. Add 2 mL of normal saline to the lyophilized powder and shake until evenly dispersed. Observe the reconstitution and dispersibility using an Olympus CX41 microscope.

[0232] Table 1-4 Compositions containing suspending agents

[0233] Table 1-5 Redissolution and dispersibility results

[0234] The results showed that the composition containing only common suspending agents could not be dispersed after reconstitution.

[0235] Example 2

[0236] Research on dispersants

[0237] (1) Compositions containing common dispersants

[0238] Weigh the prescribed amount of ropivacaine and dispersant according to Table 2-1 into a Schott flask. Add tert-butyl alcohol aqueous solution and heat and stir until completely dissolved. Pass the solution through a 0.22 μm filter and aliquot into 2 mL bottles. Freeze-dry according to Table 1-3. Add 2 mL of normal saline to the lyophilized powder and shake until evenly dispersed. Observe the morphology of the reconstituted ropivacaine crystals using a microscope (Olympus, CX41).

[0239] Table 2-1 Compositions containing common dispersants

[0240] Table 2-2 Redissolution and dispersibility and crystal morphology

[0241] The results showed that the addition of commonly used dispersants could improve the resolubility of the composition. However, microscopic observation showed that the morphology of the ropivacaine crystals in the reconstituted suspension was irregular. The morphology of the ropivacaine crystals after reconstitution of composition 6006 is shown in Figure 1. The morphology of the ropivacaine after reconstitution of other dispersant compositions was similar to that in Figure 1. At the same time, the crystals showed aggregation and the crystal sizes varied greatly.

[0242] (2) Compositions containing phospholipid dispersants

[0243] Weigh the prescribed amount of ropivacaine and phospholipid dispersant according to Table 2-3 into a Schott flask. Add tert-butyl alcohol aqueous solution and heat and stir until completely dissolved. Pass the solution through a 0.22 μm filter and aliquot into 1.5 mL bottles. Freeze-dry according to Table 1-3. Add 1.5 mL of normal saline to the lyophilized powder and shake until evenly dispersed. Observe the morphology of the reconstituted ropivacaine crystals using a microscope (Olympus, CX41).

[0244] Table 2-3 Compositions containing phospholipid dispersants

[0245] *6012 and 6017 showed precipitation in the solution before lyophilization and were not further studied.

[0246] Table 2-4 Redissolution and dispersibility and crystal morphology

[0247] The results showed that the addition of phospholipid dispersants, except HSPC and DSPC, could improve the resolubility of the composition. However, microscopic observation showed that the morphology of the resolubilized ropivacaine crystals was irregular, similar to Figure 1. At the same time, the crystals were aggregated and the crystal sizes varied greatly.

[0248] (3) Study on the effect of dispersant dosage on crystal morphology

[0249] Using polysorbate 20 and DMPC as examples, the effects of different molar ratios of ropivacaine to dispersant on crystal morphology were investigated. The prescribed amounts of ropivacaine and dispersant were weighed into a Schott flask according to Tables 2-5 and 2-6. Aqueous tert-butyl alcohol solution was added and heated and stirred until completely dissolved. The solution was filtered through a 0.22 μm filter and aliquoted into 2 mL bottles. Freeze-dried according to Table 1-3 was performed. 2 mL of normal saline was added to the lyophilized powder and shaken until uniformly dispersed. The morphology of the reconstituted ropivacaine crystals was observed using an Olympus, CX41 microscope.

[0250] Table 2-5 Compositions with different DMPC dosages

[0251] Table 2-6 Compositions with different amounts of polysorbate 20

[0252] The results showed that a molar ratio of ropivacaine to dispersant ranging from 50:1 to 1:1 improved the resolubility of the composition. However, microscopic observation revealed irregular morphology of the ropivacaine crystals, similar to Figure 1. The crystals also exhibited aggregation and large variations in size. The amount of dispersant only affected the speed of dispersibility and did not affect the crystal morphology.

[0253] As can be seen from Example 2, after adding dispersant, the ropivacaine crystal form is irregular in the suspension, and crystal size or size are uneven, and there is easily crystal aggregation phenomenon. And these will all cause when it is used as injection, the quality instability and quality of the suspension product are uncontrollable, and also easily cause the adverse consequences such as needle blocking when injection is used subsequently. Therefore, the present invention is intended to improve the crystal form and crystal size of ropivacaine in the suspension by screening and adding suitable additives and the ratio between each component, and then control the product quality of the suspension.

[0254] Example 3

[0255] Crystal morphology improvement research

[0256] (1) Study on solvent ratio

[0257] Using DMPC as a dispersant, the effects of different tert-butyl alcohol / water ratios on crystal morphology were investigated. The prescribed amounts of ropivacaine and DMPC were weighed according to Table 3-1 into a Schott flask. The tert-butyl alcohol aqueous solution was added and heated and stirred until completely dissolved. After filtering through a 0.22 μm filter, the solution was aliquoted into 2 mL bottles and freeze-dried according to Table 1-3. 2 mL of normal saline was added to the freeze-dried powder and shaken until uniformly dispersed. The morphology of the reconstituted ropivacaine crystals was observed using a microscope (Olympus, CX41).

[0258] Table 3-1 Prescription composition

[0259] Table 3-2 Crystal morphology

[0260] The results showed that when the proportion of tert-butyl alcohol was changed on the basis of containing only the dispersant, ropivacaine was irregular crystals with no significant improvement in morphology. The morphology of ropivacaine crystals of compositions 6030 to 6035 is shown in FIG2 .

[0261] (2) Addition of alcohol or sugar additives

[0262] Using DMPC and TW20 as dispersants, and adding various alcohol additives, we unexpectedly discovered that higher alcohol additives affect the crystal morphology of ropivacaine. Weigh the prescribed amounts of ropivacaine, dispersant, and additives according to Tables 3-3 and 3-4 into a Schott flask. Add tert-butyl alcohol aqueous solution and heat and stir until completely dissolved. After filtering through a 0.22μm filter, dispense 2mL / bottle and freeze-dry according to Table 1-3. Add 2mL of normal saline to the lyophilized powder and shake until evenly dispersed. The morphology of the reconstituted ropivacaine crystals was observed using an Olympus CX41 microscope.

[0263] Table 3-3 Compositions containing water-soluble alcohol or sugar additives

[0264] * Compositions 6038 and 6043 containing lactose were not soluble and were not studied further.

[0265] Table 3-4 Compositions containing water-insoluble alcohol additives

[0266] Table 3-5 Crystal morphology results

[0267] The results showed that according to the screening results of alcohol additives, the ropivacaine in the compositions of water-soluble alcohols or sugar additives after reconstitution was irregular crystals, as shown in Figure 3; among the water-insoluble alcohol additives, it was unexpectedly found that only the addition of cholesterol and octadecyl alcohol could improve the crystal morphology, making the crystals regular rod-shaped or block-shaped, while the other alcohol additives were irregular crystals (similar to Figure 3). Figure 4 shows the crystal morphology of ropivacaine in compositions 6046 and 6049.

[0268] Taking cholesterol as an example, the crystal morphology of ropivacaine in different dispersants was investigated. The prescribed amounts of ropivacaine, dispersants, and additives were weighed according to Tables 3-6 and 3-7 into a Schott flask. Aqueous tert-butyl alcohol solution was added and heated and stirred until completely dissolved. After filtering through a 0.22 μm filter, the solution was aliquoted into 2 mL bottles and freeze-dried according to Table 1-3. 2 mL of normal saline was added to the freeze-dried powder and shaken until uniformly dispersed. The reconstituted ropivacaine crystal morphology was observed using a microscope (Olympus, CX41), which showed similarities to Figure 4. The D50 and D90 values ​​were measured using a laser particle size analyzer (OMEC, Topsizer).

