Non-addictive analgesic sustained-release drug delivery system and preparation method thereof

Abstract

A non-addictive analgesic sustained-release drug delivery system, comprising: (1) a narcotic analgesic drug having a concentration of 1 mg/ml-160 mg/ml, the drug being selected from a group consisting of: a local analgesic drug, and the combination of the local analgesic drug and a nonsteroidal analgesic drug and/or an opioid analgesic drug; (2) a drug menstruum in a proportion of 1%-75% (v/v), the menstruum being selected from a group consisting of benzyl alcohol, ethanol, benzyl benzoate, ethyl lactate, and tetrahydrofurfuryl polyethylene glycol ether; and (3) a drug sustained-release formulation having a proportion of 25%-99% (v/v), the sustained-release formulation being selected from a group consisting of natural vegetable oil, synthetic lipid, artificially improved half-natural lipid and derivative thereof. Also disclosed are a preparation process and use of the sustained-release drug delivery system.

Claims

1. A non-addictive sustained-release drug delivery system comprising: i) 12-50 mg/ml (w/v) of an anesthetic analgesic comprising a local anesthetic or a combination of a local anesthetic and at least one of parecoxib or dezocine; ii) 10%-40% (v/v) of a drug menstruum comprising benzyl alcohol and/or benzyl benzoate, or a combination of ethanol together with benzyl alcohol and/or benzyl benzoate; and iii) 60%-90% (v/v) of a drug sustained-release agent comprising soybean oil and/or castor oil, wherein the local anesthetic is selected from the group consisting of ropivacaine free base or a methanesulfonate, hydrochloride, citrate, sulfate, lactate, succinate, fumarate, glutamate, ethylsulfonate, benzenesulfonate, salicylate, or maleate salt thereof, and wherein the non-addictive sustained-release drug delivery system is oily, homogenous, and configured for injection.

2. The non-addictive sustained-release drug delivery system of claim 1, wherein the anesthetic analgesic is ropivacaine free base.

Description

BRIEF DESCRIPTION OF THE FIGURES

(1) FIG. 1: Sensory nerve block vs. time profile with intramuscular injection of a ropivacaine sustained-release formulation (Prescribed composition 1) in rats

(2) FIG. 2: Sensory nerve block vs. time profile with intramuscular injection of a ropivacaine sustained-release formulation (Prescribed composition 2) in rats

(3) FIG. 3: Sensory nerve block vs. time profile with intramuscular injection of a ropivacaine sustained-release formulation (Prescribed composition 3) in rats

(4) FIG. 4: Sensory nerve block vs. time profile with intramuscular injection of a ropivacaine sustained-release formulation (Prescribed composition 4) in rats

(5) FIG. 5: Sensory nerve block vs. time profile with intramuscular injection of a ropivacaine sustained-release formulation (Prescribed composition 5) in rats

(6) FIG. 6: Sensory nerve block vs. time profile with intramuscular injection of a ropivacaine sustained-release formulation (Prescribed composition 6) in rats

(7) FIG. 7: Sensory nerve block vs. time profile with intramuscular injection of a ropivacaine sustained-release formulation (Prescribed composition 7) in rats

(8) FIG. 8: Sensory nerve block vs. time profile with intramuscular injection of a ropivacaine sustained-release formulation (Prescribed composition 8) in rats

(9) FIG. 9: Sensory nerve block vs. time histogram with intramuscular injection of ropivacaine sustained-release formulations of different prescribed compositions

(10) In these figures, the prescribed compositions 1-8 are prepared according to the formulae in Table 4.

DETAILED DESCRIPTION OF VARIOUS EMBODIMENTS

(11) The prescribed composition, preparation method, and use according to the present invention are further illustrated with reference to the following experimental examples and implementing examples to which the scope of the present invention is not limited.

Experimental Example 1

Solubility Tests of Ropivacaine Free Base and Corresponding Salts

(12) Ropivacaine free base and salts thereof (methanesulfonate and hydrochloride) raw drugs were each accurately weighed, into which 1 ml each of anhydrous ethanol, benzyl alcohol, glyceryl monoacetate, benzyl benzoate, ethyl lactate, sesame oil, soybean oil, ethyl oleate, corn oil, castor oil, olive oil, and tetrahydrofurfuryl polyethylene glycol ether were added respectively, and the dissolution process was observed. If a drug dissolved completely, addition of this drug was continued until saturation. Ranges of solubility of the drugs in various solvents were preliminarily determined, as shown in the table below.

(13) TABLE-US-00002 TABLE 2 Solubility of ropivacaine and corresponding salts in various solvents (in part) (25° C.) Solubility (mg/ml) Ropivacaine Ropivacaine Ropivacaine Menstruum name free base methansulfonate hydrochloride anhydrous ethanol 155 320 95 benzyl alcohol 225 550 140 glyceryl monoacetate 18 50 30 benzyl benzoate 70 2 2.5 ethyl lactate 80 198 16.5 Soybean oil 9.6 2.5 2 Sesame oil 11.7 1.7 2 ethyl oleate 14.9 2 2.2 Corn oil 9.4 1.7 2.5 castor oil 17 2 1.7 Olive oil 9.8 2 1.7 tetrahydrofurfuryl 39.6 13.2 9 polyethylene glycol ether

(14) Experimental results demonstrated that: at ambient temperature (25° C.), ropivacaine free base had superior solubility in anhydrous ethanol and benzyl alcohol, each exceeding 150 mg/ml, with less superior solubility in benzyl benzoate, ethyl lactate, and tetrahydrofurfuryl polyethylene glycol ether; ropivacaine methansulfonate had superior solubility in anhydrous ethanol, benzyl alcohol, and ethyl lactate, each exceeding 190 mg/ml, with less superior solubility in glyceryl monoacetate; ropivacaine hydrochloride had superior solubility in benzyl alcohol of more than 100 mg/ml, with less superior solubility in anhydrous ethanol, glyceryl monoacetate, and ethyl lactate. Therefore, four solvents, anhydrous ethanol, benzyl alcohol, benzyl benzoate, and ethyl lactate, may be the choices for the drug menstruum while glyceryl monoacetate and tetrahydrofurfuryl polyethylene glycol ether may be the second choices, among which anhydrous ethanol and benzyl alcohol are preferred.

Experimental Example 2

Preliminary Screening Experiments for Drug Delivery Systems (in Part) in the Sustained-Release Formulation Drug Delivery System

(15) Anhydrous ethanol, benzyl alcohol, ethyl lactate, benzyl benzoate, glyceryl monoacetate, and tetrahydrofurfuryl polyethylene glycol ether were used as drug menstruum and mixed miscible with ethyl oleate, glyceryl triacetate, castor oil, soybean oil, corn oil, sesame oil, and medium chain triglyceride respectively. White oil and hydrogenated castor oil was optionally added into some of the mixed solvents. Miscible dissolution was observed.

(16) Part of the preferable drug delivery system is shown below:

(17) benzyl alcohol/ethyl oleate

(18) benzyl alcohol/tetrahydrofurfuryl polyethylene glycol ether

(19) benzyl alcohol/glyceryl triacetate

(20) benzyl alcohol/soybean oil

(21) benzyl alcohol/sesame oil

(22) benzyl alcohol/corn oil

(23) benzyl alcohol/castor oil

(24) benzyl alcohol/medium chain triglyceride

(25) anhydrous ethanol/ethyl oleate

(26) anhydrous ethanol/tetrahydrofurfuryl polyethylene glycol ether

(27) anhydrous ethanol/benzyl benzoate

(28) anhydrous ethanol/glyceryl triacetate

(29) anhydrous ethanol/castor oil

(30) anhydrous ethanol/ethyl oleate/soybean oil

(31) anhydrous ethanol/benzyl benzoate/glyceryl triacetate

(32) anhydrous ethanol/benzyl benzoate/soybean oil

(33) anhydrous ethanol/benzyl benzoate/castor oil

(34) anhydrous ethanol/benzyl benzoate/castor oil/hydrogenated castor oil

(35) anhydrous ethanol/benzyl benzoate/corn oil

(36) anhydrous ethanol/benzyl benzoate/tetrahydrofurfuryl polyethylene glycol ether

(37) anhydrous ethanol/benzyl benzoate/sesame oil

(38) anhydrous ethanol/benzyl benzoate/medium chain triglyceride

(39) benzyl alcohol/benzyl benzoate/ethyl oleate

(40) benzyl alcohol/benzyl benzoate/tetrahydrofurfuryl polyethylene glycol ether

(41) benzyl alcohol/benzyl benzoate/glyceryl triacetate

(42) benzyl alcohol/benzyl benzoate/castor oil/hydrogenated castor oil

(43) benzyl alcohol/benzyl benzoate/soybean oil

(44) benzyl alcohol/benzyl benzoate/soybean oil/white oil

(45) benzyl alcohol/benzyl benzoate/medium chain triglyceride

(46) benzyl alcohol/ethyl oleate/soybean oil

(47) benzyl alcohol/ethyl oleate/soybean oil/white oil

(48) anhydrous ethanol/glyceryl monoacetate/tetrahydrofurfuryl polyethylene glycol ether

(49) anhydrous ethanol/glyceryl monoacetate/glyceryl triacetate

(50) benzyl alcohol/glyceryl monoacetate/tetrahydrofurfuryl polyethylene glycol ether

(51) benzyl alcohol/glyceryl monoacetate/glyceryl triacetate

(52) benzyl alcohol/glyceryl monoacetate/benzyl benzoate

(53) anhydrous ethanol/ethyl lactate/ethyl oleate

(54) anhydrous ethanol/ethyl lactate/tetrahydrofurfuryl polyethylene glycol ether

(55) anhydrous ethanol/ethyl lactate/glyceryl triacetate

(56) anhydrous ethanol/ethyl lactate/benzyl benzoate

(57) anhydrous ethanol/ethyl lactate/castor oil

(58) benzyl alcohol/ethyl lactate/ethyl oleate

(59) benzyl alcohol/ethyl lactate/glyceryl triacetate

(60) benzyl alcohol/ethyl lactate/tetrahydrofurfuryl polyethylene glycol ether

(61) benzyl alcohol/ethyl lactate/corn oil

(62) benzyl alcohol/ethyl lactate/sesame oil

(63) benzyl alcohol/ethyl lactate/soybean oil

(64) benzyl alcohol/ethyl lactate/castor oil

(65) benzyl alcohol/ethyl lactate/benzyl benzoate

(66) benzyl alcohol/ethyl lactate/medium chain triglyceride

(67) benzyl alcohol/anhydrous ethanol/castor oil/hydrogenated castor oil

(68) benzyl alcohol/anhydrous ethanol/ethyl oleate

(69) benzyl alcohol/anhydrous ethanol/soybean oil/white oil

(70) benzyl alcohol/anhydrous ethanol/corn oil

(71) benzyl alcohol/anhydrous ethanol/glyceryl triacetate

(72) benzyl alcohol/anhydrous ethanol/sesame oil

(73) benzyl alcohol/anhydrous ethanol/medium chain triglyceride

(74) The results suggested that: the mixture of ethanol and any one of benzyl alcohol, benzyl benzoate, and ethyl oleate showed excellent miscibility with one of soybean oil, sesame oil, and corn oil, whereas ethanol alone did not mix miscibly with one of soybean oil, sesame oil, and corn oil; castor oil might be mixed with any one of ethanol, benzyl alcohol, and benzyl benzoate.

