Application of schisandrin B in the preparation of analgesic drugs

Abstract

This invention discloses the pharmaceutical use of schisandrin B in the preparation of analgesic drugs, wherein the analgesia is for the treatment or prevention of chemotherapy-induced neuropathic pain, and the analgesic drug can reduce mechanical and cold hyperalgesia in a chemotherapy-induced neuropathic pain model. Pharmacodynamic studies of this invention demonstrate that oral administration of schisandrin B can reduce chemotherapy-induced neuropathic pain, thereby effectively exerting an analgesic effect, and can be used as a therapeutic or preventative analgesic drug.

Description

Technical Field

[0001] This invention belongs to the field of medicine and relates to the application of schisandrin B in the preparation of analgesic drugs, especially in the treatment and / or prevention of chemotherapy-induced neuropathic pain. Background Technology

[0002] Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting adverse reaction associated with chemotherapy drugs. A large number of chemotherapy patients develop CIPN, and 30%–40% of these cases progress to chronic neurological adverse reactions. For example, in breast cancer patients treated with docetaxel, 42% still had CIPN symptoms two years after treatment; the incidence rate was even higher at 84% in colorectal cancer patients treated with oxaliplatin two years after treatment. A survey of patients with malignant tumors showed that 47% of patients still had CIPN symptoms six years after the end of chemotherapy. Currently known chemotherapy drugs that may cause CIPN include platinum-based drugs (such as cisplatin, carboplatin, and oxaliplatin), vincristine alkaloids (such as vincristine), taxanes (such as paclitaxel and docetaxel), and proteasome or angiogenesis inhibitors (bortezomib and thalidomide). However, the pathogenesis is not fully understood, and it is currently believed that multiple factors are involved in its development. Chemotherapy-induced peripheral neuropathy (CIPN) clinically manifests as pain, numbness, and tingling. It has a high incidence (40%-90% for oxaliplatin and 61-92% for paclitaxel) and lacks effective prevention and treatment methods and effective drugs for relief.

[0003] Schisandra chinensis (Turcz.) Baill. is a commonly used astringent herb with the effects of invigorating qi and promoting body fluid production, calming the mind and soothing the nerves. It is a medicinal and edible herb. The Compendium of Materia Medica records that Schisandra chinensis is divided into two categories: northern Schisandra chinensis and southern Schisandra chinensis. The active chemical components of Schisandra chinensis mainly include lignans, polysaccharides, and volatile oils. Northern Schisandra chinensis has a higher content of volatile oils, total lignans, and polysaccharides than southern Schisandra chinensis. Among them, schisandrin B (Sch B) is extracted from Schisandra chinensis, a plant of the Magnoliaceae family, and is the most abundant biphenylcyclooctene lignan in northern Schisandra chinensis, with the chemical formula C. 23 H 28 O6, with a relative molecular mass of 400.46 and CAS number 61281-37-6, has the following structural formula.

[0004]

[0005] Schisandrin B is an active monomer extracted and purified from the traditional Chinese medicine Schisandra chinensis. Clinically, it possesses various pharmacological effects, including anti-inflammatory, antibacterial, antioxidant, antitumor, renal function improvement, anti-Alzheimer's disease, sedative-hypnotic, and neuroprotective effects, with minimal toxicity to normal cells. Currently, there are no studies on the preventive and therapeutic effects of schisandrin B on chemotherapy-induced neuropathic pain. The inventors unexpectedly discovered that schisandrin B can be used as a preventative or therapeutic analgesic, especially for chemotherapy-induced neuropathic pain. Summary of the Invention

[0006] The purpose of this invention is to provide a new pharmaceutical use for schisandrin B.

[0007] This invention provides the application of schisandrin B or a pharmaceutically usable salt of schisandrin B in the preparation of analgesic drugs.

[0008] Furthermore, the analgesia is for the treatment and / or prevention of chemotherapy-induced neuropathic pain.

[0009] Furthermore, the analgesia described therein can alleviate neuropathic pain caused by chemotherapy.

