Ropivacaine microspheres and preparation method thereof

Abstract

The invention discloses ropivacaine microspheres and a preparation method thereof, and belongs to the field of medicines. The ropivacaine microsphere comprises ropivacaine or a pharmaceutically acceptable salt thereof, at least one glucocorticoid or a pharmaceutically acceptable salt thereof, and at least one biocompatible biodegradable sustained-release material with an effective amount for prolonging the release of a drug from a preparation, wherein the time required for 80% cumulative release of ropivacaine or pharmaceutically acceptable salts thereof is more than 1.7 times of the time required for 80% cumulative release of glucocorticoid or pharmaceutically acceptable salts thereof or esters thereof.

Description

Ropivacaine microspheres and preparation method thereof

[0001] Priority claim: The present invention claims priority to Chinese patent application No. 202310893969.5 filed on July 19, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0002] The present invention relates generally to the field of pain management medicine, and more particularly to implantable biodegradable microspheres for topical drug delivery. Background Art

[0003] Postoperative pain refers to acute pain that occurs immediately after surgery and generally lasts for at least 48 to 72 hours. Local anesthetics are the most direct method of postoperative analgesia, but the half-life of local anesthetics used in clinical practice is short, requiring frequent administration every 4 to 6 hours. Ropivacaine is a new amide local anesthetic that is commonly used for postoperative analgesia, but its plasma half-life is only 1.8 hours, requiring continuous injection to achieve satisfactory analgesic effect. Currently available ropivacaine hydrochloride injection The effective analgesic time is only 6 to 8 hours, and frequent injections are required.

[0004] There is a lack of preparations in clinical practice that can maintain a sufficiently long-lasting anesthetic effect to reduce the trouble of frequent and multiple dosing required for patients.

[0005] Summary of the Invention

[0006] In one aspect, the present invention relates to ropivacaine microspheres comprising ropivacaine or a pharmaceutically acceptable salt thereof, at least one glucocorticoid or a pharmaceutically acceptable salt thereof or an ester thereof, and at least one biocompatible, biodegradable sustained-release material effective in prolonging the release of the drug from the formulation, wherein the time required for the cumulative release of ropivacaine or a pharmaceutically acceptable salt thereof to be 80% is at least 1.7 times the time required for the cumulative release of the glucocorticoid or a pharmaceutically acceptable salt thereof to be 80%.

[0007] On the other hand, the present invention relates to ropivacaine microspheres, which contain ropivacaine or a pharmaceutically acceptable salt thereof, at least one glucocorticoid or a pharmaceutically acceptable salt or ester thereof, and at least one biocompatible, biodegradable sustained-release material effective in prolonging the release of the drug from the preparation, wherein when the cumulative release of ropivacaine or a pharmaceutically acceptable salt thereof reaches 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80%, the sum of the differences between the cumulative release of the glucocorticoid or a pharmaceutically acceptable salt or ester thereof and the cumulative release of ropivacaine or a pharmaceutically acceptable salt thereof is not less than 105%.

[0008] In another aspect, the present invention relates to ropivacaine microspheres, which comprise ropivacaine or a pharmaceutically acceptable salt thereof, at least one glucocorticoid or a pharmaceutically acceptable salt thereof or an ester thereof, and at least one biocompatible, biodegradable sustained-release material effective in prolonging the release of the drug from the formulation, wherein the ropivacaine or a pharmaceutically acceptable salt thereof can be sustained-released for at least 48 hours, and the glucocorticoid or a pharmaceutically acceptable salt thereof or an ester thereof can be sustained-released for at least 24 hours.

[0009] In another aspect, the present invention relates to a ropivacaine microsphere, which comprises, by mass percentage, 40-72% of ropivacaine or a pharmaceutically acceptable salt thereof, 0.1-3% of a glucocorticoid or a pharmaceutically acceptable salt or ester thereof, 20-65% of a biodegradable sustained-release material, and 0-15% of a pore-forming agent.

[0010] In another aspect, the present invention relates to a method for preparing ropivacaine microspheres, comprising the following steps:

[0011] (1) dissolving ropivacaine or a pharmaceutically acceptable salt thereof, at least one glucocorticoid or a pharmaceutically acceptable salt or ester thereof, at least one effective amount of a biocompatible, biodegradable sustained-release material for prolonging the release of the drug from the preparation, and optionally polyethylene glycol in an organic solvent to obtain an oil phase;

[0012] (2) preparing a 1% polyvinyl alcohol aqueous solution and adjusting the pH to alkaline to obtain an aqueous phase;

[0013] (3) preparing a 0.1% polyvinyl alcohol aqueous solution and adjusting the pH to alkaline to obtain a hardening solution;

[0014] (4) The oil phase and the water phase are mixed to prepare colostrum, the colostrum is added to the hardening liquid, stirred to remove the organic solvent, and then collected, washed, and dried.

[0015] In another aspect, the present invention relates to a method for local administration to provide long-acting analgesia or nerve block, comprising administering ropivacaine microspheres, wherein the microspheres comprise ropivacaine or a pharmaceutically acceptable salt thereof, at least one glucocorticoid or a pharmaceutically acceptable salt thereof or ester thereof, and at least one biocompatible, biodegradable sustained-release material effective to prolong the release of the drug from the formulation, wherein the sum of the differences between the cumulative release amounts of the glucocorticoid or a pharmaceutically acceptable salt thereof or ester thereof and the cumulative release amount of the ropivacaine or a pharmaceutically acceptable salt thereof is not less than 105% when the cumulative release amount of the ropivacaine or a pharmaceutically acceptable salt thereof reaches 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80%.

[0016] Details

[0017] In the following description, certain specific details are included to provide a comprehensive understanding of each disclosed embodiment. However, one skilled in the relevant art will recognize that the embodiments can still be implemented without one or more of these specific details and with other methods, components, materials, etc.

[0018] Unless otherwise required herein, throughout the specification and the appended claims, the words "include", "comprising", "containing" and "having" should be interpreted as having an open and inclusive meaning, that is, "including but not limited to".

[0019] As used herein and in the appended claims, singular references without indications of quantity include plural references unless the context clearly dictates otherwise.

[0020] Reference throughout this specification to "one embodiment," "an embodiment," "in another embodiment," or "in certain embodiments" means that at least one embodiment includes the specific referenced elements, structures, or features described in connection with that embodiment. Thus, appearances of the phrases "in one embodiment," "in an embodiment," "in another embodiment," or "in certain embodiments" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the specific elements, structures, or features may be combined in any suitable manner in one or more embodiments.

[0021] It should be understood that the singular article "a," "an," and "the" used in the specification of the present invention and the appended claims includes plural referents unless the context clearly dictates otherwise. Thus, for example, a reference to a sustained-release tablet containing "a pharmaceutically acceptable excipient" includes one pharmaceutically acceptable excipient, or two or more pharmaceutically acceptable excipients.

[0022] The term "about" when referring to an amount or a numerical range means that the amount or numerical range referred to is an approximate value within the experimental variability (or within statistical experimental error). In the present invention, the term "about" should have a meaning within 10% of a specified value or range, preferably within 5%.

[0023] definition

[0024] In the present invention, the term "ropivacaine" refers to (S)-N-(2,6-dimethylphenyl)-1-propyl-2-piperidinecarboxamide.

[0025] In the present invention, the term "pharmaceutically acceptable salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are biologically or otherwise suitable and are formed using inorganic or organic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzenecarboxylic acid, 4-acetamidobenzenecarboxylic acid, camphoric acid, camphor-10-sulfonic acid, decanoic acid, hexanoic acid, octanoic acid, carbonic acid, cinnamic acid, citric acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethane Alkanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, etc.

[0026] In the present invention, the term "microsphere" refers to a tiny spherical entity formed by dissolving and / or dispersing a drug, being encapsulated and / or adsorbed in a biocompatible and biodegradable polymer matrix, and also refers to a microcapsule.

