Application of pharmaceutical composition in preparation of medicine for enhancing analgesic effect

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to application of a pharmaceutical composition in preparation of a medicine for enhancing the analgesic effect. The pharmaceutical composition disclosed by the invention comprises analgesic drugs and terpene drugs, the analgesic drugs comprise at least one of local hemp drugs and non-steroidal anti-inflammatory drugs; the terpene medicine comprises at least one of menthol, camphor, linalool and eudesmol. The analgesic drug and the terpene drug have a synergistic effect, and the terpene drug can improve the drug loading capacity of the analgesic drug under the condition that the in-vivo blood concentration of the analgesic drug is not changed, so that the pharmaceutical composition has a good analgesic effect and a long-acting analgesic effect, the duration of postoperative analgesia of Bama pigs can be prolonged to 120 hours, and the curative effect is good. And the pain-easing effect taking time is short, and the pain-easing effect taking time is short.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to the application of a pharmaceutical composition in the preparation of a drug for enhancing analgesic efficacy. Background Art

[0002] At present, postoperative analgesia in clinical practice mainly uses one or more of opioid analgesics, non-steroidal analgesics, and local anesthetics. Compared with other local anesthetic drugs, local anesthetic drugs such as bupivacaine hydrochloride injection and ropivacaine hydrochloride injection have a longer action time, but the analgesic effect of a single administration 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.

[0003] Existing long-acting postoperative analgesic drugs usually achieve the effect of prolonging analgesic efficacy by prolonging the release of bupivacaine. There are four common long-acting sustained-release preparations of bupivacaine. One is an implant (Xaracoll of Innocoll), one is a liposome (Exparel of Pacira), and the other two are gel preparations (Posimir of Durect and Zynrelef of Heron). In order to achieve better curative effects, the above four long-acting sustained-release preparations need to have a high drug loading capacity. The method of increasing the drug loading capacity is usually to increase the solvent volume. When increasing the drug loading capacity by increasing the solvent volume, the patient may need to inject a liquid medicine with a volume higher than 20 mL near the incision, which will cause swelling at the postoperative site of the patient and may produce more side effects. At the same time, among the above 4 long-acting postoperative analgesic drugs, the analgesic time of Zynrelef can only reach 72 hours, and the analgesic time of the other 3 drugs is 24 - 48 hours, which cannot well meet the clinical application requirements for longer-acting analgesic drugs.

[0004] Therefore, it is of great significance to provide the application of a pharmaceutical composition in the preparation of a drug for enhancing analgesic efficacy, which can enhance the analgesic effect and has a long analgesic efficacy while not changing the release rate of analgesic drugs. Summary of the Invention

[0005] The present invention aims to solve one or more of the above-mentioned technical problems existing in the prior art, and at least provides a beneficial choice or creation condition. Specifically, the present invention provides the application of a pharmaceutical composition in the preparation of a drug for enhancing analgesic efficacy, which can enhance the analgesic effect, prolong the analgesic time of the drug, and has a longer-acting analgesic efficacy while not changing the release rate of analgesic drugs.

[0006] Inventive concept of the present invention: The present invention provides an application of a pharmaceutical composition in the preparation of a drug for enhancing analgesic efficacy. The pharmaceutical composition includes an analgesic drug and a terpene drug; the analgesic drug includes at least one of a local anesthetic drug and a non-steroidal anti-inflammatory drug; the terpene drug includes at least one of menthol, camphor, linalool, and eucalyptol. The analgesic drug and the terpene drug of the present invention have a synergistic effect. Without changing the release characteristics of the analgesic drug, the terpene drug can increase the drug loading amount of the analgesic drug, achieving the purpose of enhancing and prolonging the analgesic efficacy. The analgesic duration for Bama pigs can be extended to 120 hours, and the long-acting analgesic effect is significantly better than the existing marketed drug Zynrelef. At the same time, the increase in the drug loading amount of the analgesic drug can make the required solvent volume of the drug lower, achieving a smaller injection volume, and improving the compliance and safety of patients.

[0007] Therefore, in the first aspect of the present invention, there is provided an application of a pharmaceutical composition in the preparation of a drug for enhancing analgesic efficacy.

[0008] Specifically, the pharmaceutical composition includes an analgesic drug and a terpene drug; the analgesic drug includes at least one of a local anesthetic drug and a non-steroidal anti-inflammatory drug; the terpene drug includes at least one of menthol, camphor, linalool, and eucalyptol.

