Slow-release analgesic pharmaceutical composition as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a sustained-release analgesic pharmaceutical composition as well as a preparation method and application thereof. The pharmaceutical composition comprises a drug, a delivery carrier and a release regulator, the medicine 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 esters thereof. According to the invention, the phospholipid compound is adopted as the release regulator, and the phospholipid compound and the delivery carrier act together to increase the initial release blood concentration of the drug in vivo, shorten the peak time of the blood concentration, enhance the analgesic drug effect at the initial stage of the operation, maintain the long-acting release of the drug, effectively relieve the postoperative pain, reduce the administration frequency, and meanwhile, improve the bioavailability of the drug. The effects of promoting skin wound healing and repairing are also achieved; a specific type of solubilizer is adopted, so that the medicine has good stability and is not easy to separate out; in addition, the pharmaceutical composition disclosed by the invention can be directly administrated through a wound and is convenient to use.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates 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 of opioid analgesics, non-steroidal anti-inflammatory drugs, and local anesthetics are mainly used for postoperative analgesia clinically. Among them, local anesthetics such as bupivacaine hydrochloride injection and ropivacaine hydrochloride injection have a short drug action time, and the analgesic effect of a single dose is only 6 - 8 hours, which cannot meet the treatment cycle of postoperative pain and is difficult to relieve the pain of patients during postoperative treatment for a long time. At the same time, there is no sustained-release long-acting dosage form for anti-inflammatory drugs yet. For example, Anjeso injection (US11253478B2) is a daily dosage form, and it is difficult to meet the demand for long-term release of multi-day drug efficacy. Therefore, the commonly used opioid drugs clinically or opioid drugs administered continuously with an analgesic pump not only have poor clinical compliance but also bring many side effects, affecting the prognosis of patients.

[0003] To solve the above problems, the foreign marketed drug Posimir (publication number CN101035562A) uses sucrose acetate isobutyrate as a sustained-release carrier and benzyl alcohol as a solvent. The concentration of bupivacaine is 132 mg / mL, and the dosage of benzyl alcohol is about 22% w / w. Since benzyl alcohol has certain neurotoxicity, a large dosage may pose safety problems; at the same time, the drug efficacy is insufficient and there are more adverse reactions at the wound. The foreign marketed drug Zynrelef (publication number CN115025099A) uses polyorthoester polymer as a sustained-release carrier for compound bupivacaine and meloxicam. After being applied to the administration site, the polyorthoester itself slowly degrades to achieve a sustained-release effect. During the prescription development, precipitation of bupivacaine was observed, and subsequently, maleic acid was added to the prescription to prevent the precipitation of raw materials. However, maleic acid is acidic and will cause adverse reactions at the wound, affecting wound healing. At the same time, its drug release rate is slow, and the peak time is long, and it cannot exert the required analgesic efficacy when the pain of patients is intense in the initial stage after surgery.

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

[0005] The present invention aims to solve one or more of the above technical problems existing in the prior art, and at least provides a beneficial choice or creation condition. Specifically, the present invention provides a sustained-release analgesic pharmaceutical composition, which can increase the initial release concentration of the drug in the body, enhance the initial analgesic efficacy and maintain long-term release, and can promote good wound healing.

[0006] Inventive concept of the present invention: The sustained-release analgesic pharmaceutical composition of the present invention comprises 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.

[0007] The present invention uses phospholipid compounds as release regulators, and their combined action with the delivery carrier can increase the initial release blood drug concentration of the drug in the body, enhance the initial analgesic efficacy and maintain long-term release, which is exactly the opposite of the prior art that delays the drug efficacy release time of the main drug and has a relatively long drug release peak time; moreover, the pharmaceutical composition of the present invention can promote good wound healing effects.

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

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

[0010] the drug is selected from at least one of local anesthetics and non-steroidal anti-inflammatory drugs;

[0011] the release regulator is selected from phospholipid compounds;

[0012] the delivery carrier is selected from saccharides and their esters.

[0013] Specifically, the inventors added phospholipids to the pharmaceutical composition to explore their effects on skin wound healing and repair. Unexpectedly, under the sustained-release system of the present invention, adding phospholipids can increase the initial release blood drug concentration of the drug in the body without obvious burst release, enhance the initial analgesic efficacy, well relieve the pain of patients in the early postoperative period and maintain long-term release of the drug, producing unexpected effects. Generally, many drugs use phospholipids as excipients to delay release, such as the in-situ gel system with the publication number CN103705442A. The above beneficial effects of the present invention are completely opposite to the technical effects of only delaying the drug efficacy release time of the main drug after adding a release regulator in the prior art.

[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, borneol, linalool, and eucalyptol.

[0016] Specifically, a solubilizer is added to the pharmaceutical composition of the present invention, which can increase the solubility of the main drug. The product prepared by the combined action of the solubilizer and other components will not precipitate the drug during the preparation process and long-term low-temperature storage, and has good stability. At the same time, by selecting a specific type of solubilizer, the adverse effects of organic acids or inorganic acids on the wound can be avoided, the pH of the wound will not be reduced, and the wound inflammation and healing will not be adversely affected.

