Sustained-release analgesic pharmaceutical composition, method for preparing same, and use thereof

Abstract

The present application belongs to the field of pharmaceutical preparations, and particularly relates to a sustained-release analgesic pharmaceutical composition, a method for preparing same, and use thereof. The pharmaceutical composition of the present application comprises a drug, a delivery carrier, and a release regulator. The drug is selected from at least one of a local anesthetic and a non-steroidal anti-inflammatory drug. The release regulator is selected from a phospholipid compound. The delivery carrier is selected from a saccharide and an esterified form thereof. According to the present application, the coaction of the phospholipid compound and the delivery carrier can increase the plasma drug concentration upon the initial release in vivo, reduce the time to peak, enhance the analgesic effect in the early stage after a surgery, and ensure the long-term release of the drug, thus effectively relieving the postoperative pain, reducing the administration frequency, and promoting skin wound healing. The use of a specific solubilizer provides good stability for the drug and prevents precipitation. The composition can be administered through the wound, making it easy to use.

Description

A sustained-release analgesic pharmaceutical composition, preparation method thereof, and application thereof Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a sustained-release analgesic pharmaceutical composition, a preparation method thereof, and an application thereof. Background Art

[0002] Pain is one of the most common complications after surgery. Currently, one or more drugs in opioid analgesics, nonsteroidal anti-inflammatory drugs, and local anesthetics are mainly used clinically for postoperative analgesia. Among them, the drug action time of local anesthetics such as bupivacaine hydrochloride injection and ropivacaine hydrochloride injection is short, and the single-dose analgesic effect is only 6h-8h, which cannot meet the treatment cycle of postoperative pain and is difficult to relieve the pain of patients' postoperative treatment for a long time. At the same time, anti-inflammatory drugs do not have a sustained-release long-acting dosage form. For example, Anjeso injection (US11253478B2) is a daily dosage form, which is difficult to meet the demand for long-term drug release for many days. Therefore, opioids commonly used clinically or opioids continuously injected with an analgesic pump not only have poor compliance in clinical use, but also bring many side effects, affecting patient recovery.

[0003] To address these issues, the marketed drug Posimir (publication number CN101035562A) uses sucrose acetate isobutyrate as a sustained-release carrier and benzyl alcohol as a solvent. The bupivacaine concentration is 132 mg / mL, and the benzyl alcohol dosage is approximately 22% w / w. Due to the neurotoxicity of benzyl alcohol, higher dosages can pose safety concerns. Furthermore, the drug suffers from insufficient efficacy and numerous adverse wound reactions. The marketed drug Zynrelef (publication number CN115025099A) uses a polyorthoester polymer as a sustained-release carrier for its combination of bupivacaine and meloxicam. After application to the administration site, the polyorthoester slowly degrades to achieve sustained release. During formulation development, bupivacaine precipitation was observed. Maleic acid was subsequently added to the formulation to prevent this. However, the acidity of maleic acid can cause adverse wound reactions, hindering wound healing. Furthermore, the drug release rate is slow, and the time to peak is prolonged, making it ineffective in achieving the desired analgesic effect during the initial postoperative period when patients experience intense pain.

[0004] Therefore, there is an urgent need to provide a sustained-release analgesic pharmaceutical composition that can increase the initial release concentration of the drug in the body, enhance the initial analgesic effect and maintain long-term release, and promote good wound healing. Summary of the Invention

[0005] The present application aims to solve one or more technical problems existing in the above-mentioned prior art and at least provide a beneficial alternative or create conditions. Specifically, the present application provides a sustained-release analgesic pharmaceutical composition that can increase the initial release concentration of the drug in the body, enhance the initial analgesic effect and maintain long-term release, and promote good wound healing.

[0006] The inventive concept of the present application: The sustained-release analgesic pharmaceutical composition of the present application comprises a drug, a delivery vehicle, and a release regulator; the drug is selected from at least one of local anesthetics and non-steroidal anti-inflammatory drugs; the release regulator is selected from phospholipid compounds; and the delivery vehicle is selected from sugars and their esters.

[0007] The present application uses phospholipid compounds as release regulators, which work together with the delivery carrier to increase the initial release blood concentration of the drug in the body, enhance the initial analgesic effect and maintain long-term release. This is exactly the opposite of the prior art in which the release time of the main drug is delayed and the peak time of drug release is longer; and the pharmaceutical composition of the present application can promote good wound healing.

[0008] Therefore, the first aspect of the present application provides a sustained-release analgesic pharmaceutical composition.

[0009] Specifically, the sustained-release analgesic pharmaceutical composition includes a drug, a delivery vehicle, and a release regulator;

[0010] The drug is selected from at least one of local anesthetics and nonsteroidal anti-inflammatory drugs;

[0011] The release modifier is selected from phospholipid compounds;

[0012] The delivery carrier is selected from sugars and esters thereof.

[0013] Specifically, the inventors added phospholipids to the pharmaceutical composition in order to explore its effect on skin wound healing and repair. What surprised the inventors was that under the sustained-release system of the present application, the addition of phospholipids can increase the initial release blood concentration of the drug in the body without producing an obvious burst release, which can enhance the initial analgesic effect, effectively relieve the patient's pain in the early postoperative period and maintain the long-term release of the drug, producing an unexpected effect. Generally, many drugs add phospholipids to delay release and use phospholipids as excipients, such as the in-situ gel system with publication number CN103705442A. The above-mentioned beneficial effects of the present application are completely opposite to the technical effect of the prior art that can only delay the release time of the main drug after adding a release regulator.

[0014] Preferably, when the drug contains a local anesthetic, the pharmaceutical composition further contains a solubilizer.

[0015] Preferably, the solubilizer is selected from at least one of menthol, camphor, camphor alcohol, linalool, and eucalyptol.

[0016] Specifically, the present application adds a solubilizer to the pharmaceutical composition to increase the solubility of the main drug. The solubilizer and other components work together to prevent drug precipitation during the preparation process and long-term low-temperature storage, resulting in excellent stability. Furthermore, by selecting a specific type of solubilizer, the adverse effects of organic or inorganic acids on wounds can be avoided, without lowering the pH of the wound or adversely affecting wound inflammation and healing.

[0017] Preferably, the local anesthetic is selected from amide anesthetics.

[0018] Preferably, the amide anesthetic is selected from at least one of bupivacaine, ropivacaine, and pharmaceutically acceptable salts and stereoisomers thereof.

[0019] Preferably, the nonsteroidal anti-inflammatory drug is selected from at least one of meloxicam, celecoxib, and pharmaceutically acceptable salts and stereoisomers thereof.