[0009] The terpene drug is especially represented by menthol. Its analgesic principle is to produce a cold sensation by stimulating the cold receptors on the skin, thereby masking the pain. The analgesic effect of menthol is related to its dose. Through transdermal administration, it plays a role in surface analgesia. When the dose is high, it may cause discomfort to the wound. While a low dose of menthol cannot exert an analgesic effect. These restrict the application of terpene drugs in acute pain in the injection scenario, especially in the field of postoperative analgesia. There is also no application of terpene drugs in long-acting postoperative analgesia clinically. Through long-term experimental research, the present invention has broken through this limitation. Through the synergistic effect of terpene drugs and analgesic drugs, without changing the release characteristics of the analgesic drug, the therapeutic effect of the analgesic drug can be improved. By increasing the drug loading amount of the analgesic drug with terpene drugs and reducing the usage amount of the drug dose, the purpose of increasing and prolonging the drug effect, increasing patient compliance, and reducing drug adverse reactions is achieved.

[0010] Preferably, the menthol is L-menthol.

[0011] Preferably, the local anesthetic drug includes at least one of bupivacaine and ropivacaine.

[0012] Preferably, the non-steroidal anti-inflammatory drug includes at least one of meloxicam and celecoxib.

[0013] Preferably, the pharmaceutical composition further comprises at least one of a delivery carrier and a solvent.

[0014] Specifically, the pharmaceutical composition is a sustained-release preparation, and the delivery carrier has a sustained-release effect.

[0015] Preferably, the delivery carrier comprises at least one of saccharides and their esters, phospholipids, polyesters, and oils.

[0016] Preferably, the solvent comprises at least one of alcohols, dimethyl sulfoxide, ethyl lactate, glycerol formal, N-methylpyrrolidone, triacetin, benzyl benzoate, dichloromethane, water, and glyceryl trioctanoate.

[0017] More preferably, the alcohols comprise 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.

[0018] Preferably, the saccharides and their esters comprise at least one of sucrose, chitosan, sucrose acetate isobutyrate, sucrose octaacetate, and sucrose monoacetate monoisobutyrate.

[0019] Preferably, the phospholipids comprise at least one of natural phospholipids and synthetic phospholipids.

[0020] Preferably, the natural phospholipids comprise at least one of soy phosphatidylcholine, egg yolk phospholipid, rapeseed phospholipid, and sunflower phospholipid.

[0021] Preferably, the synthetic phospholipids comprise at least one of dioleoylphosphatidylcholine (DEPC), dioleoylphosphatidylcholine, palmitoyl oleoyl phosphatidylcholine, distearoylphosphatidylcholine, dipalmitoyl phosphatidylglycerol (DPPG), and distearoyl phosphatidylglycerol.

[0022] Preferably, the polyesters comprise at least one of polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), polyglycolic acid (PGA), polydioxanone (PDO), polycaprolactone (PCL), poly(L-lactide-caprolactone) (PLCL), and polyorthoesters.

[0023] Preferably, the polyorthoesters are selected from non-thermoplastic polyorthoesters having the following structure:

[0024]

[0025] Wherein, the R ＊ is selected from any one of methyl, ethyl, propyl, and butyl, and n is an integer from 5 to 400,

[0026] the A is selected from R 1 、R3 any one of

[0027] said R 1 is said R 5 selected from any one of H, C 1-4 alkyl, and said R 6 is said s is an integer from 0 to 10, and said p and q are independently selected from integers from 1 to 20 respectively;

[0028] said R 3 is said x is an integer from 1 to 5.

[0029] Preferably, said oil includes at least one of castor oil, soybean oil, olive oil, palm oil, and sesame oil.

[0030] Preferably, said pharmaceutical composition further includes a delivery carrier and a solvent; and by weight, said pharmaceutical composition includes 0.01 - 22 parts of an analgesic drug, ≥0.01 part and <5 parts of a terpene drug, 1 - 95 parts of a solvent, and 0.5 - 65 parts of a delivery carrier.

[0031] More preferably, by weight, said pharmaceutical composition includes 0.01 - 20 parts of an analgesic drug, 0.01 - 4.5 parts of a terpene drug, 2 - 90 parts of a solvent, and 0.5 - 60 parts of a delivery carrier.

[0032] Preferably, the mass ratio of said local anesthetic drug to the terpene drug is (1 - 50):1.

[0033] More preferably, the mass ratio of said local anesthetic drug to the terpene drug is (2 - 50):1.

[0034] Preferably, after subcutaneous injection of said pharmaceutical composition to the back of rats, the peak time of its blood drug concentration is 0.5 - 24 h.

[0035] More preferably, after subcutaneous injection of said pharmaceutical composition to the back of rats, the peak time of its blood drug concentration is 0.5 - 12 h.

[0036] Even more preferably, after subcutaneous injection of said pharmaceutical composition to the back of rats, the peak time of its blood drug concentration is 0.5 - 2 h.

[0037] Preferably, the dosage form of said pharmaceutical composition includes any one of a gel preparation and a liposome.