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

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

[0019] Preferably, the non-steroidal anti-inflammatory drug is selected from at least one of meloxicam, celecoxib, pharmaceutically acceptable salts thereof, 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 soy phosphatidylcholine (SPC), egg yolk phospholipid (EPC), rapeseed phospholipid, and sunflower phospholipid.

[0023] Preferably, the synthetic phospholipid is selected from at least one of dielaidoyl phosphatidylcholine (DEPC), dioleoyl phosphatidylcholine (DOPC), palmitoyl oleoyl phosphatidylcholine (POPC), distearoyl phosphatidylcholine (DSPC), dipalmitoyl phosphatidylglycerol (DPPG), and distearoyl phosphatidylglycerol (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 peak time of the blood drug concentration of the local anesthetic is 0.1-8 h; when the drug is selected from non-steroidal anti-inflammatory drugs, the peak time of its blood drug concentration is 1-28 h.

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

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

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

[0030] Preferably, after injection of the pharmaceutical composition to beagle dogs, when the drug contains a local anesthetic, the peak time of the blood drug concentration of the local anesthetic is 1 - 4 h; when the drug is selected from non-steroidal anti-inflammatory drugs, the peak time of its blood drug concentration is 4 - 12 h.

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

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

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

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

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

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

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

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

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

[0040] Even more preferably, when the drug is selected from non-steroidal anti-inflammatory drugs, by weight, the sustained-release analgesic pharmaceutical composition comprises 1-5 parts of the drug, 55-68 parts of the delivery carrier, 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, by weight, the sustained-release analgesic pharmaceutical composition comprises 0.01-15 parts of the local anesthetic, 0.01-5 parts of the non-steroidal anti-inflammatory 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.

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

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

[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, by weight, the sustained-release analgesic pharmaceutical composition comprises 0.01-20 parts of the drug, 30-80 parts of a delivery carrier, more than 0 and less than or equal to 10 parts of a solubilizer, 0.05-20 parts of a release regulator, more than 0 and less than or equal to 70 parts of a solvent, and 0-5 parts of an antioxidant; when the drug is selected from non-steroidal anti-inflammatory drugs, by weight, the sustained-release analgesic pharmaceutical composition comprises 0.1-20 parts of the drug, 30-80 parts of a delivery carrier, 0-10 parts of a solubilizer, 0.05-20 parts of a release regulator, more than 0 and less than or equal to 70 parts of a solvent, and 0-5 parts of an antioxidant;

[0046] More preferably, when the drug contains a local anesthetic, by weight, the sustained-release analgesic pharmaceutical composition comprises 1-8 parts of the drug, 50-70 parts of a delivery carrier, more 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, by weight, the sustained-release analgesic pharmaceutical composition comprises 0.5-10 parts of the drug, 50-70 parts of a delivery carrier, 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] Even more preferably, when the drug contains a local anesthetic, by weight, the sustained-release analgesic pharmaceutical composition comprises 2-6 parts of the drug, 55-68 parts of a delivery carrier, more 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 parts of an antioxidant; when the drug is selected from non-steroidal anti-inflammatory drugs, by weight, the sustained-release analgesic pharmaceutical composition comprises 1-5 parts of the drug, 55-68 parts of a delivery carrier, 0-3 parts of a solubilizer, 0.05-5 parts of a release regulator, 20-40 parts of a solvent, and 0-1 parts of an antioxidant.

[0048] Preferably, when the drug is selected from local anesthetics and non-steroidal anti-inflammatory drugs, by weight, the sustained-release analgesic pharmaceutical composition comprises 0.01-15 parts of a local anesthetic, 0.01-5 parts of a non-steroidal anti-inflammatory drug, 30-80 parts of a delivery carrier, more than 0 and less than or equal to 10 parts of a solubilizer, 0.05-20 parts of a release regulator, more than 0 and less than or equal to 70 parts of a solvent, and 0-5 parts of an antioxidant.

[0049] Further preferably, when the drug is selected from local anesthetics and non-steroidal anti-inflammatory drugs, by weight, the sustained-release analgesic pharmaceutical composition comprises 1-5 parts of local anesthetic, 0.01-3 parts of non-steroidal anti-inflammatory drug, 50-70 parts of delivery carrier, more than 0 and less than or equal to 5 parts of solubilizer, 0.05-10 parts of release regulator, 20-60 parts of solvent, and 0-2 parts of antioxidant.

[0050] Even more preferably, when the drug is selected from local anesthetics and non-steroidal anti-inflammatory drugs, by weight, the sustained-release analgesic pharmaceutical composition comprises 2-4 parts of local anesthetic, 0.01-2 parts of non-steroidal anti-inflammatory drug, 55-68 parts of delivery carrier, more than 0 and less than or equal to 3 parts of solubilizer, 0.05-5 parts of release regulator, 20-40 parts of solvent, and 0-1 part of antioxidant.