Experimental Example 3

Formulation Experiment for Sustained-Release Formulation Delivery System (in Part)

(75) A certain amount of bupivacaine free base, bupivacaine hydrochloride, ropivacaine free base, ropivacaine methanesulfonate, ropivacaine hydrochloride, dezocine (an opioid analgesic), and parecoxib (a selective COX-2 inhibitor), were weighed respectively, into each of which was added drug menstruum and drug sustained-release agents, and the stabilization process of the formulations was observed. Detailed experimental procedures were similar to those in Experimental Example 2. As shown in the experimental results, part of the drug delivery system combinations that may be used in the formula of the sustained-release formulation delivery system is as follows:

(76) benzyl alcohol/ethyl oleate

(77) benzyl alcohol/glyceryl triacetate

(78) benzyl alcohol/soybean oil

(79) benzyl alcohol/castor oil

(80) benzyl alcohol/sesame oil

(81) benzyl alcohol/corn oil

(82) benzyl alcohol/medium chain triglyceride

(83) anhydrous ethanol/ethyl oleate

(84) anhydrous ethanol/benzyl benzoate

(85) anhydrous ethanol/glyceryl triacetate

(86) anhydrous ethanol/castor oil

(87) anhydrous ethanol/ethyl oleate/soybean oil

(88) anhydrous ethanol/ethyl oleate/corn oil

(89) anhydrous ethanol/ethyl oleate/sesame oil

(90) anhydrous ethanol/benzyl benzoate/glyceryl triacetate

(91) anhydrous ethanol/benzyl benzoate/soybean oil

(92) anhydrous ethanol/benzyl benzoate/castor oil

(93) anhydrous ethanol/benzyl benzoate/castor oil/hydrogenated castor oil

(94) anhydrous ethanol/benzyl benzoate/corn oil

(95) anhydrous ethanol/benzyl benzoate/tetrahydrofurfuryl polyethylene glycol ether

(96) anhydrous ethanol/benzyl benzoate/sesame oil

(97) anhydrous ethanol/benzyl benzoate/medium chain triglyceride

(98) benzyl alcohol/benzyl benzoate/ethyl oleate

(99) benzyl alcohol/benzyl benzoate/tetrahydrofurfuryl polyethylene glycol ether

(100) benzyl alcohol/benzyl benzoate/glyceryl triacetate

(101) benzyl alcohol/benzyl benzoate/castor oil

(102) benzyl alcohol/benzyl benzoate/soybean oil

(103) benzyl alcohol/benzyl benzoate/soybean oil/white oil

(104) benzyl alcohol/benzyl benzoate/medium chain triglyceride

(105) anhydrous ethanol/glyceryl monoacetate/glyceryl triacetate

(106) benzyl alcohol/glyceryl monoacetate/glyceryl triacetate

(107) benzyl alcohol/glyceryl monoacetate/benzyl benzoate

(108) anhydrous ethanol/ethyl lactate/ethyl oleate

(109) anhydrous ethanol/ethyl lactate/glyceryl triacetate

(110) anhydrous ethanol/ethyl lactate/benzyl benzoate

(111) anhydrous ethanol/ethyl lactate/castor oil

(112) benzyl alcohol/ethyl lactate/ethyl oleate

(113) benzyl alcohol/ethyl lactate/corn oil

(114) benzyl alcohol/ethyl lactate/sesame oil

(115) benzyl alcohol/ethyl lactate/soybean oil

(116) benzyl alcohol/ethyl lactate/castor oil

(117) benzyl alcohol/ethyl lactate/benzyl benzoate

(118) benzyl alcohol/ethyl lactate/medium chain triglyceride

(119) benzyl alcohol/anhydrous ethanol/castor oil

(120) benzyl alcohol/anhydrous ethanol/castor oil/hydrogenated castor oil

(121) benzyl alcohol/anhydrous ethanol/ethyl oleate

(122) benzyl alcohol/anhydrous ethanol/soybean oil

(123) benzyl alcohol/anhydrous ethanol/corn oil

(124) benzyl alcohol/anhydrous ethanol/glyceryl triacetate

(125) benzyl alcohol/anhydrous ethanol/sesame oil

(126) benzyl alcohol/anhydrous ethanol/medium chain triglyceride

(127) The experimental results suggested that ropivacaine free base, ropivacaine methanesulfonate, and ropivacaine hydrochloride showed an increased solubility in the mixture of benzyl benzoate with one of ethanol and benzyl alcohol, while dezocine and parecoxib had good solubility in ethanol, benzyl alcohol, benzyl benzoate, and ethyl lactate.

Experimental Example 4

Verification of the Solubility of Various Local Anesthetics in the Sustained-Release Drug Delivery System

(128) With reference to the results in Experimental Examples 2 and 3, drug delivery systems of benzyl alcohol/benzyl benzoate/castor oil, benzyl alcohol/ethyl oleate/castor oil, benzyl alcohol/benzyl benzoate/soybean oil, benzyl alcohol/ethyl oleate/soybean oil, ethanol/benzyl benzoate/castor oil, ethanol/ethyl oleate/castor oil, ethanol/benzyl benzoate/soybean oil, benzyl alcohol/medium chain triglyceride, ethyl oleate/soybean oil were used as examples for verification of the solubility of various local anesthetics in the sustained-release drug delivery system, which local anesthetics were selected from procaine free base, procaine hydrochloride, lidocaine free base, lidocaine hydrochloride, bupivacaine free base, bupivacaine hydrochloride, tetracaine free base, tetracaine hydrochloride, dibucaine free base, dibucaine hydrochloride, Articaine free base, and Articaine hydrochloride (12 in total). The 12 local anesthetics were each added into the selected drug delivery systems, and the dissolution process of the drugs was observed (norm: 15-20 mg/ml, observed at 25° C. for 24 hours with recordation; or observed at 4° C. for 24 hours with recordation).

(129) As shown in the results, all 12 local anesthetics were well dissolved in the various chosen drug delivery systems; at 4° C., the 12 local anesthetics had good solubility in benzyl alcohol/benzyl benzoate/castor oil, benzyl alcohol/ethyl oleate/castor oil, benzyl alcohol/benzyl benzoate/soybean oil, benzyl alcohol/ethyl oleate/soybean oil, ethanol/benzyl benzoate/castor oil, ethanol/ethyl oleate/castor oil, ethanol/benzyl benzoate/soybean oil, and benzyl alcohol/medium chain oil, and the formulations were clear; procaine and tetracaine slightly precipitated in the ethyl oleate/soybean oil drug delivery system, while the other local anesthetics showed good solubility in the ethyl oleate/soybean oil drug delivery system.

Experimental Example 5

Experiments on In Vitro Stability of the Drug Formulations

(130) On the basis of the empirical prescribed composition of the ropivacaine free base and ropivacaine methanesulfonate delivery systems selected in Experimental Example 3, benzyl alcohol/ethyl oleate, anhydrous ethanol/ethyl oleate, benzyl alcohol/anhydrous ethanol/ethyl oleate, benzyl alcohol/castor oil, benzyl alcohol/soybean oil, benzyl alcohol/benzyl benzoate/soybean oil, anhydrous ethanol/benzyl benzoate/soybean oil, anhydrous ethanol/ethyl oleate/soybean oil, anhydrous ethanol/castor oil, benzyl alcohol/ethyl oleate/soybean oil, anhydrous ethanol/ethyl oleate/castor oil, benzyl alcohol/benzyl benzoate/castor oil, anhydrous ethanol/benzyl benzoate/castor oil, benzyl alcohol/benzyl benzoate/ethyl oleate, benzyl alcohol/benzyl benzoate/ethyl oleate/soybean oil were selected for prescription. A certain amount of ropivacaine methanesulfonate or ropivacaine free base was dissolved into each of the above, left to stand at room temperature for 24 h, and dissolution stability thereof was observed and recorded; or left to stand at 4° C. for 24 h, and dissolution stability thereof was observed and recorded.