[0010] Furthermore, the neuropathic pain described herein is caused by chemotherapy drugs selected from platinum-based drugs, vincristine alkaloids, taxanes, proteasome or angiogenesis inhibitors, or combinations thereof.

[0011] Furthermore, the platinum group is selected from cisplatin, carboplatin, or oxaliplatin; the vinca alkaloid is selected from vincristine; the taxane is selected from paclitaxel or docetaxel; the proteasome or angiogenesis inhibitor is selected from bortezomib or thalidomide. Preferably, the platinum group is selected from cisplatin, carboplatin, or oxaliplatin; the taxane is selected from paclitaxel or docetaxel; more preferably, the platinum group is selected from oxaliplatin; and the taxane is selected from paclitaxel.

[0012] The purpose of this invention is to provide an analgesic drug whose active ingredient includes schisandrin B or a pharmaceutically acceptable salt of schisandrin B.

[0013] The application described in this invention refers to a pharmaceutical composition containing schisandrin B or a pharmaceutically usable salt of schisandrin B.

[0014] The pharmaceutical composition described in this invention may also contain a pharmaceutically acceptable carrier.

[0015] In the application described in this invention, the pharmaceutical composition is formulated into any pharmaceutically acceptable dosage form.

[0016] The pharmaceutical dosage form described in this invention is selected from tablets, capsules, solutions, granules, powders, ointments, pills, suspensions, suppositories, liniments, emulsions, ointments, patches, or sprays.

[0017] The application described in this invention is in the form of a unit dose, each unit dose containing schisandrin B or a pharmaceutically acceptable salt of schisandrin B: 1-10 mg, or 10-100 mg, or 100-1000 mg, or 1000-10000 mg.

[0018] The following is an explanation and description of the terminology used in this invention:

[0019] Schisandrin B: English name schisandrin B, abbreviated as Sch B, chemical formula C 23 H 28 O6, with a relative molecular mass of 400.46 and CAS number 61281-37-6, has the following structural formula:

[0020]

[0021] Schisandrin B can be purchased commercially or prepared using known methods in the prior art.

[0022] The term "pharmaceutically acceptable" means that a carrier, delivery substance, diluent, excipient, and / or the salt formed therefrom is generally chemically or physically compatible with other components constituting a drug dosage form and physiologically compatible with receptors.

[0023] The pharmaceutical composition described in this invention can be any reusable pharmaceutical formulation, such as oral, injectable, or topical forms. Oral dosage forms include, but are not limited to, tablets, capsules, oral liquids, granules, pills, and suspensions. Injectable formulations are selected from water injections and powder injections. Topical formulations are selected from patches and ointments. All formulations can be prepared according to conventional pharmaceutical techniques. For example, using any one of the compounds of this invention, or their stereoisomers, or their pharmaceutically acceptable salts as the active pharmaceutical ingredient, and adding a pharmaceutically acceptable carrier if necessary, the above-mentioned pharmaceutical dosage forms suitable for oral administration can be prepared. The unit dose of the active pharmaceutical ingredient can be 0.1 mg to 10,000 mg, such as each tablet containing 0.1 mg to 10,000 mg, preferably 5 to 500 mg, or 1 to 10 mg, or 10 to 100 mg, or 100 to 10,000 mg, or 1,000 to 10,000 mg of active pharmaceutical ingredient.

[0024] The terms "salt" and "pharmaceutical salt" refer to acidic and / or basic salts formed by the above-described compounds or their stereoisomers with inorganic and / or organic acids and bases, including zwitterionic salts (internal salts) and quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final separation and purification of the compounds. Alternatively, they can be obtained by mixing the above-described compounds or their stereoisomers with an appropriate amount (e.g., equimolar amounts) of an acid or base. These salts may be obtained by precipitating in solution and collecting by filtration, by recovery after solvent evaporation, or by freeze-drying after reaction in an aqueous medium. The salts described in this invention can be hydrochlorides, sulfates, citrates, benzenesulfonates, hydrobromides, hydrofluoric acids, phosphates, acetates, propionates, succinates, oxalates, malates, succinates, fumarates, maleates, tartrates, or trifluoroacetates of the compounds.