[0027] In the present invention, the term "polylactic acid-glycolic acid copolymer" refers to a polymer obtained by condensation polymerization of glycolic acid and lactic acid as monomers, or a polymer obtained by ring-opening polymerization of lactide and glycolide as monomers, also known as lactide-glycolide copolymer. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Various embodiments of the present invention will be described below with reference to the accompanying drawings:

[0029] FIG1 shows the cumulative release curve of ropivacaine dexamethasone acetate microspheres in Example 1 of the present invention;

[0030] FIG2 shows a graph showing the thermal pain threshold of ropivacaine acetate-dexamethasone microspheres in rats in Example 1 of the present invention;

[0031] FIG3 shows the cumulative release curve of ropivacaine dexamethasone acetate microspheres of Example 2 of the present invention;

[0032] FIG4 shows a graph showing the thermal pain threshold of rats using ropivacaine acetate-dexamethasone microspheres in Example 2 of the present invention;

[0033] FIG5 shows the cumulative release curve of ropivacaine dexamethasone acetate microspheres of Example 3 of the present invention;

[0034] FIG6 shows a graph showing the thermal pain threshold of rats subjected to ropivacaine acetate-dexamethasone microspheres in Example 3 of the present invention;

[0035] FIG7 shows the cumulative release curve of ropivacaine and dexamethasone acetate microspheres of Example 4 of the present invention;

[0036] FIG8 shows a graph showing the thermal pain threshold of rats using ropivacaine acetate-dexamethasone microspheres in Example 4 of the present invention;

[0037] FIG9 shows the cumulative release curve of ropivacaine and dexamethasone acetate microspheres of Example 5 of the present invention;

[0038] FIG10 shows a graph showing the thermal pain threshold of rats using ropivacaine acetate-dexamethasone microspheres in Example 5 of the present invention;

[0039] FIG11 shows the cumulative release curve of ropivacaine and dexamethasone acetate microspheres of Example 6 of the present invention;

[0040] FIG12 shows a graph showing the thermal pain threshold of rats using ropivacaine acetate-dexamethasone microspheres in Example 6 of the present invention;

[0041] FIG13 shows the cumulative release curve of ropivacaine and dexamethasone acetate microspheres of Example 7 of the present invention;

[0042] FIG14 shows the mechanical pain threshold curve of ropivacaine acetate and dexamethasone microspheres in Example 7 of the present invention;

[0043] FIG15 shows the incubation period curve of the heat shrinkage group of ropivacaine acetate and dexamethasone microspheres in Example 7 of the present invention;

[0044] FIG16 shows the cumulative release curve of ropivacaine and dexamethasone acetate microspheres of Example 8 of the present invention;

[0045] FIG17 shows the cumulative release curve of ropivacaine and dexamethasone acetate microspheres of Example 9 of the present invention;

[0046] FIG18 shows the cumulative release curve of ropivacaine and dexamethasone acetate microspheres of Example 10 of the present invention;

[0047] FIG19 shows the cumulative release curve of ropivacaine-dexamethasone microspheres of Example 11 of the present invention;

[0048] FIG20 shows the cumulative release curve of ropivacaine-dexamethasone microspheres of Example 12 of the present invention;

[0049] FIG21 shows the cumulative release curve of ropivacaine dexamethasone acetate microspheres of Comparative Example 1 of the present invention;

[0050] FIG22 shows a graph showing the thermal pain threshold of rats in the comparative example 1 of the present invention using ropivacaine acetate and dexamethasone microspheres;

[0051] FIG23 shows the cumulative release curve of ropivacaine dexamethasone acetate microspheres of Comparative Example 2 of the present invention;

[0052] FIG24 shows the cumulative release curve of ropivacaine dexamethasone acetate microspheres of Comparative Example 3 of the present invention;

[0053] FIG25 shows the cumulative release curve of ropivacaine dexamethasone acetate microspheres of Comparative Example 4 of the present invention. DETAILED DESCRIPTION

[0054] In one aspect, the present invention relates to ropivacaine microspheres comprising ropivacaine or a pharmaceutically acceptable salt thereof, at least one glucocorticoid or a pharmaceutically acceptable salt thereof or an ester thereof, and at least one biocompatible, biodegradable sustained-release material effective in prolonging the release of the drug from the formulation, wherein the time required for the cumulative release of ropivacaine or a pharmaceutically acceptable salt thereof to be 80% is at least 1.7 times the time required for the cumulative release of the glucocorticoid or a pharmaceutically acceptable salt thereof to be 80%.

[0055] In certain embodiments, the time required for 80% cumulative release of ropivacaine or a pharmaceutically acceptable salt thereof from the ropivacaine microspheres of the present invention is at least 1.8 times, at least 1.9 times, at least 2.0 times, at least 2.1 times, at least 2.2 times, at least 2.3 times, at least 2.4 times, at least 2.5 times, at least 2.6 times, at least 2.7 times, at least 2.8 times, at least 2.9 times, at least 3.0 times, at least 3.1 times, at least 3.2 times, at least 3.3 times, at least 3.4 times, at least 3.5 times, at least 3.6 times, at least 3.7 times, at least 3.8 times, at least 3.9 times, at least 4.0 times, at least 4.1 times, at least 4.2 times, at least 4.3 times, at least 4.4 times, at least 4.5 times, at least 4.6 times, at least 4.7 times, at least 4.8 times, at least 4.9 times or at least 5.0 times the time required for 80% cumulative release of a glucocorticoid or a pharmaceutically acceptable salt or ester thereof.

[0056] In certain embodiments, the cumulative release of ropivacaine or a pharmaceutically acceptable salt thereof in the ropivacaine microspheres of the present invention over 24 hours is not less than 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64% or 65%.

[0057] In certain embodiments, the ropivacaine microspheres of the present invention can release ropivacaine or a pharmaceutically acceptable salt thereof for at least 48 hours, 50 hours, 52 hours, 54 hours, 56 hours, 58 hours, 60 hours, 62 hours, 64 hours, 66 hours, 68 hours, 70 hours, 72 hours, 74 hours, 76 hours, 78 hours, 80 hours, 82 hours, 84 hours, 86 hours, 88 hours, 90 hours, 92 hours, 94 hours, 96 hours, hours, 98 hours, 100 hours, 102 hours, 104 hours, 106 hours, 108 hours, 110 hours, 112 hours, 114 hours, 116 hours, 118 hours, 120 hours, 122 hours, 124 hours, 126 hours, 128 hours, 130 hours, 132 hours, 134 hours, 136 hours, 138 hours, 140 hours, 142 hours, 144 hours, 146 hours, 148 hours, 150 hours , 152 hours, 154 hours, 156 hours, 158 hours, 160 hours, 162 hours, 164 hours, 166 hours, 168 hours, 170 hours, 172 hours, 174 hours, 176 hours, 178 hours, 180 hours, 182 hours, 184 hours, 186 hours, 188 hours, 190 hours, 195 hours, 200 hours, 205 hours, 210 hours, 215 hours, 220 hours, 225 hours , 230 hours, 235 hours, 240 hours, 245 hours, 250 hours, 255 hours, 260 hours, 265 hours, 270 hours, 275 hours, 280 hours, 285 hours, 290 hours, 295 hours, 300 hours, 305 hours, 310 hours, 315 hours, 320 hours, 325 hours, 330 hours, 335 hours, 340 hours, 345 hours, 350 hours, 355 hours or 360 hours.