(131) TABLE-US-00003 TABLE III Test results on dissolution stability of ropivacaine sustained- release formulations at various concentrations Ambient Low Incorpo- Concen- temper- temper- Prescribed rated tration ature ature composition drug (mg/ml) (25° C.) (4° C.) Benzyl alcohol Ropivacaine 30 Clear Clear (10%)/ethyl oleate free base (90%) Benzyl alcohol Ropivacaine 35 Clear Extremely (10%)/ethyl oleate free base trivial (90%) precipi- tation Benzyl alcohol Ropivacaine 40 Clear Trivial (10%)/ethyl oleate free base precipi- (90%) tation Anhydrous ethanol Ropivacaine 25 Clear Clear (10%)/ethyl oleate free base (90%) Anhydrous ethanol Ropivacaine 30 Clear Trivial (10%)/ethyl oleate free base precipi- (90%) tation Anhydrous ethanol Ropivacaine 35 Clear Small (10%)/ethyl oleate free base amount of (90%) precipi- tation Benzyl alcohol Ropivacaine 40 Clear Clear (8%)/anhydrous ethanol free base (8%)/ethyl oleate (84%) Benzyl alcohol Ropivacaine 45 Clear Clear (8%)/anhydrous ethanol free base (8%)/ethyl oleate (84%) Benzyl alcohol Ropivacaine 50 Clear Trivial (8%)/anhydrous ethanol free base precipi- (8%)/ethyl oleate tation (84%) Benzyl alcohol Ropivacaine 35 Clear Clear (10%)/castor oil free base (90%) Benzyl alcohol Ropivacaine 40 Clear Clear (10%)/castor oil free base (90%) Benzyl alcohol Ropivacaine 45 Clear Trivial (10%)/castor oil free base precipi- (90%) tation Benzyl alcohol Ropivacaine 25 Clear Clear (10%)/soybean oil free base (90%) Benzyl alcohol Ropivacaine 30 Clear Extremely (10%)/soybean oil free base trivial (90%) precipi- tation Benzyl alcohol Ropivacaine 35 Clear Trivial (10%)/soybean oil free base precipi- (90%) tation Anhydrous ethanol Ropivacaine 25 Clear Clear (10%)/castor oil free base (90%) Anhydrous ethanol Ropivacaine 30 Clear Trivial (10%)/castor oil free base precipi- (90%) tation Anhydrous ethanol Ropivacaine 35 Clear Trivial (10%)/castor oil free base precipi- (90%) tation Benzyl alcohol Ropivacaine 30 Clear Clear (10%)/ethyl oleate free base (30%)/soybean oil (60%) Benzyl alcohol Ropivacaine 35 Clear Extremely (10%)/ethyl oleate free base trivial (30%)/soybean oil precipi- (60%) tation Benzyl alcohol Ropivacaine 40 Clear Trivial (10%)/ethyl oleate free base precipi- (30%)/soybean oil tation (60%) Benzyl alcohol Ropivacaine 35 Clear Clear (10%)/benzyl benzoate free base (30%)/soybean oil (60%) Benzyl alcohol Ropivacaine 40 Clear Clear (10%)/benzyl benzoate free base (30%)/soybean oil (60%) Benzyl alcohol Ropivacaine 45 Clear Extremely (10%)/benzyl benzoate free base trivial (30%)/soybean oil precipi- (60%) tation Anhydrous ethanol Ropivacaine 30 Clear Clear (10%)/benzyl benzoate free base (30%)/soybean oil (60%) Anhydrous ethanol Ropivacaine 35 Clear Trivial (10%)/benzyl benzoate free base precipi- (30%)/soybean oil tation (60%) Anhydrous ethanol Ropivacaine 40 Clear precipi- (10%)/benzyl benzoate free base tation (30%)/soybean oil (60%) Anhydrous ethanol Ropivacaine 25 Clear Clear (10%)/ethyl oleate free base (30%)/soybean oil (60%) Anhydrous ethanol Ropivacaine 30 Clear Trivial (10%)/ethyl oleate free base precipi- (30%)/soybean oil tation (60%) Anhydrous ethanol Ropivacaine 35 Clear precipi- (10%)/ethyl oleate free base tation (30%)/soybean oil (60%) Anhydrous ethanol Ropivacaine 25 Clear Clear (10%)/ethyl oleate free base (30%)/castor oil (60%) Anhydrous ethanol Ropivacaine 30 Clear Clear (10%)/ethyl oleate free base (30%)/castor oil (60%) Anhydrous ethanol Ropivacaine 35 Clear Trivial (10%)/ethyl oleate free base precipi- (30%)/castor oil tation (60%) Benzyl alcohol Ropivacaine 40 Clear Clear (10%)/benzyl benzoate free base (15%)/castor oil (75%) Benzyl alcohol Ropivacaine 45 Clear Clear (10%)/benzyl benzoate free base (15%)/castor oil (75%) Benzyl alcohol Ropivacaine 50 Clear Extremely (10%)/benzyl benzoate free base trivial (15%)/castor oil precipi- (75%) tation Anhydrous ethanol Ropivacaine 30 Clear Clear (10%)/benzyl benzoate free base (15%)/castor oil (75%) Anhydrous ethanol Ropivacaine 35 Clear Clear (10%)/benzyl benzoate free base (15%)/castor oil (75%) Anhydrous ethanol Ropivacaine 40 Clear Clear (10%)/benzyl benzoate free base (15%)/castor oil (75%) Benzyl alcohol Ropivacaine 35 Clear Clear (10%)/benzyl benzoate free base (30%)/ethyl oleate (60%) Benzyl alcohol Ropivacaine 35 Clear Extremely (8%)/benzyl benzoate free base trivial (42%)/ethyl oleate precipi- (50%) tation Benzyl alcohol Ropivacaine 35 Clear Clear (10%)/benzyl benzoate free base (30%)/ethyl oleate (30%) Soybean oil (30%) Benzyl alcohol Ropivacaine 35 Clear Extremely (8%)/benzyl benzoate free base trivial (42%)/ethyl oleate (25%) precipi- Soybean oil (25%) tation Benzyl alcohol Ropivacaine 12 Clear Trivial (12%)/ethyl oleate methane- precipi- (88%) sulfonate tation Benzyl alcohol Ropivacaine 12 Clear Trivial (14%)/ethyl oleate methane- precipi- (86%) sulfonate tation Benzyl alcohol Ropivacaine 12 Clear Clear (16%)/ethyl oleate methane- (84%) sulfonate Anhydrous ethanol Ropivacaine 12 Clear Trivial (16%)/ethyl oleate methane- precipi- (84%) sulfonate tation Anhydrous ethanol Ropivacaine 12 Clear Clear (18%)/ethyl oleate methane- (82%) sulfonate Anhydrous ethanol Ropivacaine 12 Clear Clear (20%)/ethyl oleate methane- (80%) sulfonate Benzyl alcohol Ropivacaine 12 Clear Clear (6%)/anhydrous ethanol methane- (6%)/ethyl oleate sulfonate (84%) Benzyl alcohol Ropivacaine 12 Clear Clear (8%)/anhydrous ethanol methane- (8%)/ethyl oleate sulfonate (84%) Benzyl alcohol Ropivacaine 12 Clear Trivial (10%)/anhydrous ethanol methane- precipi- (10%)/ethyl oleate sulfonate tation (84%)

(132) As shown in the experimental results, at different temperature, the maximum concentration of ropivacaine free base in the prescribed composition 1 [benzyl alcohol (8%)/anhydrous ethanol (8%)/ethyl oleate (84%)], composition 2 [benzyl alcohol (10%)/castor oil (90%)], composition 3 [benzyl alcohol (10%)/ethyl oleate (30%)/soybean oil (60%)], composition 4 [benzyl alcohol (10%)/benzyl benzoate (30%)/soybean oil (60%)], composition 5 [benzyl alcohol (10%)/benzyl benzoate (15%)/castor oil (75%)], composition 6 [anhydrous ethanol (10%)/benzyl benzoate (15%)/castor oil (75%)], composition 7 [benzyl alcohol (10%)/benzyl benzoate (30%)/ethyl oleate (60%)], composition 8 [benzyl alcohol (8%)/benzyl benzoate (42%)/ethyl oleate (50%)], composition 9 [benzyl alcohol (10%)/benzyl benzoate (30%)/ethyl oleate (30%)/soybean oil (30%)], and composition 10 [benzyl alcohol (8%)/benzyl benzoate (42%)/ethyl oleate (25%)/soybean oil (25%)] was about 35 mg/ml; the maximum concentration of ropivacaine free base in the prescribed composition 11 [benzyl alcohol (10%)/ethyl oleate (90%)], 12, [benzyl alcohol (10%)/soybean oil (90%)], composition 13 [anhydrous ethanol (10%)/benzyl benzoate (30%)/soybean oil (60%)], and composition 14 [anhydrous ethanol (10%)/ethyl oleate (30%)/castor oil (60%)] was more than 30 mg/ml; meanwhile, the solubility of ropivacaine methanesulfonate in various prescribed compositions was slightly poorer than that of ropivacaine free base.

(133) On condition that each sustained-release formulation was stably dissolved, the concentration of prescribed compositions having better ropivacaine free base solubility was measured. The general procedure was as follows: prescribed compositions having good solubility after storage at 4° C. for 24 h was left to stand for 30 days and observed, and those having better degree of clarity were screened for measurement of concentration. Detailed results are shown in the table below.

(134) TABLE-US-00004 TABLE IV Experimental results for structural stability of ropivacaine sustained-release formulations (content determination) Mea- sured Incorpo- Concen- concen- Prescribed rated tration tration No. composition drug (mg/ml) (mg/ml) 1 Benzyl alcohol (10%)/benzyl Ropivacaine 35 35.5 benzoate (15%)/soybean oil free base (75%) 2 Anhydrous ethanol (10%)/benzyl Ropivacaine 30 29.7 benzoate (15%)/soybean oil free base (75%) 3 Benzyl alcohol (8%)/anhydrous Ropivacaine 45 44.3 ethanol (8%)/ethyl oleate free base (84%) 4 Benzyl alcohol (10%)/castor Ropivacaine 40 41.2 oil (90%) free base 5 Benzyl alcohol (10%)/ethyl Ropivacaine 30 30.2 oleate (30%)/soybean oil free base (60%) 6 Benzyl alcohol (10%)/benzyl Ropivacaine 45 45.9 benzoate (15%)/castor oil free base (75%) 7 Anhydrous ethanol (10%)/benzyl Ropivacaine 40 39.8 benzoate (15%)/castor oil free base (75%) 8 Benzyl alcohol (10%)/soybean Ropivacaine 30 30.3 oil (90%) free base

(135) As shown in the experimental results, ropivacaine free base in various prescribed compositions was structurally stable and did not degrade.