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

[0052] Preferably, the alcohols include at least one of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ethylene glycol, propylene glycol, glycerol, benzyl alcohol, phenethyl 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, alpha-lipoic acid, thioglycerol, dibutylhydroxytoluene, and butylated hydroxyanisole.

[0054] The second aspect of the present invention provides a preparation method of the sustained-release analgesic pharmaceutical composition according to the first aspect of the present invention.

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

[0056] Mix each raw material component to obtain the sustained-release analgesic pharmaceutical composition.

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

[0058] First, mix the local anesthetic and / or non-steroidal anti-inflammatory drug, release regulator, solubilizer, and solvent at a certain temperature, and then add the delivery carrier and antioxidant for mixing to obtain the sustained-release analgesic pharmaceutical composition.

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

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

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

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

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

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

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

[0066] Compared with the prior art, the beneficial effects of the technical solution provided by the present invention are as follows:

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

[0068] (2) Specific types of solubilizers are added to the pharmaceutical composition of the present invention, enabling the drug to have good stability, not prone to precipitation, suitable for storage at normal and low temperatures, remaining a transparent and uniform solution after being stored at room temperature for 24 hours without any precipitation; moreover, it can avoid the adverse effects of organic or inorganic acids on the wound, will not reduce the pH of the wound, and will not have an adverse impact on wound inflammation and healing.

[0069] (3) The pharmaceutical composition of the present invention can overcome the related drawbacks of treatment means such as opioid drugs and analgesic pumps, can effectively relieve the postoperative pain of patients, reduce the dosing frequency, and simplify the analgesic treatment means.

[0070] (4) The pharmaceutical composition of the present invention can be directly administered through the postoperative wound, which is convenient to use, forms a drug reservoir at the wound, slowly releases the drug, reduces the discomfort brought by the patient using an analgesic pump or an indwelling venous catheter, and can improve the compliance of the patient. Description of the Drawings

[0071] Figure 1 It is a diagram showing the precipitation situation of the pharmaceutical compositions of Example 14 and Comparative Examples 1 - 3 of the present invention;

[0072] Figure 2 It is a graph showing the plasma concentration curves of bupivacaine in SD rats after administration of the pharmaceutical compositions of Examples 13 - 15 and Comparative Example 4 of the present invention;

[0073] Figure 3 It is a graph showing the plasma concentration curves of meloxicam in SD rats after administration of the pharmaceutical compositions of Examples 13 - 15 and Comparative Example 4 of the present invention;

[0074] Figure 4 It is a schematic diagram showing the incision position of the postoperative pain test of Bama pigs;

[0075] Figure 5 It is a graph showing the results of the fiber filament stimulation test of Bama pigs after administration of the pharmaceutical compositions of Example 14, Example 61, and Comparative Examples 4 - 5 of the present invention;

[0076] Figure 6 It is a graph showing the results of the fiber filament stimulation test of SD rats after administration of the pharmaceutical compositions of Example 14 and Comparative Example 4 of the present invention;

[0077] Figure 7 It is the result of the hot plate pain test on the soles of SD rats after administration of the pharmaceutical compositions of Example 68, Comparative Example 7, and Comparative Example 8 of the present invention;

[0078] Figure 8 It is a histological section diagram of the wound of Bama pigs after administration of the pharmaceutical composition of Example 14 of the present invention;

[0079] Figure 9Wound section tissue diagram of Bama pigs after administration of drug composition Zynrelef in Comparative Example 5 of the present invention;

[0080] Figure 10 Wound section tissue diagram of Bama pigs after administration of the drug composition in Comparative Example 4 of the present invention. Detailed implementation manners

[0081] In order to make those skilled in the art more clearly understand the technical solutions described in the present invention, the following examples are listed for illustration. It should be noted that the following examples do not limit the scope of protection required by the present invention.

[0082] The raw materials, reagents or devices used in the following examples can be obtained from conventional commercial channels or can be obtained by existing known methods without special instructions.

[0083] Examples 1 - 33

[0084] The sustained-release analgesic drug compositions of Examples 1 - 33, and the raw material components and dosages (parts by weight) are shown in Table 1.

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

[0086]

[0087]

[0088]

[0089] The preparation method of the sustained-release analgesic drug compositions of Examples 1 - 33 includes the following steps:

[0090] Under the temperature condition of 60°C, add the local anesthetic, non-steroidal anti-inflammatory drug, release regulator, and solubilizer into the solvent and stir to dissolve, then successively add the delivery carrier sucrose acetate isobutyrate and antioxidant, and stir until a transparent and homogeneous solution is formed to obtain the sustained-release analgesic drug composition.

[0091] Examples 34 - 43

[0092] The sustained-release analgesic drug compositions of Examples 34 - 43, and the raw material components and dosages (parts by weight) are shown in Table 2.

[0093] Table 2: Raw material components and dosages (parts by weight) of the sustained-release analgesic drug compositions of Examples 34 - 43

[0094]

[0095]

[0096] The preparation method of the sustained-release analgesic pharmaceutical composition in Examples 34 - 43 is the same as that in Examples 1 - 33.