[0058] In certain embodiments, the glucocorticoid or its pharmaceutically acceptable salt or ester in the ropivacaine microspheres of the present invention can be sustained-released for at least 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, 40 hours, 41 hours, 42 hours, 43 hours, 44 hours, 45 hours, 46 hours, 47 hours, 48 ​​hours, 49 hours, 50 hours, 51 hours, 52 hours, 53 hours, 54 hours, 55 hours, 56 hours, 57 hours, 58 hours, 59 hours, 60 hours, 61 hours, 62 hours, 63 hours, 64 hours, 65 hours, 66 hours, 67 hours, 68 hours, 69 hours, 70 hours, 71 hours, 72 hours, 73 hours, 74 hours, 75 hours, 76 hours, 77 hours, 78 hours, 79 hours, 80 hours, 81 hours, 82 hours, 83 hours, 84 hours, 85 hours, 86 hours, 87 hours, 88 hours, 89 hours, 90 hours, 91 hours, 92 hours, 93 hours, 94 hours, 95 hours, 96 hours, 97 hours, 98 hours, 99 hours, 8 hours, 59 hours, 60 hours, 61 hours, 62 hours, 63 hours, 64 hours, 65 hours, 66 hours, 67 hours, 68 hours, 69 hours, 70 hours, 71 hours, 72 hours, 73 hours, 74 hours, 75 hours, 76 hours, 77 hours, 78 hours, 79 hours, 80 hours, 81 hours, 82 hours, 83 hours, 84 hours, 85 hours, 86 hours, 87 hours, 88 hours, 89 hours, 90 hours, 91 hours, 92 hours, 93 hours, 94 hours, 95 hours, 96 hours, 97 hours, 98 hours, 99 hours or 100 hours.

[0059] In certain embodiments, illustrative examples of glucocorticoids or pharmaceutically acceptable salts or esters thereof that can be used in the present invention include, but are not limited to, cortisone, hydrocortisone, prednisone, prednisolone, methylprednisolone, deflazacort, fludrocortisone, triamcinolone, betamethasone, dexamethasone, triamcinolone acetonide, methylprednisolone, paramethasone, beclomethasone, betamethasone or flunisolone, or pharmaceutically acceptable salts or esters thereof.

[0060] In certain embodiments, illustrative examples of glucocorticoids or pharmaceutically acceptable salts or esters thereof that can be used in the present invention include, but are not limited to, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, dexamethasone palmitate, betamethasone, and betamethasone dipropionate.

[0061] In certain embodiments, illustrative examples of biocompatible, biodegradable sustained-release materials that can be used to form the microspheres of the present invention include, but are not limited to, polyamides, polyamines, polyalkylene oxalates, polyanhydrides, polyamide esters, copoly(ether-esters), polycarbonates, polyorthoesters, polylactides, polyglycolides, polylactic acid, poly(lactic-co-glycolic acid), polyorthoesters, polycaprolactones, polyphosphazenes, polysaccharides, protein polymers, polysaccharide derivatives, soluble derivatives of protein polymers, polypeptides, polyesters, polyorthoesters, and copolymers, block copolymers, homopolymers, mixtures, and combinations thereof.

[0062] In certain embodiments, illustrative examples of biocompatible, biodegradable sustained-release materials that can be used to form the microspheres of the present invention include, but are not limited to, poly(lactic acid-co-glycolic acid) having a molar ratio of lactic acid (lactide) to glycolic acid (glycolide) of about 50:50 to about 95:5, preferably 50:50, 55:50, 60:50, 65:50, 70:50, 75:50, 80:50, 85:50, 90:50, 95:50, 50:45, 55:45, 6 ... :45, 65:45, 70:45, 75:45, 80:45, 85:45, 90:45, 95:45, 50:40, 55:40, 60:40, 65:40, 70:40, 75:40, 80:40, 85:40, 90:40, 95:40, 50:35, 55:35, 60:35, 65:35, 70:35, 75:35, 80:35, 85:35, 90:35, 95:35, 50:30, 55:30, 60:30, 65:30, 70:30, 75:30, 80:30, 85:30, 90:30, 95:30, 50:25, 55:25, 60:25, 65:25, 70:25, 75:25, 80:25, 85:25, 90:25, 95:25, 50:20, 55:20, 60:20, 65:20, 70:20, 75:20, 80:20, 85:20, 90:20, 95:25 0, 50:15, 55:15, 60:15, 65:15, 70:15, 75:15, 80:15, 85:15, 90:15, 95:15, 50:10, 55:10, 60:10, 65:10, 70:10, 75:10, 80:10, 85:10, 90:10, 95:10, 50:5, 55:5, 60:5, 65:5, 70:5, 75:5, 80:5, 85:5, 90:5, 95:5.

[0063] In certain embodiments, the intrinsic viscosity of the poly(lactic-co-glycolic acid) copolymer that can be used to form the present invention is about 0.12 dl / g to 0.21 dl / g, preferably 0.12 dl / g, 0.13 dl / g, 0.14 dl / g, 0.15 dl / g, 0.16 dl / g, 0.17 dl / g, 0.18 dl / g, 0.19 dl / g, 0.20 dl / g, 0.21 dl / g.

[0064] In certain embodiments, the poly(lactic acid-co-glycolic acid) copolymer that can be used to form the present invention is preferably Ashland / 7525.

[0065] In certain embodiments, the ropivacaine microspheres of the present invention further comprise a porogen.

[0066] In certain embodiments, illustrative examples of porogens that can be used in the present invention include, but are not limited to, amphiphilic polymers, small molecule monohydric alcohols, small molecule polyhydric alcohols, and mixtures thereof.

[0067] In certain embodiments, illustrative examples of amphiphilic polymers that can be used in the present invention include, but are not limited to, polyethylene glycol, polyethylene ether, polyethylene imine, polyvinyl pyrrolidone, polyacrylamide polymers, polyacrylic acid, polystyrene sulfonate, and mixtures thereof.

[0068] In certain embodiments, the relative molecular weight of polyethylene glycol (PEG) that can be used in the present invention is about 100 to 10,000; preferably 100, 150, 200, 250, 300, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250 , 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, 10000.

[0069] In certain embodiments, illustrative examples of small molecule monohydric alcohols that can be used in the present invention include, but are not limited to, methanol, ethanol, benzyl alcohol, and mixtures thereof.

[0070] In certain embodiments, illustrative examples of small molecule polyols that can be used in the present invention include, but are not limited to, sorbitol, propylene glycol, glycerol, and mixtures thereof.

[0071] In certain embodiments, the ropivacaine microspheres of the present invention have a drug loading of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65% or 70% of ropivacaine or a pharmaceutically acceptable salt thereof.

[0072] In certain embodiments, the ropivacaine microspheres of the present invention have a drug loading of glucocorticoid or its pharmaceutically acceptable salt or ester thereof of about 0.25%, 0.50%, 0.75%, 1.00%, 1.25%, 1.50%, 1.75%, 2.00%, 2.25%, 2.50%, 2.75%, 3.00%, 3.25%, 3.50%, 3.75%, 4.00%, 4. 25%, 4.50%, 4.75%, 5.00%, 5.25%, 5.50%, 5.75%, 6.00%, 6.25%, 6.50%, 6.75%, 7.00%, 7.25%, 7.50%, 7.75%, 8.00%, 8.25%, 8.50%, 8.75%, 9.00%, 9.25%, 9.50%, 9.75% or 10.00%.

[0073] In certain embodiments, the mass percentage of the porogen in the ropivacaine microspheres of the present invention is about 0.20%, 0.40%, 0.60%, 0.80%, 1.00%, 1.20%, 1.40%, 1.60%, 1.80%, 2.00%, 2.20%, 2.40%, 2.60%, 2.80%, 3.00%, 3.20%, 3.40%, 3.60%, 3.80% or 4.00%.

