Phospholipid complex containing ropivacaine or salt thereof as well as preparation and preparation method thereof

Abstract

The invention relates to the field of pharmaceutical preparations, and particularly provides a ropivacaine sustained-release solution preparation based on a phospholipid complex and a preparation method thereof, and the preparation has the advantages of increased drug loading capacity, good safety, no obvious stimulation to administration tissues and long sustained-release time.

Description

[0001] This application is a divisional application of application number 202510165243.9, filed on February 14, 2025, entitled "A phospholipid complex containing ropivacaine or its salt, and its formulation and preparation method". Technical Field

[0002] This invention relates to the field of pharmaceutical preparations, specifically to a ropivacaine sustained-release solution preparation based on a phospholipid complex and its preparation method. Background Technology

[0003] Postoperative pain refers to pain caused by acute trauma from surgical procedures, damage to internal organs, and inflammatory stimulation around nerve endings. Patients experience the most severe postoperative pain during the first three days after surgery and are most likely to require opioids for pain control. Postoperative pain can adversely affect a patient's cardiovascular, respiratory, neuroendocrine, immune, and psychological well-being. Currently, postoperative pain is primarily treated with medication. The main medications used clinically include opioid analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), and local anesthetics. Local anesthetics exert regional analgesia through local nerve blockade, such as bupivacaine and ropivacaine. As an amide-type local anesthetic, ropivacaine is superior to bupivacaine in terms of duration of action, neurotoxicity, and cardiotoxicity; therefore, ropivacaine is the mainstream local anesthetic used by anesthesiologists in China.

[0004] Ropivacaine injection (brand name Naropin) has an onset time of approximately 10 minutes and a short duration of action, lasting only 4-5 hours. Postoperative pain management typically requires several days, and continuous epidural infusion or intermittent single-dose administration is used clinically to achieve sustained analgesia. Continuous infusion or long-term indwelling catheters can easily lead to catheter migration and related complications, reducing patient compliance; repeated administration can increase fluctuations in blood drug concentration, resulting in systemic adverse reactions.

[0005] CN104427977B discloses a proliposome, non-aqueous local anesthetic reservoir formulation and its preparation method. In the patent examples, the highest drug concentration is 4.78% w / w. Using the disclosed preparation method, the resulting formulation quickly precipitates drug crystals when stored at room temperature, and the oil solution becomes a semi-solid gel. That is, a physically stable formulation cannot be obtained according to the patent-disclosed examples and preparation methods. Furthermore, in Example 6 of the patent, the reservoir formulation is administered subcutaneously in a human experimental pain model; the administration method is an invasive subcutaneous injection.

[0006] CN202410881834.1 discloses a phospholipid composition of ropivacaine and meloxicam, its preparation method, and its application. The phospholipid composition obtained by this invention is a lipid vesicle (Example 4, section 4.4 and...). Figure 1The preparation process of lipid vesicles is complex and energy-intensive (ultrasonic heating to prepare solution - sterilization filtration - freeze drying); they have poor storage stability and need to be stored in the form of lyophilized powder and reconstituted before use; they have poor drug compliance and are administered subcutaneously (the efficacy test section in the examples), which is invasive.

[0007] Therefore, it is necessary to develop new non-aqueous, simple-process, low-storage-requirement, room-temperature-only, non-invasive, topical-applied formulations. Summary of the Invention

[0008] Based on the above-mentioned current state of the technology, the present invention provides a ropivacaine sustained-release solution formulation based on a phospholipid complex and a method for preparing the same.

[0009] This invention utilizes a phospholipid-based sustained-release solution. After application to damaged tissue, the solvent diffuses, and the phospholipids encapsulate and solidify the drug, providing a sustained analgesic effect as the drug is slowly released. Direct application to damaged tissue eliminates the need for injection needles, offering a non-invasive drug delivery method.

[0010] This invention provides a phospholipid complex containing ropivacaine or its salt, wherein the ratio of ropivacaine or its salt to phospholipid is 1:5 to 1:15 by mass fraction, preferably 1:8 to 1:15; the optimal ratio range is 1:10 to 1:12, and by way of example, it can be 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13 or 1:14 (based on ropivacaine hydrochloride).

[0011] In this invention, as one embodiment, the phospholipid is selected from natural phospholipids; preferably from soybean lecithin, egg yolk lecithin, or a combination thereof.

[0012] In this invention, as one embodiment, the phospholipid complex contains phosphatidylcholine at a content greater than or equal to 94%; preferably 96.0% to 99.9% (percentage of phospholipid). As an example, it can be 94%, 95%, 96%, 97%, 98%, or 99%.

