Pharmaceutical composition containing ropivacaine and preparation method thereof

Abstract

The invention provides a pharmaceutical composition, the pharmaceutical composition comprises ropivacaine, an alcohol solvent, phospholipid, an ester carrier and organic acid, and the pharmaceutical composition can realize in-vivo and in-vitro slow release for 168 hours, and has the characteristics of no devitrification and good stability under different conditions.

Description

Technical Field

[0001] The present invention belongs to the field of pharmacy and mainly relates to a product with a sustained-release effect. Background Art

[0002] Postoperative pain belongs to acute nociceptive pain, which is common in thoracotomy with large trauma and joint replacement surgeries that require long-term functional exercise, etc. The general duration is 3 - 7 days. However, the efficacy of currently marketed postoperative analgesic preparations can only last for 72 hours. Ropivacaine is a new type of long-acting amide local anesthetic. In recent years, due to its low cardiac toxicity and low neurotoxicity, it has been widely used in clinical work. Currently, the marketed ropivacaine preparations at home and abroad are mainly ropivacaine hydrochloride or mesylate injection. Ropivacaine hydrochloride or mesylate injection usually takes effect within 10 - 20 minutes, but the terminal half-life of ropivacaine is only 1.8 h, and the efficacy can only last for 2 - 6 hours.

[0003] Ropivacaine has two dosage forms, salt form and free base. Usually, the free base has a better release effect than the salt. However, its long-acting preparations are often unstable, which greatly limits its application. Currently, in most marketed or in-research long-acting local anesthetic preparations, due to the low concentration of the local anesthetic, the administration volume needs to be increased during clinical use. Other high-concentration local anesthetic preparations have a crystallization phenomenon under different conditions, resulting in safety problems. Therefore, it is of great clinical application value to develop a more stable ropivacaine long-acting preparation that can provide a longer sustained-release effect and does not crystallize under different temperature conditions. Summary of the Invention

[0004] The present invention provides a pharmaceutical composition containing ropivacaine. The pharmaceutical composition can achieve in vivo and in vitro sustained release for 168 hours and has the characteristics of not crystallizing under different conditions (especially not crystallizing under the condition of long-term storage at 4 °C in the refrigerator) and good stability.

[0005] The present invention provides a pharmaceutical composition containing ropivacaine. The pharmaceutical composition comprises ropivacaine, an alcohol solvent, phospholipids, an ester carrier by weight, and the pharmaceutical composition contains an organic acid. Further, the organic acid is selected from one or more of gentisic acid, maleic acid, citric acid, and lactic acid. Further, the organic acid is selected from one or more of citric acid, maleic acid, and gentisic acid. Further, the organic acid is selected from one or more of citric acid and maleic acid or one or more of maleic acid and gentisic acid. In some embodiments, the organic acid is citric acid.

[0006] Further, the content of ropivacaine is 2-20% by weight. In certain embodiments, the content of ropivacaine is 2-15% by weight. In certain embodiments, the content of ropivacaine is 2-14% by weight. In certain embodiments, the content of ropivacaine is 2-10% by weight. In certain embodiments, the content of ropivacaine is 8.5-20% by weight. In certain embodiments, the content of ropivacaine is 8.5-15% by weight. In certain embodiments, the content of ropivacaine is 8.5-14% by weight. In certain embodiments, the content of ropivacaine is 8.5-10% by weight. In certain embodiments, the content of ropivacaine is 10-20% by weight. In certain embodiments, the content of ropivacaine is 10-15% by weight. In certain embodiments, the content of ropivacaine is 10-14% by weight. In certain embodiments, the content of ropivacaine is 14-20% by weight. In certain embodiments, the content of ropivacaine is 14-15% by weight. In certain embodiments, the content of ropivacaine is 15-20% by weight.