[0038] Preferably, the administration forms of said gel preparation and liposome include an injection and are administered by injection.

[0039] Preferably, the liposome includes any one of multilamellar liposomes and multi-vesicular liposomes.

[0040] Preferably, the gel preparation is an in-situ gel preparation.

[0041] Preferably, when the dosage form of the pharmaceutical composition is a liposome, by weight parts, the pharmaceutical composition includes 0.01 - 22 parts of analgesic drugs, ≥0.01 part and <5 parts of terpene drugs, 0.5 - 33 parts of phospholipids, and 60 - 95 parts of solvent.

[0042] More preferably, when the dosage form of the pharmaceutical composition is a liposome, by weight parts, the pharmaceutical composition includes 0.01 - 20 parts of analgesic drugs, 0.01 - 4.5 parts of terpene drugs, 0.5 - 30 parts of phospholipids, and 60 - 90 parts of solvent.

[0043] Preferably, when the dosage form of the pharmaceutical composition is an in-situ gel preparation, by weight parts, the pharmaceutical composition includes 0.01 - 22 parts of analgesic drugs, ≥0.01 part and <5 parts of terpene drugs, 2 - 60 parts of saccharides and their esters or polyorthoesters, and 2 - 60 parts of solvent.

[0044] More preferably, when the dosage form of the pharmaceutical composition is an in-situ gel preparation, by weight parts, the pharmaceutical composition includes 0.01 - 20 parts of analgesic drugs, 0.01 - 4.5 parts of terpene drugs, 3 - 50 parts of saccharides and their esters or polyorthoesters, and 2 - 50 parts of solvent.

[0045] Preferably, the preparation method of the pharmaceutical composition includes the following steps:

[0046] Mix the raw material components to obtain the pharmaceutical composition.

[0047] Preferably, when the dosage form of the pharmaceutical composition is a liposome, the preparation method of the pharmaceutical composition includes the following steps:

[0048] Dissolve the phospholipids in the solvent to obtain Solution 1; dissolve the analgesic drugs and terpene drugs in water to obtain Solution 2; mix Solution 1 and Solution 2 to form a primary emulsion, obtain a multiple emulsion by shearing, and obtain a pharmaceutical composition with a liposome dosage form after displacement and concentration.

[0049] Preferably, when the dosage form of the pharmaceutical composition is an in-situ gel preparation, the preparation method of the pharmaceutical composition includes the following steps:

[0050] Mix the raw material components, heat and stir to dissolve, and perform aseptic filtration or moist heat sterilization to obtain a pharmaceutical composition with an in-situ gel preparation dosage form.

[0051] Compared with the prior art, the beneficial effects of the technical solution provided by the present invention are as follows:

[0052] (1) The analgesic drugs and terpene drugs of the present invention act synergistically. Without changing the release of the blood drug concentration of the analgesic drugs in the body, the terpene drugs are used to increase the drug loading capacity of the analgesic drugs, unexpectedly achieving the purpose of enhancing and prolonging the analgesic effect. In the experiment on the postoperative analgesic effect of Bama pigs, at 120 h after surgery, the drug composition still had a good analgesic effect, that is, the postoperative analgesic duration for Bama pigs could be extended to 120 hours, and its long-acting analgesic effect was significantly better than that of the existing marketed drug Zynrelef. In addition, the analgesic onset time of the drug composition of the present invention is fast. For SD rats, good analgesic efficacy can be exerted 0.5 h after administration, and the maximum analgesic threshold equivalent to that before surgery can be reached 2 h after administration; for Bama pigs, the analgesic threshold equivalent to that before surgery can be reached 1 h after administration.

[0053] (2) Through long-term experimental research, the present invention breaks through the limitation that when the dosage of terpene drugs is small, the analgesic effect is poor, and when the dosage is high, it will cause discomfort such as redness and swelling of the wound. Through the synergistic effect of terpene drugs and analgesic drugs, the terpene drugs are used to increase the drug loading capacity of the analgesic drugs, reduce the dosage of the drug, the solvent amount required for the drug is lower, a smaller injection volume can be achieved, the patient compliance is increased, the drug adverse reactions are reduced, and at the same time, the analgesic effect can be increased and prolonged.

[0054] (3) Sucrose acetate isobutyrate (SAIB) in the delivery carrier of the present invention also has the function of a solubilizer, which can further increase the drug loading capacity, and thus make the analgesic effect better.