[0013] In this invention, as one embodiment, the phospholipid complex further includes an antioxidant. As one embodiment, the antioxidant is selected from cysteine ​​hydrochloride, ascorbic acid, tocopherol, thioglycerol, tert-butylhydroxyanisole, butylated hydroxytoluene, or ascorbyl palmitate, or a combination of two or more thereof; preferably, tocopherol.

[0014] In this invention, as one embodiment, the ropivacaine or its salt is selected from ropivacaine free base, ropivacaine hydrochloride, or ropivacaine mesylate, preferably ropivacaine hydrochloride.

[0015] In this invention, as one embodiment, the antioxidant is used in the phospholipid complex at an amount of 0.02% to 1.8%, preferably 0.05% to 1.0%, with an optimal range of 0.05% to 0.2%.

[0016] In this invention, as one embodiment, the phospholipid complex further includes an organic solvent selected from anhydrous ethanol, dimethyl sulfoxide, or N-methylpyrrolidone.

[0017] In this invention, as one embodiment, the amount of organic solvent in the phospholipid complex is 5% to 15%, preferably 7% to 13%, and the optimal range is 8% to 10%; as an example, it is 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or 15%.

[0018] This invention provides a ropivacaine sustained-release solution formulation based on a phospholipid complex, wherein the sustained-release solution formulation comprises, by mass fraction, the following components:

[0019]

[0020] The ropivacaine sustained-release solution formulation of the present invention forms a drug-phospholipid complex, wherein the drug-phospholipid complex is formed by hydrogen bonding between the amide group of ropivacaine and the ester group of phospholipid, thereby increasing the solubility of the drug in the solvent and thus increasing the drug concentration in the formulation. The addition of injectable oil to the drug-phospholipid complex is to adjust the solution viscosity and reduce the organic solvent content in the formulation.

[0021] In this invention, as one embodiment, the injectable oil is selected from soybean oil, castor oil, sesame oil, olive oil, rapeseed oil, sunflower seed oil, corn oil, dipalmitoylphosphatidylglycerol, ethyl oleate, dioleoylglycerol, tricaprylic acid glycerol, medium-chain triglycerides or medium-chain triglycerides, or a combination of two or more of them. The injectable oil may be of natural origin or artificially synthesized.

[0022] In this invention, the injectable oil contains higher fatty acids or esters, which include saturated fatty acids or esters and unsaturated fatty acids or esters, and the content of unsaturated fatty acid esters is higher than that of saturated fatty acid esters. The content of unsaturated fatty acids or esters is greater than 85%, for example, 85%~100%: 86%, 87%, 88%, 89%; for example, 90%~100%: 91%, 92%, 93%, 94%; for example, 95%~100%: 96%, 97%, 98%, 99%.

[0023] In this invention, as one embodiment, the content of ropivacaine or its salt is 3% to 5%, and as one embodiment, the preferred content is 3% to 4%.

[0024] In this invention, as one embodiment, the phospholipid content is 30% to 39%, for example 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38% or 39%.

[0025] In this invention, as one embodiment, the amount of antioxidant is 0.05% to 0.2%, and for example, it can be 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, or 0.19%.

[0026] In this invention, as a preferred embodiment, the amount of anhydrous ethanol used is 8% to 10%, and as an example, it can be 9%.

[0027] In this invention, as a preferred embodiment, the amount of the injection oil is 45% to 50%, and for example, it can be 46%, 47%, 48%, or 49%.

[0028] In this invention, the administration route of the preparation is topical application.

[0029] In this invention, as one embodiment, the sustained-release solution formulation is selected from any one of the following groups: by mass fraction,

[0030]

[0031]

[0032]

[0033]

[0034] or

[0035]

[0036] The present invention also provides a method for preparing the above-mentioned phospholipid complex containing ropivacaine or its salt and the preparation thereof, the method comprising the following steps:

[0037] (1) Mix ropivacaine or its salt, antioxidant, phospholipid and anhydrous ethanol, and stir under heating to dissolve to obtain a complex solution;

[0038] (2) Add the oil for injection to the complex solution, stir and mix well to obtain a clear sustained-release solution;

[0039] (3) Cool the sustained-release solution to room temperature, dispense it into vials, fill with nitrogen, and cap;

[0040] (4) Sterilize at 0.3-0.4 MPa for 15-20 min to obtain sterile preparation.