Experimental Example 6

Preliminary Study on Compound Compositions of Non-Addictive Anesthetic Analgesic Sustained-Release Formulations

(136) On the basis of the prescribed compositions in Table IV, dezocine, an opioid analgesic, and parecoxib, a selective COX-2 inhibitor, were respectively incorporated into the drug delivery systems of the above prescribed compositions, and the formulation stability was observed at ambient temperature (25° C.) and low temperature (4° C.) (for a duration of about 24 h). Detailed results suggested that the solubility of parecoxib in the drug delivery systems was above 20 mg/ml (for a regular injection formulation, 40 mg/dose, 1 dose/6-12 h, daily dosage not more than 80 mg) while the solubility of dezocine in the drug delivery systems was above 30 mg/ml (for a regular injection formulation, 10 mg/dose, 1 dose/2-4 h, daily dosage not more than 120 mg). As such, a mixture of ropivacaine free base together with dezocine or parecoxib in such drug delivery systems may be used so as to formulate a sustained-release analgesic compound formulation having a synergistic analgesic effect (analgesics with different targets used in combination show certain synergistic effect).

Experimental Example 7

Effect in Wound Healing in Rats with Intramuscular Injection of Various Prescribed Compositions

(137) Experiment grouping and dosing regimen: about 65 male SD rats of 230-250 g were adaptively fed for 2-3 days, and then screened and divided into 10 groups with 6 rats in each group according to their weight. The groups were respectively: model control group, ropivacaine injection solution group, ropivacaine formulation-1 group, ropivacaine formulation-2 group, ropivacaine formulation-3 group, ropivacaine formulation-4 group, ropivacaine formulation-5 group, ropivacaine formulation-6 group, ropivacaine formulation-7 group, and ropivacaine formulation-8 group (see Table IV for detailed prescribed composition and specification). The model control group was injected with physiological saline, and ropivacaine injection solution group and ropivacaine formulations 1-8 groups were given at a dosage of 0.5 ml/rat.

(138) Basic experimental procedures: after the test animals were screened and grouped according to their weight, hair on the back of the rats in each experimental groups were removed; on the next day, 2 cm*1 cm rat back full-thickness defect wound models were established upon operation, designated as D0, and photographs were recorded. The rats were randomly grouped, and administrated in groups by means of multi-site intramuscular injection at wound proximity.

(139) Observation indicators: at different timepoints on D1, D3, D7, D14, and D21 after administration, healing of wounds in rats from each group was observed respectively, rated according to area of healed wounds and recovery state, and photographs were then recorded.

(140) Results assessment: as shown in Table V, wound healing in rats in different groups and at various observation timepoints was comparatively assessed, and the results suggested that sustained-release ropivacaine formulations of different prescribed composition might not have substantially different impact on wound healing in rats.

(141) TABLE-US-00005 TABLE V Rating of wound healing in rats given ropivacaine formulations of different prescribed composition (n = 6) Groups D 1 D 3 D 7 D 14 D 21 Blank control group — 18.37% 49.36% 88.38% 97.39% Ropivacaine — 22.41% 55.31% 79.27% 96.37% methanesulfonate injection solution group Ropivacaine formulation 1 — 19.32% 61.97% 89.26% 98.13% group Ropivacaine formulation 2 — 24.42% 49.12% 90.15% 96.58% group Ropivacaine formulation 3 — 28.18% 57.30% 93.27% 94.96% group Ropivacaine formulation 4 — 20.21% 54.18% 87.36% 98.46% group Ropivacaine formulation 5 — 22.87% 57.26% 81.25% 99.15% group Ropivacaine formulation 6 — 19.90% 51.74% 78.54% 96.33% group Ropivacaine formulation 7 — 23.45% 62.57% 85.42% 99.37% group Ropivacaine formulation 8 — 19.81% 58.22% 79.48% 96.75% group

Experimental Example 8

Study on Efficacy of Ropivacaine Sustained-Release Formulations of Prescribed Compositions (Thermal Stimulation)

(142) Experiment grouping and dosing regimen: about 110 male SD rats of 230-250 g were adaptively fed for 2-3 days, and then subjected to experiments. The rats were divided into 17 groups which were respectively: ropivacaine injection solution group, ropivacaine formulation-1 group, solvent 1 group, ropivacaine formulation-2 group, solvent 2 group, ropivacaine formulation-3 group, solvent 3 group, ropivacaine formulation-4 group, solvent 4 group, ropivacaine formulation-5 group, solvent 5 group, ropivacaine formulation-6 group, solvent 6 group, ropivacaine formulation-7 group, solvent 7 group, ropivacaine formulation-8 group, solvent 8 group (see Table IV for detailed prescribed composition and specification), with a dosage of 0.5 ml/rat for each group.

(143) Details experimental procedures were as follows:

(144) 1. Sensory nerve blocking tests: 102 animals that had a response time of 6-8 s were screened and chosen from 110 male SD rats (the screening method is a thermal radiation method, see the Measurement section below for detailed procedures) and divided into 17 groups, as described in details in the previous paragraph. Each group was injected with ropivacaine methanesulfonate injection solution, ropivacaine sustained-release formulations of various prescribed compositions and corresponding blank solvents, with a dosage of 0.5 ml/rat. Detailed operation procedures were as below: the rats were anesthetized with an appropriate amount of diethyl ether; a needle was inserted at approximately ⅓ along the elongation of the right humeral motor, in the anteromedial direction with the end of the needle tilted up at 45°, retracted for 1 mm when the needle tip reached the bone, and the drug was then injected.

(145) Measurement: thermal radiation/foot-lifting method; the rats were allowed to freely stand on a glass panel, and measurements were taken after the animals calmed down. A beam with a diameter of about 4 millimeters was emitted from the radiation source after focalized through a lens, and the radiation intensity was adjusted (about 52° C.). The radiation light source was positioned below the glass panel, and the sole of the rats' rear feet was irradiated through the glass panel. The light source was connected to a timer, i.e., a stopwatch that was activated immediately when the radiation started, and the light source automatically turned off and the timing was stopped once the rear feet of the animal was lifted. The measured time interval was the latency of the evasion reaction (foot-lifting) of the rats. The maximum of irradiation time was set as 15 sec, and recorded as 15 sec when exceeded. The duration from placement on the hotplate to retraction of the tested rear feet of rats was recorded, with each rear foot tested twice (in order to avoid burning of the sole of feet of the rats, if the duration was measured as 13 sec at the first time, a second measurement was unnecessary). The time interval between repeated measurements of the same rear foot should be more than 10 min, and the average of two measurements was the pain threshold of each rear foot.

(146) Time of measurement: for each experimental group, foot-lifting duration at the administrated side of rats in each group before administration as well as 1 h, 2 h, 4 h, 8 h, 24 h, 32 h, 48 h, 56 h, 72 h after administration was recorded, and measured twice, the average of which two measurements was the post-drug latency (DL) of the rear foot at that side at the given point of time.

(147) 2. Measurement for motor nerve blocking: at the same time when sensory blocking was observed, a four-level rating method was used for the assessment of motor nerve blocking in rats in each treatment groups:

(148) Level 1: claw motion was normal, capable of dorsiflexing, stretching, and eversing;

(149) Level 2: claw was capable of dorsiflexing, stretching out again after curling (bending and adducting) with weaker stretching ability;

(150) Level 3: claw was capable of dorsiflexing, but not able to stretching out again after curling (bending and adducting);

(151) Level 4: claw failed to dorsiflex, stretch, or everse, and defects in gait were exhibited in rats.

(152) Particularly, level 1 indicated no motion blocking, level 2 indicated partial motion blocking, and level 3 and 4 indicated complete motion blocking. 1 h, 2 h, 4 h, 8 h, 24 h, 32 h, 48 h, 56 h, and 72 h after administration, motion blocking at rear feet at the administrated side of rats in each group was observed, the assessed level was recorded, and the duration of motion blocking was investigated.

(153) Statistical Processing

(154) Statistical processing was carried out by using the SPSS software. Quantitative data was compared by one-factor variance analysis, with the results represented in average±standard deviation (x±s). Rating levels for motion blocking were converted (level 1 was equivalent to 1, level 2 was equivalent to 2, level 3 was equivalent to 3, and level 4 was equivalent to 4), and then compared in rank sum test. P<0.05 indicates a statistical difference, and P<0.01 indicates a substantial statistical significance.

(155) Experimental Results

(156) Results were shown in Table VII and VIII and FIGS. 1-8. Ropivacaine sustained-release formulations of various prescribed compositions all showed some continuous analgesic effect, with part of the formulations lasting for 24 h or even more than 32 h, and different solvents in the prescribed compositions had no substantial interference with the efficacy of the principle agent, as shown in Table IX and X and FIGS. 1-8.

Experimental Example 9

Study on Efficacy of Ropivacaine Sustained-Release Formulations of Prescribed Compositions (Post-Operative Stimulation)

(157) Experiment animals: about 70 male SD rats of 300-330 g were adaptively fed for 2-3 days, and then subjected to establishment of post-operative (hereinafter simply referred to as “P.O.”) pain models.

(158) P.O. pain model establishment: rats were anesthetized by intraperitoneal injection of 10% chloral hydrate. An incision of 1 cm in length was cut laterally across the sole of the right rear foot of the rats, with a distance of about 0.5 cm from the right heel, by using a scalpel. Thereafter, the hamstring and muscle under the skin were located and lifted up by using bend tweezers, across which was cut laterally for 3-4 times (the hamstring was maintained undetached from the muscle) to cause lesion. Blood bled out was drained with adsorbent cotton, and the skin at the sole of feet was stitched up with mattress sutures. Finally, 50 mg sodium ampicillin was intramuscularly injected in the left hind limb to prevent infection.