[0055] (4) The preparation method of the drug composition of the present invention is simple, easy to operate, has a low cost, and is suitable for large-scale industrial production. Description of the Drawings

[0056] Figure 1 It is the blood drug concentration curve of bupivacaine in rats after administration of the drug compositions of Examples 2-3, Comparative Examples 1, 3, and 5 of the present invention;

[0057] Figure 2 It is the blood drug concentration curve of menthol in rats after administration of the drug compositions of Examples 2-3, Comparative Examples 2, 4, and 5 of the present invention;

[0058] Figure 3 It is the analgesic effect diagram of the drug compositions of Example 2 and Comparative Examples 3-4 of the present invention on rats;

[0059] Figure 4 It is the analgesic effect diagram of the drug compositions of Examples 1-3, Example 8, and Comparative Example 6 of the present invention on rats;

[0060] Figure 5 This is the analgesic effect diagram of the drug compositions of Examples 4-5 and Comparative Example 7 and the existing analgesic drug Zynrelef of Comparative Example 8 after administration to Bama miniature pigs. Detailed implementation manners

[0061] In order to make those skilled in the art more clearly understand the technical solutions of 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.

[0062] 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.

[0063] The polyorthoester in the examples and comparative examples of the present invention is tri(ethyleneglycol)poly(orthoester).

[0064] The raw material components and dosages of the drug compositions of Examples 1-9 and Comparative Examples 1-7 of the present invention are shown in Table 1, and "-" in Table 1 indicates that the corresponding component is not added.

[0065] Table 1: Raw material components and dosages (parts by weight) of the drug compositions of Examples 1-9 and Comparative Examples 1-7.

[0066]

[0067]

[0068] Example 1

[0069] Use of a drug composition in the preparation of a drug for enhancing analgesic efficacy, and the raw material components and dosages of the drug composition are shown in Table 1.

[0070] The preparation method of the drug composition of Example 1 includes the following steps:

[0071] Mix bupivacaine, L-menthol, glycerol formal, and SAIB, heat and stir to dissolve at 65 °C, and perform sterile filtration to obtain the drug composition (in-situ gel preparation).

[0072] Example 2

[0073] Use of a drug composition in the preparation of a drug for enhancing analgesic efficacy, and the raw material components and dosages of the drug composition are shown in Table 1.

[0074] The preparation method of the drug composition of Example 2 includes the following steps:

[0075] Mix bupivacaine, L-menthol, glycerol formal, and polyorthoester, and heat and stir to dissolve at 65°C, then perform aseptic filtration to obtain the prepared pharmaceutical composition (in-situ gel preparation).

[0076] Example 3

[0077] Use of a pharmaceutical composition in the preparation of a drug for enhancing analgesic efficacy, wherein the raw material components and dosages of the pharmaceutical composition are shown in Table 1.

[0078] Preparation method of the pharmaceutical composition of Example 3, comprising the following steps:

[0079] Mix bupivacaine, L-menthol, glycerol formal, and castor oil to obtain the pharmaceutical composition.

[0080] Example 4

[0081] Use of a pharmaceutical composition in the preparation of a drug for enhancing analgesic efficacy, wherein the raw material components and dosages of the pharmaceutical composition are shown in Table 1.

[0082] Preparation method of the pharmaceutical composition of Example 4, comprising the following steps:

[0083] Mix bupivacaine, L-menthol, celecoxib, glycerol formal, and SAIB, and heat and stir to dissolve at 65°C, then perform aseptic filtration to obtain the pharmaceutical composition (in-situ gel preparation).

[0084] Example 5

[0085] Use of a pharmaceutical composition in the preparation of a drug for enhancing analgesic efficacy, wherein the raw material components and dosages of the pharmaceutical composition are shown in Table 1.

[0086] Preparation method of the pharmaceutical composition of Example 5, comprising the following steps:

[0087] Mix bupivacaine, L-menthol, celecoxib, glycerol formal, and SAIB, and heat and stir to dissolve at 65°C, then perform aseptic filtration to obtain the pharmaceutical composition (in-situ gel preparation).

[0088] Example 6

[0089] Use of a pharmaceutical composition in the preparation of a drug for enhancing analgesic efficacy, wherein the raw material components and dosages of the pharmaceutical composition are shown in Table 1.

[0090] Preparation method of the pharmaceutical composition of Example 6, comprising the following steps:

[0091] Mix bupivacaine, L-menthol, glycerol formal, and polyorthoester, and heat and stir to dissolve at 65°C, then perform aseptic filtration to obtain the pharmaceutical composition (in-situ gel preparation).

[0092] Example 7

[0093] Use of a pharmaceutical composition in the preparation of a drug for enhancing analgesic efficacy, wherein the raw material components and dosages of the pharmaceutical composition are shown in Table 1.

[0094] Preparation method of the pharmaceutical composition of Example 7, comprising the following steps:

[0095] Mix bupivacaine, L-menthol, glycerol formal, and polyorthoester, heat and stir to dissolve at 65 °C, and perform sterile filtration to obtain the pharmaceutical composition (in-situ gel preparation).