[0041] The present invention also provides another method for preparing the above-mentioned formulation, the method comprising the following steps:

[0042] (1) Mix ropivacaine or its salt, antioxidant, and anhydrous ethanol, and stir under heating to dissolve, thereby obtaining a clear drug solution;

[0043] (2) Add the drug solution from step (1) to the phospholipid and injection oil at a temperature of ≥60℃, heat at a temperature of 65℃-80℃, preferably 70-75℃, and stir to obtain a clear sustained-release solution;

[0044] (3) Cool the sustained-release solution to room temperature, dispense it into vials, fill with nitrogen, and cap;

[0045] (4) Sterilize at 0.3-0.4 MPa for 15-20 min (e.g., 18 min) to obtain sterile preparation.

[0046] In the preparation method described above in this invention, the heating conditions in step (1) are 65℃-80℃ water bath heating, including 70℃ water bath heating.

[0047] The key point of this invention is:

[0048] (1) Infrared characterization revealed that the drug and phospholipids can form non-chemical bonds, thereby increasing the drug loading capacity by up to 6%;

[0049] (2) By combining the physical and chemical stability of the formulation, an antioxidant suitable for this non-polar system is screened;

[0050] (3) Apply the medication directly to the damaged tissue to reduce irritation;

[0051] (4) It has a sustained-release effect, and the sustained-release time of the formulation is 3.3 to 6.7 times that of ordinary injections.

[0052] The advantages of this invention are: (1) increased drug loading; (2) good safety and no obvious irritation to the administration tissue; and (3) long sustained release time.

[0053] This invention has undergone animal pharmacokinetic experiments and tissue irritation observations, demonstrating good safety and sustained drug release capability.

[0054] This invention first prepares a phospholipid complex by combining ropivacaine with phospholipids. In addition, by screening for antioxidants more suitable for this non-aqueous system, the drug content can be increased to 6%. Furthermore, the resulting formulation exhibits slow impurity growth after being placed at a high temperature of 60°C for 30 days, and the antioxidant content does not decrease during the stability period.

[0055] The sustained-release solution obtained by this invention has a viscosity of 600 mPs (25°C), which helps to apply the drug to damaged tissue, thereby avoiding secondary damage caused by local infiltration injection. Attached Figure Description

[0056] Figure 1 Infrared spectrum of ropivacaine hydrochloride;

[0057] Figure 2 Infrared spectrum of ropivacaine hydrochloride-phospholipid complex. Detailed Implementation

[0058] The following examples are provided to further illustrate the present invention, but are not intended to limit the scope of the invention in any way.

[0059] Example 1: Comparison of methods for preparing ropivacaine sustained-release solution

[0060]

[0061] Preparation method of formulation 1:

[0062] Add all the prescribed amount of excipients to the vial, stir in a 75°C water bath until completely dissolved, add the prescribed amount of drug, heat and stir until clear, let stand at room temperature, and observe the appearance.

[0063] Preparation method of formulation 2:

[0064] The prescribed amount of drug, egg yolk phosphatidylcholine, and ethanol were stirred in a 75°C water bath until completely dissolved. The prescribed amount of castor oil was then added, stirred until well mixed, and left at room temperature to observe the appearance.

[0065] Results: Formulation 1 showed drug crystal precipitation after one day of storage at room temperature; Formulation 2 remained a clear solution after one month of storage at room temperature. Based on these results, it is inferred that during the preparation of Formulation 2, the drug and phospholipids were bonded together non-chemically, thereby improving drug solubility.

[0066] Based on the above results, the drug and the phospholipid-drug complex prepared at a mass ratio of 1 / 6.5 were characterized by infrared spectroscopy, and the spectra are shown below. Figure 1 As shown, the secondary amide group of ropivacaine hydrochloride molecule is 1657.37 cm⁻¹. -1 The disappearance or shift of the absorption peak at the point indicates that the amide group of the drug has undergone non-chemical bonding with the phospholipid.

[0067] Example 2: Comparison of different phospholipids

[0068] The phospholipids selected are soybean phosphatidylcholine (phosphatidylcholine content >94%), egg yolk phosphatidylcholine (phosphatidylcholine content >96%), and hydrogenated soybean phosphatidylcholine. The prescription is as follows:

[0069]

[0070] Preparation method:

[0071] Weigh the prescribed amounts of ropivacaine hydrochloride, cysteine ​​hydrochloride, phosphatidylcholine, and ethanol into a vial. Heat and stir at 75°C until clear. Add the prescribed amount of castor oil and heat and stir until well mixed to obtain a clear and transparent solution. Cool to room temperature, dispense into 5mL vials, fill with nitrogen, and cap.