[0269] 3-6 Compositions containing common dispersants

[0270] Table 3-7 Compositions containing phospholipid dispersants

[0271] (3) Research on cholesterol analogs

[0272] For investigation, substances with a similar structure to cholesterol were selected. Ropivacaine, dispersants, and additives were weighed in the prescribed amounts according to Tables 3-8 and 3-9 into a Schott flask. Aqueous tert-butyl alcohol solution was added and heated and stirred until completely dissolved. After filtering through a 0.22 μm filter, the solution was aliquoted into 2 mL bottles and freeze-dried according to Table 1-3. 2 mL of normal saline was added to the freeze-dried powder and shaken until evenly dispersed. The morphology of the reconstituted ropivacaine crystals was observed using an Olympus CX41 microscope.

[0273] Table 3-8 Composition Information

[0274] Table 3-9 Composition Information

[0275] Table 3-10 Crystal morphology results

[0276] The results show that the present invention unexpectedly discovered that bile acid and its derivatives or salts can improve the crystal morphology, making the crystals regular rod-shaped or block-shaped.

[0277] (4) Addition of metal ion additives

[0278] Metal ion additives were added to the dispersant to investigate their effects on ropivacaine crystal morphology. The prescribed amounts of ropivacaine, dispersant, and additives were weighed into a Schott flask according to Tables 3-11 and 3-12. Aqueous tert-butyl alcohol solution was added and heated and stirred until completely dissolved. After filtering through a 0.22 μm filter, the solution was aliquoted into 1.5 mL or 2 mL bottles and freeze-dried according to Table 1-3. 2 mL of normal saline was added to the freeze-dried powder and shaken until uniformly dispersed. The morphology of the reconstituted ropivacaine crystals was observed using an Olympus CX41 microscope.

[0279] Table 3-11 Compositions containing metal ions

[0280] Table 3-12 Compositions containing metal ions

[0281] The results show that the present invention unexpectedly discovered that adding metal ions to the system can reduce large-particle crystals, while improving the uniformity of product crystal distribution and appropriately improving the crystal morphology. A comparison of the crystal morphology of ropivacaine after reconstitution of a composition without metal ions (composition 6010) and a composition containing metal ions (composition 6064) is shown in Figure 5.

[0282] Example 4

[0283] Cholesterol research

[0284] Using DMPC as a dispersant, the effects of varying molar ratios of the active ingredient to cholesterol on dispersibility and crystal morphology were investigated. The prescribed amounts of ropivacaine, DMPC, and cholesterol were weighed into a Schott flask according to Table 4-1. Aqueous tert-butyl alcohol solution was added and heated and stirred until completely dissolved. After filtering through a 0.22 μm filter, the solution was aliquoted into 2 mL bottles and freeze-dried according to Table 1-3. 2 mL of normal saline was added to the lyophilized powder and shaken until uniformly dispersed. The morphology of the reconstituted ropivacaine crystals was observed using a microscope (Olympus, CX41), and the D50 and D90 values ​​were measured using a laser particle size analyzer (OMEC, Topsizer). A cholesterol-free composition was used as a comparison. The settling time of the ropivacaine crystals was observed after stabilization (see Table 4-2).

[0285] Table 4-1 Compositions with different cholesterol dosages

[0286] Table 4-2 Dispersibility and crystal morphology

[0287] The results showed that the cholesterol-free composition formed irregular crystals, as shown in composition 6074 in Figure 6. When the ropivacaine:cholesterol molar ratio was greater than 7:1, a small amount of rod-shaped crystals were observed, but a large amount of irregular crystals remained, as shown in composition 6076 in Figure 6. When the ropivacaine:cholesterol molar ratio was ≤7:1, rod-shaped crystals were essentially formed, as shown in composition 6078 in Figure 6. Furthermore, the addition of cholesterol prolonged the settling time of the ropivacaine crystals and increased the physical stability of the reconstituted solution.

[0288] Example 5

[0289] Research on Metal Ion Salts

[0290] (1) Research on types of metal ion salts

[0291] Using DMPC as a dispersant, the effects of monovalent and divalent metal ion salts on crystal morphology were investigated. The prescribed amounts of ropivacaine, DMPC, and various metal ion salts were weighed into a Schott flask according to Tables 5-1 and 5-2. Aqueous tert-butyl alcohol solution was added and heated and stirred until completely dissolved. After filtering through a 0.22 μm filter, the solution was aliquoted into 2 mL bottles and freeze-dried according to Table 1-3. 2 mL of normal saline was added to the freeze-dried powder and shaken until uniformly dispersed. The morphology of the reconstituted ropivacaine crystals was observed using a microscope (Olympus, CX41), and the D50 and D90 values ​​were measured using a laser particle size analyzer (OMEC, Topsizer).

[0292] Table 5-1 Compositions containing monovalent metal ion salts

[0293] Table 5-2 Compositions containing divalent metal ion salts

[0294] The results showed that both monovalent metal ion and divalent metal ion salts can reduce the size of large crystals and appropriately improve the crystal morphology, making the crystals shorter and thicker. The divalent metal ion salts have a more significant effect. The crystal morphologies of ropivacaine of composition 6083 and composition 6087 are shown in Figure 7.

[0295] (2) Study on metal ion dosage

[0296] The effect of the ratio of active ingredient to metal ion on crystal morphology was investigated. Sodium ions were selected for monovalent metal ions, and magnesium ions for divalent metal ions. Considering the route of injection, sodium chloride and magnesium chloride were selected for investigation. The prescribed amounts of ropivacaine, DMPC, and various metal ion salts were weighed according to Tables 5-3 and 5-4 into a Schott flask. Aqueous tert-butyl alcohol solution was added and heated and stirred until completely dissolved. After filtering through a 0.22 μm filter, the solution was aliquoted into 2 mL bottles and freeze-dried according to Table 1-3. 2 mL of normal saline was added to the freeze-dried powder and shaken until uniformly dispersed. The morphology of the reconstituted ropivacaine crystals was observed using a microscope (Olympus, CX41), and the D50 and D90 values ​​were measured using a laser particle size analyzer (OMEC, Topsizer).

[0297] Table 5-3 Compositions containing monovalent metal ion salts

[0298] Table 5-4 Compositions containing divalent metal ion salts

[0299] The results show that adding a certain amount of metal ions can reduce the large-size crystals and appropriately improve the crystal morphology. The compositions 6091, 6097, 6098 and 6104 are shown in Figure 8.

[0300] (3) Research on the method of introducing metal ions

[0301] To further investigate the influence of metal ions, the freeze-dried powder was reconstituted with a solution containing a metal ion salt after lyophilization to examine the effect of the metal ion addition method on crystal morphology. Sodium chloride and magnesium chloride aqueous solutions were prepared separately and added to composition 6105 (Table 5-5) at a molar ratio of ropivacaine:metal ion of 1:1.37. After shaking until uniformly dispersed, the morphology of the reconstituted ropivacaine crystals was observed using a microscope (Olympus, CX41), as shown in Figure 9.

[0302] Table 5-5 Composition information

[0303] Table 5-6 Crystal morphology after re-dissolution

[0304] The results showed that metal ions must be added to the initial formulation in order to reduce the size of large crystals and appropriately improve the crystal morphology.