[0096] Example 8

[0097] Use of a pharmaceutical composition in the preparation of a drug for enhancing analgesic efficacy, wherein the raw material components and dosages of the pharmaceutical composition are shown in Table 1.

[0098] The dosage form of the pharmaceutical composition of Example 8 is liposome, and the preparation method of the pharmaceutical composition comprises the following steps:

[0099] Mix DEPC and DPPG in glyceryl trioctanoate to obtain Solution 1; mix bupivacaine and L-menthol in water to obtain Solution 2; mix Solution 1 and Solution 2 to form primary emulsion, obtain multiple emulsion by shearing, and obtain the pharmaceutical composition (liposome preparation) after displacement and concentration.

[0100] Example 9

[0101] Use of a pharmaceutical composition in the preparation of a drug for enhancing analgesic efficacy, wherein the raw material components and dosages of the pharmaceutical composition are shown in Table 1.

[0102] Preparation method of the pharmaceutical composition of Example 9, comprising the following steps:

[0103] Mix bupivacaine, L-menthol, benzyl alcohol, and SAIB, heat and stir to dissolve at 65 °C, and perform sterile filtration to obtain the pharmaceutical composition (in-situ gel preparation).

[0104] Comparative Example 1

[0105] The difference between Comparative Example 1 and Example 1 is that in Comparative Example 1, L-menthol is replaced with an equal amount of bupivacaine, i.e., L-menthol is not contained, the dosage of glycerol formal is 10 parts, SAIB is not contained, and the others are the same as in Example 1.

[0106] Comparative Example 2

[0107] The difference between Comparative Example 2 and Example 1 is that in Comparative Example 2, bupivacaine is replaced with an equal amount of L-menthol, i.e., bupivacaine is not contained, the dosage of glycerol formal is 10 parts, SAIB is not contained, and the others are the same as in Example 1.

[0108] Comparative Example 3

[0109] The difference between Comparative Example 3 and Example 1 is only that in Comparative Example 3, bupivacaine is used to replace L-menthol in equal amount, that is, it does not contain terpenoid drugs, and the others are the same as in Example 1.

[0110] Comparative Example 4

[0111] The difference between Comparative Example 4 and Example 1 is only that in Comparative Example 4, L-menthol is used to replace bupivacaine in equal amount, that is, it does not contain analgesic drugs, and the others are the same as in Example 1.

[0112] Comparative Example 5

[0113] The difference between Comparative Example 5 and Examples 1-3 is that Comparative Example 5 does not contain a delivery carrier, and the amount of formaldehyde glycerol acetal used is 10 parts, and the others are the same as in Examples 1, 2 or 3.

[0114] Comparative Example 6

[0115] The difference between Comparative Example 6 and Example 6 is only that the amount of L-menthol in Comparative Example 6 is 5 parts, that is, the amount of L-menthol is increased, and the others are the same as in Example 6.

[0116] Comparative Example 7

[0117] The difference between Comparative Example 7 and Example 4 is only that Comparative Example 7 does not contain L-menthol, and the others are the same as in Example 4.

[0118] Comparative Example 8

[0119] Comparative Example 8 is the existing analgesic drug Zynrelef.

[0120] Performance Test

[0121] 1. Bupivacaine Release Test

[0122] By studying the pharmacokinetics in rats, the drug concentration of bupivacaine in rats was measured, and then it was judged whether menthol has an effect on the release of bupivacaine in animals.

[0123] The specific test process of the pharmacokinetics study in rats is as follows:

[0124] Select SD rats (male) weighing approximately 200 - 250 g, and subcutaneously administer the drug compositions of Example 2 - 3, Comparative Example 1, Comparative Example 3, and Comparative Example 5 to the dorsal part of the SD rats respectively, with the administration dose being 30.0 mg / kg; collect approximately 0.5 mL of blood samples from the SD rats at 0.25, 0.5, 1, 2, 3, 6, 12, 24, 48, 72, and 96 hours after administration, place them in blood collection tubes anticoagulated with EDTA - 2K+, centrifuge the whole blood at 8000 rpm for 5 minutes, collect the plasma, and then detect the drug concentration of bupivacaine in the plasma samples of the SD rats by liquid chromatography - tandem mass spectrometry (LC - MS / MS).

[0125] The logarithmic curves of the blood drug concentration of the local anesthetic drug bupivacaine in rats after administration of the drug compositions of Example 2 - 3, Comparative Example 1, Comparative Example 3, and Comparative Example 5 are as Figure 1 shown. Among them, lgC on the vertical axis represents the logarithm of the blood drug concentration.