[0025] In some embodiments, one or more compounds of the present invention may be used in combination with each other. Alternatively, the compounds of the present invention may be used in combination with any other active agent to prepare a medicament or pharmaceutical composition for regulating cell function or treating disease. If a group of compounds is used, these compounds may be administered to the test subject simultaneously, separately, or sequentially.

[0026] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0027] The beneficial technical effects of this invention are as follows: This invention studies and constructs two neuropathic pain models induced by oxaliplatin and paclitaxel in rats, evaluates the preventive and therapeutic effects of schisandrin B on chemotherapy-induced neuropathic pain, and demonstrates through pharmacodynamic experiments that gavage administration of schisandrin B can reduce mechanical and cold pain sensitivity in the chemotherapy-induced neuropathic pain model, thereby exerting an analgesic effect, indicating that schisandrin B can be used as an analgesic drug. Attached Figure Description

[0028] Figure 1 In Example 1, prophylactic administration of schisandrin B reduced oxaliplatin-induced mechanical pain (A) and cold pain (B) in rats; at the same time point, compared with the oxaliplatin model group, P < 0.001 was indicated by "***"; P < 0.01 was indicated by "**".

[0029] Figure 2In Example 2, therapeutic administration of schisandrin B reduced oxaliplatin-induced mechanical hyperalgesia in rats. At the same time point, compared with the oxaliplatin model group, P < 0.0001 was indicated by "****"; P < 0.001 was indicated by "***"; P < 0.01 was indicated by "**". In the same administration group, compared with Pre-drug (before administration), P < 0.0001 was indicated by "####".

[0030] Figure 3 In Example 3, therapeutic administration of schisandrin B reduced oxaliplatin-induced cold pain sensitivity in rats. At the same time point, compared with the oxaliplatin model group, P < 0.05 was indicated by "*". In the same administration group, compared with Pre-drug (before administration), P < 0.0001 was indicated by "####"; P < 0.01 was indicated by "##".

[0031] Figure 4 In Example 4, therapeutic administration of schisandrin B can reduce mechanical pain hypersensitivity in rats induced by paclitaxel; at the same time point, P < 0.05 compared with the paclitaxel model group is indicated by "*", and in the same administration group, P < 0.01 compared with Pre-drug is indicated by "##".

[0032] Figure 5 In Example 5, the therapeutic administration of schisandrin B can alleviate the cold pain sensitivity induced by paclitaxel in rats. In the same administration group, P < 0.01 compared with Pre-drug (before administration) is indicated by "##". Detailed Implementation

[0033] The present invention is further illustrated by the following examples, but these are not intended to limit the invention.

[0034] Example 1: Prophylactic administration of schisandrin B can reduce oxaliplatin-induced mechanical and cold hyperalgesia in rats.

[0035] Experimental methods: Male SD rats weighing 180-220g were randomly divided into three groups: oxaliplatin model group, schisandrin B 30mg / kg group, and schisandrin B 100mg / kg group, with 6 rats in each group.

[0036] Before the experiment, mechanical pain and cold pain baseline values ​​were measured in all rats. Subsequently, all rats were injected intraperitoneally with 4 mg / kg oxaliplatin once a day for 5 consecutive days to establish the CIPN model.

[0037] Schisandrin B was prepared into two suspensions with concentrations of 3 mg / ml and 10 mg / ml using 0.5% CMC-Na solution. Starting from the first day of modeling, rats were administered the different concentrations of schisandrin B suspension by gavage to achieve final doses of 30 and 100 mg / kg, once daily for 19 days. The paw withdrawal thresholds of the rats were measured using an electromechanical analgesia device at different time points; the response latency to cold pain was measured using the dry ice method.