[0007] Furthermore, the content of the organic acid is 4-20% by weight. In some embodiments, the content of the organic acid is 5-20% by weight. In some embodiments, the content of the organic acid is 10-20% by weight. In some embodiments, the content of the organic acid is 10-12% by weight. In some embodiments, the content of the organic acid is 5-12% by weight. In some embodiments, the content of the organic acid is 5-10% by weight. In some embodiments, the content of the organic acid is 5-9% by weight. In some embodiments, the content of the organic acid is 5-7% by weight. In some embodiments, the content of the organic acid is 5-6.5% by weight. In some embodiments, the content of the organic acid is 5-6% by weight. In some embodiments, the content of the organic acid is 6-20% by weight. In some embodiments, the content of the organic acid is 6-12% by weight. In some embodiments, the content of the organic acid is 6-10% by weight. In some embodiments, the content of the organic acid is 6-9% by weight. In some embodiments, the content of the organic acid is 6-7% by weight. In some embodiments, the content of the organic acid is 6-6.5% by weight. In some embodiments, the content of the organic acid is 6.5-20% by weight. In some embodiments, the content of the organic acid is 6.5-12% by weight. The content of the organic acid is 6.5-10% by weight. In some embodiments, the content of the organic acid is 6.5-9% by weight. In some embodiments, the content of the organic acid is 6.5-7% by weight. In some embodiments, the content of the organic acid is 7-20% by weight. In some embodiments, the content of the organic acid is 7-12% by weight. In some embodiments, the content of the organic acid is 7-10% by weight. In some embodiments, the content of the organic acid is 7-9% by weight.

[0008] Furthermore, the alcohol solvent is selected from one or more of benzyl alcohol, ethanol, and propylene glycol. The combination of benzyl alcohol and ethanol is preferred. The content of the benzyl alcohol is 10%-20% by weight. In some embodiments, the content of the benzyl alcohol is 10-15.5% by weight. In some embodiments, the content of the benzyl alcohol is 15.5-20% by weight. In some embodiments, the content of the benzyl alcohol is 10%, 15%, 15.5%, 20% by weight. The content of the ethanol is 10%-20% by weight. In some embodiments, the content of the ethanol is 10-15.5% by weight. In some embodiments, the content of the ethanol is 15.5-20% by weight. In some embodiments, the content of the ethanol is 10%, 15%, 15.5%, 20% by weight.

[0009] Further, the phospholipid is selected from lecithin, such as soybean lecithin and egg yolk lecithin. The content of the phospholipid is 15-50% by weight. In certain embodiments, the phospholipid content is 15-42% by weight. In certain embodiments, the content of the phospholipid is 20-42% by weight. In certain embodiments, the content of the phospholipid is 15-20% by weight.

[0010] Further, the ester carrier is selected from one or more of medium-chain triglycerides, monoglycerides, diglycerides, and triglycerides, preferably medium-chain triglycerides. The content of the ester carrier is 5-50% by weight, preferably 5-45% by weight. In certain embodiments, the content of the ester carrier is 5-43% by weight. In certain embodiments, the content of the ester carrier is 5-41% by weight. In certain embodiments, the content of the ester carrier is 5-30% by weight. In certain embodiments, the content of the ester carrier is 5-20% by weight. In certain embodiments, the content of the ester carrier is 5-18% by weight. In certain embodiments, the content of the ester carrier is 5-12% by weight. In certain embodiments, the content of the ester carrier is 12-45% by weight. In certain embodiments, the content of the ester carrier is 12-43% by weight. In certain embodiments, the content of the ester carrier is 12-41% by weight. In certain embodiments, the content of the ester carrier is 12-30% by weight. In certain embodiments, the content of the ester carrier is 12-20% by weight. In certain embodiments, the content of the ester carrier is 12-18% by weight. In certain embodiments, the content of the ester carrier is 18-45% by weight. In certain embodiments, the content of the ester carrier is 18-43% by weight. In certain embodiments, the content of the ester carrier is 18-41% by weight. In certain embodiments, the content of the ester carrier is 18-30% by weight. In certain embodiments, the content of the ester carrier is 18-20% by weight. In certain embodiments, the content of the ester carrier is 20-45% by weight. In certain embodiments, the content of the ester carrier is 20-43% by weight. In certain embodiments, the content of the ester carrier is 20-41% by weight. In certain embodiments, the content of the ester carrier is 20-30% by weight. In certain embodiments, the content of the ester carrier is 30-45% by weight. In certain embodiments, the content of the ester carrier is 30-43% by weight. In certain embodiments, the content of the ester carrier is 30-41% by weight. In certain embodiments, the content of the ester carrier is 41-45% by weight. In certain embodiments, the content of the ester carrier is 41-43% by weight. In certain embodiments, the content of the ester carrier is 43-45% by weight.