[0074] In certain embodiments, the ropivacaine microspheres of the present invention have a drug loading ratio of ropivacaine or its pharmaceutically acceptable salt to its glucocorticoid or its pharmaceutically acceptable salt or ester thereof of 30:1 to 500:1; preferably 30-32:1, 32-34:1, 34-36:1, 36-38:1, 38-40:1, 40-42:1, 42-44:1, 44-46:1, 46-48:1, 48-50:1, 50-52:1, 52-54:1, 54-56:1, 56-58:1, 58-59:1, 59-61:1, 61-63:1, 63-65:1, 65-67:1, 67-69:1, 69-71:1, 71-7 3:1, 73-75:1, 75-77:1, 77-79:1, 79-81:1, 81-83:1, 83-85:1, 85-87:1, 87-89:1, 89-91:1, 91-93:1, 93-95:1, 95-97:1, 97-99:1, 99-101:1, 101-103 :1, 103-105:1, 105-107:1, 107-109:1, 111-113:1, 113-115:1, 115-117:1, 117-119:1, 121-123:1, 123-125:1, 125-127:1, 127-129:1, 129-131:1, 13 1-133:1, 133-135:1, 135-137:1, 137-139:1, 141-143:1, 143-145:1, 145-147:1, 147-149:1, 151-153:1, 153-155:1, 155-157:1, 157-159:1, 159-16 1:1, 161-163:1, 163-165:1, 165-167:1, 167-169:1, 169-171:1, 171-173:1, 173-175:1, 175-177:1, 177-179:1, 179-181:1, 181-183:1, 183-185:1, 1 85-187:1, 187-189:1, 189-191:1, 191-193:1, 193-195:1, 195-197:1, 197-199:1, 199-201:1, 201-203:1, 203-205:1, 205-207:1, 207-209:1, 211-2 13:1, 213-215:1, 215-217:1, 217-219:1, 219-221:1, 221-223:1, 223-225:1, 225-227:1, 227-229:1, 231-233:1, 233-235:1, 235-237:1, 237-239:1,241-243:1、243-245:1、245-247:1、247-249:1、249-251:1、251-253:1、253-255:1、255-257:1、257-259:1、259-261:1、261-263:1、263-265:1、265-267:1、267-269:1、269-271:1、271-273:1、273-275:1、275-277:1、277-279:1、279-281:1、281-283:1、283-285:1、285-287:1、287-289:1、289-291:1、291-293:1、293-295:1、295-297:1、297-299:1、299-301:1、301-303:1、303-305:1、305-307:1、307-309:1、309-311:1、311-313:1、313-315:1、315-317:1、317-319:1、319-321:1、321-323:1、323-325:1、325-327:1、327-329:1、329-331:1、 331-333:1、333-335:1、335-337:1、337-339:1、339-341:1、341-343:1、343-345:1、345-347:1、347-349:1、349-351:1、351-353:1、353-355:1、355-357:1、357-359:1、359-361:1、361-363:1、363-365:1、365-367:1、367-369:1、369-371:1、371-373:1、373-375:1、375-377:1、377-379:1、379-381:1、381-383:1、383-385:1、385-387:1、387-389:1、389-391:1、391-393:1、393-395:1、395-397:1、397-399:1、399-401:1、401-403:1、403-405:1、405-407:1、407-409:1、409-411:1、411-413:1、413-415:1、415-417:1、417-419:1、419-321:1、421-423:1、423-425:1、425-427:1、427-429:1、429-431:1、431-433:1、433-335:1、435-437:1、437-439:1、439-441:1、441-443:1、443-445:1、445-447:1、447-449:1、449-451:1、451-453:1、453-455:1、455-457:1、457-459:1、459-461:1、461-463:1、463-465:1、465-467:1、467-469:1、469-471:1、 471-473:1、473-475:1、475-477:1、477-479:1、479-481:1、481-483:1、483-485:1、485-487:1、487-489:1、489-491:1、491-493:1、493-495:1、495-497:1、497-499:1、499-500:1.

[0075] In certain embodiments, the ropivacaine microspheres of the present invention have a particle size D10 of about 5 μm, 6 μm, 7 μm, 8 μm, 9 μm, 10 μm, 11 μm, 12 μm, 13 μm, 14 μm, 15 μm, 16 μm, 17 μm, 18 μm, 19 μm, 20 μm, 21 μm, 22 μm, 23 μm, 24 μm, 25 μm, 26 μm, 27 μm, 28 μm, 29 μm, 30 μm, 31 μm, 32 μm, 33 μm, 34 μm, 35 μm, 36 μm, 37 μm, 38 μm, 39 μm, 40 μm, 41 μm, 42 μm, 43 μm, 44 μm, 45 μm, 46 μm, 47 μm, 48 μm, 49 μm or 50 μm.

[0076] In certain embodiments, the ropivacaine microspheres of the present invention have a particle size D50 of about 10 μm, 11 μm, 12 μm, 13 μm, 14 μm, 15 μm, 16 μm, 17 μm, 18 μm, 19 μm, 20 μm, 21 μm, 22 μm, 23 μm, 24 μm, 25 μm, 26 μm, 27 μm, 28 μm, 29 μm, 30 μm, 31 μm, 32 μm, 33 μm, 34 μm, 35 μm, 36 μm, 37 μm, m, 38μm, 39μm, 40μm, 41μm, 42μm, 43μm, 44μm, 45μm, 46μm, 47μm, 48μm, 49μm, 50μm, 51μm, 52μm, 53μm, 5 4μm, 55μm, 56μm, 57μm, 58μm, 59μm, 60μm, 61μm, 62μm, 63μm, 64μm, 65μm, 66μm, 67μm, 68μm, 69μm or 70μm.

[0077] In certain embodiments, the ropivacaine microspheres of the present invention have a particle size D90 of about 20 μm, 21 μm, 22 μm, 23 μm, 24 μm, 25 μm, 26 μm, 27 μm, 28 μm, 29 μm, 30 μm, 31 μm, 32 μm, 33 μm, 34 μm, 35 μm, 36 μm, 37 μm, 38 μm, 39 μm, 40 μm, 41 μm, 42 μm, 43 μm, 44 μm, 45 μm, 46 μm, 47 μm, 48 μm, 49 μm, 50 μm, 51 μm, 52 μm, 53 μm, 54 μm, 55 μm, 56 μm, 57 μm, m, 58μm, 59μm, 60μm, 61μm, 62μm, 63μm, 64μm, 65μm, 66μm, 67μm, 68μm, 69μm, 70μm, 71μm, 72μm, 73μm, 74μm, 75μm, 76μm, 77μm, 78μm, 79 μm, 80μm, 81μm, 82μm, 83μm, 84μm, 85μm, 86μm, 87μm, 88μm, 89μm, 90μm, 91μm, 92μm, 93μm, 94μm, 95μm, 96μm, 97μm, 98μm, 99μm or 100μm.

[0078] On the other hand, the present invention relates to ropivacaine microspheres, which contain ropivacaine or a pharmaceutically acceptable salt thereof, at least one glucocorticoid or a pharmaceutically acceptable salt or ester thereof, and at least one biocompatible, biodegradable sustained-release material effective in prolonging the release of the drug from the preparation, wherein when the cumulative release of ropivacaine or a pharmaceutically acceptable salt thereof reaches 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80%, the sum of the differences between the cumulative release of the glucocorticoid or a pharmaceutically acceptable salt or ester thereof and the cumulative release of ropivacaine or a pharmaceutically acceptable salt thereof is not less than 105%.

[0079] In certain embodiments, when the cumulative release of ropivacaine or its pharmaceutically acceptable salt in the ropivacaine microspheres of the present invention reaches 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80%, the sum of the differences between the cumulative release of glucocorticoid or its pharmaceutically acceptable salt or ester and ropivacaine or its pharmaceutically acceptable salt is not less than 110%, 115%, 120%, 125%, 130%, 135%, 140%, 145%, 150%, 155%, 160%, 165%, 170%, 175%, 180%, 185%, 190%, 195% or 200%.

[0080] In certain embodiments, the cumulative release of ropivacaine or a pharmaceutically acceptable salt thereof in the ropivacaine microspheres of the present invention over 24 hours is not less than 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64% or 65%.