[0020] Preferably, the delivery carrier is selected from at least one of sucrose, chitosan, sucrose acetate isobutyrate, sucrose octaacetate, and sucrose monoacetate monoisobutyrate.

[0021] Preferably, the phospholipid compound is selected from at least one of natural phospholipids and synthetic phospholipids.

[0022] Preferably, the natural phospholipid is selected from at least one of soybean phosphatidylcholine (SPC), egg yolk phospholipid (EPC), rapeseed phospholipid, and sunflower phospholipid.

[0023] Preferably, the synthetic phospholipid is selected from at least one of dieucoylphosphatidylcholine (DEPC), dioleoylphosphatidylcholine (DOPC), palmitoyloleoylphosphatidylcholine (POPC), distearoylphosphatidylcholine (DSPC), dipalmitoylphosphatidylglycerol (DPPG), and distearoylphosphatidylglycerol (DSPG).

[0024] Preferably, the mass content of phosphatidylcholine (PC) in the SPC is 60%-99%.

[0025] Preferably, the menthol is L-menthol.

[0026] Preferably, after the pharmaceutical composition is administered to an animal, when the drug contains a local anesthetic, the time for the local anesthetic to reach its peak blood concentration is 0.1h-8h; when the drug is selected from non-steroidal anti-inflammatory drugs, the time for the local anesthetic to reach its peak blood concentration is 1h-28h.

[0027] Further preferably, after the pharmaceutical composition is administered to an animal, when the drug contains a local anesthetic, the time for the local anesthetic to reach its peak blood concentration is 0.4h-4h; when the drug is selected from non-steroidal anti-inflammatory drugs, the time for the local anesthetic to reach its peak blood concentration is 2h-10h.

[0028] Preferably, after the pharmaceutical composition is injected into SD rats, when the drug contains a local anesthetic, the time for the blood concentration of the local anesthetic to reach its peak is 0.2h-4h; when the drug is selected from non-steroidal anti-inflammatory drugs, the time for the blood concentration to reach its peak is 4h-24h.

[0029] Further preferably, after the pharmaceutical composition is injected into SD rats, when the drug contains a local anesthetic, the time for the blood concentration of the local anesthetic to reach its peak is 0.5h-2h; when the drug is selected from non-steroidal anti-inflammatory drugs, the time for the blood concentration to reach its peak is 8h-20h.

[0030] Preferably, after the pharmaceutical composition is injected into beagle dogs, when the drug contains a local anesthetic, the time for the local anesthetic to reach a peak in blood concentration is 1 hour to 4 hours; when the drug is selected from non-steroidal anti-inflammatory drugs, the time for the local anesthetic to reach a peak in blood concentration is 4 hours to 12 hours.

[0031] Further preferably, after the pharmaceutical composition is injected into beagle dogs, when the drug contains a local anesthetic, the time for the local anesthetic to reach a peak in blood concentration is 2h-3h; when the drug is selected from non-steroidal anti-inflammatory drugs, the time for the local anesthetic to reach a peak in blood concentration is 4h-8h.

[0032] Preferably, the sustained-release analgesic pharmaceutical composition comprises, by weight, 0.01-20 parts of the drug, 30-80 parts of the delivery vehicle, and 0.05-20 parts of the release regulator.

[0033] Further preferably, the sustained-release analgesic pharmaceutical composition comprises, by weight, 0.01-8 parts of the drug, 50-75 parts of the delivery vehicle, and 0.05-10 parts of the release regulator.

[0034] More preferably, the sustained-release analgesic pharmaceutical composition comprises, by weight, 0.01-6 parts of the drug, 55-68 parts of the delivery vehicle, and 0.05-5 parts of the release regulator.

[0035] Preferably, when the drug contains a local anesthetic, the sustained-release analgesic pharmaceutical composition comprises, by weight, 0.01-20 parts of the drug, 30-80 parts of a delivery vehicle, greater than 0 and less than or equal to 10 parts of a solubilizer, and 0.05-20 parts of a release modifier;

[0036] Further preferably, when the drug contains a local anesthetic, the sustained-release analgesic pharmaceutical composition comprises, by weight, 1-8 parts of the drug, 50-70 parts of a delivery vehicle, greater than 0 and less than or equal to 5 parts of a solubilizer, and 0.05-10 parts of a release regulator.

[0037] More preferably, when the drug contains a local anesthetic, the sustained-release analgesic pharmaceutical composition comprises, by weight, 2-6 parts of the drug, 55-68 parts of a delivery vehicle, greater than 0 and less than or equal to 3 parts of a solubilizer, and 0.05-5 parts of a release regulator.

[0038] Preferably, when the drug is selected from nonsteroidal anti-inflammatory drugs, the sustained-release analgesic pharmaceutical composition comprises, by weight, 0.1-20 parts of the drug, 30-80 parts of the delivery vehicle, 0-10 parts of the solubilizer, and 0.05-20 parts of the release regulator.

[0039] Further preferably, when the drug is selected from nonsteroidal anti-inflammatory drugs, the sustained-release analgesic pharmaceutical composition comprises, by weight, 0.5-10 parts of the drug, 50-70 parts of the delivery vehicle, 0-5 parts of the solubilizer, and 0.05-10 parts of the release regulator.

[0040] More preferably, when the drug is selected from nonsteroidal anti-inflammatory drugs, the sustained-release analgesic pharmaceutical composition comprises, by weight, 1-5 parts of the drug, 55-68 parts of the delivery vehicle, 0-3 parts of the solubilizer, and 0.05-5 parts of the release regulator.

[0041] Preferably, when the drug is selected from local anesthetics and non-steroidal anti-inflammatory drugs, the sustained-release analgesic pharmaceutical composition comprises, by weight, 0.01-15 parts of local anesthetics, 0.01-5 parts of non-steroidal anti-inflammatory drugs, 30-80 parts of delivery vehicles, greater than 0 and less than or equal to 10 parts of solubilizers, and 0.05-20 parts of release regulators.

[0042] Further preferably, when the drug is selected from local anesthetics and non-steroidal anti-inflammatory drugs, the sustained-release analgesic pharmaceutical composition comprises, by weight, 1-5 parts of local anesthetics, 0.01-3 parts of non-steroidal anti-inflammatory drugs, 50-70 parts of a delivery vehicle, greater than 0 and less than or equal to 5 parts of a solubilizer, and 0.05-10 parts of a release regulator.

[0043] More preferably, when the drug is selected from local anesthetics and non-steroidal anti-inflammatory drugs, the sustained-release analgesic pharmaceutical composition comprises, by weight, 2-4 parts of local anesthetics, 0.01-2 parts of non-steroidal anti-inflammatory drugs, 55-68 parts of delivery vehicles, greater than 0 and less than or equal to 3 parts of solubilizers, and 0.05-5 parts of release regulators.