[0011] Further, the ratio of ropivacaine to phospholipid is greater than 1:9 by weight, preferably greater than 1:5, preferably 1:0.8-1:5, preferably 1:0.8-1:4 or 1:1-1:4 or 1:1-1:5, preferably 1:4.

[0012] Furthermore, the present invention provides a pharmaceutical composition, which comprises the following components by weight:

[0013] Name Proportion (%) Ropivacaine 2-20％ Benzyl Alcohol 10-20％ Ethanol 10-20％ Organic Acid 5-20％ Medium-chain Triglycerides 5-45％ Lecithin 15-42％

[0014] wherein the organic acid is selected from citric acid, lactic acid, maleic acid, and gentisic acid;

[0016] Preferably, the pharmaceutical composition comprises the following components by weight:

[0017] Name Proportion (%) Ropivacaine 8.5-20％ Benzyl Alcohol 10-20％ Ethanol 10-20％ Organic Acid 5-20％ Medium-chain Triglycerides 5-45％ Lecithin 15-42％ ;

[0018] In certain embodiments, the pharmaceutical composition comprises the following components by weight:

[0019] Name Proportion (%) Ropivacaine 2-20％ Benzyl Alcohol 10-20％ Ethanol 10-20％ Lactic Acid 5-20％ Medium-chain Triglycerides 5-45％ Lecithin 15-42％ ;

[0020] Preferably, the pharmaceutical composition comprises the following components by weight:

[0021] Name Proportion (%) Ropivacaine 10-20％ Benzyl Alcohol 10-20％ Ethanol 10-20％ Lactic Acid 5-20％ Medium-chain Triglycerides 5-45％ Lecithin 15-42％ ;

[0022] Preferably, the pharmaceutical composition comprises the following components by weight:

[0023] Name Proportion (%) Ropivacaine 10％ Benzyl Alcohol 15.5％ Ethanol 15.5％ Lactic Acid 5.0％ Medium-chain Triglycerides 12.0％ Lecithin 42.0％ ;

[0024] In certain embodiments, the pharmaceutical composition comprises the following components by weight:

[0025] Name Proportion (%) Ropivacaine 2-15％ Benzyl Alcohol 10-20％ Ethanol 10-20％ Citric Acid 6.5-12％ Medium-chain Triglycerides 12-41％ Lecithin 15-42％ ;

[0026] Preferably, the pharmaceutical composition comprises the following components by weight:

[0027] Name Proportion (%) Ropivacaine 8.5-15％ Benzyl Alcohol 10-20％ Ethanol 10-20％ Citric Acid 6.5-12％ Medium-chain Triglycerides 12-41％ Lecithin 15-42％ ;

[0028] Preferably, the pharmaceutical composition comprises the following components by weight:

[0029] Name Proportion (%) Ropivacaine 8.5％ Benzyl Alcohol 15.5％ Ethanol 15.5％ Citric Acid 6.5％ Medium-chain Triglycerides 12.0％ Lecithin 42.0％ ;

[0030] In certain embodiments, the pharmaceutical composition comprises the following components by weight:

[0031] Name Proportion (%) Ropivacaine 2-20％ Benzyl Alcohol 10-20％ Ethanol 10-20％ Maleic Acid 5-20％ Medium-chain Triglycerides 5-45％ Lecithin 15-20％ ;

[0032] Preferably, the pharmaceutical composition comprises the following components by weight:

[0033]

[0034] ;

[0035] Preferably, the pharmaceutical composition comprises the following components by weight:

[0036] Name Proportion (%) Ropivacaine 14％ Benzyl Alcohol 20％ Ethanol 10％ Maleic Acid 6％ Medium-chain Triglycerides 30％ Lecithin 20％ 。

[0037] In certain embodiments, the pharmaceutical composition comprises the following components by weight:

[0038] Name Proportion (%) Ropivacaine 2-15％ Benzyl Alcohol 10-20％ Ethanol 10-20％ Gentisic Acid 6.5-12％ Medium-chain Triglycerides 12-43％ Lecithin 15-42％

[0039] ; Preferably, the pharmaceutical composition comprises the following components by weight:

[0040] Name Proportion (%) Ropivacaine 8.5-15％ Benzyl Alcohol 10-20％ Ethanol 10-20％ Gentisic Acid 6.5-12％ Medium-chain Triglycerides 12-43％ Lecithin 15-42％ ;