[0081] In certain embodiments, the ropivacaine microspheres of the present invention can release ropivacaine or a pharmaceutically acceptable salt thereof for at least 48 hours, 50 hours, 52 hours, 54 hours, 56 hours, 58 hours, 60 hours, 62 hours, 64 hours, 66 hours, 68 hours, 70 hours, 72 hours, 74 hours, 76 hours, 78 hours, 80 hours, 82 hours, 84 hours, 86 hours, 88 hours, 90 hours, 92 hours, 94 hours, 96 hours, hours, 98 hours, 100 hours, 102 hours, 104 hours, 106 hours, 108 hours, 110 hours, 112 hours, 114 hours, 116 hours, 118 hours, 120 hours, 122 hours, 124 hours, 126 hours, 128 hours, 130 hours, 132 hours, 134 hours, 136 hours, 138 hours, 140 hours, 142 hours, 144 hours, 146 hours, 148 hours, 150 hours , 152 hours, 154 hours, 156 hours, 158 hours, 160 hours, 162 hours, 164 hours, 166 hours, 168 hours, 170 hours, 172 hours, 174 hours, 176 hours, 178 hours, 180 hours, 182 hours, 184 hours, 186 hours, 188 hours, 190 hours, 195 hours, 200 hours, 205 hours, 210 hours, 215 hours, 220 hours, 225 hours , 230 hours, 235 hours, 240 hours, 245 hours, 250 hours, 255 hours, 260 hours, 265 hours, 270 hours, 275 hours, 280 hours, 285 hours, 290 hours, 295 hours, 300 hours, 305 hours, 310 hours, 315 hours, 320 hours, 325 hours, 330 hours, 335 hours, 340 hours, 345 hours, 350 hours, 355 hours or 360 hours.

[0082] In certain embodiments, the glucocorticoid or its pharmaceutically acceptable salt or ester in the ropivacaine microspheres of the present invention can be sustained-released for at least 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, 40 hours, 41 hours, 42 hours, 43 hours, 44 hours, 45 hours, 46 hours, 47 hours, 48 ​​hours, 49 hours, 50 hours, 51 hours, 52 hours, 53 hours, 54 hours, 55 hours, 56 hours, 57 hours, 58 hours, 59 hours, 60 hours, 61 hours, 62 hours, 63 hours, 64 hours, 65 hours, 66 hours, 67 hours, 68 hours, 69 hours, 70 hours, 71 hours, 72 hours, 73 hours, 74 hours, 75 hours, 76 hours, 77 hours, 78 hours, 79 hours, 80 hours, 81 hours, 82 hours, 83 hours, 84 hours, 85 hours, 86 hours, 87 hours, 88 hours, 89 hours, 90 hours, 91 hours, 92 hours, 93 hours, 94 hours, 95 hours, 96 hours, 97 hours, 98 hours, 99 hours, 8 hours, 59 hours, 60 hours, 61 hours, 62 hours, 63 hours, 64 hours, 65 hours, 66 hours, 67 hours, 68 hours, 69 hours, 70 hours, 71 hours, 72 hours, 73 hours, 74 hours, 75 hours, 76 hours, 77 hours, 78 hours, 79 hours, 80 hours, 81 hours, 82 hours, 83 hours, 84 hours, 85 hours, 86 hours, 87 hours, 88 hours, 89 hours, 90 hours, 91 hours, 92 hours, 93 hours, 94 hours, 95 hours, 96 hours, 97 hours, 98 hours, 99 hours or 100 hours.

[0083] In another aspect, the present invention relates to ropivacaine microspheres, which comprise ropivacaine or a pharmaceutically acceptable salt thereof, at least one glucocorticoid or a pharmaceutically acceptable salt thereof or an ester thereof, and at least one biocompatible, biodegradable sustained-release material effective in prolonging the release of the drug from the formulation, wherein the ropivacaine or a pharmaceutically acceptable salt thereof can be sustained-released for at least 48 hours, and the glucocorticoid or a pharmaceutically acceptable salt thereof or an ester thereof can be sustained-released for at least 24 hours.

[0084] In certain embodiments, the ropivacaine microspheres of the present invention can release ropivacaine or a pharmaceutically acceptable salt thereof for at least 48 hours, 50 hours, 52 hours, 54 hours, 56 hours, 58 hours, 60 hours, 62 hours, 64 hours, 66 hours, 68 hours, 70 hours, 72 hours, 74 hours, 76 hours, 78 hours, 80 hours, 82 hours, 84 hours, 86 hours, 88 hours, 90 hours, 92 hours, 94 hours, 96 hours, 98 hours, 99 hours, 100 hours, 101 hours, 102 hours, 103 hours, 104 hours, 105 hours, 106 hours, 107 hours, 108 hours, 109 hours, 110 hours, 111 hours, 112 hours, 113 hours, 114 hours, 115 hours, 116 hours, 117 hours, 118 hours, 119 hours, 120 hours, 121 hours, 122 hours, 123 hours, 124 hours, 125 hours 4 hours, 96 hours, 98 hours, 100 hours, 102 hours, 104 hours, 106 hours, 108 hours, 110 hours, 112 hours, 114 hours, 116 hours, 118 hours, 120 hours, 122 hours, 124 hours, 126 hours, 128 hours, 130 hours, 132 hours, 134 hours, 136 hours, 138 hours, 140 hours, 142 hours, 144 hours, 146 hours hours, 148 hours, 150 hours, 152 hours, 154 hours, 156 hours, 158 hours, 160 hours, 162 hours, 164 hours, 166 hours, 168 hours, 170 hours, 172 hours, 174 hours, 176 hours, 178 hours, 180 hours, 182 hours, 184 hours, 186 hours, 188 hours, 190 hours, 195 hours, 200 hours, 205 hours, 210 hours, 215 hours, 220 hours, 225 hours, 230 hours, 235 hours, 240 hours, 245 hours, 250 hours, 255 hours, 260 hours, 265 hours, 270 hours, 275 hours, 280 hours, 285 hours, 290 hours, 295 hours, 300 hours, 305 hours, 310 hours, 315 hours, 320 hours, 325 hours, 330 hours, 335 hours, 340 hours, 345 hours, 350 hours, 355 hours or 360 hours.

[0085] In certain embodiments, the glucocorticoid or its pharmaceutically acceptable salt or ester in the ropivacaine microspheres of the present invention can be sustained-released for at least 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, 40 hours, 41 hours, 42 hours, 43 hours, 44 hours, 45 hours, 46 hours, 47 hours, 48 ​​hours, 49 hours, 50 hours, 51 hours, 52 hours, 53 hours, 54 hours, 55 hours, 56 hours, 57 hours, 58 hours, 59 hours, 60 hours, 61 hours, 62 hours, 63 hours, 64 hours, 65 hours, 66 hours, 67 hours, 68 hours, 69 hours, 70 hours, 71 hours, 72 hours, 73 hours, 74 hours, 75 hours, 76 hours, 77 hours, 78 hours, 79 hours, 80 hours, 81 hours, 82 hours, 83 hours, 84 hours, 85 hours, 86 hours, 87 hours, 88 hours, 89 hours, 90 hours, 91 hours, 92 hours, 93 hours, 94 hours, 95 hours, 96 hours, 97 hours, 98 hours, 99 hours, 8 hours, 59 hours, 60 hours, 61 hours, 62 hours, 63 hours, 64 hours, 65 hours, 66 hours, 67 hours, 68 hours, 69 hours, 70 hours, 71 hours, 72 hours, 73 hours, 74 hours, 75 hours, 76 hours, 77 hours, 78 hours, 79 hours, 80 hours, 81 hours, 82 hours, 83 hours, 84 hours, 85 hours, 86 hours, 87 hours, 88 hours, 89 hours, 90 hours, 91 hours, 92 hours, 93 hours, 94 hours, 95 hours, 96 hours, 97 hours, 98 hours, 99 hours or 100 hours.

[0086] In another aspect, the present invention relates to ropivacaine microspheres, which comprise, by mass percentage, 40-72% of ropivacaine or a pharmaceutically acceptable salt thereof, 0.1-3% of a glucocorticoid or a pharmaceutically acceptable salt or ester thereof, 20-65% of a biodegradable sustained-release material, and 0-15% of a pore-forming agent.

[0087] In some embodiments, the ropivacaine microspheres include, by mass percentage, 44-69% ropivacaine or a pharmaceutically acceptable salt thereof, 0.1-2.5% glucocorticoid or a pharmaceutically acceptable salt or ester thereof, 25-60% biodegradable sustained-release material, and 0-10% pore-forming agent.

[0088] In some embodiments, the ropivacaine microspheres include, by mass percentage, 46-67% ropivacaine or a pharmaceutically acceptable salt thereof, 0.1-2% glucocorticoid or a pharmaceutically acceptable salt or ester thereof, 30-56% biodegradable sustained-release material, and 0-8% pore-forming agent.