[0044] Preferably, the sustained-release analgesic pharmaceutical composition further comprises a solvent; or, the sustained-release analgesic pharmaceutical composition further comprises a solvent and an antioxidant.

[0045] Preferably, when the drug contains a local anesthetic, the sustained-release analgesic pharmaceutical composition comprises, by weight, 0.01-20 parts of the drug, 30-80 parts of a delivery vehicle, greater than 0 and less than 10 parts of a solubilizer, 0.05-20 parts of a release modifier, greater than 0 and less than 70 parts of a solvent, and 0-5 parts of an antioxidant; when the drug is selected from non-steroidal anti-inflammatory drugs, the sustained-release analgesic pharmaceutical composition comprises, by weight, 0.1-20 parts of the drug, 30-80 parts of a delivery vehicle, 0-10 parts of a solubilizer, 0.05-20 parts of a release modifier, greater than 0 and less than 70 parts of a solvent, and 0-5 parts of an antioxidant;

[0046] Further preferably, when the drug contains a local anesthetic, the sustained-release analgesic pharmaceutical composition comprises, by weight, 1-8 parts of the drug, 50-70 parts of a delivery vehicle, greater than 0 and less than or equal to 5 parts of a solubilizer, 0.05-10 parts of a release regulator, 20-60 parts of a solvent, and 0-2 parts of an antioxidant; when the drug is selected from non-steroidal anti-inflammatory drugs, the sustained-release analgesic pharmaceutical composition comprises, by weight, 0.5-10 parts of the drug, 50-70 parts of a delivery vehicle, 0-5 parts of a solubilizer, 0.05-10 parts of a release regulator, 20-60 parts of a solvent, and 0-2 parts of an antioxidant.

[0047] Further preferably, when the drug contains a local anesthetic, the sustained-release analgesic pharmaceutical composition comprises, by weight, 2-6 parts of the drug, 55-68 parts of a delivery vehicle, greater than 0 and less than or equal to 3 parts of a solubilizer, 0.05-5 parts of a release regulator, 20-40 parts of a solvent, and 0-1 part of an antioxidant; when the drug is selected from non-steroidal anti-inflammatory drugs, the sustained-release analgesic pharmaceutical composition comprises, by weight, 1-5 parts of the drug, 55-68 parts of a delivery vehicle, 0-3 parts of a solubilizer, 0.05-5 parts of a release regulator, 20-40 parts of a solvent, and 0-1 part of an antioxidant.

[0048] Preferably, when the drug is selected from local anesthetics and non-steroidal anti-inflammatory drugs, the sustained-release analgesic pharmaceutical composition comprises, by weight, 0.01-15 parts of local anesthetics, 0.01-5 parts of non-steroidal anti-inflammatory drugs, 30-80 parts of delivery vehicles, greater than 0 and less than or equal to 10 parts of solubilizers, 0.05-20 parts of release regulators, greater than 0 and less than or equal to 70 parts of solvents, and 0-5 parts of antioxidants.

[0049] Further preferably, when the drug is selected from local anesthetics and non-steroidal anti-inflammatory drugs, the sustained-release analgesic pharmaceutical composition comprises, by weight, 1-5 parts of local anesthetics, 0.01-3 parts of non-steroidal anti-inflammatory drugs, 50-70 parts of delivery vehicles, greater than 0 and less than or equal to 5 parts of solubilizers, 0.05-10 parts of release modifiers, 20-60 parts of solvents, and 0-2 parts of antioxidants.

[0050] Further preferably, when the drug is selected from local anesthetics and non-steroidal anti-inflammatory drugs, the sustained-release analgesic pharmaceutical composition comprises, by weight, 2-4 parts of local anesthetics, 0.01-2 parts of non-steroidal anti-inflammatory drugs, 55-68 parts of delivery vehicles, greater than 0 and less than or equal to 3 parts of solubilizers, 0.05-5 parts of release modifiers, 20-40 parts of solvents, and 0-1 parts of antioxidants.

[0051] Preferably, the solvent is selected from at least one of alcohols, N-methylpyrrolidone, benzyl benzoate, dimethyl sulfoxide, and triacetin.

[0052] Preferably, the alcohol includes at least one of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ethylene glycol, propylene glycol, glycerol, benzyl alcohol, phenylethyl alcohol, and polyethylene glycol.

[0053] Preferably, the antioxidant is selected from at least one of vitamin C (ascorbic acid), cysteine ​​hydrochloride, vitamin E (tocopherol), ascorbyl palmitate, glutathione, α-lipoic acid, monothioglycerol, butylated hydroxytoluene, and butylated hydroxyanisole.

[0054] The second aspect of the present application provides a method for preparing the sustained-release analgesic pharmaceutical composition described in the first aspect of the present application.

[0055] Specifically, the method for preparing the sustained-release analgesic pharmaceutical composition comprises the following steps:

[0056] The various raw material components are mixed to prepare the sustained-release analgesic pharmaceutical composition.

[0057] Preferably, the preparation method of the sustained-release analgesic pharmaceutical composition is:

[0058] First, local anesthetics and / or nonsteroidal anti-inflammatory drugs, release regulators, solubilizers and solvents are mixed at a certain temperature, and then a delivery carrier and an antioxidant are added and mixed to prepare the sustained-release analgesic pharmaceutical composition.

[0059] Preferably, the temperature is 50°C-70°C; more preferably, the temperature is 55°C-65°C.

[0060] Preferably, the preparation method of the sustained-release analgesic pharmaceutical composition can also be: first, the release regulator and the solvent are mixed, a delivery carrier and an antioxidant are added at a certain temperature to obtain a mixed solution, and finally the local anesthetic and / or non-steroidal anti-inflammatory drug are added and mixed to obtain the sustained-release analgesic pharmaceutical composition.

[0061] Preferably, the temperature is 40°C-60°C; more preferably, the temperature is 45°C-55°C.

[0062] Preferably, the mixed solution is heated before adding the anesthetic and nonsteroidal anti-inflammatory drug.

[0063] Preferably, the temperature after heating is 50°C-70°C; more preferably, the temperature after heating is 55°C-65°C.

[0064] The third aspect of the present application provides a pharmaceutical preparation.

[0065] Specifically, the pharmaceutical preparation includes the sustained-release analgesic pharmaceutical composition described in the first aspect of the present application.