[0041] Preferably, the pharmaceutical composition comprises the following components by weight:

[0042] Name Proportion (%) Ropivacaine 10-15％ Benzyl Alcohol 10-20％ Ethanol 10-20％ Gentisic Acid 7-12％ Medium-chain Triglycerides 18-43％ Lecithin 15-20％ ;

[0044] Preferably, the pharmaceutical composition comprises the following components by weight:

[0045] Name Proportion (%) Ropivacaine 10％ Benzyl Alcohol 10％ Ethanol 10％ Gentisic Acid 7％ Medium-chain Triglycerides 43％ Lecithin 20％ 。

[0046] Furthermore, the pharmaceutical composition can be prepared in the form of a phase change gel or the like.

[0047] Furthermore, the present invention provides a method for preparing the above-mentioned pharmaceutical composition, the method comprising the following steps: weighing ropivacaine, benzyl alcohol, ethanol and an acid, dissolving, adding medium-chain triglyceride, adding phospholipid, and oscillating until the phospholipid is completely dissolved or weighing ropivacaine, benzyl alcohol, ethanol, an acid, phospholipid and medium-chain triglyceride, and mixing and dissolving.

[0048] The beneficial effects of the present invention are as follows: the prepared pharmaceutical composition can achieve sustained release in vivo and in vitro for 168 hours, and does not crystallize, and has good stability under low temperature and light.

[0049] Specific implementation examples

[0050] The technical solutions of the present invention will be further elaborated in detail below in combination with specific implementation examples of the specification, but the implementation of the present invention is not limited thereto. Equivalent substitutions, combinations, improvements, or modifications made by those skilled in the art to the technical solutions of the present invention according to the description of the present invention should all be covered by the protection scope of the present invention.

[0051] Unless otherwise specified, the reagents, methods, and equipment used in the present invention are conventional reagents, methods, and equipment in the technical field. Unless otherwise specified, the reagents and materials used in the following examples are all commercially available products.

[0052] The following examples are investigated in the following ways:

[0053] Stability investigation: Each formulation was placed naked under light conditions (4500Lx ± 500Lx) for 5 days or 10 days, and cross-effects caused by other conditions were avoided as much as possible to investigate the stability; and conventional HPLC detection methods were used for detection to determine single impurities and total impurities.

[0054] The data of the present invention are all three-time averages, with a reasonable error range (p < 0.05), and are statistically significant.

[0055] Example 1 The preparations of Formulations 1-4 are shown in Table 1:

[0056] Table 1

[0057]

[0058]

[0059] Preparation process:

[0060] Preparation method of Formulation 1: Weigh ropivacaine, benzyl alcohol, ethanol, and various acids according to the formulation amount into a container, shake to dissolve, and the obtained samples are all clear liquids. Then weigh the medium-chain triglycerides according to the formulation amount into it, and then weigh the phospholipids and shake until the phospholipids are completely dissolved.

[0061] Preparation methods of Formulations 2-3: Weigh all the raw and auxiliary materials into a vial, heat and stir in a 45°C water bath, raise the temperature of the magnetic stirrer to 60°C and continue stirring, and heat and ultrasonicate at 40°C to obtain the samples.

[0062] Preparation method of Formulation 4: Weigh ropivacaine, medium-chain triglycerides, phospholipids, benzyl alcohol, and fish oil according to the formulation amount into a pre-weighed round-bottom flask, weigh, add an excessive amount of absolute ethanol, and then place the flask in a water bath ultrasonic wave to ultrasonically disperse the phospholipids completely and dissolve all components. At this time, connect the round-bottom flask to a suitable rotary evaporator and evaporate under reduced pressure until the change in the weight of the round-bottom flask indicates that the absolute ethanol has been removed completely. The obtained medicinal liquid is sub-packed and sealed.

[0063] Crystallization results:

[0064] Stored at 4°C for 48 hours, only Prescription 4 crystallized out; stored under light for 5 days, only Prescription 1 did not crystallize out. The results are shown in Table 2.