[0089] In some embodiments, the ropivacaine microspheres include, by mass percentage, 46-67% ropivacaine or a pharmaceutically acceptable salt thereof, 0.1-1.6% glucocorticoid or a pharmaceutically acceptable salt or ester thereof, 32-54% biodegradable sustained-release material, and 0-6% pore-forming agent.

[0090] In another aspect, the present invention relates to a method for preparing ropivacaine microspheres, comprising the following steps:

[0091] (1) dissolving ropivacaine or a pharmaceutically acceptable salt thereof, at least one glucocorticoid or a pharmaceutically acceptable salt or ester thereof, at least one effective amount of a biocompatible, biodegradable sustained-release material for prolonging the release of the drug from the preparation, and optionally polyethylene glycol in an organic solvent to obtain an oil phase;

[0092] (2) preparing a 1% polyvinyl alcohol aqueous solution and adjusting the pH to alkaline to obtain an aqueous phase;

[0093] (3) preparing a 0.1% polyvinyl alcohol aqueous solution and adjusting the pH to alkaline to obtain a hardening solution;

[0094] (4) The oil phase and the water phase are mixed to prepare colostrum, the colostrum is added to the hardening liquid, stirred to remove the organic solvent, and then collected, washed, and dried.

[0095] In certain embodiments, illustrative examples of organic solvents that can be used in the present invention include, but are not limited to, dichloromethane, ethyl acetate, acetone, chloroform, tetrahydrofuran, or mixtures thereof.

[0096] In certain embodiments, illustrative examples of colostrum preparation methods that can be used in the present invention include, but are not limited to, shearing, stirring, or static mixing.

[0097] In another aspect, the present invention relates to a method for local administration to provide long-acting analgesia or nerve block, which comprises administering ropivacaine microspheres, wherein the microspheres contain ropivacaine or a pharmaceutically acceptable salt thereof, at least one glucocorticoid or a pharmaceutically acceptable salt or ester thereof, and at least one biocompatible, biodegradable sustained-release material effective in extending the release of the drug from the formulation.

[0098] In certain embodiments, the microspheres that can be used in the administration method of the present invention have a cumulative release amount of ropivacaine or a pharmaceutically acceptable salt thereof of 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80%, and the sum of the differences between the cumulative release amount of the glucocorticoid or its pharmaceutically acceptable salt or ester and the cumulative release amount of ropivacaine or a pharmaceutically acceptable salt thereof is not less than 105%, 110%, 115%, 120%, 125%, 130%, 135%, 140%, 145%, 150%, 155%, 160%, 165%, 170%, 175%, 180%, 185%, 190%, 195%, or 200%.

[0099] In certain embodiments, the microspheres that can be used in the administration method of the present invention have a 24-hour cumulative release of ropivacaine or a pharmaceutically acceptable salt thereof of not less than 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64% or 65%.

[0100] In certain embodiments, the microspheres that can be used in the administration method of the present invention have a cumulative release time of 80% of ropivacaine or its pharmaceutically acceptable salt that is at least 1.7 times, at least 1.8 times, at least 1.9 times, at least 2.0 times, at least 2.1 times, at least 2.2 times, at least 2.3 times, at least 2.4 times, at least 2.5 times, at least 2.6 times, at least 2.7 times, at least 2.8 times, at least 2.9 times, at least 3.0 times, at least 3.1 times, at least 3.2 times, at least 3.3 times, at least 3.4 times, at least 3.5 times, at least 3.6 times, at least 3.7 times, at least 3.8 times, at least 3.9 times, at least 4.5 times, at least 4.6 times, at least 4.7 times, at least 4.8 times, at least 4.9 ... At least 2.8 times, at least 2.9 times, at least 3.0 times, at least 3.1 times, at least 3.2 times, at least 3.3 times, at least 3.4 times, at least 3.5 times, at least 3.6 times, at least 3.7 times, at least 3.8 times, at least 3.9 times, at least 4.0 times, at least 4.1 times, at least 4.2 times, at least 4.3 times, at least 4.4 times, at least 4.5 times, at least 4.6 times, at least 4.7 times, at least 4.8 times, at least 4.9 times, or at least 5.0 times.

[0101] In certain embodiments, the microspheres that can be used in the administration method of the present invention can release ropivacaine or a pharmaceutically acceptable salt thereof for at least 48 hours, 50 hours, 52 hours, 54 hours, 56 hours, 58 hours, 60 hours, 62 hours, 64 hours, 66 hours, 68 hours, 70 hours, 72 hours, 74 hours, 76 hours, 78 hours, 80 hours, 82 hours, 84 hours, 86 hours, 88 hours, 90 hours, 92 hours, 94 hours, hours, 96 hours, 98 hours, 100 hours, 102 hours, 104 hours, 106 hours, 108 hours, 110 hours, 112 hours, 114 hours, 116 hours, 118 hours, 120 hours, 122 hours, 124 hours, 126 hours, 128 hours, 130 hours, 132 hours, 134 hours, 136 hours, 138 hours, 140 hours, 142 hours, 144 hours, 146 hours, 148 hours, 1 50 hours, 152 hours, 154 hours, 156 hours, 158 hours, 160 hours, 162 hours, 164 hours, 166 hours, 168 hours, 170 hours, 172 hours, 174 hours, 176 hours, 178 hours, 180 hours, 182 hours, 184 hours, 186 hours, 188 hours, 190 hours, 195 hours, 200 hours, 205 hours, 210 hours, 215 hours, 220 hours, 225 hours, 230 hours, 235 hours, 240 hours, 245 hours, 250 hours, 255 hours, 260 hours, 265 hours, 270 hours, 275 hours, 280 hours, 285 hours, 290 hours, 295 hours, 300 hours, 305 hours, 310 hours, 315 hours, 320 hours, 325 hours, 330 hours, 335 hours, 340 hours, 345 hours, 350 hours, 355 hours or 360 hours.

[0102] In certain embodiments, the microspheres that can be used in the administration method of the present invention, wherein the glucocorticoid or its pharmaceutically acceptable salt or ester can be sustained-released for at least 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, 40 hours, 41 hours, 42 hours, 43 hours, 44 hours, 45 hours, 46 hours, 47 hours, 48 ​​hours, 49 hours, 50 hours, 51 hours, 52 hours, 53 hours, 54 hours, 55 hours, 56 hours, 57 hours, 58 hours, 59 hours, 60 hours, 61 hours, 62 hours, 63 hours, 64 hours, 65 hours, 66 hours, 67 hours, 68 hours, 69 hours, 70 hours, 71 hours, 72 hours, 73 hours, 74 hours, 75 hours, 76 hours, 77 hours, 78 hours, 79 hours, 80 hours, 81 hours, 82 hours, 83 hours, 84 hours, 85 hours, 86 hours, 87 hours, 88 hours, 89 hours, 90 hours, 91 hours, 92 hours, 93 hours, 94 hours, 95 hours, 96 hours, 97 hours, 98 hours, 99 hours, hours, 58 hours, 59 hours, 60 hours, 61 hours, 62 hours, 63 hours, 64 hours, 65 hours, 66 hours, 67 hours, 68 hours, 69 hours, 70 hours, 71 hours, 72 hours, 73 hours, 74 hours, 75 hours, 76 hours, 77 hours, 78 hours, 79 hours, 80 hours, 81 hours, 82 hours, 83 hours, 84 hours, 85 hours, 86 hours, 87 hours, 88 hours, 89 hours, 90 hours, 91 hours, 92 hours, 93 hours, 94 hours, 95 hours, 96 hours, 97 hours, 98 hours, 99 hours or 100 hours.

[0103] In certain embodiments, the microspheres of the invention provide long-acting analgesia or nerve block for a duration of at least about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or longer.

[0104] In certain embodiments, the ropivacaine or its pharmaceutically acceptable salt and the glucocorticoid or its pharmaceutically acceptable salt or ester in the microspheres of the present invention are released at a specific ratio or rate to provide a more sustained analgesic or nerve block effect.