[0066] Compared with the prior art, the technical solution provided by this application has the following beneficial effects:

[0067] (1) The present application adopts a specific type of release regulator (phospholipid compound), which works together with the delivery carrier to increase the initial release blood concentration of the drug in the body, enhance the initial analgesic effect and maintain long-term release. After the pharmaceutical composition is administered to animals, when the drug contains a local anesthetic, the blood concentration of the local anesthetic reaches a peak time of 0.1h-8h; when the drug is selected from non-steroidal anti-inflammatory drugs, the blood concentration reaches a peak time of 1h-28h, and even when the drug contains a local anesthetic, the blood concentration of the local anesthetic reaches a peak time of 0.4h-4h; when the drug is selected from non-steroidal anti-inflammatory drugs, the blood concentration reaches a peak time of 2h-10h. The blood concentration peak time is short, which is exactly the opposite of the prior art in which the drug release time of the main drug is delayed and the drug release peak time is longer. At the same time, when local anesthetics and nonsteroidal anti-inflammatory drugs are present simultaneously, the analgesic effect is still good 72 hours after surgery. When the drug is selected from nonsteroidal anti-inflammatory drugs, the analgesic effect is still good 24 hours to 72 hours after surgery, indicating that the drug in the pharmaceutical composition of the present application has a good long-term release effect. In addition, the addition of phospholipids can also promote good wound healing.

[0068] (2) The addition of a specific type of solubilizer to the pharmaceutical composition of the present application makes the drug have good stability, is not easy to precipitate, and is suitable for storage at room temperature and low temperature. After being stored at room temperature for 24 hours, it remains a transparent and uniform solution without any precipitation. It can also avoid the adverse effects of organic or inorganic acids on wounds, will not lower the pH of the wound, and will not have adverse effects on wound inflammation and healing.

[0069] (3) The pharmaceutical composition of the present application can overcome the shortcomings of treatment methods such as opioids and analgesic pumps, effectively relieve patients' postoperative pain, reduce the frequency of medication, and simplify analgesic treatment methods.

[0070] (4) The pharmaceutical composition of the present application can be directly administered through the postoperative wound, is easy to use, forms a drug reservoir in the wound, slowly releases the drug, reduces the discomfort caused by the patient using an analgesic pump or intravenous catheter, and can improve patient compliance. BRIEF DESCRIPTION OF THE DRAWINGS

[0071] FIG1 is a diagram showing the precipitation of the pharmaceutical compositions of Example 14 and Comparative Examples 1-3 of the present application;

[0072] FIG2 is a graph showing the blood concentration of bupivacaine in SD rats after administration of the pharmaceutical compositions of Examples 13-15 and Comparative Example 4 of the present application;

[0073] FIG3 is a graph showing the blood concentration of meloxicam in SD rats after administration of the pharmaceutical compositions of Examples 13-15 of the present application and Comparative Example 4;

[0074] Figure 4 is a schematic diagram of the incision location for the postoperative pain test in Bama pigs;

[0075] FIG5 is a graph showing the results of a Bama pig fiber stimulation test after administration of the pharmaceutical compositions of Example 14, Example 61, and Comparative Examples 4-5 of the present application;

[0076] FIG6 is a graph showing the results of a fiber stimulation test on SD rats after administration of the pharmaceutical compositions of Example 14 and Comparative Example 4 of the present application;

[0077] FIG7 is the results of a hot plate pain test on the soles of the feet of SD rats after administration of the pharmaceutical compositions of Example 68, Comparative Example 7, and Comparative Example 8 of the present application;

[0078] FIG8 is a histological diagram of a wound section of a Bama pig after administration of the pharmaceutical composition of Example 14 of the present application;

[0079] Figure 9 is a histological diagram of a wound section of a Bama pig after administration of the pharmaceutical composition Zynrelef in Comparative Example 5 of the present application;

[0080] Figure 10 is a histological diagram of a wound section of a Bama pig after administration of the pharmaceutical composition of Comparative Example 4 of the present application. DETAILED DESCRIPTION

[0081] In order to make the technical solution of this application more clearly understood by those skilled in the art, the following examples are given for illustration. It should be noted that the following examples do not limit the scope of protection claimed in this application.

[0082] Unless otherwise specified, the raw materials, reagents, or devices used in the following examples can be obtained from conventional commercial sources or by existing known methods.

[0083] Examples 1-33

[0084] The raw material components and dosage (parts by weight) of the sustained-release analgesic pharmaceutical composition of Example 1-33 are shown in Table 1.

[0085] Table 1: Raw material components and dosages of the sustained-release analgesic pharmaceutical composition of Examples 1-33 (parts by weight)

[0086] The preparation method of the sustained-release analgesic pharmaceutical composition of Example 1-33 comprises the following steps:

[0087] At a temperature of 60°C, a local anesthetic, a nonsteroidal anti-inflammatory drug, a release regulator, and a solubilizer are added to a solvent and stirred to dissolve, and then a delivery carrier sucrose acetate isobutyrate and an antioxidant are added in sequence and stirred until a transparent and uniform solution is formed to prepare a sustained-release analgesic pharmaceutical composition.

[0088] Examples 34-43

[0089] The raw material components and dosages (parts by weight) of the sustained-release analgesic pharmaceutical compositions of Examples 34-43 are shown in Table 2.

[0090] Table 2: Raw material components and dosages (parts by weight) of the sustained-release analgesic pharmaceutical compositions of Examples 34-43

[0091] The preparation method of the sustained-release analgesic pharmaceutical composition of Examples 34-43 is the same as that of Examples 1-33.

[0092] Examples 44-53

[0093] The raw material components and dosages (parts by weight) of the sustained-release analgesic pharmaceutical compositions of Examples 44-53 are shown in Table 3.

[0094] Table 3: Raw material components and dosages of the sustained-release analgesic pharmaceutical compositions of Examples 44-53 (parts by weight)

[0095] The preparation method of the sustained-release analgesic pharmaceutical composition of Examples 44-53 comprises the following steps:

[0096] A release modifier is added to a solvent (dimethyl sulfoxide or benzyl alcohol), stirred and dissolved at 50°C, and a delivery carrier, sucrose acetate isobutyrate, triacetin, and an antioxidant are added in sequence while stirring until a transparent and uniform solution is formed. The temperature is then raised to 60°C, and a non-steroidal anti-inflammatory drug, meloxicam, and a local anesthetic, ropivacaine, are added to the solution, and stirred until a transparent and uniform solution is formed, thereby preparing a sustained-release analgesic pharmaceutical composition.

[0097] Examples 54-62

[0098] The raw material components and dosages (by weight) of the sustained-release analgesic pharmaceutical compositions of Examples 54-62 are shown in Table 4.