[0065] Table 2

[0066] Prescription 1 Prescription 2 Prescription 3 Prescription 4 Illuminated for 5 days No crystal precipitation A large amount of crystal precipitation A large amount of crystal precipitation A relatively large amount of long needle-shaped crystal precipitation

[0067] The prescriptions of Example 2, Prescriptions 5 - 7, are as shown in Table 3:

[0068] Table 3

[0069]

[0070]

[0071] Preparation process:

[0072] Weigh ropivacaine, benzyl alcohol, ethanol, and lactic acid according to the prescription amounts. The obtained samples after shaking and dissolving are all clear liquids. Then add the medium-chain triglycerides in the prescription amount to them, and then add the phospholipids in the prescription amount. Shake until the phospholipids are completely dissolved to obtain the product.

[0073] Stability investigation:

[0074] 1. Under the two conditions of storage at 4°C for 2 months and storage under light for 5 days, under these two conditions, Prescriptions 5 - 7 did not crystallize out.

[0075] 2. The stability investigation under light for 5 days and 10 days is shown in Table 4

[0076] Table 4

[0077]

[0078] The prescriptions of Example 3, Prescriptions 8 - 10, are as shown in Table 5:

[0079] Table 5

[0080]

[0081] Preparation process:

[0082] Weigh ropivacaine, benzyl alcohol, ethanol, and citric acid according to the prescription amounts. The obtained samples after shaking and dissolving are all clear liquids. Then add the medium-chain triglycerides in the prescription amount to them, and then add the phospholipids in the prescription amount. Shake until the phospholipids are completely dissolved to obtain the product.

[0083] Stability investigation:

[0084] 1. Stored at 4°C for 2 months and stored under light for 5 days, under these two conditions, Prescriptions 8 - 10 did not crystallize out.

[0085] 2. The stability investigation under light for 5 days and 10 days is shown in Table 6

[0086] Table 6

[0087]

[0088] The prescriptions of Examples 4, 11 - 14 are shown in Table 7 as follows:

[0089] Table 7

[0090]

[0091] Preparation process:

[0092] Weigh ropivacaine, benzyl alcohol, ethanol and maleic acid according to the prescription amount. The obtained samples are all clear liquids after shaking and dissolving. Then add medium-chain triglycerides in the prescription amount thereto, and then add phospholipids in the prescription amount. Shake until the phospholipids are completely dissolved to obtain the product.

[0093] Stability investigation:

[0094] 1. Under the two conditions of storing at 4°C for 2 months and storing under light for 5 days, the prescriptions of 11 - 14 do not crystallize under the above two conditions.

[0095] 2. The stability investigations under light for 5 days and 10 days are shown in Table 8

[0096] Table 8

[0097]

[0098]

[0099] Note: N.D. represents not detected.

[0100] The prescriptions of Examples 5, 15 - 17 are shown in Table 9 as follows:

[0101] Table 9

[0102]

[0103] Preparation process:

[0104] Weigh ropivacaine, benzyl alcohol, ethanol and gentisic acid according to the prescription amount. The obtained samples are all clear liquids after shaking and dissolving. Then add medium-chain triglycerides in the prescription amount thereto, and then add phospholipids in the prescription amount. Shake until the phospholipids are completely dissolved to obtain the product.

[0105] Stability investigation:

[0106] 1. Under the two conditions of storing at 4°C for 2 months and storing under light for 5 days, the prescriptions of 15 - 17 do not crystallize under the above two conditions.

[0107] 2. The stability investigations under light for 5 days and 10 days are shown in Table 10

[0108] Table 10

[0109]

[0110] In vitro release study of Example 6

[0111] In vitro release study: Weigh three portions of the sample, place them in a dialysis bag with Mw 3500, put them in a sedimentation basket, and place them in a 37 °C 900 ml PBS (pH 7.4, containing 0.5% SDS) medium to study the release. The paddle method is used with a rotation speed of 100 rpm. The sampling time points are 2, 6, 12, 24, 48, 72, 96, 120, 144, and 168 hours.

[0112] The in vitro release results of Formulations 6, 9, 12, and 16 are shown in Table 11:

[0113] Table 11

[0114] Time h Prescription 6 Prescription 9 Prescription 12 Prescription 16 2 21.8 12.45 8.5 8.6 6 36 21.87 25.7 16.3 12 46.2 25.04 47.1 22.2 24 52.4 27.75 62.6 29 48 59.9 31.14 73.3 37.2 72 70.2 34.27 77.3 42.8 96 70.5 38.64 78.2 52.9 120 70.7 43.27 81.6 54.6 144 73.7 47.52 83.5 56.5 168 76.0 52.17 86.5 59.8

[0115] In vivo pharmacokinetics study of Example 7 in rats

[0116] 1) Species: SD rats (SPF grade), Source: The animals were transferred from the animal reserve of the experimental institution (999M-017).