[0072] Experimental results: Clarified samples were obtained from formulations 3 and 4; after stirring and mixing formulation 5 and restoring it to room temperature, material precipitation was observed.

[0073] The results above show that a clear solution can be prepared using natural phospholipids.

[0074] Example 3: Investigation of Drug / Phospholipid Ratio

[0075] The appearance of the solution was examined at different drug / phospholipid ratios (1 / 6.5-1 / 12). The formulation is as follows:

[0076]

[0077] Preparation method:

[0078] Weigh the prescribed amounts of ropivacaine hydrochloride, egg yolk phosphatidylcholine, and ethanol into a vial. Heat and stir at 70°C until clear. Add the prescribed amount of castor oil and heat and stir until well mixed to obtain a clear and transparent solution. Cool to room temperature, dispense into 5mL vials, fill with nitrogen, crimp the caps, and sterilize.

[0079] Results: Clarified samples were obtained from formulations 6 to 8.

[0080] Example 4: Comparison of different antioxidants

[0081] This product uses easily oxidized oil-based excipients and employs a heating process; therefore, the types of antioxidants used were screened. Solutions were prepared using cysteine ​​hydrochloride, tocopherol, and thioglycerol, respectively, and the product stability was investigated. The formulation is as follows:

[0082]

[0083] Preparation method:

[0084] Weigh the prescribed amounts of ropivacaine hydrochloride, antioxidant, and ethanol into vials. Heat and stir at 70°C until clear. Add the prescribed amounts of egg yolk phosphatidylcholine and castor oil, and heat and stir until well mixed to obtain a clear and transparent solution. Cool to room temperature, dispense into 5mL vials, fill with nitrogen, crimp the caps, and sterilize. Place the above samples at 60°C and take samples at 10 days and 30 days to test the drug content, related substances, carbonyl value, and acid value.

[0085] The stability results are as follows:

[0086]

[0087] The results show that formulations 9 to 13, after being examined at 60℃ for 30 days, did not show a decrease in drug content and had relatively low total impurities. Formulation 11 had a higher carbonyl value than the other formulations, which usually indicates a higher degree of oxidation in the oil, suggesting the formation of harmful substances such as aldehydes and ketones. After being placed at 60℃ for 30 days, formulations 9, 11, and 13 had higher acid values ​​than formulations 10 and 12, reflecting the degree of rancidity in the oil. Considering the results of related substances, carbonyl values, and acid values, formulation 10 is the optimal formulation.

[0088] Example 5: Preliminary Pharmacokinetic Study in Beagle Dogs

[0089] Materials and methods:

[0090] This experiment used 24 healthy Beagle dogs (half male and half female), randomly divided into 3 groups of 8 each: a positive control group, Formulation 1 (Formulation 7), and Formulation 2 (Formulation 9). On the day of surgery, after anesthesia, a longitudinal incision of approximately 5-6 cm was made on the inner thigh of each group. After incising the skin and subcutaneous fascia, a longitudinal incision of approximately 2 cm depth was made in the inner thigh muscles at the incision site. After the incision was completed, the corresponding drug solution was applied to the wound of each animal in Formulation 1 and Formulation 2; the animals in the positive control group did not receive any drug. Subsequently, the muscles and skin of each group were sutured sequentially, and the wound was disinfected with iodine. The animals in the positive control group received multiple subcutaneous injections of the corresponding ropivacaine hydrochloride injection solution after suturing. The total amount of drug administered to the formulation groups and the positive control group was the same.

[0091] Blood samples were collected from all animals in the positive control group before drug administration and at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after drug administration. Blood samples were collected from all animals in formulation groups 1 and 2 before drug administration and at 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h, 32 h, 48 h, 72 h, and 96 h after drug administration. Drug concentration (ropivacaine) and elimination half-life (t) were then measured at each time point. 1 / 2 Area under the plasma drug concentration-time curve (AUC) 0-∞ Peak concentration (C) max ) and peak time (T) max ), calculate the mean residence time (MRT) 0-∞ .

[0092] The results are shown in the table below:

[0093]

[0094] Compared with the positive control group (subcutaneous injection of ropivacaine hydrochloride solution, Naropin, manufacturer AstraZeneca AB), after applying an equivalent dose of the solution to the wound, the T-cell activity of ropivacaine in vivo was significantly reduced. 1 / 2 T max MRT last The duration of sustained release was prolonged, indicating that the formulation group had the characteristic of slow release at the administration site; the sustained release time of the formulation group was 3.3 to 6.7 times that of the positive control group.