(159) Experiment grouping and dosing regimen: after the operation was completed, the rats were left to recover overnight. In the morning of the next day, after the pain threshold was measured (mechanical puncture/foot-lifting method), the rats were randomly divided into 10 groups with 6 rats in each group according to their pain threshold values, which were respectively: model control group, ropivacaine methanesulfonate injection solution 1 group, ropivacaine formulation-2 group, solvent 2 group, ropivacaine formulation-3 group, solvent 3 group, ropivacaine formulation-4 group, solvent 4 group, ropivacaine formulation-5 group, and solvent 5 group (see Table VI for detailed prescribed composition and specification). The ropivacaine injection solution group, ropivacaine formulation 2-5 groups and solvent 2-5 groups were each given a dosage of 0.5 ml/rat.

(160) Route of administration: a needle was inserted at approximately ⅓ of the connection between the right humeral motor and the ischial tuberosity of the rats, in the anteromedial direction with the end of the needle tilted up at 45°, retracted for 1 mm when the needle tip reached the bone, and the drug was finally injected.

(161) Measurement: mechanic puncture/foot-lifting method; the rats were allowed to freely stand on a wire gauze, and measurements were taken at the right rear feet thereof by using a electronic Von Frey needle after the rats calmed down. The max value was taken as the pain threshold. Each rat was subjected to two measurements with an interval of 5 minutes or more therebetween, and the two measurements were then averaged.

(162) Time of measurement: before administration (hereinafter abbreviated as “pre-admin.”); 1 h, 2 h, 4 h, 8 h, 24 h, 32 h, 48 h, 56 h, 72 h after administration.

(163) Data analysis: statistical processing was carried out by using the SPSS software. Quantitative data was compared by one-factor variance analysis, represented in average±standard deviation (x±s). P<0.05 indicates a statistical difference, and P<0.01 indicates a substantial statistical significance.

(164) TABLE-US-00006 TABLE VI Prescribed Composition for P.O. pain experiments Mea- sured Incorpo- Concen- concen- Prescribed rated tration tration No. composition drug (mg/ml) (mg/ml) 1 Water for injection ropivacaine 12 11.8 (100%)/medicinal grade methane- sodium chloride sulfonate 2 benzyl alcohol (10%)/benzyl ropivacaine 45 45.7 benzoate (15%)/castor oil free base (75%) 3 Ethanol (10%)/benzyl ropivacaine 50 49.2 benzoate (15%)/castor oil free base (75%) 4 benzyl alcohol (10%)/benzyl ropivacaine 35 35.1 benzoate (15%)/soybean oil free base (75%) 5 anhydrous ethanol ropivacaine 30 31.1 (10%)/benzyl free base benzoate (15%)/soybean oil (75%) Note: ropivacaine methanesulfonate was prepared according to commercial standards.

(165) Experimental results: as shown in Table XI and FIG. 9, the administrated dosage of ropivacaine injection solution was relatively low (movement abnormality or even motality of animals might occur if the administrated dosage was the same as the sustained-release formulations) and continuous analgesia might last for about 2 h; whereas, ropivacaine sustained-release formulations of various experimental compositions had a continuous analgesic duration of at least 24 h, with some prescription achieving a duration of 32 h or more, and therefore the ropivacaine sustained-release formulations exhibited a superior continuous analgesic efficacy.

(166) TABLE-US-00007 TABLE VII Statistics of sensory nerve blocking time with intramuscular injection of ropivacaine sustained-release formulations of various prescribed compositions in rats (x ± s , n = 6) Pre- Groups admin. 1 h 2 h 4 h 8 h Ropivacaine  8.98 ± 1.09 14.92 ± 0.13** 14.77 ± 0.44**  8.93 ± 1.67  8.13 ± 1.11 injection solution group Ropivacaine  9.36 ± 1.31 14.87 ± 0.22** 14.48 ± 0.57** 14.27 ± 0.85** 14.58 ± 0.54** sustained- release formulation 1 group Ropivacaine  9.30 ± 1.03 14.83 ± 0.32** 14.72 ± 0.43** 13.95 ± 1.05** 14.45 ± 1.05** sustained- release formulation 2 group Ropivacaine  9.28 ± 1.66  14.7 ± 0.43** 14.83 ± 0.29** 14.18 ± 0.80** 14.12 ± 0.99** sustained- release formulation 3 group Ropivacaine  9.03 ± 1.57 14.98 ± 0.04** 14.68 ± 0.38**  14.1 ± 1.00** 11.18 ± 1.00** sustained- release formulation 4 group Ropivacaine  8.97 ± 1.23 14.95 ± 0.08** 14.72 ± 0.43** 14.52 ± 0.86** 14.43 ± 0.65** sustained- release formulation 5 group Ropivacaine  9.33 ± 1.54  14.6 ± 1.36** 14.68 ± 0.55** 14.62 ± 0.51** 14.47 ± 0.52** sustained- release formulation 6 group Ropivacaine  9.03 ± 1.52  14.1 ± 1.36** 13.13 ± 1.13**  12.5 ± 1.08** 10.72 ± 1 .76* sustained- release formulation 7 group Ropivacaine  9.07 ± 1.60 14.87 ± 0.21** 14.75 ± 0.39** 14.23 ± 0.63** 14.37 ± 0.73** sustained- release formulation 8 group Groups 24 h 32 h 48 h 56 h 72 h Ropivacaine  9.03 ± 1.31  9.42 ± 2.33  9.02 ± 1.91  8.82 ± 1.61  9.27 ± 0.97 injection solution group Ropivacaine 13.63 ± 1.15** 12.17 ± 1.70** 10.43 ± 0.79*  9.53 ± 1.57  8.93 ± 1.49 sustained- release formulation 1 group Ropivacaine  14.2 ± 1.01** 12.38 ± 1.48** 10.43 ± 1.40*  9.25 ± 1.60 10.73 ± 2.00 sustained- release formulation 2 group Ropivacaine 11.07 ± 1.28*  8.83 ± 1.11  9.1 ± 2.13  8.97 ± 2.28  9.25 ± 2.07 sustained- release formulation 3 group Ropivacaine  9.62 ± 0.60  8.45 ± 1.69  8.93 ± 1.91  8.42 ± 2.74  8.45 ± 1.58 sustained- release formulation 4 group Ropivacaine 12.42 ± 1.09** 10.68 ± 1.65*  9.03 ± 1.66  9.23 ± 1.33  8.52 ± 1.48 sustained- release formulation 5 group Ropivacaine 12.67 ± 0.97** 10.83 ± 1.85*  9.55 ± 1.30  9.93 ± 1.27  9.33 ± 1.42 sustained- release formulation 6 group Ropivacaine 11.15 ± 0.87*  8.97 ± 1.11  8.62 ± 1.48  8.47 ± 1.65  8.52 ± 1.56 sustained- release formulation 7 group Ropivacaine 13.57 ± 1.27**  10.9 ± 1.34*  9.2 ± 1.50  9.52 ± 2.24  9.73 ± 1.79 sustained- release formulation 8 group Note: as compared to the control group, **P < 0.01, *P < 0.05.

(167) TABLE-US-00008 TABLE VIII Statistics of motor nerve blocking time with intramuscular injection of ropivacaine sustained-release formulations of various prescribed compositions in rats (x ± s , n = 6) Pre- admin. 1 h 2 h 4 h 8 h Ropivacaine   1 ± 0.0  2.5 ± 0.55** 1.83 ± 0.41** 1.17 ± 0.41   1 ± 0 injection solution group Ropivacaine   1 ± 0.0 2.33 ± 0.52**   2 ± 0.63**   2 ± 0.63** 1.33 ± 0.82** sustained- release formulation 1 group Ropivacaine   1 ± 0.0   2 ± 0.63**   2 ± 0.63** 1.67 ± 0.52**  1.5 ± 0.55** sustained- release formulation 2 group Ropivacaine   1 ± 0.0 2.83 ± 0.41** 2.83 ± 0.41** 2.33 ± 0.52** 2.17 ± 0.41** sustained- release formulation 3 group Ropivacaine   1 ± 0.0 2.33 ± 0.52**   2 ± 0.00**   2 ± 0.00** 1.33 ± 0.52* sustained- release formulation 4 group Ropivacaine   1 ± 0.0  2.5 ± 0.55** 2.17 ± 0.41** 2.17 ± 0.41**  1.5 ± 0.55* sustained- release formulation 5 group Ropivacaine   1 ± 0.0  2.5 ± 0.55** 2.33 ± 0.52** 2.17 ± 0.41** 2.17 ± 0.41** sustained- release formulation 6 group Ropivacaine   1 ± 0.0  2.5 ± 0.55** 2.17 ± 0.41** 2.17 ± 0.41**  1.5 ± 0.84** sustained- release formulation 7 group Ropivacaine   1 ± 0.0   2 ± 0.63** 2.33 ± 0.52** 1.83 ± 0.75** 1.83 ± 0.75** sustained- release formulation 8 group 24 h 32 h 48 h 56 h 72 h Ropivacaine   1 ± 0   1 ± 0   1 ± 0   1 ± 0   1 ± 0 injection solution group Ropivacaine 1.17 ± 0.41*   1 ± 0   1 ± 0   1 ± 0   1 ± 0 sustained- release formulation 1 group Ropivacaine 1.33 ± 0.52*   1 ± 0   1 ± 0   1 ± 0   1 ± 0 sustained- release formulation 2 group Ropivacaine 2.17 ± 0.41** 1.33 ± 0.52* 1.17 ± 0.41 1.17 ± 0.41 1.17 ± 0.41 sustained- release formulation 3 group Ropivacaine 1.33 ± 0.52*   1 ± 0   1 ± 0   1 ± 0   1 ± 0 sustained- release formulation 4 group Ropivacaine 1.17 ± 0.41 1.17 ± 0.41 1.17 ± 0.41   1 ± 0   1 ± 0 sustained- release formulation 5 group Ropivacaine   2 ± 0** 1.33 ± 0.52*   1 ± 0   1 ± 0   1 ± 0 sustained- release formulation 6 group Ropivacaine  1.5 ± 0.84** 1.17 ± 0.41 1.17 ± 0.41 1.17 ± 0.41   1 ± 0 sustained- release formulation 7 group Ropivacaine 1.83 ± 0.75** 1.17 ± 0.41 1.17 ± 0.41 1.17 ± 0.41   1 ± 0 sustained- release formulation 8 group Note: as compared to the control group, **P < 0.01,*P < 0.05.