[0097] Examples 44 - 53

[0098] For the sustained-release analgesic pharmaceutical composition in Examples 44 - 53, the raw material components and their dosages (parts by weight) are shown in Table 3.

[0099] Table 3: Raw material components and dosages (parts by weight) of the sustained-release analgesic pharmaceutical composition in Examples 44 - 53

[0100]

[0101] The preparation method of the sustained-release analgesic pharmaceutical composition in Examples 44 - 53 includes the following steps:

[0102] Add the release regulator to the solvent (dimethyl sulfoxide or benzyl alcohol), stir and dissolve at 50 °C, and successively add the delivery carriers sucrose acetate isobutyrate and triacetin, and the antioxidant, stirring while adding until a transparent and homogeneous solution is formed; then raise the temperature to 60 °C, add the non-steroidal anti-inflammatory drug meloxicam and the local anesthetic ropivacaine to the solution and stir until a transparent and homogeneous solution is formed to obtain the sustained-release analgesic pharmaceutical composition.

[0103] Examples 54 - 62

[0104] For the sustained-release analgesic pharmaceutical composition in Examples 54 - 62, the raw material components and their dosages (parts by weight) are shown in Table 4.

[0105] Table 4: Raw material components and dosages (parts by weight) of the sustained-release analgesic pharmaceutical composition in Examples 54 - 62

[0106]

[0107] The preparation method of the sustained-release analgesic pharmaceutical composition in Examples 54 - 62 includes the following steps:

[0108] Under the temperature condition of 60 °C, add the local anesthetic bupivacaine, the release regulator, and the solubilizer to the solvent and stir to dissolve, then successively add the delivery carrier sucrose acetate isobutyrate and the antioxidant, and stir until a transparent and homogeneous solution is formed to obtain the sustained-release analgesic pharmaceutical composition.

[0109] Examples 63 - 70

[0110] For the sustained-release analgesic pharmaceutical composition in Examples 63 - 70, the raw material components and their dosages (parts by weight) are shown in Table 5.

[0111] Table 5: Raw material components and dosages (parts by weight) of the sustained-release analgesic pharmaceutical composition in Examples 63 - 70

[0112]

[0113] Preparation method of drug composition for sustained-release analgesia in Examples 63 - 70, comprising the following steps:

[0114] Under the temperature condition of 60°C, add the non-steroidal anti-inflammatory drug meloxicam and the release regulator into the solvent and stir to dissolve, then successively add the delivery carrier sucrose acetate isobutyrate and the antioxidant, and stir until a transparent and homogeneous solution is formed to obtain the drug composition for sustained-release analgesia.

[0115] Comparative Example 1

[0116] The difference between Comparative Example 1 and Example 14 is only that Comparative Example 1 does not contain the solubilizer menthol, and the dosage of the solvent triacetin is 25.77 parts, and the others are the same as Example 14.

[0117] Comparative Example 2

[0118] The difference between Comparative Example 2 and Example 14 is only that Comparative Example 2 uses an equal amount of the solubilizer arginine to replace the menthol in Example 14, and the others are the same as Example 14.

[0119] Comparative Example 3

[0120] The difference between Comparative Example 3 and Example 14 is only that Comparative Example 3 uses an equal amount of the solubilizer maleic acid to replace the menthol in Example 14, and the others are the same as Example 14.

[0121] Comparative Example 4

[0122] The difference between Comparative Example 4 and Example 14 is only that Comparative Example 4 uses an equal amount of the release regulator castor oil to replace the SPC in Example 14, and the others are the same as Example 14.

[0123] Comparative Example 5

[0124] Comparative Example 5 is the foreign marketed drug Zynrelef.

[0125] Comparative Example 6

[0126] The difference between Comparative Example 6 and Example 68 is only that Comparative Example 6 uses an equal amount of the release regulator sesame oil to replace the SPC in Example 68, and the others are the same as Example 68.

[0127] Comparative Example 7

[0128] Comparative Example 7 is the domestic marketed drug Meixi (Meloxicam Injection, Qilu).

[0129] Comparative Example 8

[0130] Comparative Example 8 is the domestic marketed drug Mobic (meloxicam tablets, Shanghai Boehringer Ingelheim Pharmaceuticals Co., Ltd.).

[0131] Performance Test

[0132] 1. Observation of drug precipitation

[0133] The drug 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 drug compositions was observed. The results are as Figure 1 shown, Figure 1 where A in Figure 1 is the precipitation diagram of Example 14, and B, C, and D in

[0134] are the precipitation diagrams of Comparative Examples 1-3, respectively. Figure 1 It can be seen that after the drug composition of Example 14 added with the solubilizer menthol was stored at room temperature of 25°C for 24 hours, it was still a transparent and homogeneous solution, and no precipitation occurred. However, for the drug compositions of Comparative Example 1 (without solubilizer), Comparative Example 2 (added with solubilizer arginine), and Comparative Example 3 (added with solubilizer maleic acid), after being stored at room temperature of 25°C for 24 hours, the originally transparent and homogeneous solution became turbid, and precipitation of the local anesthetic bupivacaine occurred. It shows that adding the solubilizer menthol to the drug composition of the present invention can increase the solubility of the main drug, so that the product will not precipitate the drug during the preparation process and long-term storage at room temperature, and has good stability.