[0126] It can be seen from Figure 1 that the peak time of the blood drug concentration of bupivacaine in Comparative Example 1 and Comparative Example 5 is approximately 1 h respectively, and there is no sustained - release characteristic, indicating that the addition of the terpene drug L - menthol does not change the release of bupivacaine; both the formulations of Comparative Example 3 and Examples 2 and 3 contain bupivacaine and a sustained - release carrier. In Comparative Example 3 and Examples 2 - 3, the blood drug concentration of bupivacaine has a sustained - release characteristic. Although L - menthol is added in both Examples 2 and 3, the release characteristics of bupivacaine in the rat body are not changed under these two sustained - release systems with or without the addition of L - menthol. It shows that the addition of terpene drugs does not change the release of analgesic drugs in the body.

[0127] 2. Blood drug concentration test of menthol

[0128] Using the same test method as the above - mentioned bupivacaine blood drug concentration test, test the blood drug concentration of menthol in rats after administration of the drug compositions of Example 2 - 3, Comparative Example 2, Comparative Example 4, and Comparative Example 5.

[0129] The logarithmic curves of the blood drug concentration of the terpene drug menthol in rats after administration of the drug compositions of Example 2 - 3, Comparative Example 2, Comparative Example 4, and Comparative Example 5 are as Figure 2 shown. Among them, lgC on the vertical axis represents the logarithm of the blood drug concentration.

[0130] It can be seen from Figure 2 that after administration of the drug compositions of Comparative Example 2 and Comparative Example 5, the blood drug concentration of menthol in rats has no sustained - release characteristic; in Comparative Example 4, and Examples 2 and 3, all contain menthol and a delivery carrier, and the blood drug concentration in their bodies has a sustained - release characteristic and can last for more than 120 hours.

[0131] 3. Analgesic effect test

[0132] (1) Study on the analgesic effect of the drug on SD rats

[0133] To study the analgesic effect of the drug composition of the present invention on rats, the postoperative analgesic effect on the plantar surface of rats was studied for the drug compositions of Example 2 and Comparative Examples 3-4. The specific process is as follows:

[0134] SPF (Specific Pathogen Free)-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, infiltration injection was given beside the incision. Each SD rat was given the drug compositions of Example 2 and Comparative Examples 3-4 at 15 mg / kg respectively. Before surgery and drug administration (0 h) and at 0.5, 2, 4, 8, 12, 24, 48, 72 hours after drug administration, the Von Frey mechanical hyperalgesia test was 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 analgesic effects of the drug compositions of Example 2 and Comparative Examples 3-4 after drug administration are as Figure 3 shown. The smaller the ordinate data, the more obvious the pain and the lower the drug effect.

[0135] From Figure 3 the test results, it can be seen that the drug composition system of bupivacaine and L-menthol compounded in Example 2 of the present invention can exert good analgesic drug effects 0.5 h after drug administration, can reach the maximum analgesic threshold equivalent to that before surgery 2 h after drug administration, and can still maintain an analgesic effect basically equivalent to that at 0.5 h after drug administration 72 h after drug administration. It shows that the drug composition system of bupivacaine and L-menthol compounded in the present invention has good analgesic drug effects, can prolong the time for the drug to exert analgesic effects, that is, has a long-acting analgesic effect; in addition, the time for the analgesic to take effect after drug administration is short.

[0136] Comparative Example 3 does not contain L-menthol and is a single-component sustained-release system of bupivacaine. It has a certain analgesic effect and long-acting analgesic effect, but both the analgesic effect and the long-acting analgesic effect are inferior to those of Example 2, especially the long-acting analgesic effect. Comparative Example 4 does not contain bupivacaine and is a single-component sustained-release system of menthol. Its analgesic effect is not obvious, and there is a small increase in the pain threshold at 24 h, 48 h, and 72 h, and the analgesic effect is slightly improved. This may be because, on the one hand, the menthol in Comparative Example 4 has a sustained-release effect, and on the other hand, the metabolism of rats is fast. As time goes by, the wounds of the rats gradually recover and heal. It shows that the compound use of bupivacaine and L-menthol can make the pharmaceutical composition have good analgesic effect, long-acting analgesic effect, and shorten the onset time of analgesia.

[0137] Using the same test method for the postoperative analgesic effect on the rat's sole as above, the analgesic effects of the pharmaceutical compositions of Examples 1-3, Example 8, and Comparative Example 6 were studied. The analgesic effects of the pharmaceutical compositions of Examples 1-3, Example 8, and Comparative Example 6 on rats after administration are as Figure 4 shown.

[0138] It can be seen from Figure 4 that Examples 1-3 of the present invention are sustained-release systems composed of the compound of bupivacaine and menthol and using different delivery carriers. Their analgesic effects and the duration of the analgesic effect are quite the same, and both can exert good analgesic effects and long-acting analgesic effects.