[0305] Example 6

[0306] Composition containing cholesterol and metal ions

[0307] Cholesterol and metal ions were simultaneously added to the composition to investigate their effects on crystal morphology. Sodium chloride and magnesium chloride were selected as the metal ion salts for investigation. Ropivacaine, cholesterol, and metal ions were added at a molar ratio of 1:0.18:1.37. The prescribed amounts of ropivacaine, DMPC, cholesterol, and metal ions were weighed according to Table 6-1 into a Schott flask. Aqueous tert-butyl alcohol solution was added and heated and stirred until completely dissolved. After filtering through a 0.22 μm filter, the solution was dispensed into 2 mL bottles and freeze-dried according to Table 1-3. 2 mL of normal saline was added to the freeze-dried powder and shaken until uniformly dispersed. The morphology of the reconstituted ropivacaine crystals was observed using a microscope (Olympus, CX41), and the D50 and D90 values ​​were measured using a laser particle size analyzer (OMEC, Topsizer).

[0308] Table 6-1 Composition information

[0309] The results showed that the co-addition of cholesterol and metal ions had a synergistic effect, allowing ropivacaine to form more regular rod-shaped crystals. The ropivacaine crystal morphology of compositions 6106 and 6107 is shown in Figure 10. After the crystals of composition 6106 were separated and photographed using a scanning electron microscope (Quanta FEG 250, FEI, USA), three-dimensional regular rod-shaped crystals were observed, as shown in Figure 11.

[0310] The effect of varying metal ion dosages on crystal morphology was investigated by maintaining a fixed molar ratio of ropivacaine to cholesterol. The prescribed amounts of ropivacaine, DMPC, cholesterol, and metal ions were weighed according to Tables 6-2 and 6-3 into a Schott flask. Aqueous tert-butyl alcohol solution was added and heated and stirred until completely dissolved. The solution was filtered through a 0.22 μm filter and aliquoted into 2 mL bottles. Freeze-dried according to Table 1-3 was performed. 2 mL of normal saline was added to the lyophilized powder and shaken until uniformly dispersed. The morphology of the reconstituted ropivacaine crystals was observed using a microscope (Olympus, CX41), and the D50 and D90 values ​​were measured using a laser particle size analyzer (OMEC, Topsizer).

[0311] Table 6-2 Composition information

[0312] Table 6-3 Composition information

[0313] The results showed that when the molar ratio of ropivacaine to cholesterol was fixed and a certain amount of metal ions was added, the ropivacaine crystals were consistent with those in Figure 10.

[0314] The effect of varying cholesterol dosages on crystal morphology was investigated by maintaining a fixed molar ratio of ropivacaine to metal ions. The prescribed amounts of ropivacaine, DMPC, cholesterol, and metal ions were weighed according to Table 6-4 into a Schott flask. TBA aqueous solution was added and heated and stirred until completely dissolved. The solution was filtered through a 0.22 μm filter, aliquoted into 2 mL bottles, and freeze-dried according to Table 1-3. 2 mL of normal saline was added to the freeze-dried powder and shaken until uniformly dispersed. The morphology of the reconstituted ropivacaine crystals was observed using a microscope (Olympus, CX41), and the D50 and D90 values ​​were measured using a laser particle size analyzer (OMEC, Topsizer).

[0315] Table 6-4 Composition information

[0316] The results showed that when the molar ratio of ropivacaine to metal ions was fixed and the molar ratio of ropivacaine to cholesterol was ≤7:1, the ropivacaine crystals were consistent with those in Figure 10.

[0317] Example 7

[0318] Compositions of different dispersant types and amounts

[0319] (1) Compositions of different dispersant types

[0320] Cholesterol and metal ions were added simultaneously to the composition, and the type of dispersant was varied to examine the effect on crystal morphology. Sodium chloride was selected as the metal ion salt for this study. Ropivacaine, dispersant, cholesterol, and metal ions were weighed according to Table 7-1 into a Schott flask. A tert-butyl alcohol / water solution was added and heated and stirred until completely dissolved. After filtering through a 0.22 μm filter, the solution was dispensed into 2 mL bottles and freeze-dried according to Table 1-3. 2 mL of normal saline was added to the freeze-dried powder and shaken until uniformly dispersed. The morphology of the reconstituted ropivacaine crystals was observed using a microscope (Olympus, CX41), and the D50 and D90 values ​​were measured using a laser particle size analyzer (OMEC, Topsizer).

[0321] Table 7-1 Compositions of different dispersant types

[0322] The results showed that the ropivacaine crystals after reconstitution of the above composition were all rod-shaped crystals, as shown in FIG12 , indicating that the type of dispersant did not affect the crystal morphology.

[0323] (2) Compositions with different dispersant dosages

[0324] Cholesterol and metal ions were simultaneously added to the composition, with DMPC and polysorbate 20 used as dispersants to investigate the effect of dispersant dosage on crystal morphology. Sodium chloride was selected as the metal ion salt for this study. Ropivacaine, dispersant, cholesterol, and metal ions were weighed in the prescribed amounts according to Tables 7-2 to 7-4 into a Schott flask. A tert-butyl alcohol / water solution was added and heated and stirred until completely dissolved. The solution was filtered through a 0.22 μm filter, aliquoted into 2 mL bottles, and freeze-dried according to Table 1-3. 2 mL of normal saline was added to the freeze-dried powder and shaken until uniformly dispersed. The morphology of the reconstituted ropivacaine crystals was observed using a microscope (Olympus, CX41), and the D50 and D90 values ​​were measured using a laser particle size analyzer (OMEC, Topsizer).

[0325] Table 7-2 Compositions with different dispersant dosages

[0326] Table 7-3 Compositions with different dispersant dosages

[0327] Table 7-4 Compositions with different dispersant dosages

[0328] The results showed that the ropivacaine crystals after reconstitution of the above composition were all rod-shaped crystals, which was consistent with FIG12 , indicating that the amount of dispersant used within the above molar ratio range did not affect the crystal morphology.

[0329] Example 8

[0330] Study of different solvent ratios

[0331] Cholesterol and metal ions were added simultaneously to the composition, and the tert-butyl alcohol / water ratio was varied to investigate their effects on crystal morphology. Sodium chloride was selected as the metal ion salt, and DMPC was selected as the dispersant. Ropivacaine, DMPC, cholesterol, and sodium chloride were weighed according to Table 8-1 into a Schott flask. The tert-butyl alcohol / water solution was added and heated and stirred until completely dissolved. The solution was filtered through a 0.22 μm filter and aliquoted into 2 mL bottles. Freeze-dried according to Table 1-3, 2 mL of normal saline was added to the lyophilized powder and shaken until uniformly dispersed. The morphology of the reconstituted ropivacaine crystals was observed using a microscope (Olympus, CX41), and the D50 and D90 values ​​were measured using a laser particle size analyzer (OMEC, Topsizer).

[0332] Table 8-1 Compositions of different solvent ratios

[0333] The results showed that the compositions with different tert-butanol ratios all formed regular rod-shaped crystals after redissolution, and the ropivacaine crystal morphology of composition 6129 was shown in FIG13 .

[0334] Example 9

[0335] Ropivacaine can be prepared directly by alkalizing a pharmaceutically acceptable salt of ropivacaine.

[0336] If the active ingredient is a salt, the crystal morphology can be improved by adding a base containing metal ions, such as sodium hydroxide, potassium hydroxide, or sodium bicarbonate. Weigh the prescribed amount of ropivacaine hydrochloride, DMPC, cholesterol, and metal ions according to Table 9-1 into a Schott flask. Add aqueous tert-butyl alcohol solution and heat and stir until completely dissolved. Pass the solution through a 0.22 μm filter, aliquot into 2 mL bottles, and freeze-dry according to Table 1-3. Add 2 mL of normal saline to the lyophilized powder and shake until evenly dispersed. Observe the morphology of the reconstituted ropivacaine crystals using a microscope (Olympus, CX41) and measure the D50 and D90 values ​​using a laser particle size analyzer (OMEC, Topsizer).