[0135] 2. Performance test for drug concentration peak

[0136] (1) In order to determine the drug concentration peak time in the drug composition of the present invention, that is, the onset time of postoperative analgesia, a pharmacokinetic study of the drug compositions of Examples 13-15 and Comparative Example 4 in rats was carried out. The specific process is as follows:

[0137] SD rats (male) weighing about 200-250 g were selected. The drug compositions of Examples 13-15 and Comparative Example 4 were used to administer drugs subcutaneously to the back of SD rats, and the administration dose was 30.0 mg / Kg; about 0.5 mL of blood samples of SD rats were collected at 0.25, 0.5, 1, 2, 3, 6, 12, 24, 48, 72, and 96 hours after drug administration, placed in blood collection tubes anticoagulated with EDTA-2K+, and the whole blood was centrifuged at 8000 rpm for 5 min to collect plasma, and then the drug concentration in the plasma sample was detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS).

[0138] The blood drug concentration curves of the local anesthetic bupivacaine and the non-steroidal anti-inflammatory drug meloxicam in the drug compositions of Examples 13-15 and Comparative Example 4 after drug administration are respectively as Figure 2 ,Figure 3 as shown

[0139] It can be seen from Figure 2 and Figure 3 that after adding the release regulator (SPC) to the pharmaceutical compositions of Examples 13 - 15 of the present invention, the peak time of the blood drug concentration of bupivacaine in SD rats is 1 hour, and the peak time of the blood drug concentration of meloxicam is 6 hours; while after adding the release regulator castor oil to the pharmaceutical composition of Comparative Example 4, the peak time of the blood drug concentration of bupivacaine in SD rats is 2 hours, and the peak time of the blood drug concentration of meloxicam is 24 hours. This shows that after adding phospholipid compounds as release regulators to the pharmaceutical compositions of the present invention, through their combined action with other components, the peak time of the blood drug concentration of the drug can be shortened, the onset time of postoperative analgesia can be accelerated, and the pharmaceutical compositions of Examples 13 - 15 all show a sustained release effect, with stable and long-lasting release, which can significantly relieve the pain and discomfort of patients in the early postoperative period and reduce the dosing frequency. The technical effect that adding phospholipid compounds as release regulators to the pharmaceutical compositions of the present invention can shorten the peak time of the blood drug concentration and accelerate the onset time of postoperative analgesia is exactly contrary to the conventional theoretical knowledge in this field and the revelation in the prior art that release regulators can delay the pharmacodynamic release time of the main drug.

[0140] (2) Select SD rats (male) weighing about 200 - 250 g, and subcutaneously administer the pharmaceutical compositions of Example 68 and Comparative Example 6 to the SD rats on the back respectively, with the dosing dose being 30.0 mg / Kg; collect about 0.5 mL of blood samples from the SD rats at 0.5, 1, 2, 4, 8, 12, 24, 48, 72, and 96 hours after dosing, place them in blood collection tubes anticoagulated with EDTA - 2K+, collect the plasma after centrifuging the whole blood at 8000 rpm for 5 min, and then detect the drug concentration in the plasma samples by liquid chromatography - tandem mass spectrometry (LC - MS / MS). The blood drug concentration data of meloxicam in SD rats after administering the pharmaceutical compositions of Example 68 and Comparative Example 6 of the present invention are shown in Table 6.

[0141] Table 6: Blood drug concentration data of meloxicam in SD rats after administering the pharmaceutical compositions of Example 68 and Comparative Example 6

[0142]

[0143]

[0144] Among them, C max represents the peak concentration of the drug, T max represents the peak time of the drug action, and T 1 / 2 represents the drug half - life.

[0145] As can be seen from Table 6, after adding a release regulator (SPC) to the pharmaceutical composition of Example 68 of the present invention, the time to peak plasma concentration of meloxicam in SD rats was 4 hours; while the time to peak plasma concentration of meloxicam in the SD rats of Comparative Example 6 was 8 hours. This shows that after adding a phospholipid compound as a release regulator to the pharmaceutical composition of the present invention, its combined action with other components can shorten the time to peak plasma concentration of the drug and accelerate the onset time of postoperative analgesia. Moreover, the pharmaceutical composition of Example 68 showed a sustained release effect (as can be seen from subsequent Table 7, compared with Comparative Examples 7 and 8, the release of Example 68 was more persistent), which can significantly relieve the pain and discomfort of patients for a longer time after surgery and reduce the dosing frequency.