[0139] Example 8 is a liposome system using phospholipids as a delivery carrier. It has a good analgesic effect, but the duration of the drug effect intensity is inferior to that of Examples 1-3.

[0140] In Comparative Example 6, the dosage of L-menthol is 5 parts, that is, increasing the dosage of L-menthol has a good long-acting analgesic effect. However, during the experiment, there was a small amount of redness and swelling at the administration site. It can be seen that a higher proportion of menthol use will produce local irritation, reducing safety and patient compliance.

[0141] In addition, based on the possible side effects such as redness and swelling at the animal administration site, using the same method as the above administration method, whether there is redness and swelling at the administration site after the administration of the pharmaceutical compositions of Examples 6 and 7 was observed.

[0142] The states of the administration sites after the administration of the pharmaceutical compositions of Examples 6-7 and Comparative Example 6 are shown in Table 2.

[0143] Table 2: States of the administration sites after the administration of the pharmaceutical compositions of Examples 6-7 and Comparative Example 6

[0144] Group Dosage of bupivacaine and menthol Whether there is swelling and redness at the administration site Other side effects Comparative Example 6 1 part of bupivacaine and 5 parts of menthol Yes None Example 6 1 part of bupivacaine and 1 part of menthol No None Example 7 1 part of bupivacaine and 0.5 part of menthol No None

[0145] As can be seen from Table 2, in Comparative Example 6, redness and swelling occurred at the drug administration site. In Examples 6 and 7, the dosage of menthol was reduced, and there was no redness and swelling or other side effects at the animal drug administration site. Therefore, the dosage ratio of bupivacaine to menthol should not be lower than 1:1.

[0146] (2) Study on the Analgesic Effect of Drugs on Bama Miniature Pigs

[0147] To study the analgesic effect of the pharmaceutical composition of the present invention on Bama miniature pigs, analgesic tests were conducted on the postoperative acute pain models of Bama miniature pigs using the pharmaceutical compositions of Examples 4-5, Comparative Example 7, and the existing analgesic drug Zynrelef of Comparative Example 8. The specific process is as follows:

[0148] Bama miniature pigs of the specific pathogen-free (SPF) level were selected and induced anesthesia by intravenous injection of propofol injection (2-4 mg / kg.bw) through the femoral vein. A 7-cm-long longitudinal incision was made along the left side 3 cm from the spinal column line of the lower back using a scalpel, and blunt separation of the skin and fascia layers was performed with hemostatic forceps. The pharmaceutical compositions of Example 4, Example 5, and Comparative Example 7, and the existing analgesic drug Zynrelef of Comparative Example 8 were administered at 10 mg / kg. After suturing, the incision was disinfected with iodophor to prevent infection. Von Frey mechanical hyperalgesia tests were performed on Bama miniature pigs at 0 h (before surgery) and 1 h, 3 h, 5 h, 24 h (1 day after surgery), 48 h (2 days after surgery), 72 h (3 days after surgery), and 120 h (5 days after surgery) after drug administration. Nine intensities of Von Frey filaments (equivalent to 1.4, 2, 4, 6, 8, 10, 15, 26, and 60 g respectively) were used, and the "up-and-down" method was used to detect and record the test results and calculate the pain threshold.

[0149] The analgesic effects of the pharmaceutical compositions of Example 4, Example 5, Comparative Example 7, and the analgesic drug Zynrelef of Comparative Example 8 on Bama miniature pigs after drug administration are as Figure 5 shown. The smaller the ordinate data, the more obvious the pain and the lower the drug effect.

[0150] From Figure 5 it can be seen that the pharmaceutical compositions of Examples 4 and 5 of the present invention are drug systems using the local anesthetic bupivacaine, the non-steroidal anti-inflammatory drug meloxicam, and the terpene drug L-menthol. It can reach an analgesic threshold equivalent to that before surgery 1 h after drug administration, and the duration of the analgesic drug effect can be as long as 120 h, with good postoperative analgesic effect and long-acting analgesic effect. Especially for Example 4, it can still reach the same pain threshold as before surgery 48 h after drug administration, with excellent analgesic effect and long-acting property.

[0151] Comparative Example 7 did not add L-menthol. It had good postoperative analgesic effect within 24 hours, but as time continued to extend, its analgesic effect was significantly worse than that of Examples 4-5, indicating that its long-acting analgesic effect was poor.