[0337] Table 9-1 Composition information

[0338] The results showed that the morphology of ropivacaine crystals after reconstitution was rod-shaped, which was consistent with Figure 10.

[0339] Example 10

[0340] Combinations of different active ingredients

[0341] Weigh the prescribed amount of active ingredient, DMPC, cholesterol, and sodium chloride according to Table 10-1 into a Schott flask. Add tert-butyl alcohol aqueous solution and heat and stir until completely dissolved. Pass the solution through a 0.22 μm filter, aliquot into 2 mL bottles, and freeze-dry according to Table 1-3. Add 2 mL of normal saline to the lyophilized powder and shake until evenly dispersed. Observe the crystal morphology of the reconstituted active ingredient using an Olympus CX41 microscope. All crystals are irregular, with no regular crystals forming.

[0342] Table 10-1 Composition information

[0343] Example 11

[0344] Compositions containing different lyoprotectants

[0345] Weigh the prescribed amounts of ropivacaine, DMPC, cholesterol, sodium chloride, and lyoprotectant according to Table 11-1 into a Schott flask. Add tert-butyl alcohol aqueous solution and heat and stir until completely dissolved. Pass the solution through a 0.22 μm filter, aliquot into 2 mL bottles, and freeze-dry according to Table 1-3. Add 2 mL of normal saline to the lyophilized powder and shake until evenly dispersed. Observe the morphology of the reconstituted ropivacaine crystals using a microscope (Olympus, CX41), which is consistent with Figure 10. Simultaneously, use a laser particle size analyzer (OMEC, Topsizer) to measure the D90, which is consistently within the 10-50 μm range.

[0346] Table 11-1 Compositions containing different lyophilization protective agents

[0347] Example 12

[0348] In vivo administration of the composition

[0349] Pharmacokinetics in rats

[0350] SD rats weighing approximately 200 g were given free access to water and food throughout the experiment. Each group received medication by subcutaneous injection. Sample information is shown in Table 12-1.

[0351] Weigh the prescribed amount of ropivacaine, DMPC, cholesterol, and sodium chloride according to Table 12-1 into a Schott flask. Add tert-butyl alcohol aqueous solution and heat and stir until completely dissolved. Pass the mixture through a 0.22 μm filter and aliquot into 2 mL bottles. Freeze-dry according to Table 1-3. Add 2 mL of normal saline to the lyophilized powder and shake until uniformly dispersed to a 20 mg / mL suspension. Measure the D50 and D90 values ​​using a laser particle size analyzer (OMEC, Topsizer).

[0352] Each SD rat was dosed with 20 mg / kg. Approximately 0.3 mL of blood was collected from each group of animals at 0 hour before administration and at 15 minutes, 30 minutes, 1, 2, 4, 8, 10, 24, 32, 48, 56, and 72 hours after administration into EDTA-2K+ anticoagulant blood collection tubes. The whole blood was centrifuged at 8000 rpm for 5 minutes, and the plasma was collected. The drug concentration in the plasma samples was then detected by LC-MS / MS. The blood drug concentration curve is shown in Figure 14.

[0353] Table 12-1 Composition of the composition

[0354] The results showed that the compositions of the present invention all had good sustained-release effects.

[0355] Example 13

[0356] Pharmaceutical compositions at different pH

[0357] Acidic / alkaline regulators were added to the pharmaceutical composition or different pH buffers were used for reconstitution. The pH of the reconstituted drug solution was adjusted to investigate the effect of pH on free drug (drug dissolved in solution), ropivacaine crystal particle size, and sustained release.

[0358] (1) Pharmaceutical compositions containing acidity regulators

[0359] Weigh the prescribed amounts of ropivacaine, DMPC, cholesterol, sodium chloride, and maleic acid according to Table 13-1 into a Schott flask. Add tert-butyl alcohol aqueous solution and heat and stir until completely dissolved. Pass through a 0.22 μm filter and dispense into 2 mL bottles. Freeze-dry according to Table 1-3. Add 2 mL of normal saline to the lyophilized powder and shake until evenly dispersed. The pH, particle size distribution, and free drug content of the reconstituted composition were examined.

[0360] Table 13-1 Pharmaceutical compositions containing different amounts of acidity regulators

[0361] Table 13-2 pH, free drug and particle size distribution

[0362] The results showed that pH affected the concentration of free drug after reconstitution but did not affect the particle size distribution. Compositions 6133 and 6144 were subjected to in vitro release studies. The reconstituted drug solution was placed in a dialysis bag, placed in 200 mL of PBS 7.4 buffer, and shaken at 37°C and 50 rpm. Samples were then collected and tested for drug release. The results are shown in Table 13-3.

[0363] Table 13-3 In vitro release results

[0364] The results showed that adding an acidic regulator to the composition changed the free drug concentration in the composition, thereby increasing the drug release after 30 minutes.

[0365] (2) Pharmaceutical compositions containing alkaline regulators

[0366] Weigh the prescribed amounts of ropivacaine hydrochloride, DMPC, cholesterol, sodium hydroxide, and sodium chloride according to Table 13-4 into a Schott flask. Add tert-butyl alcohol aqueous solution and heat and stir until completely dissolved. Pass through a 0.22 μm filter and dispense into 2 mL bottles. Freeze-dry according to Table 1-3. Add 2 mL of normal saline to the lyophilized powder and shake until evenly dispersed. The pH and free drug content of the reconstituted composition were examined.

[0367] Table 13-4 Pharmaceutical compositions containing different amounts of alkaline regulators

[0368] Table 13-5 pH and free drugs

[0369] The results showed that the release of the drug could be regulated by adjusting the ratio of ropivacaine salt to alkaline regulator to control the free drug concentration.

[0370] (3) Compositions reconstituted using different pH buffers

[0371] The composition 6133 in Table 13-1 was reconstituted with buffer solutions of pH 5.0 to 7.4, and the pH and free drug of the composition were investigated.

[0372] Table 13-6 pH and free drug results

[0373] The results showed that the free drug concentration varied when the composition was reconstituted using different pH buffers. The release of the drug could be regulated by adjusting the pH of the reconstitution buffer to control the free drug concentration.

[0374] (4) In vivo administration of compositions with different pH values

[0375] Pharmacokinetics in rats

[0376] SD rats weighing approximately 200 g were given free access to water and food throughout the experiment. Each group was administered with subcutaneous injection. Sample information is shown in Table 13-7. Each SD rat was administered with a dose of 20 mg / kg. Blood samples of approximately 0.3 μg were collected from each group of animals at 0 hour before administration and at 15 minutes, 30 minutes, 1, 2, 4, 8, 10, 24, 32, 48, 56, and 72 hours after administration. m The whole blood was centrifuged at 8000 rpm for 5 minutes in EDTA-2K+ anticoagulant tubes, and plasma was collected. The drug concentration in the plasma sample was then determined by LC-MS / MS. Pharmacokinetic parameters are shown in Table 13-8.

[0377] Table 13-7 Composition of the composition

[0378] Table 13-8 Differences in blood drug concentrations in the early stage (0 to 2 hours)

[0379] The results showed that changing the pH of the composition only changed the initial Cmax and did not affect the overall sustained-release effect.