[0146] 3. Analgesic effect test

[0147] (1) The analgesic effects of the pharmaceutical compositions of Example 14, Example 61 and Comparative Example 4, Comparative Example 5 (Zynrelef) were tested using a postoperative pain model of Bama pigs. The specific process was as follows:

[0148] Select Bama mini-pigs weighing 8 - 12 Kg. After anesthesia with isoflurane, make an incision 7 cm long and 3 cm to the left of the spine at the lower back of each group of Bama pigs, with the depth reaching the fascia layer, and separate the skin and muscle layers on both sides; directly perfuse and administer drugs at the wound site of each group. Each Bama pig was given the pharmaceutical compositions of normal saline, Example 14, Example 61, Comparative Example 4, and Comparative Example 5 at 100 mg / Kg respectively, and then suture the wound; for each group of Bama pigs, before drug administration (0 h) and at 1, 3, 5, 7, 12, 24, 48, 72, 96, 120, 144, and 168 hours after drug administration, use a Von Frey analgesimeter for filament stimulation test. Use 9 kinds of Von Frey filaments with different intensities (equivalent to 1.4, 2, 4, 6, 8, 10, 15, 26, and 60 g respectively), and use the "up-and-down" method to detect and record the test results and calculate the pain threshold. The schematic diagram of the incision position for the postoperative pain test of Bama pigs is as Figure 4 shown, where H3\M1\R2 are the test points respectively, and spine line represents the dorsal midline of the Bama pig. The filament stimulation test results of the pharmaceutical compositions of Example 14, Example 61, Comparative Example 4, and Comparative Example 5 within 168 hours after drug administration are as Figure 5 shown. The smaller the ordinate data, the more obvious the pain and the lower the drug effect.

[0149] From Figure 5It can be seen that at 24 h after surgery, the analgesic effect of Zynrelef in Comparative Example 5 and the pharmaceutical composition in Comparative Example 4 began to weaken, and on the 1st - 3rd days after surgery, the analgesic effects of Comparative Examples 5 and 4 were significantly worse than those of the pharmaceutical composition of Example 14 of the present invention. This shows that the pharmaceutical composition of Example 14 of the present invention has a better and longer - lasting postoperative analgesic effect than the marketed drug Zynrelef.

[0150] When comparing the pharmaceutical composition of Example 14 with that of Example 61, the analgesic effects within 48 h after surgery were basically the same. From 72 h, the efficacy of Example 61 began to decline, while Example 14 still had efficacy, indicating that adding meloxicam to the prescription of the present invention will result in a longer - lasting postoperative analgesic effect.

[0151] (2) The analgesic effects of the pharmaceutical compositions of Example 14 and Comparative Example 4 were tested using a postoperative pain model in SD rats. The specific process was as follows:

[0152] SPF - level SD rats (5 - 6 weeks old, male) were selected. After anesthesia with isoflurane, a 1.0 - cm incision was made on the plantar surface, cutting through the muscle without affecting its origin, insertion, and attachment. After suturing, drugs were infiltrated and injected beside the incision. Each SD rat was given physiological saline, the pharmaceutical composition of Example 14, and the pharmaceutical composition of Comparative Example 4 at 30 mg / Kg respectively. Before surgery (0 h) and 0.5, 2, 4, 8, 12, 24, 48, and 72 hours after drug administration, Von Frey mechanical hyperalgesia tests were performed on the SD rats. Nine intensities of Von Frey filaments (equivalent to 1, 1.4, 2, 4, 6, 8, 10, 15, and 26 g respectively) were used, and the "up - and - down" method was adopted to detect and record the test results and calculate the pain threshold. The results of filament stimulation tests within 72 h after administration of the pharmaceutical compositions of Example 14 and Comparative Example 4 are as Figure 6 shown. The smaller the ordinate data, the more obvious the pain and the lower the drug efficacy.

[0153] As Figure 6 can be seen, at 0.5 h and 2.0 h after surgery, the analgesic effect of the pharmaceutical composition of Example 14 was significantly better than that of Comparative Example 4. As time extended, the analgesic effect from 4th - 48th h after surgery was also slightly better than that of Comparative Example 4. This shows that the pharmaceutical composition of Example 14 of the present invention has a better postoperative analgesic effect than that of Comparative Example 4, especially in the initial stage after surgery. And as time extends, the analgesic effect of the pharmaceutical composition of Example 14 is also better than that of Comparative Example 4 as a whole. It can be seen that the analgesic effect of the pharmaceutical composition of the present invention after adding the release - regulating phospholipid compound is significantly better than that after adding other release regulators such as castor oil, especially in the initial stage after surgery.

[0154] (3) The analgesic effects of the pharmaceutical compositions of Example 68 and Comparative Examples 7 and 8 were tested using a postoperative pain model in SD rats. The specific procedure was as follows:

[0155] SD rats (5 - 6 weeks old, male) of specific pathogen - free (SPF) grade were selected. After anesthesia with isoflurane, a 1.0 cm incision was made on the plantar surface, and after suturing, the drugs were administered by infiltration injection beside the incision. Each SD rat was given physiological saline, the pharmaceutical composition of Example 68, Comparative Example 7, and Comparative Example 8 at a dose of 30 mg / Kg respectively. Before surgery and drug administration (0 h) and 0.5, 2, 4, 8, 12, 24, 48, and 72 hours after drug administration, a hot - plate pain test for the plantar surface was conducted. The hot - plate instrument was turned on (temperature set at 56 °C). After the hot - plate temperature was constant, the surgical plantar surface of the experimental rat was placed on the hot - plate. Timing started when the rat's foot touched the hot - plate and ended when the rat lifted its foot for the first time. The tolerance time of the rat on the hot - plate (in seconds) was recorded. Each rat was tested 3 times, with an interval of no less than 30 seconds between each test. The cut - off time was set at 12 seconds. Rats that did not lift their feet after 12 seconds were considered insensitive to heat pain and were no longer tested. The average value of the 3 measurements was used as the test result at a specific time point.