[0117] 2) Test procedure: The grouping and test procedure are specifically shown in Table 12 below:

[0118] Table 12

[0119]

[0120]

[0121] 3) Administration method: Each rat was administered by single-point subcutaneous injection. Blood sampling time points: 0 h before administration, 0.5, 1, 2, 3, 6, 8, 12, 24, 36, 48, 60, 72, 96, 120, 144, and 168 hours after administration. Blood was collected through the submandibular vein or other appropriate methods, 0.2 mL / time point, anticoagulated with K2-EDTA. The blood samples were centrifuged within 1 h after collection to obtain plasma (centrifugation conditions: 6800 g, 6 minutes, 2 - 8 °C), and the samples to be tested were stored in a -80 °C refrigerator before analysis. Subsequently, the drug concentration in plasma was determined by LC-MS / MS-13 (TQ5500). The test results of the Naropin group, Formulations 6, 9, and 12 are shown in Table 13 respectively:

[0122] Table 13

[0123]

Claims

1. A pharmaceutical composition containing ropivacaine, characterized in that It comprises ropivacaine, alcohol solvent, phospholipid, ester carrier and organic acid by weight; the organic acid is preferably selected from one or more of gentisic acid, maleic acid, citric acid and lactic acid; more preferably one or more of citric acid, maleic acid and gentisic acid; most preferably citric acid and maleic acid, preferably citric acid.

2. The pharmaceutical composition according to claim 1, characterized in that The content of ropivacaine is 2-20%; the content of organic acid is 5-20% by weight.

3. The pharmaceutical composition according to claim 1, characterized in that The alcohol solvent is selected from one or more of benzyl alcohol, ethanol and propylene glycol, preferably a combination of benzyl alcohol and ethanol; the content of the benzyl alcohol is 10%-20% by weight, and the content of the ethanol is 10%-20% by weight.

4. The pharmaceutical composition according to claim 1, characterized in that The phospholipid is lecithin, and the content of the lecithin is 15-42% by weight.

5. The pharmaceutical composition according to claim 1, characterized in that The ester carrier is selected from one or more of medium chain triglyceride, monoglyceride, diglyceride and triglyceride, preferably medium chain triglyceride; the content of the ester carrier is 5-45% by weight.

6. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition comprises the following ingredients by weight: wherein the organic acid is selected from citric acid, lactic acid, maleic acid and gentisic acid; Preferably, the pharmaceutical composition comprises the following ingredients by weight: 。 7. The pharmaceutical composition according to claim 6, characterized in that The pharmaceutical composition comprises the following ingredients by weight: ； Preferably, the pharmaceutical composition comprises the following ingredients by weight: ； Preferably, the pharmaceutical composition comprises the following ingredients by weight: 。 8. The pharmaceutical composition according to claim 6, characterized in that The pharmaceutical composition comprises the following ingredients by weight: Preferably, the pharmaceutical composition comprises the following ingredients by weight: Preferably, the pharmaceutical composition comprises the following ingredients by weight: 。 9. The pharmaceutical composition according to claim 6, characterized in that The pharmaceutical composition comprises the following ingredients by weight: Preferably, the pharmaceutical composition comprises the following ingredients by weight: Preferably, the pharmaceutical composition comprises the following ingredients by weight: 。 10. The pharmaceutical composition according to claim 6, characterized in that The pharmaceutical composition comprises the following ingredients by weight: Preferably, the pharmaceutical composition comprises the following ingredients by weight: Preferably, the pharmaceutical composition comprises the following ingredients by weight: More preferably, the pharmaceutical composition comprises the following ingredients by weight: 。 11. A method for preparing the pharmaceutical composition according to any one of claims 1 to 10, characterized in that The method comprises the following steps: weighing ropivacaine, benzyl alcohol, ethanol and acid, dissolving them, adding medium-chain triglycerides, adding phospholipids, and shaking until the phospholipids are completely dissolved; or weighing ropivacaine, benzyl alcohol, ethanol, acid, phospholipids and medium-chain triglycerides, and mixing and dissolving them.

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