[0152] In addition, the drug load of the local anesthetic and non-steroidal anti-inflammatory drug in Example 5 was half of that in Example 4 and also half of that in Comparative Example 7. However, due to the presence of L-menthol in Example 5, even when the drug load of the local anesthetic and non-steroidal anti-inflammatory drug was significantly reduced, the analgesic threshold of Example 5 at 120 hours of drug administration was still significantly higher than that of Comparative Example 7, that is, its long-acting analgesic effect was significantly better than that of Comparative Example 7. It can be seen that terpenoid drugs can effectively extend the time for analgesic drugs to exert good analgesic effects. That is, when analgesic drugs and terpenoid drugs are used in combination, the drug composition can have good analgesic efficacy and long-acting analgesic effect.

[0153] From 3 hours after drug administration, the analgesic effect of the drug Zynrelef in Comparative Example 8 began to be worse than that of Examples 4 and 5. As time extended, the analgesic effect of Zynrelef decreased significantly and was significantly worse than that of Examples 4 and 5. This shows that the long-acting analgesic effect of the drug composition prepared by the present invention is significantly better than that of the marketed drug Zynrelef.

[0154] The drug compositions in Examples 6, 7, and 9 of the present invention also have good long-acting analgesic effects.

[0155] In summary, the analgesic drugs and terpenoid drugs of the present invention have a synergistic effect. Without changing the blood drug concentration of the analgesic drug in the body, the terpenoid drug can increase the drug load of the analgesic drug, making the drug composition have good analgesic effects and long-acting analgesic effects. The postoperative analgesia duration for Bama minipigs can be extended to 120 hours, which is significantly better than 72 hours of the existing marketed drugs, and the analgesic onset time is fast.

[0156] The above examples 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. Use of a pharmaceutical composition in the preparation of a drug for enhancing analgesic efficacy, characterized in that: The pharmaceutical composition includes analgesic drugs and terpene drugs; The analgesic drugs include at least one of local anesthetics and non-steroidal anti-inflammatory drugs; The terpene drugs include at least one of menthol, camphor, linalool and eucalyptol.

2. The use according to claim 1, characterized in that: The local anesthetic includes at least one of bupivacaine and ropivacaine; and / or the non-steroidal anti-inflammatory drug includes at least one of meloxicam and celecoxib.

3. The use according to claim 1, characterized in that: The pharmaceutical composition further comprises at least one of a delivery carrier and a solvent.

4. The use according to claim 3, characterized in that: The delivery carrier includes at least one of sugars and their esters, phospholipids, polyesters, and oils; and / or the solvent includes at least one of alcohols, dimethyl sulfoxide, ethyl lactate, glycerol formal, N-methylpyrrolidone, triacetin, benzyl benzoate, dichloromethane, water, and tricaprylin.

5. The use according to claim 4, characterized in that: The sugar and its esterification product include at least one of sucrose, chitosan, sucrose acetate isobutyrate, sucrose octaacetate, and sucrose monoacetate monoisobutyrate; and / or, the phospholipid includes at least one of natural phospholipid and synthetic phospholipid; and / or, the oil includes at least one of castor oil, soybean oil, olive oil, palm oil, and sesame oil; and / or, the polyester includes at least one of polylactic acid, polylactic acid-glycolic acid copolymer, polyglycolic acid, polydioxane, polycaprolactone, poly-L-lactide-caprolactone, and polyorthoester.

6. The use according to claim 5, characterized in that: The natural phospholipids include at least one of soybean phosphatidylcholine, egg yolk phospholipids, rapeseed phospholipids, and sunflower phospholipids; and / or the synthetic phospholipids include at least one of dierucoyl phosphatidylcholine, dioleoyl phosphatidylcholine, palmitoyl oleoyl phosphatidylcholine, distearoyl phosphatidylcholine, dipalmitoyl phosphatidylglycerol, and distearoyl phosphatidylglycerol.

7. The use according to claim 5, characterized in that: The polyorthoester is selected from the non-thermoplastic polyorthoester of the following structure: Among them, the R ＊ Any one selected from methyl, ethyl, propyl and butyl, wherein n is an integer from 5 to 400, The A is selected from R 1 , R 3 Any of the following: The R 3 for The x is an integer from 1 to 5.

8. The use according to claim 3, characterized in that: The pharmaceutical composition also includes a delivery vehicle and a solvent; and by weight, the pharmaceutical composition includes 0.01-22 parts of analgesics, 0.01 parts or more and less than 5 parts of terpene drugs, 1-95 parts of solvents, and 0.5-65 parts of delivery vehicles.

9. The use according to claim 8, characterized in that: The mass ratio of the local anesthetic to the terpene drug is (1-50):

1.

10. The use according to any one of claims 1 to 9, characterized in that: The pharmaceutical composition may be in the form of a gel preparation or a liposome.

11. The use according to any one of claims 1 to 9, characterized in that: The preparation method of the pharmaceutical composition comprises the following steps: The components are mixed to prepare the pharmaceutical composition.

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