[0099] Table 4: Raw material components and dosages of the sustained-release analgesic pharmaceutical compositions of Examples 54-62 (parts by weight)

[0100] The preparation method of the sustained-release analgesic pharmaceutical composition of Examples 54-62 comprises the following steps:

[0101] At 60°C, the local anesthetic bupivacaine, a release regulator, and a solubilizer are added to a solvent and stirred to dissolve. Then, a delivery carrier sucrose acetate isobutyrate and an antioxidant are added in sequence and stirred until a transparent and uniform solution is formed to prepare a sustained-release analgesic pharmaceutical composition.

[0102] Examples 63-70

[0103] The raw material components and dosages (parts by weight) of the sustained-release analgesic pharmaceutical compositions of Examples 63-70 are shown in Table 5.

[0104] Table 5: Raw material components and dosages of the sustained-release analgesic pharmaceutical compositions of Examples 63-70 (parts by weight)

[0105] The preparation method of the sustained-release analgesic pharmaceutical composition of Examples 63-70 comprises the following steps:

[0106] At 60°C, the non-steroidal anti-inflammatory drug meloxicam and a release regulator are added to a solvent and stirred to dissolve, and then the delivery carrier sucrose acetate isobutyrate and an antioxidant are added in sequence and stirred until a transparent and uniform solution is formed to prepare a sustained-release analgesic pharmaceutical composition.

[0107] Comparative Example 1

[0108] The only difference between Comparative Example 1 and Example 14 is that Comparative Example 1 does not contain the solubilizer menthol, and the amount of the solvent triacetic acid is 25.77 parts. The rest is the same as Example 14.

[0109] Comparative Example 2

[0110] The only difference between Comparative Example 2 and Example 14 is that Comparative Example 2 uses an equal amount of solubilizing agent arginine to replace the menthol in Example 14, and the rest is the same as Example 14.

[0111] Comparative Example 3

[0112] The only difference between Comparative Example 3 and Example 14 is that Comparative Example 3 uses an equal amount of solubilizing agent maleic acid to replace the menthol in Example 14, and the rest is the same as Example 14.

[0113] Comparative Example 4

[0114] The only difference between Comparative Example 4 and Example 14 is that Comparative Example 4 uses an equal amount of release modifier castor oil to replace the SPC in Example 14, and the rest is the same as Example 14.

[0115] Comparative Example 5

[0116] Comparative Example 5 is the overseas marketed drug Zynrelef.

[0117] Comparative Example 6

[0118] The only difference between Comparative Example 6 and Example 68 is that Comparative Example 6 uses an equal amount of release modifier sesame oil to replace the SPC in Example 68, and the rest is the same as Example 68.

[0119] Comparative Example 7

[0120] Comparative Example 7 is the domestically marketed drug Meloxicam (meloxicam injection, Qilu).

[0121] Comparative Example 8

[0122] Comparative Example 8 is the domestically marketed drug Mobic (Meloxicam tablets, Shanghai Boehringer Ingelheim Pharmaceuticals Co., Ltd.).

[0123] Performance Testing

[0124] 1. Drug precipitation observation

[0125] The pharmaceutical compositions prepared in Example 14 and Comparative Examples 1-3 were stored at room temperature (25° C.) for 24 hours, and the precipitation of the pharmaceutical compositions was observed. The results are shown in FIG1 , where A in FIG1 is a precipitation diagram of Example 14, and B, C, and D in FIG1 are precipitation diagrams of Comparative Examples 1-3, respectively.

[0126] As can be seen from Figure 1, the pharmaceutical composition of Example 14 with the addition of the solubilizer menthol remains a transparent and uniform solution after being stored at room temperature of 25°C for 24 hours, and no precipitation occurs. However, the pharmaceutical compositions of Comparative Example 1 (without a solubilizer), Comparative Example 2 (with the addition of a solubilizer arginine), and Comparative Example 3 (with the addition of a solubilizer maleic acid) are stored at room temperature of 25°C for 24 hours. The originally transparent and uniform solution becomes turbid, and precipitation of the local anesthetic bupivacaine occurs. This indicates that the addition of the solubilizer menthol to the pharmaceutical composition of the present application can increase the solubility of the main drug, so that the product will not precipitate the drug during the preparation process and when stored at room temperature for a long time, and has good stability.

[0127] 2. Drug concentration peak performance test

[0128] (1) In order to determine the time when the drug concentration in the pharmaceutical composition of the present application reaches peak, i.e., the time when postoperative analgesia takes effect, the pharmaceutical compositions of Examples 13-15 and Comparative Example 4 were subjected to a pharmacokinetic study in rats. The specific process is as follows:

[0129] SD rats (male) weighing about 200 g-250 g were selected, and the pharmaceutical compositions of Examples 13-15 and Comparative Example 4 were administered subcutaneously to the back of the SD rats, respectively, at a dose of 30.0 mg / Kg; approximately 0.5 mL of blood samples were collected from the SD rats at 0.25, 0.5, 1, 2, 3, 6, 12, 24, 48, 72, and 96 hours after administration, and placed in EDTA-2K + anticoagulant blood collection tubes. The whole blood was centrifuged at 8000 rpm for 5 min, and the plasma was collected. The drug concentration in the plasma sample was then detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS).

[0130] The blood concentration curves of the local anesthetic bupivacaine and the nonsteroidal anti-inflammatory drug meloxicam after administration of the pharmaceutical compositions of Examples 13-15 and Comparative Example 4 are shown in Figures 2 and 3, respectively.

[0131] As can be seen from Figures 2 and 3, after the release modifier (SPC) was added to the pharmaceutical compositions of Examples 13-15 of the present application, the time for the peak blood concentration of bupivacaine in SD rats was 1 hour, and the time for the peak blood concentration of meloxicam was 6 hours; while after the release modifier castor oil was added to the pharmaceutical composition of Comparative Example 4, the time for the peak blood concentration of bupivacaine in SD rats was 2 hours, and the time for the peak blood concentration of meloxicam was 24 hours. This shows that after the addition of phospholipid compounds as release modifiers to the pharmaceutical compositions of the present application, they work together with other components to shorten the time for the peak blood concentration of the drug and accelerate the time for postoperative analgesia to take effect. In addition, the pharmaceutical compositions of Examples 13-15 all showed a sustained release effect, with a smooth and long-lasting release, which can significantly relieve the pain and discomfort of patients in the early postoperative period and reduce the frequency of administration. The addition of a release regulator phospholipid compound to the pharmaceutical composition of the present application can shorten the time to peak blood drug concentration and accelerate the onset of postoperative analgesia. This technical effect is exactly the opposite of the conventional theoretical knowledge and prior art in this field that the release regulator can delay the release time of the main drug.