[0105] Hereinafter, the present invention will be explained in detail by the following examples so that various aspects of the present invention and its advantages are better understood. However, it should be understood that the following examples are non-limiting and are only used to illustrate certain embodiments of the present invention.

[0106] [Example]

[0107] The reagents and equipment used in the examples of the present invention are conventional and commercially available. For example:

[0108] Table 1 Sources of raw and auxiliary materials

[0109] Table 2 Main experimental instruments and equipment

[0110] The formulations of the ropivacaine acetate dexamethasone microspheres of Examples 1-6 are shown in Table 3.

[0111] Table 3 Note: * Removed during the process and not counted in the intermediate or finished products.

[0112] The formulations of the ropivacaine acetate dexamethasone microspheres of Examples 7-10 are shown in Table 4.

[0113] Table 4 Note: * Removed during the process and not counted in the intermediate or finished products.

[0114] The formulas of the ropivacaine dexamethasone acetate microspheres of Comparative Examples 1-4 are shown in Table 5.

[0115] Table 5 Note: * Removed during the process and not counted in the intermediate or finished products.

[0116] The formula of the ropivacaine acetate dexamethasone microspheres of Examples 11-12 is shown in Table 6.

[0117] Table 6 Note: * Removed during the process and not counted in the intermediate or finished products.

[0118] Table 7 Model and viscosity of poly (lactic acid-co-glycolic acid)

[0119] Preparation methods of Examples 1-6 and Comparative Examples 1-2:

[0120] The prescribed amount of ropivacaine, dexamethasone acetate, poly(lactic-co-glycolic acid), and polyethylene glycol were weighed and dissolved in dichloromethane to obtain an oil phase, an appropriate amount of PVA was weighed and dissolved in water to prepare a 1% solution, and the pH was adjusted to alkaline to obtain an aqueous phase, which was cooled to 15°C, the remaining amount of PVA in the prescription was dissolved in water to prepare a 0.1% solution, and the pH was adjusted to alkaline to obtain a hardening solution, which was cooled to 15°C; under shear conditions, the oil phase was added to the aqueous phase for emulsification and then slowly added to the hardening solution, stirred in a water bath and blown to remove the organic solvent, the microspheres were collected, washed with water to remove the residual PVA, dried, and sieved to obtain the microspheres.

[0121] Preparation methods of Examples 7-12 and Comparative Examples 3-4:

[0122] The invention discloses a method for preparing a sclerosing liquid by weighing a prescribed amount of ropivacaine, dexamethasone or dexamethasone acetate, and poly(lactic acid-co-glycolic acid) and dissolving them in dichloromethane to obtain an oil phase; weighing an appropriate amount of PVA and dissolving them in water to prepare a 1% solution; adjusting the pH to alkaline to obtain an aqueous phase; cooling the mixture to 15°C; dissolving the remaining amount of PVA in water to prepare a 0.1% solution; adjusting the pH to alkaline to obtain a sclerosing liquid; cooling the mixture to 15°C and stirring the mixture in a water bath; connecting a static mixer, connecting the oil phase and the aqueous phase to an inlet end of the static mixer, controlling the liquid inlet speed by a peristaltic pump, connecting an outlet end of the static mixer to the sclerosing liquid, firstly starting the peristaltic pump for controlling the aqueous phase, allowing the aqueous phase to first enter the sclerosing liquid through the static mixer, and then immediately starting the peristaltic pump for controlling the oil phase, and after the oil phase is completely infused, removing the aqueous phase tube from the aqueous phase; continuing to start the peristaltic pump to allow all liquid in the static mixer to flow out; and finally closing the peristaltic pump. The hardening liquid is blown with air to remove the organic solvent, the microspheres are collected by filtration, washed with water to remove the residual PVA, dried, and sieved to obtain the microspheres.

[0123] Example 13 Microsphere Particle Size Detection

[0124] Table 8 Microsphere particle size test results

[0125] Example 14 In vitro release curve determination

[0126] Release determination:

[0127] Preparation method of release medium pH 7.4 phosphate solution: Weigh 34g potassium dihydrogen phosphate, 1g polysorbate 80, 1g polysorbate 20, 7g sodium hydroxide, and 1g sodium azide, add to water, stir to dissolve, and adjust the volume to 5L. Add a small amount of sodium hydroxide solution to adjust the pH to 7.4, and sterilize by moist heat at 121℃ for 15min.

[0128] Release determination method: water bath temperature 37 ° C, stand, release medium is pH 7.4 phosphate solution, medium volume is 100 mL. Weigh 20 mg of the sample to be tested (microspheres prepared in Examples 1-12 and Comparative Examples 1-4) in a blue-capped bottle, add 100 mL of release medium, and stand in a 37 ° C water bath. Take 1 mL of sample at 1h, 4h, 8h, 24h, 48h, 72h, 120h, 168h, and 216h and add 1 mL of fresh release medium. Centrifuge (8000rpm, 10min), take 0.5 mL of supernatant into a liquid phase vial for release determination. Calculate the cumulative release of ropivacaine and dexamethasone acetate or dexamethasone at different release times.

[0129] Table 9

[0130] Figures 1, 3, 5, 7, 9, 11, 13, and 16-18 respectively show the cumulative release curves of ropivacaine dexamethasone acetate microspheres of Examples 1-10 of the present invention.

[0131] Figures 19-20 respectively show the cumulative release curves of ropivacaine-dexamethasone microspheres of Examples 11-12 of the present invention.

[0132] Figures 21 and 23 show the cumulative release curves of the ropivacaine acetate and dexamethasone microspheres of Comparative Examples 1 and 2 of the present invention, respectively. It can be seen that the release rate of the microspheres of Comparative Example 1 is too fast, and the release rate of the microspheres of Comparative Example 2 is too slow.

[0133] FIG24 and FIG25 respectively show the cumulative release curves of ropivacaine dexamethasone acetate microspheres of Comparative Examples 3 and 4 of the present invention.

[0134] Example 15: Evaluation of drug efficacy in rat sciatic nerve block model

[0135] The microspheres prepared in Examples 1-6 and Comparative Examples 1-2 were subjected to a local anesthesia test using thermal delay to evaluate the effect of the microspheres. Specifically, the duration of functional sciatic nerve block was tested by the delay in leg withdrawal in rats obtained by a noxious thermal stimulus of approximately 56°C applied to the plantar surface of the paw. The normal delay in paw withdrawal was approximately 2 seconds, while "maximum sensory block" was characterized by a delay of approximately 12 seconds.

[0136] A 200 mg / kg dose (calculated as ropivacaine) of microsphere suspension was injected around the sciatic nerve of the inner thigh of the left hind limb of the rat according to the rat's body weight. Heat pain was tested before administration and 30 minutes, 2 hours, 4 hours, 8 hours, 24 hours, 1.5 days, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, and 9 days after administration. The time from the rat touching the hot plate to the paw withdrawal was recorded as the heat pain threshold (TWL). If the rat did not respond for more than 12 seconds, contact with the hot plate was stopped, that is, 12 seconds was the maximum heat pain threshold.

[0137] Figures 2, 4, 6, 8, 10 and 12 show the thermal pain response threshold curves of ropivacaine acetate-dexamethasone microspheres of Examples 1-6 of the present invention.

[0138] FIG22 shows a curve diagram of the thermal pain response threshold of the ropivacaine acetate and dexamethasone microspheres of Comparative Example 1. Since the release rate of the microspheres is too fast, the analgesic effect can only be maintained for 1 day.

[0139] The ropivacaine acetate and dexamethasone microspheres in Comparative Example 2 were not effective because they were released too slowly.