[0156] The results of the hot - plate pain test on the plantar surface of SD rats within 72 hours after administration of the pharmaceutical compositions of Example 68, Comparative Example 7, and Comparative Example 8 are as Figure 7 shown. The smaller the ordinate data, the more obvious the pain and the lower the drug effect. At the same time, at the same time points, namely before surgery and drug administration (0 h) and 0.5, 2, 4, 8, 12, 24, 48, and 72 hours after drug administration, approximately 0.5 mL of blood samples were collected from SD rats and placed in blood collection tubes anticoagulated with EDTA - 2K+. After centrifugation of the whole blood at 8000 rpm for 5 minutes, the plasma was collected. Then, the drug concentration in the plasma samples was detected by liquid chromatography - tandem mass spectrometry (LC - MS / MS). The plasma drug concentration data of the pharmaceutical compositions of Example 68, Comparative Examples 7 and 8 in SD rats after administration are shown in Table 7.

[0157] It can be seen from Figure 7 the results that within 24 h after surgery, the analgesic effect of the pharmaceutical composition of Example 68 was better than that of Comparative Example 7. And as time extended, from 24 - 72 h after surgery, the analgesic effect of the pharmaceutical composition of Example 68 was significantly better than that of Comparative Example 7, and still had a relatively high pain threshold, indicating that compared with Comparative Example 7, the pharmaceutical composition of Example 68 had a longer - lasting analgesic effect on SD rats after surgery. It can be seen that the pharmaceutical composition of the present invention is superior to the marketed immediate - release dosage form (injection) of anti - inflammatory drugs, especially in terms of the analgesic effect from 24 - 72 h after surgery.

[0158] In addition, the analgesic effect of the pharmaceutical composition of Example 68 is also significantly better than that of Comparative Example 8, and the long-acting analgesic effect is also significantly better than that of Comparative Example 8, indicating that the injection administration method of the pharmaceutical composition of the present invention is superior to the marketed oral immediate-release dosage form.

[0159] Table 7: Plasma drug concentration data of the pharmaceutical compositions of Example 68, Comparative Example 7, and Comparative Example 8 in SD rats after administration

[0160] Example / Comparative Example Drug <![CDATA[C max > <![CDATA[T 1 / 2 > Example 68 Meloxicam 8312 31.0 Comparative Example 7 Moxi 10354 8.9 Comparative Example 8 Mobic (oral) 4191 11.7

[0161] Among them, C max represents the peak concentration of the drug, and T 1 / 2 represents the drug half-life.

[0162] As can be seen from Table 7, compared with the marketed injection or oral immediate-release dosage forms, the pharmaceutical composition of the present invention has a higher peak concentration of the drug and a longer half-life, indicating that Example 68 of the present invention has good analgesic effect and longer-lasting drug effect in the early postoperative period.

[0163] 4. Skin healing test

[0164] The skin healing effects of the pharmaceutical compositions of Example 14, Comparative Example 5 (Zynrelef), and Comparative Example 4 (the release regulator is castor oil) were tested. The specific process was as follows:

[0165] 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. After hematoxylin-eosin staining (HE staining), the wound tissues were observed. The wound sections of Bama pigs after administration of the pharmaceutical compositions of Example 14, Comparative Example 5, and Comparative Example 4 were respectively as Figure 8 , 9 , and shown in Figure 10.

[0166] As Figure 8 can be seen, 16 days after administration of the pharmaceutical composition of Example 14, from the epidermis to the subcutaneous adipose tissue, two deep vertical wounds were seen, and both were closed. The wound surface had been covered by the epidermis. In one place, the number of epidermal cell layers increased to 10 - 12 layers, and in the other place, the surface epidermal cells were 5 - 7 layers, with a small amount of scab remaining on the epidermal surface; in the dermis, vertical linear fibrous tissue hyperplasia was seen in the wound, and there were still many fibroblasts, moderate collagen fiber formation, a small amount of mucinous matrix deposition, and no obvious capillary hyperplasia (1 - 3 blood vessel cross-sections / HPF), a small amount of red blood cell exudation, and no obvious lymphocyte and histiocyte infiltration (1 - 4 cells / HPF), and no obvious neutrophil and eosinophil infiltration; in the subcutaneous adipose tissue, fibrous hyperplasia was seen, a small amount of adipose tissue necrosis and dissolution occurred, forming a granuloma structure, and focal dense lymphocyte infiltration; no foreign bodies were seen in the wound.