[0095] Example 6: Observation of local irritation after administration to animals

[0096] During the pharmacokinetic study in Example 4, the surgical wound sites of the animals in each group were observed to examine the local irritation of different drug administration groups. The results are shown in the table below:

[0097] Observation of drug administration site in dogs

[0098]

[0099] Note: Edema score 1 = barely visible edema; edema score 2 = visible edema.

[0100] Visual observation of skin irritation at the administration site revealed that only animal 1M001 showed visible edema on postoperative day four; 1M002 and 2F004 showed barely visible edema on postoperative day three; all other animals showed no abnormal irritation at the administration site. Only a few animals exhibited mild skin irritation, which was considered unrelated to the test substance.

[0101] The above observations indicate that topical application of medication is less irritating than subcutaneous multi-point injection.

Claims

1. A sustained-release solution formulation containing a phospholipid complex of ropivacaine or its salt, characterized in that, The sustained-release solution formulation comprises, by mass fraction:

2. The formulation according to claim 1, characterized in that, In the phospholipid complex of ropivacaine or its salt, the ratio of ropivacaine or its salt to phospholipid is 1:10 to 1:12 by mass fraction.

3. The formulation according to claim 1 or 2, characterized in that, The phospholipids are selected from natural phospholipids; preferably from soybean lecithin, egg yolk lecithin, or combinations thereof.

4. The formulation according to claim 1 or 2, characterized in that, The phospholipid contains 94% or more of phosphatidylcholine; preferably 96.0% to 99.9%.

5. The formulation according to claim 1, characterized in that, The antioxidant is selected from cysteine ​​hydrochloride, ascorbic acid, tocopherol, thioglycerol, tert-butylhydroxyanisole, butylated hydroxytoluene, or ascorbyl palmitate, or a combination of two or more thereof; tocopherol is preferred.

6. The formulation according to claim 1, characterized in that, The ropivacaine or its salt is selected from ropivacaine free base, ropivacaine hydrochloride or ropivacaine mesylate, preferably ropivacaine hydrochloride.

7. The formulation according to claim 1, characterized in that, The injectable oil is selected from soybean oil, castor oil, sesame oil, olive oil, rapeseed oil, sunflower seed oil, corn oil, dipalmitoylphosphatidylglycerol, ethyl oleate, dioleoylglycerol, tricaprylic acid glycerol, or medium-chain triglycerides, or a combination of two or more of them, and the injectable oil is of natural origin or artificially synthesized.

8. The formulation according to claim 7, characterized in that, The injectable oil contains higher fatty acids or esters, which include saturated fatty acids or esters and unsaturated fatty acids or esters, with the content of unsaturated fatty acid esters being higher than that of saturated fatty acid esters, and the content of unsaturated fatty acids or esters being 85% to 100%.

9. The formulation according to claim 1, characterized in that, The administration route of the preparation is topical application.

10. The formulation according to claim 1, characterized in that, The sustained-release solution formulation is selected from any one of the following groups: by mass fraction, or 11. A method for preparing the formulation according to any one of claims 1 to 10, characterized in that, The method includes the following steps: (1) Mix ropivacaine or its salt, antioxidant, phospholipid and anhydrous ethanol, and stir under heating to dissolve to obtain a complex solution; (2) Add the oil for injection to the complex solution, stir and mix well to obtain a clear sustained-release solution; (3) Cool the sustained-release solution to room temperature, dispense it into vials, fill with nitrogen, and cap; (4) Sterilize at 0.3-0.4 MPa for 15-20 min to obtain sterile preparation.

12. A method for preparing the formulation according to any one of claims 1 to 10, characterized in that, The method includes the following steps: (1) Mix ropivacaine or its salt, antioxidant, and anhydrous ethanol, and stir under heating to dissolve, thereby obtaining a clear drug solution; (2) The drug solution described in step (1) is added to phospholipids and injection oil at a temperature of ≥60°C, heated at a temperature of 65°C-80°C, preferably 70°C-75°C, and stirred to obtain a clear sustained-release solution; (3) Cool the sustained-release solution to room temperature, dispense it into vials, fill with nitrogen, and cap; (4) Sterilize at 0.3-0.4 MPa for 15-20 min to obtain sterile preparation.

13. The preparation method according to claim 11 or 12, characterized in that, The heating conditions in step (1) are 65℃-80℃ water bath heating.

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