(168) TABLE-US-00009 TABLE IX Statistics of sensory nerve blocking time with intramuscular injection of solvents in ropivacaine sustained-release formulations of various prescribed compositions in rats (x ± s , n = 6) Pre- admin. 1 h 2 h 4 h 8 h Ropivacaine  8.98 ± 1.09 14.92 ± 0.13** 14.77 ± 0.44**  8.93 ± 1.67  8.13 ± 1.11 injection solution group Solvent 1  9.15 ± 1.03  12.9 ± 1.28** 12.85 ± 0.85**  12.4 ± 1.33**  10.8 ± 0.32** group Solvent 2  9.28 ± 0.97 12.62 ± 1.05**  12.1 ± 1.39** 11.68 ± 0.91* 11.25 ± 0.92** group Solvent 3  8.97 ± 1.91  8.9 ± 1.37  8.82 ± 1.55  8.25 ± 1.34  8.87 ± 1.71 group Solvent 4  8.88 ± 1.51  8.93 ± 1.62  8.08 ± 1.24  9.5 ± 1.24  9.15 ± 1.68 group Solvent 5  9.3 ± 1.78 13.15 ± 1.66** 10.33 ± 1.78  9.43 ± 1.30  8.6 ± 2.48 group Solvent 6  8.87 ± 1.68  9.7 ± 1.46  8.42 ± 1.38  8.55 ± 1.05  8.68 ± 1.72 group Solvent 7  8.92 ± 1.43 12.43 ± 1.67** 11.07 ± 0.72*  8.35 ± 2.11  8.57 ± 1.25 group Solvent 8  8.72 ± 1.17  8.9 ± 1.29  9.12 ± 1.16  8.95 ± 1.87  9.05 ± 1.57 group 24 h 32 h 48 h 56 h 72 h Ropivacaine  9.03 ± 1.31  9.42 ± 2.33  9.02 ± 1.91  8.82 ± 1.61  9.27 ± 0.97 injection solution group Solvent 1 10.17 ± 1.40  9.28 ± 12.23  8.68 ± 2.18  9.05 ± 1.26  8.7 ± 1.61 group Solvent 2 10.28 ± 1.02 10.02 ± 2.01  9.02 ± 1.72  9.68 ± 1.60  9.5 ± 1.99 group Solvent 3  9.5 ± 1.11    9 ± 1.32  8.92 ± 1.53  9.23 ± 1.79  9.02 ± 1.60 group Solvent 4  8.47 ± 1.62  8.93 ± 2.28  8.7 ± 1.76  9.22 ± 2.36  9.22 ± 1.80 group Solvent 5  8.55 ± 1.54  8.73 ± 2.05  9.13 ± 1.08  8.83 ± 1.37  9.1 ± 1.46 group Solvent 6  8.78 ± 1.49  9.07 ± 1.85  9.2 ± 1.41  8.68 ± 1.41  9.03 ± 1.58 group Solvent 7  8.95 ± 1.30  8.53 ± 1.19  8.83 ± 1.63  8.98 ± 1.20  8.38 ± 1.25 group Solvent 8  8.47 ± 1.34  8.95 ± 1.65  8.72 ± 1.53  8.67 ± 0.83   9 ± 1.34 group Note: as compared to the control group, **P < 0.01, *P < 0.05.

(169) TABLE-US-00010 TABLE X Statistics of motor nerve blocking time with intramuscular injection of solvents in ropivacaine sustained-release formulations of various prescribed compositions in rats (x ± s , n = 6) Pre- admin. 1 h 2 h 4 h 8 h 24 h 32 h 48 h 56 h 72 h ropivacaine injection 1 ± 0  2.5 ± 0.55** 1.83 ± 0.41** 1.17 ± 0.41   1 ± 0 1 ± 0 1 ± 0 1 ± 0 1 ± 0 1 ± 0 solution group Solvent 1 group 1 ± 0   2 ± 0.89** 1.67 ± 0.52** 1.67 ± 0.52**   1 ± 0 1 ± 0 1 ± 0 1 ± 0 1 ± 0 1 ± 0 Solvent 2 group 1 ± 0 2.17 ± 0.75** 1.17 ± 0.41 1.17 ± 0.41   1 ± 0 1 ± 0 1 ± 0 1 ± 0 1 ± 0 1 ± 0 Solvent 3 group 1 ± 0 2.33 ± 0.52**  1.5 ± 0.55*   1 ± 0 2.33 ± 0.52** 1 ± 0 1 ± 0 1 ± 0 1 ± 0 1 ± 0 Solvent 4 group 1 ± 0 2.17 ± 0.41** 1.67 ± 0.52*   1 ± 0   1 ± 0 1 ± 0 1 ± 0 1 ± 0 1 ± 0 1 ± 0 Solvent 5 group 1 ± 0 2.17 ± 0.41** 1.33 ± 0.52*   1 ± 0   1 ± 0 1 ± 0 1 ± 0 1 ± 0 1 ± 0 1 ± 0 Solvent 6 group 1 ± 0 1.67 ± 0.52* 1.33 ± 0.52*   1 ± 0   1 ± 0 1 ± 0 1 ± 0 1 ± 0 1 ± 0 1 ± 0 Solvent 7 group 1 ± 0 2.33 ± 0.52** 1.83 ± 0.41** 1.67 ± 0.82**   1 ± 0 1 ± 0 1 ± 0 1 ± 0 1 ± 0 1 ± 0 Solvent 8 group 1 ± 0 1.83 ± 0.75** 1.17 ± 0.41 1.17 ± 0.41   1 ± 0 1 ± 0 1 ± 0 1 ± 0 1 ± 0 1 ± 0 Note: as compared to the control group, **P < 0.01,*P < 0.05.

(170) TABLE-US-00011 TABLE XI Statistics of sensory nerve blocking time with intramuscular injection of ropivacaine sustained-release formulations of various prescribed compositions in rats (P.O. pain model) (x ± s , n = 6) Time 1 h 2 h 4 h 8 h 24 h Model group  8.18 ± 2.44  7.8 ± 2.79  9.73 ± 2.92  7.43 ± 1.15 10.83 ± 3.41 Ropivacaine  8.02 ± 2.45 61.25 ± 5.28** 50.47 ± 3.90**  10.2 ± 1.99**  11.4 ± 3.32 methanesulfonate injection solution 1 group Ropivacaine  8.35 ± 2.36  59.3 ± 6.75** 44.51 ± 6.05** 53.32 ± 6.42** 45.05 ± 3.93** sustained-release formulation 2 group Solvent 2 group  8.83 ± 2.34  16.2 ± 10.50**  9.8 ± 1.92 10.63 ± 3.25* 11.77 ± 2.54 Ropivacaine  8.55 ± 2.37 53.17 ± 13.13** 47.58 ± 7.44** 47.17 ± 5.16** 41.67 ± 10.18** sustained-release formulation 3 group Solvent 3 group  8.87 ± 3.63 20.65 ± 12.83** 11.45 ± 4.68 10.75 ± 2.83* 11.95 ± 5.21 Ropivacaine  8.58 ± 2.28  59.3 ± 7.21**  52.8 ± 7.99** 44.93 ± 12.88** 41.92 ± 6.33** sustained-release formulation 4 group Solvent 4 group  8.37 ± 1.85 14.33 ± 7.34* 12.05 ± 7.15  9.57 ± 4.91 11.25 ± 5.22 Ropivacaine  7.80 ± 1.07 61.43 ± 6.72** 58.45 ± 4.67** 59.88 ± 5.49** 36.40 ± 9.81** sustained-release formulation 5 group Solvent 5 group  8.60 ± 1.50 17.93 ± 3.93 13.20 ± 5.57 10.38 ± 4.15 14.87 ± 3.08 Time 28 h 32 h 48 h 56 h 72 h Model group 13.13 ± 2.67 12.32 ± 2.56 13.87 ± 3.32 14.68 ± 2.99 19.55 ± 3.19 Ropivacaine 12.25 ± 4.58 14.23 ± 3.74 15.48 ± 3.04 16.03 ± 3.14 18.22 ± 4.20 methanesulfonate injection solution 1 group Ropivacaine 39.72 ± 3.41** 20.58 ± 3.50** 17.65 ± 7.34* 16.57 ± 4.05 18.92 ± 7.13 sustained-release formulation 2 group Solvent 2 group 12.57 ± 5.17  14.8 ± 3.86 14.13 ± 4.15 15.03 ± 2.51 16.57 ± 5.06 Ropivacaine 38.82 ± 6.54** 23.88 ± 8.01** 22.42 ± 8.56* 16.53 ± 4.92  18.5 ± 4.03 sustained-release formulation 3 group Solvent 3 group  10.1 ± 5.52 13.82 ± 5.33 13.03 ± 3.05 15.42 ± 6.13 17.63 ± 4.56 Ropivacaine 34.72 ± 8.87** 24.43 ± 8.43** 19.52 ± 5.29* 19.47 ± 6.82* 18.53 ± 6.35 sustained-release formulation 4 group Solvent 4 group 11.07 ± 5.71 12.13 ± 5.36  15.4 ± 5.66 16.03 ± 4.47 15.72 ± 4.80 Ropivacaine 31.42 ± 3.74** 25.30 ± 5.81** 22.17 ± 2.93* 20.77 ± 6.35 23.73 ± 4.41 sustained-release formulation 5 group Solvent 5 group 12.68 ± 2.53 12.80 ± 3.19  14.8 ± 3.37 17.42 ± 4.86 16.45 ± 5.25 Note: as compared to the control group, **P < 0.01, *P < 0.05.