[0167] AsFigure 9 It can be seen that 16 days after administration of the pharmaceutical composition of Comparative Example 5, from the epidermis to the subcutaneous adipose tissue, two deep vertical wounds were observed and both were closed; the wound surface had been covered by the epidermis, and the number of epidermal cell layers increased to 10 - 12 layers, with a small amount of scab remaining on the epidermis; in the wound within the dermis, vertical linear fibrous tissue hyperplasia was observed, and there were still a relatively large number of fibroblasts, moderate collagen fiber formation, a small amount of mucoid matrix deposition, mild capillary hyperplasia (5 - 8 vascular cross-sections / HPF), a small amount of red blood cell exudation, and lymphocyte and histiocyte infiltration was not obvious (2 - 5 cells / HPF), and no obvious neutrophil and eosinophil infiltration was observed. In the subcutaneous adipose tissue, fibrous hyperplasia occurred, a small amount of adipose tissue necrosis and dissolution occurred, forming a granuloma structure, and lymphocyte infiltration was not obvious; no foreign body was observed in the wound.

[0168] From Figure 10 It can be seen that 16 days after administration of the pharmaceutical composition of Comparative Example 4, from the epidermis to the subcutaneous adipose tissue, one wound was observed, which was oblique within the dermis and had been closed. The wound surface had been covered by the epidermis, and the number of epidermal cell layers increased to 8 - 10 layers, with a small amount of scab remaining on the epidermal surface, and neutrophils and necrotic substances were observed in the scab. In the wound within the dermis, vertical linear fibrous tissue hyperplasia was observed, and there were still a relatively large number of fibroblasts, moderate collagen fiber formation, the hyperplasia width was greater than that of Group C, a small amount of mucoid matrix deposition, mild capillary hyperplasia (5 - 8 vascular cross-sections / HPF), a small amount of red blood cell exudation, less lymphocyte and histiocyte infiltration (2 - 9 cells / HPF), and no neutrophil and eosinophil infiltration was observed. The hair follicles around the wound were deformed and distorted due to fibrous hyperplasia. In the subcutaneous adipose tissue, there was more fibrous hyperplasia, multi-focal dense lymphocyte infiltration, scattered a small amount of lymphocyte infiltration (11 - 15 cells / HPF), individual eosinophil infiltration, and no neutrophil infiltration was observed. No foreign body was observed in the wound.

[0169] It can be seen from the HE results of the postoperative sections of the above Bama pigs that the pharmaceutical composition of Example 14 of the present invention has good performance in promoting skin healing. It has better effects than the marketed drug Zynrelef of Comparative Example 5 and other non-phospholipid release regulators of Comparative Example 4 in terms of skin healing, and its angiogenesis and inflammation-related pathological observations are also superior to those of Comparative Example 5 and Comparative Example 4. It shows that using phospholipid compounds as release regulators in the present invention can achieve good effects in promoting the healing and repair of skin wounds.

[0170] In addition, the pharmaceutical compositions of other examples of the present invention also have the effects of shortening the peak time of blood drug concentration, accelerating the onset time of postoperative analgesia, having good analgesic effects in the initial stage of postoperative period, and the drug can be released in a long-acting manner. At the same time, they have good stability and effects in promoting skin healing.

[0171] In summary, the present invention uses phospholipid compounds as release regulators, which can increase the initial released blood drug concentration of local anesthetics and non-steroidal anti-inflammatory drugs in the body, achieve a better analgesic effect in the early postoperative period, enhance the analgesic efficacy in the initial postoperative stage, relieve the pain of patients in the initial postoperative stage and maintain a long-term release. At the same time, it also has the effect of promoting skin wound healing and repair. In addition, the present invention uses a specific type of solubilizer, making the drug have good stability and not easily precipitating. The technical effect that the peak time of blood drug concentration can be shortened and the onset time of postoperative analgesia can be accelerated after adding the release regulator phospholipid to the pharmaceutical composition of the present invention is exactly opposite to the technical enlightenment taught by the conventional theoretical knowledge and the prior art in this field that the release regulator can delay the drug efficacy release time of the main drug, which is an accidental discovery by the inventor in the process of continuous experimental exploration.

[0172] The above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit the protection scope of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. A pharmaceutical composition, characterized in that, It includes 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, characterized in that, 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, characterized in that, 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 dierucoyl 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 - 8 h; when the drug is selected from non-steroidal anti-inflammatory drugs, the peak time of its blood drug concentration is 1 - 28 h.

7. The pharmaceutical composition according to claim 1, wherein By weight, the pharmaceutical composition includes 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, wherein When the drug contains a local anesthetic, by weight, the pharmaceutical composition includes 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 includes a solvent; or, the pharmaceutical composition further includes a solvent and an antioxidant.

10. The pharmaceutical composition according to claim 9, characterized in that, By weight, the pharmaceutical composition includes 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 includes 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 includes 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, It includes the following steps: Mix the raw material components to obtain the pharmaceutical composition.

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

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