[0380] Pharmacokinetics in dogs

[0381] Beagle dogs weighing approximately 10 kg were given free access to water and food throughout the experiment. Each group received drug administration by subcutaneous injection. Sample information is shown in Table 13-9. Each beagle dog was dosed at a dose of 6 mg / kg. Approximately 0.3 mL of blood was collected from each group of animals at 0 hour before dosing and at 15 minutes, 30 minutes, and 1, 2, 4, 8, 10, 24, 32, 48, 56, 72, 96, 120, 144, and 168 hours after dosing. The whole blood was centrifuged at 8000 rpm for 5 minutes, and plasma was collected. Drug concentrations in the plasma samples were then determined by LC-MS / MS. Pharmacokinetic parameters are shown in Table 13-10.

[0382] Table 13-9 Composition Prescription

[0383] Table 13-10 Differences in blood drug concentrations in the early stage (0 to 2 hours)

[0384] The results showed that by adjusting the pH of the composition, the early drug release can be improved, the blood drug concentration can be increased within 0.25h to 2h, and the purpose of rapid onset of effect can be achieved.

[0385] Example 14

[0386] Comparative study with existing technologies

[0387] The long-acting aqueous sustained-release systems for ropivacaine currently disclosed in patent literature mainly include conventional suspension systems, liposome systems, microspheres, etc. Due to the various limitations of microspheres, the applicant selected conventional suspension systems and liposome systems for comparative research.

[0388] (1) Comparative study with ordinary suspension system

[0389] Common suspension systems commonly used in published patent literature use Tween or poloxamer as dispersants and sodium carboxymethyl cellulose as suspending agents. The crystal particle size is controlled by shearing. The preparation method is as follows:

[0390] Sodium carboxymethyl cellulose, sodium chloride and poloxamer 188 were weighed and dissolved in 45 ml of water for injection. After complete dissolution, ropivacaine was weighed and added to the above solution. High shear was applied at 8000 rpm for 10 minutes to fully disperse the ropivacaine. The volume was then made up to 45 ml with water for injection and the solution was dispensed into 2 ml bottles as Comparative Example 1.

[0391] The pharmacokinetic studies of the composition 6106 of the present invention and the composition of comparative example 1 were conducted in rats and dogs, respectively. The results are as follows:

[0392] Pharmacokinetic study in rats

[0393] Sprague-Dawley rats weighing approximately 200 g were given free access to water and food throughout the experiment. Each group received drug administration via subcutaneous injection. Sample information is shown in Table 14-1. Each SD rat was dosed at 20 mg / kg. Approximately 0.3 mL of blood was collected from each group at 0 hour before dosing and at 15 minutes, 30 minutes, and 1, 2, 4, 8, 10, 24, 32, 48, 56, and 72 hours after dosing. Blood samples were collected into EDTA-2K+ anticoagulant tubes. Whole blood was centrifuged at 8000 rpm for 5 minutes, and plasma was collected. Drug concentrations in plasma samples were then determined by LC-MS / MS. Pharmacokinetic parameters are shown in Table 14-2.

[0394] Table 14-1 Composition Information

[0395] Table 14-2 Pharmacokinetic parameters

[0396] Pharmacokinetic study in dogs

[0397] Beagle dogs weighing approximately 10 kg were given free access to water and food throughout the experiment. Each group received drug administration via subcutaneous injection. Sample information is shown in Table 14-3. Each beagle dog was dosed at 6 mg / kg. Approximately 0.3 mL of blood was collected from each group of animals at 0 hour before dosing and at 15 minutes, 30 minutes, and 1, 2, 4, 8, 10, 24, 32, 48, 56, 72, 96, 120, 144, and 168 hours after dosing. Blood samples were collected into EDTA-2K+ anticoagulant tubes. Whole blood was centrifuged at 8000 rpm for 5 minutes, and plasma was collected. Drug concentrations in plasma samples were then determined by LC-MS / MS. Pharmacokinetic parameters are shown in Table 14-4.

[0398] Table 14-3 Composition Information

[0399] Table 14-4 Pharmacokinetic parameters

[0400] The results showed that compared with the common suspension system, the suspension injection of the present application has excellent pharmacokinetic properties in vivo, for example, T 1 / 2 During the scale-up production process, the suspension injection of the present application can be filtered and sterilized, and the sterility is highly guaranteed.

[0401] (2) Comparative study with liposome system

[0402] The liposome systems disclosed in the patents are mainly multilamellar liposomes and multivesicular liposomes. Among them, multilamellar liposomes are in the clinical research stage, and multivesicular liposomes already have a marketed preparation EXPAREL with bupivacaine as the active ingredient.

[0403] Multilamellar liposomes were prepared as Comparative Examples 2 and 3 as follows:

[0404] Weigh the prescribed amount of active ingredient, DMPC, and cholesterol into a Schott flask. Add tert-butyl alcohol aqueous solution and heat and stir until completely dissolved. Pass through a 0.22 μm filter and aliquot into 5 mL bottles. Freeze at -45°C for 120 minutes, dry once at 0°C for 720 minutes, and then freeze at 30°C for 1080 minutes. Add 5 mL of normal saline to the lyophilized powder and shake until evenly dispersed. For comparative analysis,

[0405] Pharmacokinetic studies and comparative local safety studies were conducted in rats. Using EXPAREL as a control drug, pharmacokinetic studies in dogs and pharmacodynamic studies in guinea pigs were also conducted. The results are as follows:

[0406] Pharmacokinetic study in rats

[0407] SD rats weighing approximately 200 g were given free access to water and food throughout the experiment. Each group received drug administration by subcutaneous injection. Sample information is shown in Table 14-5. Each SD rat was dosed at 20 mg / kg. Approximately 0.3 mL of blood was collected from each group of animals at 0 hour before dosing and at 15 minutes, 30 minutes, and 1, 2, 4, 8, 10, 24, 32, 48, 56, and 72 hours after dosing. Blood samples were collected into EDTA-2K+ anticoagulant tubes. Whole blood was centrifuged at 8000 rpm for 5 minutes, and plasma was collected. Drug concentrations in plasma samples were then determined by LC-MS / MS. Pharmacokinetic parameters are shown in Table 14-6.

[0408] Table 14-5 Composition Information

[0409] Table 14-6 Pharmacokinetic parameters

[0410] Pharmacokinetic study in dogs

[0411] Beagle dogs weighing approximately 10 kg were given free access to water and food throughout the experiment. The marketed formulation EXPAREL was used as a control group, and composition 6144 and EXPAREL were administered by subcutaneous injection. Composition information is shown in Table 14-7. Each beagle dog was dosed at 6 mg / kg. Approximately 0.3 mL of blood was collected from each group of animals at 0 hour before dosing and at 15 minutes, 30 minutes, 1, 2, 4, 8, 10, 24, 32, 48, 56, 72, 96, 120, 144, and 168 hours after dosing. The whole blood was centrifuged at 8000 rpm for 5 minutes, and plasma was collected. The drug concentration in the plasma samples was then determined by LC-MS / MS. Pharmacokinetic parameters are shown in Table 14-8.

[0412] Table 14-7 Composition Information

[0413] Table 14-8 Pharmacokinetic parameters

[0414] In vivo pharmacodynamic study in rats

[0415] The marketed multivesicular liposome EXPAREL was used as a control group, and Composition 6144 and EXPAREL were administered subcutaneously. Composition information is shown in Table 14-7. The EXPAREL group received 6.65 mg per animal, and Composition 6144 received 10 mg per animal (equivalent to EXPAREL).