BEST MODE FOR CARRYING OUT THE INVENTION

Example 1

Formula: Ropivacaine Free Base

(171) TABLE-US-00012  10 mg benzyl alcohol 0.1 ml ethyl oleate (or vegetable oil such as soybean oil) to a total of 10 ml

(172) Preparation process: 10 mg ropivacaine free base was added into a prescribed amount of benzyl alcohol until it was fully dissolved to obtain a drug solution; ethyl oleate (or vegetable oil such as soybean oil) was then slowly added into the drug solution to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 2

Formula: Ropivacaine Free Base

(173) TABLE-US-00013 1600 mg benzyl alcohol  7.5 ml ethyl oleate (or vegetable oil such as soybean oil) to a total of 2.5 ml

(174) Preparation process: 1600 mg ropivacaine free base was slowly added in batches into a prescribed amount of benzyl alcohol, and vortexed until it was fully dissolved to obtain a drug solution; ethyl oleate (or vegetable oil such as soybean oil) was then slowly added into the drug solution to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 3

Formula: Ropivacaine Free Base

(175) TABLE-US-00014  10 mg ethanol 0.1 ml ethyl oleate (or castor oil) to a total of 10 ml

(176) Preparation process: 10 mg ropivacaine free base was slowly added into a prescribed amount of ethanol, and vortexed until it was fully dissolved to obtain a drug solution; ethyl oleate (or castor oil) was then slowly added into the drug solution to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 4

Formula: Ropivacaine Free Base

(177) TABLE-US-00015 750 mg ethanol .sup. 5 ml ethyl oleate (or castor oil) to a total of 10 ml

(178) Preparation process: 750 mg ropivacaine free base was slowly added in batches into a prescribed amount of ethanol, and vortexed until it was fully dissolved to obtain a drug solution; ethyl oleate (or castor oil) was then slowly added into the drug solution to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 5

Formula: Ropivacaine Free Base

(179) TABLE-US-00016  10 mg benzyl benzoate 0.1 ml ethyl oleate (or vegetable oil such as soybean oil) to a total of 10 ml

(180) Preparation process: 10 mg ropivacaine free base was added into a prescribed amount of benzyl benzoate, and vortexed until it was fully dissolved to obtain a drug solution; ethyl oleate (or vegetable oil such as soybean oil) was then slowly added into the drug solution to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 6

Formula: Ropivacaine Free Base

(181) TABLE-US-00017 500 mg benzyl benzoate .sup. 7 ml ethyl oleate (or vegetable oil such as soybean oil) to a total of 10 ml

(182) Preparation process: 500 mg ropivacaine free base was slowly added into a prescribed amount of benzyl benzoate, and vortexed until it was fully dissolved to obtain a drug solution; ethyl oleate (or vegetable oil such as soybean oil) was then slowly added into the drug solution to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 7

Formula: Ropivacaine Free Base

(183) TABLE-US-00018  50 mg benzyl alcohol 0.1 ml ethyl oleate (or vegetable oil such as soybean oil) to a total of 10 ml

(184) Preparation process: 50 mg ropivacaine free base was added into a prescribed amount of benzyl alcohol and a small amount of ethyl oleate (or vegetable oil such as soybean oil), and vortexed until it was fully dissolved to obtain a drug solution; ethyl oleate (or vegetable oil such as soybean oil) was then slowly added into the drug solution to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 8

Formula: Ropivacaine Free Base

(185) TABLE-US-00019 1000 mg benzyl alcohol   4 ml ethyl oleate (or vegetable oil such as soybean oil) to a total of 10 ml

(186) Preparation process: 1000 mg ropivacaine free base was slowly added into a prescribed amount of benzyl alcohol, and vortexed until it was fully dissolved to obtain a drug solution; ethyl oleate (or vegetable oil such as soybean oil) was then slowly added into the drug solution to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 9

Formula: Ropivacaine Free Base

(187) TABLE-US-00020  50 mg ethanol 0.1 ml ethyl oleate (or castor oil) to a total of 10 ml

(188) Preparation process: 50 mg ropivacaine free base was added into a prescribed amount of ethanol and a small amount of ethyl oleate (or castor oil), and vortexed until it was fully dissolved to obtain a drug solution; ethyl oleate (or castor oil) was then slowly added into the drug solution to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 10

Formula: Ropivacaine Free Base

(189) TABLE-US-00021 600 mg ethanol .sup. 4 ml ethyl oleate (or castor oil) to a total of 10 ml

(190) Preparation process: 600 mg ropivacaine free base was added into a prescribed amount of ethanol, and vortexed until it was fully dissolved to obtain a drug solution; ethyl oleate (or castor oil) was then slowly added into the drug solution to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 11

Formula: Ropivacaine Free Base

(191) TABLE-US-00022 300 mg benzyl alcohol .sup. 1 ml ethyl oleate to a total of 10 ml

(192) Preparation process: 300 mg ropivacaine free base was slowly added into a prescribed amount of benzyl alcohol, heated gently and vortexed until it was fully dissolved to obtain a drug solution; ethyl oleate was then slowly added into the drug solution to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 12

Formula: Ropivacaine Free Base

(193) TABLE-US-00023 250 mg ethanol  1 ml ethyl oleate to a total of 10 ml

(194) Preparation process: 250 mg ropivacaine free base was slowly added into a prescribed amount of ethanol, heated gently and vortexed until it was fully dissolved to obtain a drug solution; ethyl oleate was then slowly added into the drug solution to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 13

Formula: Ropivacaine Free Base

(195) TABLE-US-00024 450 mg ethanol  0.8 ml benzyl alcohol  0.8 ml ethyl oleate to a total of 10 ml

(196) Preparation process: 450 mg ropivacaine free base was slowly added into a prescribed amount of benzyl alcohol and ethanol, heated gently and vortexed until it was fully dissolved to obtain a drug solution; ethyl oleate was then slowly added into the drug solution to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 14

Formula: Ropivacaine Free Base

(197) TABLE-US-00025 350 mg benzyl alcohol  1 ml castor oil to a total of 10 ml

(198) Preparation process: 350 mg ropivacaine free base was slowly added into a prescribed amount of benzyl alcohol, heated gently and vortexed until it was fully dissolved to obtain a drug solution; castor oil was then slowly added into the drug solution to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 15

Formula: Ropivacaine Free Base

(199) TABLE-US-00026 300 mg benzyl alcohol  1 ml soybean oil to a total of 10 ml

(200) Preparation process: 300 mg ropivacaine free base was slowly added into a prescribed amount of benzyl alcohol, heated gently and vortexed until it was fully dissolved to obtain a drug solution; soybean oil was then slowly added into the drug solution to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 16

Formula: Ropivacaine Free Base

(201) TABLE-US-00027 250 mg ethanol  1 ml castor oil to a total of 10 ml

(202) Preparation process: 250 mg ropivacaine free base was slowly added into a prescribed amount of ethanol, heated gently and vortexed until it was fully dissolved to obtain a drug solution; castor oil was then slowly added into the drug solution to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 17

Formula: Ropivacaine Free Base

(203) TABLE-US-00028 300 mg benzyl alcohol  1 ml ethyl oleate  3 ml soybean oil to a total of 10 ml

(204) Preparation process: 300 mg ropivacaine free base was slowly added into a prescribed amount of benzyl alcohol and ethyl oleate, heated gently and vortexed until it was fully dissolved to obtain a drug solution; soybean oil was then slowly added into the drug solution to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 18

Formula: Ropivacaine Free Base

(205) TABLE-US-00029 300 mg benzyl alcohol  1 ml benzyl benzoate  3 ml soybean oil to a total of 10 ml

(206) Preparation process: 300 mg ropivacaine free base was added into a prescribed amount of benzyl alcohol and benzyl benzoate, heated gently and vortexed until it was fully dissolved to obtain a drug solution; soybean oil was then slowly added into the drug solution to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 19

Formula: Ropivacaine Free Base

(207) TABLE-US-00030 250 mg ethanol  1 ml ethyl oleate  3 ml soybean oil to a total of 10 ml

(208) Preparation process: 250 mg ropivacaine free base was added into a prescribed amount of ethanol and ethyl oleate, and vortexed until it was fully dissolved to obtain a drug solution; soybean oil was then slowly added into the drug solution to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 20

Formula: Ropivacaine Free Base

(209) TABLE-US-00031 300 mg ethanol  1 ml benzyl benzoate  3 ml soybean oil to a total of 10 ml

(210) Preparation process: 300 mg ropivacaine free base was added into a prescribed amount of ethanol and benzyl benzoate, heated gently and vortexed until it was fully dissolved to obtain a drug solution; soybean oil was then slowly added into the drug solution to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 21

Formula: Ropivacaine Free Base

(211) TABLE-US-00032 450 mg benzyl alcohol  1 ml benzyl benzoate  1.5 ml castor oil to a total of 10 ml

(212) Preparation process: 450 mg ropivacaine free base was slowly added into a prescribed amount of benzyl alcohol and benzyl benzoate, heated gently and vortexed until it was fully dissolved to obtain a drug solution; castor oil was then slowly added into the drug solution to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 22

Formula: Ropivacaine Free Base

(213) TABLE-US-00033 300 mg ethanol  1 ml ethyl oleate  3 ml castor oil to a total of 10 ml

(214) Preparation process: 300 mg ropivacaine free base was slowly added into a prescribed amount of ethanol and ethyl oleate, heated gently and vortexed until it was fully dissolved to obtain a drug solution; castor oil was then slowly added into the drug solution to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 23

Formula: Ropivacaine Free Base

(215) TABLE-US-00034 400 mg ethanol  1 ml benzyl benzoate  1.5 ml castor oil to a total of 10 ml