[0132] (2) SD rats (male) weighing about 200g-250g were selected, and the pharmaceutical compositions of Example 68 and Comparative Example 6 were administered subcutaneously to the back of the SD rats, with the dosage of 30.0mg / kg; about 0.5mL of blood samples were collected from the SD rats at 0.5, 1, 2, 4, 8, 12, 24, 48, 72, and 96 hours after administration, and placed in EDTA-2K+ anticoagulant blood collection tubes. The whole blood was centrifuged at 8000rpm for 5min, and the plasma was collected. The drug concentration in the plasma sample was then detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). The blood concentration data of meloxicam in SD rats after administration of the pharmaceutical compositions of Example 68 and Comparative Example 6 of the present application are shown in Table 6.

[0133] Table 6: Meloxicam blood concentration data in SD rats after administration of the pharmaceutical compositions of Example 68 and Comparative Example 6

[0134] Among them, C max represents the peak concentration of the drug, T max Indicates the peak time of drug effect, T 1 / 2 Represents the half-life of the drug.

[0135] As can be seen from Table 6, after the release regulator (SPC) was added to the pharmaceutical composition of Example 68 of the present application, the time for the blood concentration of meloxicam in SD rats to reach peak was 4 hours; while the time for the blood concentration of meloxicam in SD rats of Comparative Example 6 to reach peak was 8 hours. This indicates that after the phospholipid compound is added as a release regulator to the pharmaceutical composition of the present application, it and other components work together to shorten the time for the blood concentration of the drug to reach peak, accelerate the time for postoperative analgesia to take effect, and the pharmaceutical composition of Example 68 shows a sustained release effect (as can be seen from the subsequent Table 7, Example 68 has a more sustained release compared with Comparative Examples 7 and 8), which can significantly relieve the patient's pain and discomfort for a longer period of time after surgery and reduce the frequency of administration.

[0136] 3. Analgesic effect test

[0137] (1) The analgesic effects of the pharmaceutical compositions of Example 14, Example 61 and Comparative Examples 4 and 5 (Zynrelef) were tested on a Bama pig postoperative pain model. The specific process was as follows:

[0138] 8Kg-12Kg Bama miniature pigs were selected and anesthetized with isoflurane. A 7cm incision was made 3cm to the left of the spine below the back of each group of Bama pigs, deep to the fascia layer, and the skin and muscle layers on both sides were separated. Each group was directly perfused at the wound. Each Bama pig was given 100mg / Kg of physiological saline, Example 14, Example 61, Comparative Example 4, and Comparative Example 5, respectively, and then the wound was sutured. Each group of Bama pigs was subjected to a fiber stimulation test using a Von Frey analgesic before administration (0h) and 1, 3, 5, 7, 12, 24, 48, 72, 96, 120, 144, and 168 hours after administration. 9 intensities of Von Frey analgesia were used. Frey filaments (equivalent to 1.4, 2, 4, 6, 8, 10, 15, 26, and 60 g, respectively) were used to detect and record the test results and calculate the pain threshold using the "up-and-down" method. A schematic diagram of the incision position for the postoperative pain test in Bama pigs is shown in Figure 4, where H3, M1, and R2 are test points, respectively, and the spine line represents the dorsal midline of the Bama pig. The results of the fiber filament stimulation test within 168 hours after administration of the pharmaceutical composition of Example 14, Example 61, Comparative Example 4, and Comparative Example 5 are shown in Figure 5. The smaller the vertical coordinate data, the more obvious the pain and the lower the efficacy.

[0139] As can be seen from Figure 5, the analgesic effects of Zynrelef in Comparative Example 5 and the pharmaceutical composition in Comparative Example 4 began to weaken 24 hours after surgery, and on days 1 to 3 after surgery, the analgesic effects of Comparative Examples 5 and 4 were significantly worse than those of the pharmaceutical composition in Example 14 of the present application. This indicates that the pharmaceutical composition in Example 14 of the present application has a better and longer-lasting postoperative analgesic effect than the marketed drug Zynrelef.

[0140] Compared with Example 61, the analgesic effect of the pharmaceutical composition of Example 14 within 48 hours after surgery is basically the same. From 72 hours, the efficacy of Example 61 begins to decline, while Example 14 still has efficacy, indicating that the addition of meloxicam to the prescription of this application will have a longer-lasting postoperative analgesic effect.

[0141] (2) The analgesic effects of the pharmaceutical compositions of Example 14 and Comparative Example 4 were tested on a SD rat postoperative pain model. The specific process was as follows:

[0142] SD rats (5-6 weeks old, male) of specific pathogen-free (SPF) grade were selected. After isoflurane anesthesia, a 1.0 cm incision was made on the sole of the foot. The muscle was cut but its origin and attachment were not affected. After suturing, the infiltration injection was given next to the incision. Each SD rat was given normal saline, the pharmaceutical composition of Example 14, and the pharmaceutical composition of Comparative Example 4 at 30 mg / kg. Before surgery (0 h) and 0.5, 2, 4, 8, 12, 24, 48, and 72 hours after administration, the SD rats were subjected to Von Frey mechanical hyperalgesia test, using 9 strengths of Von Frey filaments (equivalent to 1, 1.4, 2, 4, 6, 8, 10, 15, and 26 g, respectively). The test results were detected and recorded using the "up-and-down" method, and the pain threshold was calculated. The results of the fiber filament stimulation test within 72 h after administration of the pharmaceutical compositions of Example 14 and Comparative Example 4 are shown in Figure 6. The smaller the ordinate data, the more obvious the pain and the lower the efficacy.

[0143] As can be seen from Figure 6, the analgesic effect of the pharmaceutical composition of Example 14 was significantly better than that of Comparative Example 4 at 0.5 h and 2.0 h after surgery. As time went on, the analgesic effect from 4 h to 48 h after surgery was also slightly better than that of Comparative Example 4. This indicates that the pharmaceutical composition of Example 14 of the present application has a better postoperative analgesic effect than that of Comparative Example 4, especially the analgesic effect in the early postoperative period. As time went on, the analgesic effect of the pharmaceutical composition of Example 14 was also better than that of Comparative Example 4 overall. It can be seen that the analgesic effect of the pharmaceutical composition of the present application after adding the release modifier phospholipid compound is significantly better than that of adding other release modifiers such as castor oil, especially the analgesic effect in the early postoperative period.