[0416] Basal pain threshold tests were performed two days before surgery (Day 2 and Day 1) and on the day of surgery (Day 0). The incisional postoperative pain model was then prepared. All rats were first anesthetized with 3.5-4% isoflurane in oxygen, and then maintained with 1.5-2% isoflurane. The foot skin was prepared with povidone-iodine solution and alcohol. Under sterile conditions, a 1 cm long longitudinal incision was made 0.5 cm from the posterior to the plantar aspect of each rat using a No. 11 scalpel blade. The fascia and muscle were separated, the flexor muscles were elevated, and the muscles were cut longitudinally. The wound was held open with a sterile cotton swab for 2 hours. Two discontinuous sutures were then made at the incision site with 3-0 silk sutures. The skin was then sutured and the skin at the incision site was smeared with povidone-iodine. After surgery, the rats were returned to their cages for recovery. Basal pain thresholds were measured 24 hours after surgery (designated as Day 1) before drug administration. Drugs were then administered, and pain thresholds were measured at different times after drug administration. The results are shown in Figure 15.

[0417] Topical safety study in rats

[0418] SD rats weighing approximately 200 g were given free access to water and food throughout the experiment. Each group received subcutaneous dosing. Sample information is shown in Table 14-9. Each SD rat received a dose of 20 mg / kg. Animals in each group were sacrificed 72 hours after dosing. The epidermis was dissected along the dosing site to observe the subcutaneous presence of the formulation and local irritation. The results are shown in Figure 16.

[0419] Table 14-9 Composition Information

[0420] Table 14-11 Inflammation

[0421] From the above results, it can be seen that compared with the existing liposome system, the suspension injection of the present invention has excellent pharmacokinetic properties in vivo, for example, its T 1 / 2The effect of local anesthesia (pain threshold) is better than that of the existing preparation EXPAREL; and the inflammatory reaction of the suspension injection is less or lighter, and the safety is also improved.

[0422] The embodiments of the present invention have been described above by way of example. However, the scope of protection of the present invention is not limited to the above-described exemplary embodiments. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principles of the present invention shall be included within the scope of protection of the claims of this application.

Claims

1. A suspension of ropivacaine or a pharmaceutically acceptable salt thereof, comprising: a) ropivacaine or a pharmaceutically acceptable salt thereof; in, The ropivacaine or pharmaceutically acceptable salt thereof in the suspension is present in a particle form, for example, in a crystal form, preferably in a regular crystal form, such as a rod-shaped crystal form or a block-shaped crystal form; Preferably, the D90 particle size of ropivacaine or a pharmaceutically acceptable salt thereof in the suspension is less than or equal to 200 μm, or less than or equal to 150 μm, or less than or equal to 120 μm, or less than or equal to 100 μm; preferably, the D90 particle size of ropivacaine or a pharmaceutically acceptable salt thereof in the suspension is 10 to 90 μm, for example 10 to 80 μm, preferably 10 to 70 μm, more preferably 10 to 60 μm; And / or, the pharmaceutically acceptable salt of ropivacaine is an acid salt of ropivacaine, i.e., an addition salt of ropivacaine and a pharmaceutically acceptable acid; for example, the acid salt of ropivacaine includes, but is not limited to, one or more of the following salts of ropivacaine selected from: acetate, benzoate, benzenesulfonate, hydrobromide, camphorsulfonate, hydrochloride, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hydroiodide, isethionate, lactate, lactobionate, dodecyl sulfate, malate, maleate, methanesulfonate, naphthoate, naphthylate, nitrate, stearate, palmitate, myristate, laurate, oleate, oxalate, pamoate, phosphate, polygalacturonate, succinate, sulfate, sulfosalicylate, tartrate, toluenesulfonate, trifluoroacetate.

2. The suspension according to claim 1, characterized in that The suspension may further comprise: b) a pharmaceutically acceptable stabilizer; Preferably, the pharmaceutically acceptable stabilizer is selected from high carbon alcohols (such as C 18 ~C 30 High carbon alcohol), C 18 ~C 30 One or more acids or their salts; Preferably, the pharmaceutically acceptable stabilizer is selected from one or more of cholesterol, octadecyl alcohol, cholic acid or its salt, deoxycholic acid or its salt, taurodeoxycholic acid or its salt, ursodeoxycholic acid or its salt, chenodeoxycholic acid or its salt, glycocholic acid or its salt; Preferably, the pharmaceutically acceptable stabilizer is selected from one or more of cholesterol, octadecyl alcohol, cholic acid, deoxycholic acid, taurodeoxycholic acid, ursodeoxycholic acid, chenodeoxycholic acid, glycocholic acid, sodium cholate, sodium deoxycholate, sodium taurodeoxycholate, sodium ursodeoxycholate, sodium chenodeoxycholate, and sodium glycocholate; Preferably, the molar ratio of ropivacaine or a pharmaceutically acceptable salt thereof to the stabilizer is 0.5:1 to 30:1, preferably 1:1 to 15:1, preferably 1:1 to 10:1, and more preferably 1:1 to 7:1; And / or, the suspension optionally further comprises: c) a pharmaceutically acceptable dispersant; Preferably, the pharmaceutically acceptable dispersant is selected from one or more of polysorbate (Tween), poloxamer, polyoxyethylene fatty acid esters, polyoxyethylene fatty acid ethers, sucrose fatty acid esters, sodium lauryl sulfate, polyethylene glycol-15 hydroxystearate (HS-15), and phospholipids; Preferably, the polysorbate is selected from one or more of polysorbate 80 (Tween 80) and polysorbate 20 (Tween 20); Preferably, the phospholipid is selected from one or more of DMPC (dimyristoylphosphatidylcholine), DPPC (dipalmitoylphosphatidylcholine), DLPC (dilauroylphosphatidylcholine), SPC soybean phosphatidylcholine (soy lecithin), EPC (egg yolk phospholipids), DEPC (dierucoylphosphatidylcholine), DOPC (dioleoylphosphatidylcholine), POPC (palmitoyloleoylphosphatidylcholine); Preferably, the molar ratio of ropivacaine or a pharmaceutically acceptable salt thereof to the pharmaceutically acceptable dispersant is 50:1 to 1:1, preferably 40:1 to 2:1, more preferably 30:1 to 2:1, more preferably 20:1 to 2:1; And / or, the suspension optionally further comprises: d) clinically acceptable diluent; Preferably, clinically acceptable diluents include but are not limited to one or more of water for injection, sodium chloride injection, glucose injection, lactated Ringer's solution, sucrose aqueous solution, xylitol aqueous solution, and pH buffer solution; Preferably, the suspension is a suspension injection; Preferably, in the suspension, the concentration of ropivacaine or a pharmaceutically acceptable salt thereof is about 0.1 mg / mL to about 300 mg / mL, preferably about 1 mg / mL to about 50 mg / mL, more preferably about 2.5 mg / mL to about 40 mg / mL; And / or, the suspension optionally further comprises: e) pharmaceutically acceptable inorganic salts; Preferably, the pharmaceutically acceptable inorganic salt has a water solubility of greater than 10 g / 100 mL at 20°C; Preferably, the pharmaceutically acceptable inorganic salt is selected from one or more of sodium chloride, sodium sulfate, potassium chloride, potassium sulfate, potassium phosphate, ammonium sulfate, ammonium chloride, magnesium chloride, magnesium sulfate, calcium chloride, and barium chloride; preferably one or more of sodium chloride, potassium sulfate, magnesium chloride, magnesium sulfate, potassium chloride, and calcium chloride; Preferably, the molar ratio of the ropivacaine or its pharmaceutically acceptable salt to the pharmaceutically acceptable inorganic salt is ≥1:0.02, preferably 1:0.02 to 1:2.0; And / or, the suspension optionally further comprises: f) a pharmaceutically acceptable pH adjusting agent; Preferably, the pH adjuster is selected from alkaline pH adjusters and acidic pH adjusters; Preferably, the alkaline pH regulator is selected from one or more of meglumine, tromethamine, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, magnesium hydroxide, calcium hydroxide, sodium phosphate, disodium hydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, sodium citrate, sodium acetate, potassium acetate, ammonium acetate, triethylamine, ethanolamine, and diethanolamine; preferably one or more of sodium hydroxide, potassium hydroxide, magnesium hydroxide, sodium bicarbonate, and calcium hydroxide; Preferably, the acidic pH regulator is selected from one or more of citric acid, tartaric acid, maleic acid, malic acid, fumaric acid, succinic acid, succinic acid, hydrochloric acid, phosphoric acid, ascorbic acid, lactic acid, acetic acid, methanesulfonic acid, oxalic acid, sulfuric acid, glycine, sodium dihydrogen phosphate, and potassium dihydrogen phosphate; preferably one or more of citric acid, tartaric acid, maleic acid, malic acid, fumaric acid, succinic acid, succinic acid, hydrochloric acid, phosphoric acid, lactic acid, and acetic acid; Preferably, the pH value of the suspension is 6.0 to 9.0, preferably 6.0 to 8.5, preferably 6.0 to 8.0, more preferably 6.0 to 7.5; Preferably, the ropivacaine in the suspension can also be prepared in situ, for example, by reacting a pharmaceutically acceptable salt of ropivacaine with a base, preferably by reacting a pharmaceutically acceptable salt of ropivacaine with an alkaline pH regulator; wherein the pharmaceutically acceptable salt of ropivacaine has the definition described above; Preferably, when ropivacaine is prepared in situ as described above, the molar ratio of the pharmaceutically acceptable salt of ropivacaine to the alkaline pH regulator may be 1:0.5 to 1:2.0, preferably 1:0.8 to 1:1.5, preferably 1:1.0 to 1:1.2; And / or, the suspension optionally further comprises: g) pharmaceutically acceptable osmotic pressure regulator; Preferably, the osmotic pressure regulator is selected from one or more of sodium chloride, mannitol, lactose, glucose, sorbitol, sorbitol and glycerol, preferably one or more of sodium chloride, glucose, sorbitol and mannitol; Preferably, the osmotic pressure of the suspension injection is equivalent to the physiological osmotic pressure; And / or, the suspension optionally further comprises: h) a pharmaceutically acceptable lyoprotectant; Preferably, the pharmaceutically acceptable lyoprotectant is selected from one or more of mannitol, lactose, trehalose, sucrose, maltose, dextrin, stachyose, gelatin, pectin, sugar alcohol, sorbitol, proline, histidine, lysine, arginine, polyethylene glycol or polyvinyl pyrrolidine, preferably one or more of mannitol, lactose, trehalose, sucrose and polyvinyl pyrrolidine.