(216) Preparation process: 400 mg ropivacaine free base was slowly added into a prescribed amount of ethanol and benzyl benzoate, heated gently and vortexed until it was fully dissolved to obtain a drug solution; castor oil was then slowly added into the drug solution to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 24

Formula: Ropivacaine Free Base

(217) TABLE-US-00035 500 mg ethanol  1 ml benzyl benzoate  3 ml castor oil to a total of 10 ml

(218) Preparation process: 500 mg ropivacaine free base was added into a prescribed amount of ethanol and benzyl benzoate, heated gently and vortexed until it was fully dissolved to obtain a drug solution; castor oil was then slowly added into the drug solution to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 25

Formula: Ropivacaine Methanesulfonate

(219) TABLE-US-00036 120 mg ethanol  1.8 ml ethyl oleate 10 ml

(220) Preparation process: 120 mg ropivacaine methanesulfonate was added into a prescribed amount of ethanol, and vortexed until it was fully dissolved to obtain a drug solution; ethyl oleate was then slowly added into the drug solution to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 26

Formula: Ropivacaine Methanesulfonate

(221) TABLE-US-00037 120 mg benzyl alcohol  1.6 ml ethyl oleate (or vegetable oil such as soybean oil) to a total of 10 ml

(222) Preparation process: 120 mg ropivacaine methanesulfonate was added into a prescribed amount of benzyl alcohol, and vortexed until it was fully dissolved to obtain a drug solution; ethyl oleate (or vegetable oil such as soybean oil) was then slowly added into the drug solution to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 27

Formula: Ropivacaine Methanesulfonate

(223) TABLE-US-00038 120 mg benzyl alcohol  0.8 ml ethanol  0.8 ml ethyl oleate (or vegetable oil such as soybean oil) to a total of 10 ml

(224) Preparation process: 120 mg ropivacaine methanesulfonate was added into a prescribed amount of benzyl alcohol and ethanol, and vortexed until it was fully dissolved to obtain a drug solution; ethyl oleate (or vegetable oil such as soybean oil) was then slowly added into the drug solution to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 28

Formula: Ropivacaine Free Base

(225) TABLE-US-00039 450 mg ethyl lactate  5 ml ethyl oleate to a total of 10 ml

(226) Preparation process: 450 mg ropivacaine free base was slowly added into a prescribed amount of ethyl lactate, heated gently and vortexed until it was fully dissolved to obtain a drug solution; ethyl oleate was then slowly added into the drug solution to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 29

Formula: Ropivacaine Free Base

(227) TABLE-US-00040 400 mg ethyl lactate  5 ml glyceryl triacetate to a total of 10 ml

(228) Preparation process: 400 mg ropivacaine free base was added into a prescribed amount of ethyl lactate, and vortexed until it was fully dissolved to obtain a drug solution; glyceryl triacetate was then slowly added into the drug solution to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 30

Formula: Ropivacaine Free Base

(229) TABLE-US-00041 350 mg ethanol  0.6 ml benzyl alcohol  0.8 ml ethyl oleate  4 ml soybean oil to a total of 10 ml

(230) Preparation process: 350 mg ropivacaine free base was slowly added into a prescribed amount of ethanol and benzyl alcohol, heated gently and vortexed until it was fully dissolved to obtain a drug solution; 4 ml ethyl oleate was slowed added into the drug solution and uniformly mixed, and soybean oil was then slowly added to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 31

Formula: Ropivacaine Free Base

(231) TABLE-US-00042 250 mg ethanol  1 ml castor oil (containing 15% (w/v) hydrogenated castor oil) to a total of 10 ml

(232) Preparation process: 250 mg ropivacaine free base was slowly added into a prescribed amount of ethanol, heated gently and vortexed until it was fully dissolved to obtain a drug solution; castor oil (containing 15% (w/v) hydrogenated castor oil) was then slowly added to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 32

Formula: Ropivacaine Free Base

(233) TABLE-US-00043 300 mg benzyl alcohol  1 ml castor oil (containing 15% (w/v) hydrogenated castor oil) to a total of 10 ml

(234) Preparation process: 300 mg ropivacaine free base was slowly added into a prescribed amount of benzyl alcohol, heated gently and vortexed until it was fully dissolved to obtain a drug solution; castor oil (containing 15% (w/v) hydrogenated castor oil) was then slowly added to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 33

Formula: Ropivacaine Free Base

(235) TABLE-US-00044 300 mg benzyl alcohol  1 ml soybean oil (containing 15% (w/v) white oil) to a total of 10 ml

(236) Preparation process: 300 mg ropivacaine free base was slowly added into a prescribed amount of benzyl alcohol, heated gently and vortexed until it was fully dissolved to obtain a drug solution; soybean oil (containing 15% (w/v) white oil) was then slowly added to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 34

Formula: Ropivacaine Free Base

(237) TABLE-US-00045 350 mg dezocine 350 mg benzyl alcohol  1 ml benzyl benzoate  1.5 ml soybean oil to a total of 10 ml

(238) Preparation process: 350 mg ropivacaine free base and 350 mg dezocine was slowly added into a prescribed amount of benzyl alcohol and benzyl benzoate, heated gently and vortexed until it was fully dissolved to obtain a drug solution; soybean oil was then slowly added to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 35

Formula: Ropivacaine Free Base

(239) TABLE-US-00046 300 mg dezocine 350 mg anhydrous ethanol  1 ml benzyl benzoate  1.5 ml soybean oil to a total of 10 ml

(240) Preparation process: 300 mg ropivacaine free base and 350 mg dezocine was slowly added into a prescribed amount of anhydrous ethanol and benzyl benzoate, heated gently and vortexed until it was fully dissolved to obtain a drug solution; soybean oil was then slowly added to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 36

Formula: Ropivacaine Free Base

(241) TABLE-US-00047 450 mg dezocine 400 mg benzyl alcohol  1 ml benzyl benzoate  1.5 ml castor oil to a total of 10 ml

(242) Preparation process: 450 mg ropivacaine free base and 400 mg dezocine was slowly added into a prescribed amount of benzyl alcohol and benzyl benzoate, heated gently and vortexed until it was fully dissolved to obtain a drug solution; castor oil was then slowly added to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 37

Formula: Ropivacaine Free Base

(243) TABLE-US-00048 300 mg dezocine 350 mg benzyl alcohol  1 ml ethyl oleate  3 ml soybean oil to a total of 10 ml

(244) Preparation process: 300 mg ropivacaine free base and 350 mg dezocine was slowly added into a prescribed amount of benzyl alcohol, heated gently and vortexed until it was fully dissolved to obtain a drug solution; a prescribed amount of ethyl oleate was added thereinto and uniformly mixed, and soybean oil was then slowly added to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 38

Formula: Ropivacaine Free Base

(245) TABLE-US-00049 350 mg parecoxib 350 mg benzyl alcohol  1 ml benzyl benzoate  1.5 ml soybean oil to a total of 10 ml

(246) Preparation process: 350 mg ropivacaine free base and 350 mg parecoxib was slowly added into a prescribed amount of benzyl alcohol and benzyl benzoate, heated gently and vortexed until it was fully dissolved to obtain a drug solution; soybean oil was then slowly added to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 39

Formula: Ropivacaine Free Base

(247) TABLE-US-00050 300 mg parecoxib 250 mg benzyl alcohol  1 ml soybean oil to a total of 10 ml

(248) Preparation process: 300 mg ropivacaine free base and 250 mg parecoxib was slowly added into a prescribed amount of benzyl alcohol, heated gently and vortexed until it was fully dissolved to obtain a drug solution; soybean oil was then slowly added to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 40

Formula: Ropivacaine Free Base

(249) TABLE-US-00051 450 mg parecoxib 450 mg benzyl alcohol  0.8 ml anhydrous ethanol  0.8 ml ethyl oleate to a total of 10 ml

(250) Preparation process: 450 mg ropivacaine free base and 450 mg parecoxib was slowly added into a prescribed amount of benzyl alcohol and anhydrous ethanol, heated gently and vortexed until it was fully dissolved to obtain a drug solution; ethyl oleate was then slowly added to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 41

Formula: Ropivacaine Free Base

(251) TABLE-US-00052 400 mg parecoxib 350 mg benzyl alcohol  1.0 ml castor oil to a total of 10 ml

(252) Preparation process: 400 mg ropivacaine free base and 350 mg parecoxib was slowly added into a prescribed amount of benzyl alcohol, heated gently and vortexed until it was fully dissolved to obtain a drug solution; castor oil was then slowly added to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 42

Formula: Procaine Free Base

(253) TABLE-US-00053 150 mg benzyl alcohol  1.0 ml benzyl benzoate  3.0 ml castor oil to a total of 10 ml

(254) Preparation process: 150 mg procaine free base was slowly added into a prescribed amount of benzyl alcohol and benzyl benzoate, and vortexed until it was fully dissolved to obtain a drug solution; castor oil was then slowly added into the drug solution to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 43

Formula: Dibucaine Free Base

(255) TABLE-US-00054 150 mg benzyl alcohol  1.0 ml benzyl benzoate  3.0 ml castor oil to a total of 10 ml

(256) Preparation process: 150 mg dibucaine free base was slowly added into a prescribed amount of benzyl alcohol and benzyl benzoate, heated gently and vortexed until it was fully dissolved to obtain a drug solution; castor oil was then slowly added into the drug solution to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.

Example 44

Formula: Articaine Free Base

(257) TABLE-US-00055 180 mg ethanol  1.0 ml benzyl benzoate  3.0 ml soybean oil to a total of 10 ml

(258) Preparation process: 180 mg etidocaine free base was slowly added into a prescribed amount of ethanol and benzyl benzoate, heated gently and vortexed until it was fully dissolved to obtain a drug solution; soybean oil was then slowly added into the drug solution to a total of 10 ml and uniformly mixed with vortexing; the mixture was filtered through a film to remove impurities and bacteria, separately charged into penicillin bottles and sealed, and then packed after passing lamp inspection.