[0144] (3) The analgesic effects of the pharmaceutical compositions of Example 68 and Comparative Examples 7 and 8 were tested on a SD rat postoperative pain model. The specific process was as follows:

[0145] SD rats (5-6 weeks old, male) of specific pathogen-free (SPF) grade were selected. After isoflurane anesthesia, a 1.0 cm incision was made on the sole of the foot. After suturing, the drug was injected into the incision. Each SD rat was given 30 mg / kg of normal saline, the pharmaceutical composition of Example 68, Comparative Example 7, and Comparative Example 8, respectively. The foot hot plate pain test experiment was performed before surgery (0 h) and 0.5, 2, 4, 8, 12, 24, 48, and 72 hours after administration. The hot plate instrument was turned on (the temperature was set to 56 ° C). After the hot plate temperature was constant, the surgical sole of the experimental rat was placed on the hot plate. The timing started when the rat's foot touched the hot plate and ended when the foot was lifted for the first time. The tolerance time of the rat on the hot plate was recorded (in seconds). Each rat was measured 3 times, with an interval of not less than 30 seconds each time. The cutoff time was set to 12 seconds. Rats that did not lift their feet for more than 12 seconds were considered to be insensitive to heat pain and were no longer tested. The average of the three values ​​was used as the test result at a specific time point.

[0146] The results of the hot plate pain test on the soles of SD rats within 72 hours after administration of the pharmaceutical compositions of Example 68, Comparative Example 7, and Comparative Example 8 are shown in Figure 7. The smaller the vertical coordinate data, the more obvious the pain and the lower the efficacy. At the same time, about 0.5 mL of blood samples from SD rats were collected at the same time points, i.e., before surgical administration (0 h) and 0.5, 2, 4, 8, 12, 24, 48, and 72 hours after administration, and placed in EDTA-2K+ anticoagulant blood collection tubes. The whole blood was centrifuged at 8000 rpm for 5 min to collect plasma, and then the drug concentration in the plasma samples was detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). The blood drug concentration data of the SD rats after administration of the pharmaceutical compositions of Example 68, Comparative Examples 7, and 8 are shown in Table 7.

[0147] As can be seen from Figure 7, within 24 hours after surgery, the analgesic effect of the pharmaceutical composition of Example 68 was superior to that of Comparative Example 7. Furthermore, as time progressed, the analgesic effect of the pharmaceutical composition of Example 68 was significantly superior to that of Comparative Example 7 from 24 hours to 72 hours after surgery, maintaining a high pain threshold. This indicates that compared with Comparative Example 7, Example 68 of the present application has a more prolonged analgesic effect on SD rats after surgery. This indicates that the pharmaceutical composition of the present application is superior to the marketed sustained-release (injection) formulation of anti-inflammatory drugs, particularly in terms of analgesia from 24 hours to 72 hours after surgery.

[0148] In addition, the analgesic effect of the pharmaceutical composition of Example 68 is significantly better than that of Comparative Example 8, and the long-term analgesia is also significantly better than that of Comparative Example 8, indicating that the pharmaceutical composition of the present application is superior to the oral administration sustained-release dosage form that has been marketed when administered by injection.

[0149] Table 7: Blood drug concentration data of SD rats after administration of the pharmaceutical compositions of Example 68, Comparative Examples 7 and 8

[0150] Among them, C max represents the peak concentration of the drug, T 1 / 2 Represents the half-life of the drug.

[0151] As can be seen from Table 7, the pharmaceutical composition of the present application has a higher peak concentration of the drug and a longer half-life compared with the injectable or oral sustained-release dosage forms already on the market, indicating that Example 68 of the present application has a good analgesic effect in the early postoperative period and a longer-lasting efficacy.

[0152] 4. Skin healing test

[0153] The skin healing effects of the pharmaceutical compositions of Example 14, Comparative Example 5 (Zynrelef), and Comparative Example 4 (the release modifier is castor oil) were tested. The specific process is as follows:

[0154] In the analgesic effect test, on the 16th day after administration, wound tissue sections of Bama pigs after administration of the pharmaceutical compositions of Example 14, Comparative Example 4, and Comparative Example 5 were taken, and the wound tissues were observed after hematoxylin-eosin staining (HE staining). The wound tissue sections of Bama pigs after administration of the pharmaceutical compositions of Example 14, Comparative Example 5, and Comparative Example 4 are shown in Figures 8, 9, and 10, respectively.

[0155] As can be seen from Figure 8, 16 days after administration of the pharmaceutical composition of Example 14, two deep vertical wounds were observed from the epidermis to the subcutaneous fat tissue, both of which were closed. The wound surface was covered by the epidermis, with one epidermal cell layer increasing to 10-12 layers and the other 5-7 layers of epidermal cells. A small amount of scab remained on the epidermal surface. The wound in the dermis showed vertical linear fibrous tissue proliferation, with more fibroblasts, moderate collagen fiber formation, a small amount of myxoid matrix deposition, and no obvious capillary proliferation (1-3 blood vessel sections / HPF). A small amount of red blood cell exudate, no obvious lymphocyte and tissue cell infiltration (1-4 / HPF), and no obvious neutrophil and eosinophil infiltration. Fiber hyperplasia in the subcutaneous fat tissue, a small amount of fat tissue necrosis and dissolution, formed a granuloma structure, and small focal dense lymphocyte infiltration. No foreign matter was found in the wound.

[0156] As can be seen from Figure 9, 16 days after administration of the pharmaceutical composition of Comparative Example 5, two deep vertical wounds were seen from the epidermis to the subcutaneous fat tissue, both of which were closed; the wound surface was covered by the epidermis, the epidermal cell layer increased to 10-12 layers, and a small amount of scab remained on the epidermis; the wound in the dermis showed vertical linear fibrous tissue hyperplasia, still with a large number of fibroblasts, moderate collagen fiber formation, a small amount of myxoid matrix deposition, mild capillary hyperplasia (5-8 blood vessel sections / HPF), a small amount of red blood cell exudation, and no obvious infiltration of lymphocytes and tissue cells (2-5 / HPF). No obvious infiltration of neutrophils and eosinophils was seen. Fiber hyperplasia in the subcutaneous fat tissue, a small amount of necrosis and dissolution of fat tissue, forming a granuloma structure, and no obvious lymphocyte infiltration; no foreign matter was seen in the wound.

[0157] As can be seen from Figure 10, after 16 days of administration of the pharmaceutical composition of Comparative Example 4, a wound was seen from the epidermis to the subcutaneous fat tissue, which was obliquely located in the dermis and had closed. The wound surface was covered by the epidermis, and the epidermal cell layer increased to 8-10 layers. A small amount of scab was left on the epidermal surface, and neutrophils and necrotic material were seen in the scab. Vertical linear fibrous tissue hyperplasia was seen in the dermal wound, and more fibroblasts were still seen. Moderate collagen fiber formation was observed, and the hyperplasia width was greater than that of Group C. A small amount of myxoid matrix was deposited, and mild capillary hyperplasia (5-8 blood vessel sections / HPF) was observed. A small amount of red blood cell exudation was observed, and lymphocytes and tissue cell infiltration were less (2-9 / HPF). No neutrophil and eosinophil infiltration was seen. The hair follicles around the wound were deformed and distorted due to fibrous hyperplasia. The subcutaneous adipose tissue showed extensive fibrosis, multifocal dense lymphocytic infiltration, scattered small lymphocyte infiltration (11-15 cells / HPF), and occasional eosinophil infiltration, but no neutrophil infiltration. No foreign body was found in the wound.