3. A solid composition of ropivacaine or a pharmaceutically acceptable salt thereof, characterized in that: The solid composition comprises: i) ropivacaine or a pharmaceutically acceptable salt thereof; Wherein, the ropivacaine or a pharmaceutically acceptable salt thereof in the solid composition exists in the form of particles, such as in the form of crystals, preferably in the form of rod-shaped or block-shaped crystals; Preferably, in the solid composition, the D90 particle size of ropivacaine or its pharmaceutically acceptable salt is less than or equal to 200 μm, or less than or equal to 150 μm, or less than or equal to 120 μm, or less than or equal to 100 μm; preferably, the D90 particle size of ropivacaine or its pharmaceutically acceptable salt in the suspension is 10 to 90 μm, for example 10 to 80 μm, preferably 10 to 70 μm, more preferably 10 to 60 μm; And / or, the pharmaceutically acceptable salt of ropivacaine is an acid salt of ropivacaine, i.e., an addition salt of ropivacaine and a pharmaceutically acceptable acid; for example, the acid salt of ropivacaine includes, but is not limited to, one or more of the following salts of ropivacaine selected from: acetate, benzoate, benzenesulfonate, hydrobromide, camphorsulfonate, hydrochloride, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hydroiodide, isethionate, lactate, lactobionate, dodecyl sulfate, malate, maleate, methanesulfonate, naphthoate, naphthylate, nitrate, stearate, palmitate, myristate, laurate, oleate, oxalate, pamoate, phosphate, polygalacturonate, succinate, sulfate, sulfosalicylate, tartrate, toluenesulfonate, trifluoroacetate.

4. The solid composition according to claim 3, characterized in that The solid composition may further comprise: ii) a pharmaceutically acceptable stabilizer; Preferably, the pharmaceutically acceptable stabilizer is selected from high carbonic acid (such as C 18 ~C 30 High carbon alcohol), C 18 ~C 30 One or more acids or their salts; Preferably, the pharmaceutically acceptable stabilizer is selected from one or more of cholesterol, octadecyl alcohol, cholic acid or its salt, deoxycholic acid or its salt, taurodeoxycholic acid or its salt, ursodeoxycholic acid or its salt, chenodeoxycholic acid or its salt, glycocholic acid or its salt; Preferably, the pharmaceutically acceptable stabilizer is selected from one or more of cholesterol, octadecanol, cholic acid, deoxycholic acid, ursodeoxycholic acid, chenodeoxycholic acid, glycocholic acid, sodium cholate, sodium deoxycholate, and sodium taurodeoxycholate; Preferably, the molar ratio of ropivacaine or a pharmaceutically acceptable salt thereof to the stabilizer is 0.5:1 to 30:1, preferably 1:1 to 15:1, preferably 1:1 to 10:1, and more preferably 1:1 to 7:1; And / or, the solid composition optionally further comprises: iii) a pharmaceutically acceptable dispersant; Preferably, the pharmaceutically acceptable dispersant is selected from one or more of polysorbate (Tween), poloxamer, polyoxyethylene fatty acid esters, polyoxyethylene fatty acid ethers, sucrose fatty acid esters, sodium lauryl sulfate, polyethylene glycol-15 hydroxystearate (HS-15), and phospholipids; Preferably, the polysorbate is selected from one or more of polysorbate 80 (Tween 80) and polysorbate 20 (Tween 20); Preferably, the phospholipid is selected from one or more of DMPC (dimyristoylphosphatidylcholine), DPPC (dipalmitoylphosphatidylcholine), DLPC (dilauroylphosphatidylcholine), SPC soybean phosphatidylcholine (soy lecithin), EPC (egg yolk phospholipids), DEPC (dierucoylphosphatidylcholine), DOPC (dioleoylphosphatidylcholine), POPC (palmitoyloleoylphosphatidylcholine); Preferably, the molar ratio of ropivacaine or a pharmaceutically acceptable salt thereof to the pharmaceutically acceptable dispersant is 50:1 to 1:1, preferably 40:1 to 2:1, more preferably 30:1 to 2:1, more preferably 20:1 to 2:1; And / or, the solid composition optionally further comprises: iv) pharmaceutically acceptable inorganic salts; Preferably, the solubility of the pharmaceutically acceptable inorganic salt in water at 20°C is greater than 10 g / 100 mL; Preferably, the solid composition optionally comprises: an inorganic salt selected from one or more of sodium chloride, sodium sulfate, potassium chloride, potassium sulfate, potassium phosphate, ammonium sulfate, ammonium chloride, magnesium chloride, magnesium sulfate, calcium chloride, and barium chloride; preferably one or more of sodium chloride, potassium sulfate, magnesium chloride, magnesium sulfate, potassium chloride, and calcium chloride; Preferably, the molar ratio of ropivacaine or a pharmaceutically acceptable salt thereof to a pharmaceutically acceptable inorganic salt is ≥1:0.02, preferably 1:0.02 to 1:2.0; And / or, the solid composition optionally further comprises: v) a pharmaceutically acceptable pH adjusting agent; Preferably, the pH adjuster is selected from alkaline pH adjusters and acidic pH adjusters; Preferably, the alkaline pH regulator is selected from one or more of meglumine, tromethamine, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, magnesium hydroxide, calcium hydroxide, sodium phosphate, disodium hydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, sodium citrate, sodium acetate, potassium acetate, ammonium acetate, triethylamine, ethanolamine, and diethanolamine; preferably one or more of sodium hydroxide, potassium hydroxide, magnesium hydroxide, sodium bicarbonate, and calcium hydroxide; Preferably, the acidic pH regulator is selected from one or more of citric acid, tartaric acid, maleic acid, malic acid, fumaric acid, succinic acid, succinic acid, hydrochloric acid, phosphoric acid, ascorbic acid, lactic acid, acetic acid, methanesulfonic acid, oxalic acid, sulfuric acid, glycine, sodium dihydrogen phosphate, potassium dihydrogen phosphate; preferably one or more of citric acid, tartaric acid, maleic acid, malic acid, fumaric acid, succinic acid, succinic acid, hydrochloric acid, phosphoric acid, lactic acid, acetic acid; Preferably, the solid composition is reconstituted to form a suspension; Preferably, the pH value of the suspension is 6.0 to 9.0, preferably 6.0 to 8.5, preferably 6.0 to 8.0, more preferably 6.0 to 7.5; And / or, the solid composition optionally further comprises: vi) a pharmaceutically acceptable osmotic pressure regulator; Preferably, the pharmaceutically acceptable osmotic pressure regulator is selected from one or more of sodium chloride, mannitol, lactose, glucose, sorbitol, sorbitol and glycerol, preferably one or more of sodium chloride, glucose, sorbitol and mannitol; And / or, the solid composition optionally further comprises: vii) a pharmaceutically acceptable lyoprotectant; Preferably, the pharmaceutically acceptable lyoprotectant is selected from one or more of mannitol, lactose, trehalose, sucrose, maltose, dextrin, stachyose, gelatin, pectin, sugar alcohol, sorbitol, proline, histidine, lysine, arginine, polyethylene glycol or polyvinyl pyrrolidine, preferably one or more of mannitol, lactose, trehalose, sucrose and polyvinyl pyrrolidine.