[0140] Example 16: Study on the efficacy of the rat plantar incision pain model

[0141] After 1 week of animal adaptation feeding (animals were subjected to environmental adaptation training for mechanical pain and thermal pain every day for the next 3 days), the mechanical pain threshold and thermal paw withdrawal threshold of all rats were measured before surgery, and they were grouped according to the mechanical pain threshold and thermal paw withdrawal threshold. After grouping, the model was established. On the day of modeling, the rats that needed modeling were anesthetized by inhalation of isoflurane, and a disinfected drape was placed on the left hind paw. A 1 cm long longitudinal incision was made 0.5 cm proximal to the sole of the foot. The plantar muscle was lifted with ophthalmic forceps and cut longitudinally, keeping the muscle origin and attachment intact. After pressing to stop bleeding, 100 μL of the test substance (microspheres prepared in Example 7) was injected subcutaneously into the sole of the foot before closing the incision. The fascia and skin were then closed with two needles using absorbable fine sutures. The day of modeling was designated as D0.

[0142] (1) Mechanical pain threshold (PWT) test: All rats were tested once before surgery and 2, 4, 24, 48, 72, 120, and 168 hours after surgery using a Von Fery electronic analgesia. Positive responses were recorded if the animals licked their paws, raised their legs, or avoided the pain.

[0143] FIG14 shows the mechanical pain threshold curve of ropivacaine acetate-dexamethasone microspheres according to Example 7 of the present invention.

[0144] (2) Thermal Withdrawal Latency (TWL) Test: Once before surgery, and 2.5 h, 4.5 h, 24.5 h, 48.5 h, 72.5 h, 120.5 h, and 168.5 h after surgery, a thermal radiation light source (radiation intensity 5%) was used to directly illuminate the center of the wound. The device was automatically cut off when the rat withdrew its paw (lifted or licked its hind paw). The time from the start of irradiation to the withdrawal reaction was recorded as the TWL. To avoid burns, the irradiation was stopped if it exceeded 35 s, and 35 s was considered the maximum pain threshold.

[0145] FIG15 shows the latent period curve of the heat shrinkage group of ropivacaine acetate and dexamethasone microspheres according to Example 7 of the present invention.

[0146] In the present invention, relational terms such as first and second, etc. are used merely to distinguish one entity or operation from another entity or operation, but do not necessarily require or imply any actual relationship or order between these entities or operations.

[0147] It will be appreciated from the foregoing that although specific embodiments of the present invention have been described for illustrative purposes, various modifications or variations may be made by those skilled in the art without departing from the spirit and scope of the present invention. Such modifications or variations should fall within the scope of the appended claims.

Claims

1. Ropivacaine microspheres, comprising ropivacaine or a pharmaceutically acceptable salt thereof, at least one glucocorticoid or a pharmaceutically acceptable salt thereof or an ester thereof, and at least one effective amount of a biocompatible, biodegradable sustained-release material for prolonging the release of the drug from a preparation, wherein the time required for the cumulative release of ropivacaine or a pharmaceutically acceptable salt thereof to be 80% is at least 1.7 times the time required for the cumulative release of the glucocorticoid or a pharmaceutically acceptable salt thereof or an ester thereof to be 80%.

2. The ropivacaine microspheres as claimed in claim 1, wherein the cumulative release of ropivacaine or its pharmaceutically acceptable salt within 24 hours is not less than 25%.

3. The ropivacaine microspheres according to claim 1 or 2, wherein ropivacaine or a pharmaceutically acceptable salt thereof can be sustained-released for at least 48 hours.

4. The ropivacaine microspheres according to any one of claims 1 to 3, wherein the glucocorticoid or its pharmaceutically acceptable salt or ester thereof can be sustained-released for at least 24 hours.

5. The ropivacaine microspheres of any one of claims 1 to 4, wherein the glucocorticoid or its pharmaceutically acceptable salt or ester is cortisone, hydrocortisone, prednisone, prednisolone, methylprednisolone, deflazacort, fludrocortisone, triamcinolone, betamethasone, dexamethasone, triamcinolone acetonide, methylprednisolone, paramethasone, beclomethasone, flunisolone, or one or more of its pharmaceutically acceptable salt or ester, preferably one or more of dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, dexamethasone palmitate, betamethasone, and betamethasone dipropionate.

6. Ropivacaine microspheres comprising ropivacaine or a pharmaceutically acceptable salt thereof, at least one glucocorticoid or a pharmaceutically acceptable salt or ester thereof, and at least one effective amount of a biocompatible, biodegradable sustained-release material that prolongs the release of the drug from the formulation, wherein: When the cumulative release of ropivacaine or its pharmaceutically acceptable salt reaches 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80%, the sum of the differences between the cumulative release of glucocorticoid or its pharmaceutically acceptable salt or ester and ropivacaine or its pharmaceutically acceptable salt is not less than 105%.

7. The ropivacaine microspheres according to claim 6, wherein the cumulative release of ropivacaine or a pharmaceutically acceptable salt thereof in 24 hours is not less than 25%.

8. The ropivacaine microspheres according to claim 6 or 7, wherein ropivacaine or a pharmaceutically acceptable salt thereof can be sustained-released for at least 48 hours.

9. Ropivacaine microspheres as claimed in claim 6 or 7, wherein the glucocorticoid or its pharmaceutically acceptable salt or ester can be sustained-released for at least 24 hours.

10. Ropivacaine microspheres as claimed in claim 6, wherein the glucocorticoid or its pharmaceutically acceptable salt or ester is cortisone, hydrocortisone, prednisone, prednisolone, methylprednisolone, deflazacort, fludrocortisone, triamcinolone, betamethasone, dexamethasone, triamcinolone acetonide, methylprednisolone, paramethasone, beclomethasone, betamethasone, flunisolone, or one or more of its pharmaceutically acceptable salt or ester.

11. Ropivacaine microspheres comprising ropivacaine or a pharmaceutically acceptable salt thereof, at least one glucocorticoid or a pharmaceutically acceptable salt or ester thereof, and at least one effective amount of a biocompatible, biodegradable sustained-release material that prolongs the release of the drug from the preparation, wherein: The ropivacaine or a pharmaceutically acceptable salt thereof can be sustained-released for at least 48 hours, and the glucocorticoid or a pharmaceutically acceptable salt or ester thereof can be sustained-released for at least 24 hours.

12. The ropivacaine microspheres according to claim 11, wherein the cumulative release of ropivacaine or a pharmaceutically acceptable salt thereof in 24 hours is not less than 25%.

13. Ropivacaine microspheres as claimed in claim 11 or 12, wherein the glucocorticoid or its pharmaceutically acceptable salt or ester is cortisone, hydrocortisone, prednisone, prednisolone, methylprednisolone, deflazacort, fludrocortisone, triamcinolone, betamethasone, dexamethasone, triamcinolone acetonide, methylprednisolone, paramethasone, beclomethasone, betamethasone, flunisolone, or one or more of its pharmaceutically acceptable salt or ester.

14. A ropivacaine microsphere, characterized in that: Calculated by mass percentage, the invention comprises 40-72% of ropivacaine or a pharmaceutically acceptable salt thereof, 0.1-3% of a glucocorticoid or a pharmaceutically acceptable salt thereof or an ester thereof, 20-65% of a biodegradable sustained-release material and 0-15% of a pore-forming agent.

15. A method for preparing the ropivacaine microspheres as claimed in any one of claims 1 to 14, comprising the following steps: (1) dissolving ropivacaine or a pharmaceutically acceptable salt thereof, at least one glucocorticoid or a pharmaceutically acceptable salt or ester thereof, at least one effective amount of a biocompatible, biodegradable sustained-release material for prolonging the release of the drug from the preparation, and optionally polyethylene glycol in an organic solvent to obtain an oil phase; (2) preparing a 1% polyvinyl alcohol aqueous solution and adjusting the pH to alkaline to obtain an aqueous phase; (3) preparing a 0.1% polyvinyl alcohol aqueous solution and adjusting the pH to alkaline to obtain a hardening solution; (4) The oil phase and the water phase are mixed to prepare colostrum, the colostrum is added to the hardening liquid, stirred to remove the organic solvent, and then washed, collected and dried.

16. A method of local administration to provide long-acting analgesia or nerve block, comprising administering the ropivacaine microspheres of any one of claims 1 to 14 to an individual in need thereof.

17. The method of claim 16, wherein the duration of analgesia or nerve blockade after the first administration of the microspheres is at least about 1 day.

Images