[0158] As can be seen from the HE results of the postoperative sections of the Bama pigs described above, the pharmaceutical composition of Example 14 of the present application has excellent skin healing performance. In terms of skin healing, it has a superior effect than the marketed drug Zynrelef in Comparative Example 5 and the other non-phospholipid release modifiers in Comparative Example 4. Its angiogenesis and inflammation-related pathological observations are also better than those in Comparative Examples 5 and 4. This shows that the use of phospholipid compounds as release modifiers in this application can achieve excellent results in promoting the healing and repair of skin wounds.

[0159] In addition, the pharmaceutical compositions of other embodiments of the present application also shorten the time to peak blood drug concentration, accelerate the onset of postoperative analgesia, provide good analgesic effect in the early postoperative period, and enable long-term drug release. Furthermore, they exhibit good stability and promote skin healing.

[0160] In summary, the present application adopts phospholipid compounds as release regulators to increase the initial release blood concentration of local anesthetics and non-steroidal anti-inflammatory drugs in the body, achieve better analgesic effect in the early postoperative period, enhance the analgesic efficacy in the early postoperative period, reduce the pain of patients in the early postoperative period and maintain long-lasting release, and at the same time, also has the effect of promoting skin wound healing and repair. In addition, the present application adopts a specific type of solubilizer so that the drug has good stability and is not easy to precipitate. The addition of the release regulator phospholipid to the pharmaceutical composition of the present application can shorten the peak time of blood drug concentration and accelerate the time of postoperative analgesia. The technical effect is exactly the opposite of the conventional theoretical knowledge in this field and the technical enlightenment of the release regulator taught by the prior art that the drug release time of the main drug can be delayed. This is an unexpected discovery made by the inventor in the process of continuous experimental exploration.

[0161] The above embodiments are only used to illustrate the technical solutions of the present application and are not intended to limit the scope of protection of the present application. Although the present application has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present application may be modified or replaced by equivalents without departing from the essence and scope of the technical solutions of the present application.

Claims

1. A pharmaceutical composition, characterized in that, Comprising a drug, a delivery carrier, and a release regulator; The drug is selected from at least one of local anesthetics and non-steroidal anti-inflammatory drugs; The release regulator is selected from phospholipid compounds; The delivery carrier is selected from saccharides and their esters.

2. The pharmaceutical composition according to claim 1, wherein When the drug contains a local anesthetic, the pharmaceutical composition further contains a solubilizer; preferably, the solubilizer is selected from at least one of menthol, camphor, borneol, linalool, and eucalyptol.

3. The pharmaceutical composition according to claim 1, wherein The local anesthetic is selected from amide anesthetics; preferably, the amide anesthetic is selected from at least one of bupivacaine, ropivacaine, their pharmaceutically acceptable salts, and stereoisomers; the non-steroidal anti-inflammatory drug is selected from at least one of meloxicam and celecoxib, their pharmaceutically acceptable salts, and stereoisomers.

4. The pharmaceutical composition according to claim 1, wherein The delivery carrier is selected from at least one of sucrose, chitosan, sucrose acetate isobutyrate, sucrose octaacetate, and sucrose monoacetate monoisobutyrate.

5. The pharmaceutical composition according to claim 1, wherein The phospholipid compound is selected from at least one of natural phospholipids and synthetic phospholipids; preferably, the natural phospholipid is selected from at least one of soybean phosphatidylcholine, egg yolk phospholipid, rapeseed phospholipid, and sunflower phospholipid; the synthetic phospholipid is selected from at least one of dilauroyl phosphatidylcholine, dioleoyl phosphatidylcholine, palmitoyl oleoyl phosphatidylcholine, distearoyl phosphatidylcholine, dipalmitoyl phosphatidylglycerol, and distearoyl phosphatidylglycerol.

6. The pharmaceutical composition according to any one of claims 1-5, characterized in that, After the pharmaceutical composition is administered to an animal, when the drug contains a local anesthetic, the peak time of the blood drug concentration of the local anesthetic is 0.1 h - 8 h; when the drug is selected from non-steroidal anti-inflammatory drugs, the peak time of its blood drug concentration is 1 h - 28 h.

7. The pharmaceutical composition according to claim 1, wherein By weight, the pharmaceutical composition comprises 0.01 - 20 parts of the drug, 30 - 80 parts of the delivery carrier, and 0.05 - 20 parts of the release regulator.

8. The pharmaceutical composition according to claim 2, characterized in that, When the drug contains a local anesthetic, by weight, the pharmaceutical composition comprises 0.01 - 20 parts of the drug, 30 - 80 parts of the delivery carrier, more than 0 and less than or equal to 10 parts of the solubilizer, and 0.05 - 20 parts of the release regulator.

9. The pharmaceutical composition according to any one of claims 1-5, characterized in that, The pharmaceutical composition further comprises a solvent; or, the pharmaceutical composition further comprises a solvent and an antioxidant.

10. The pharmaceutical composition according to claim 9, wherein By weight, the pharmaceutical composition comprises 0.01 - 20 parts of the drug, 30 - 80 parts of the delivery carrier, 0.05 - 20 parts of the release regulator, more than 0 and less than or equal to 70 parts of the solvent, and 0 - 5 parts of the antioxidant.

11. The pharmaceutical composition according to claim 10, wherein When the drug contains a local anesthetic, by weight, the pharmaceutical composition comprises 0.01 - 20 parts of the drug, 30 - 80 parts of the delivery carrier, more than 0 and less than or equal to 10 parts of the solubilizer, 0.05 - 20 parts of the release regulator, more than 0 and less than or equal to 70 parts of the solvent, and 0 - 5 parts of the antioxidant; when the drug is selected from non-steroidal anti-inflammatory drugs, by weight, the pharmaceutical composition comprises 0.1 - 20 parts of the drug, 30 - 80 parts of the delivery carrier, 0 - 10 parts of the solubilizer, 0.05 - 20 parts of the release regulator, more than 0 and less than or equal to 70 parts of the solvent, and 0 - 5 parts of the antioxidant.

12. A method for preparing the pharmaceutical composition according to any one of claims 1-11, characterized in that, Including the following steps: Mixing the raw material components to obtain the pharmaceutical composition.

13. A pharmaceutical preparation, characterized in that, Including the pharmaceutical composition according to any one of claims 1 - 11.

Images