5. A method for preparing a solid pharmaceutical composition, the method comprising: Drying the solution containing the active pharmaceutical ingredient to obtain the solid composition; In the solid pharmaceutical composition obtained after drying, the pharmaceutically active ingredient exists in the form of particles, such as in the form of crystals, preferably in the form of rod-shaped crystals or block-shaped crystals; Preferably, the preparation method comprises: sterilizing and filtering a solution containing a pharmaceutically active ingredient, and drying to obtain a solid composition of ropivacaine or a pharmaceutically acceptable salt thereof; Preferably, the drying method includes evaporative drying, freeze drying, spray drying, preferably freeze drying; Preferably, the freeze drying comprises a pre-freezing process and a drying process; Preferably, the pharmaceutically active ingredient may be dissolved in a solvent to form the solution containing the pharmaceutically active ingredient; Preferably, the solvent can be selected from an inorganic solvent, an organic solvent or a mixture thereof suitable for dissolving the active pharmaceutical ingredient; for example, the solvent is water, an organic solvent or a co-solvent system comprising water and an organic solvent, preferably one or more of water, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, acetone, acetonitrile, dichloromethane, and dimethyl sulfoxide, more preferably water, ethanol, isopropanol, tert-butanol, or a co-solvent system comprising water and one or more of the following organic solvents: A variety of co-solvent systems: methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, acetone, acetonitrile, dichloromethane, dimethyl sulfoxide; for example, the co-solvent system is selected from a co-solvent system comprising water and one of the following organic solvents: ethanol, isopropanol, tert-butanol; Preferably, in the co-solvent system of water and organic solvent, the volume percentage of the organic solvent is 1% to 99%, such as 10% to 90%, preferably 50% to 90%; Preferably, the solid pharmaceutical composition can be selected from a solid composition of ropivacaine or a pharmaceutically acceptable salt thereof, preferably a solid composition of ropivacaine or a pharmaceutically acceptable salt thereof according to claim 3 or 4; Preferably, when the pharmaceutically active ingredient in the solution is a pharmaceutically acceptable salt, such as a pharmaceutically acceptable acid addition salt or base addition salt, it can react with a pH adjuster in the solution to prepare in situ the corresponding free active ingredient, such as a free alkaline active ingredient or a free acidic active ingredient.

6. A method for preparing a suspension, comprising re-dissolving the solid composition according to any one of claims 3 to 4 or the solid pharmaceutical composition according to claim 5 to obtain the suspension; Preferably, the preparation method comprises mixing the solid composition according to any one of claims 3 to 4 or the solid pharmaceutical composition according to claim 5 with a clinically acceptable diluent to obtain a suspension; Preferably, the clinically acceptable diluent includes but is not limited to one or more of water for injection, sodium chloride injection, glucose injection, lactated Ringer's solution, sucrose solution, xylitol solution, and pH buffer solution.

7. Use of a pharmaceutically acceptable inorganic salt and / or a pharmaceutically acceptable stabilizer as a stabilizer for particles (e.g., crystals) of ropivacaine or a pharmaceutically acceptable salt thereof; Preferably, the pharmaceutically acceptable inorganic salt and / or pharmaceutically acceptable stabilizer is used as a stabilizer for particles (e.g., crystals) of ropivacaine or its pharmaceutically acceptable salt in the method for preparing the above-mentioned suspension of ropivacaine or its pharmaceutically acceptable salt, or the solid composition of ropivacaine or its pharmaceutically acceptable salt.

8. The use according to claim 7, characterized in that The pharmaceutically acceptable inorganic salt and / or pharmaceutically acceptable stabilizer is used to promote the stable existence of ropivacaine or its pharmaceutically acceptable salt in the form of particles (such as crystals) in the suspension or solid composition, preferably in the form of regular crystals, such as rod-shaped or block-shaped crystals.

9. The use according to claim 7 or 8, characterized in that The inorganic salt is selected from pharmaceutically acceptable inorganic salts having a solubility in water greater than 10 g / 100 mL of water at 20°C; Preferably, the inorganic salt is selected from one or more of sodium chloride, sodium sulfate, potassium chloride, potassium sulfate, potassium phosphate, ammonium sulfate, ammonium chloride, magnesium chloride, magnesium sulfate, calcium chloride, and barium chloride, for example, selected from one or more of sodium chloride, potassium sulfate, magnesium chloride, magnesium sulfate, potassium chloride, and calcium chloride; Preferably, the pharmaceutically acceptable stabilizer is selected from C 18 ~C 30 High carbon alcohol, C 18 ~C 30 Acid or salt thereof, for example, one or more selected from the group consisting of cholesterol, octadecyl alcohol, cholic acid, deoxycholic acid, ursodeoxycholic acid, chenodeoxycholic acid, glycocholic acid, sodium cholate, sodium deoxycholate, and sodium taurodeoxycholate.

10. Use of the suspension according to any one of claims 1 to 2 or the solid composition according to any one of claims 3 to 4 in the preparation of a medicament for producing anesthesia or relieving pain, or in the preparation of a medicament for treating and / or preventing pain; Preferably, the suspension or solid composition is applied around a nerve or to a surgical wound; Preferably, the administration is parenteral and / or topical; Preferably, parenteral administration is selected from intravenous, intramuscular, subcutaneous, intraarticular, epidural, subarachnoid, incisional, infiltration and nerve block, preferably intramuscular, subcutaneous, intraarticular, epidural, subarachnoid, incisional, infiltration and nerve block; Preferably, the pain is chronic postoperative pain or labor pain.

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