[0038] Experimental Results: Following continuous injections of oxaliplatin, rats gradually showed a decrease in mechanical withdrawal threshold and a shortening of the latency period for cold pain response. Starting from day 9 (day 0 of the first oxaliplatin injection), compared with the oxaliplatin model group, rats in both groups treated with schisandrin showed some relief in both mechanical and cold pain sensitivity. Furthermore, at certain time points, compared with the oxaliplatin model group, the schisandrin group significantly increased the mechanical withdrawal threshold and prolonged the latency period for cold pain response. Results are shown in Tables 1 and 2 and the attached diagram in the instruction manual. Figure 1 .

[0039] Table 1. Results of mechanical pain sensitivity testing in rats of each group in Example 1.

[0040]

[0041] Table 2. Results of cold pain sensitivity test in rats of each group in Example 1.

[0042]

[0043] Example 2: Therapeutic administration of schisandrin B can reduce oxaliplatin-induced mechanical hyperalgesia in rats.

[0044] Experimental methods: Male SD rats weighing 180-220g were randomly divided into 4 groups: oxaliplatin model group (n=8), schisandrin B 30mg / kg group (n=7), schisandrin B 100mg / kg group (n=8), and schisandrin B 300mg / kg group (n=7).

[0045] Before the experiment, mechanical pain baseline values ​​were measured in all rats. Subsequently, all rats were injected intraperitoneally with 4 mg / kg oxaliplatin once a day for 5 consecutive days to establish the CIPN model.

[0046] Schisandrin B was prepared into suspensions with concentrations of 3, 10, and 30 mg / ml using 0.5% CMC-Na solution. After modeling, the mechanical withdrawal thresholds of rats were measured using an electronic analgesic device. Once the mechanical withdrawal thresholds of the rats significantly decreased, the different concentrations of schisandrin B suspension were administered by gavage to achieve final dosages of 30, 100, and 300 mg / kg. The mechanical withdrawal thresholds of rats in each group were measured again at 1 h, 2 h, and 4 h after administration.

[0047] Experimental Results: Intraperitoneal injection of oxaliplatin was used to induce a mechanical pain threshold in rats. Results from D9-D13 (D0 being the day of the first oxaliplatin injection) before administration showed a significant decrease in the mechanical pain threshold in all groups compared to pre-induction levels, with statistically significant differences. Gavage administration of schisandrin at doses of 30, 100, and 300 mg / kg resulted in relief of mechanical pain sensitivity in rats 1 hour after administration, with significant differences compared to pre-administration levels, which persisted for up to 4 hours. Schisandrin at doses of 30, 100, and 300 mg / kg significantly increased the mechanical withdrawal threshold in rats in a dose-dependent manner. See Table 3 and the attached diagram in the instruction manual for the results. Figure 2 .

[0048] Table 3. Results of mechanical pain sensitivity testing in rats of each group in Example 2.

[0049]

[0050] Example 3: Therapeutic administration of schisandrin B can alleviate oxaliplatin-induced cold pain sensitivity in rats.

[0051] Experimental methods: Male SD rats weighing 180-220g were randomly divided into two groups: an oxaliplatin model group (n=8) and a schisandrin B group (n=6).

[0052] Before the experiment, the cold pain baseline value of all rats was measured. Subsequently, all rats were injected intraperitoneally with 4 mg / kg oxaliplatin once a day for 5 consecutive days to establish the CIPN model.

[0053] Schisandrin B was prepared into a suspension with a concentration of 10 mg / ml using 0.5% CMC-Na solution. After modeling, the response latency of rats to cold pain was measured using dry ice. Once the response latency of rats to cold pain was significantly reduced, the schisandrin B suspension was administered by gavage to achieve a final dosage of 100 mg / kg. The response latency of rats to cold pain was further measured at 1 h, 2 h, and 4 h after administration.

[0054] Experimental Results: Intraperitoneal injection of oxaliplatin was used to establish the cold pain model. Pre-administration measurements from D9 to D17 (D0 being the day of the first oxaliplatin injection) showed a significantly shortened latency period for cold pain response in all groups of rats. Gavage administration of 100 mg / kg schisandrin resulted in relief of cold pain sensitivity in rats 1 hour after administration, which persisted until 4 hours post-administration. At the 1-hour and 2-hour time points, the latency period for cold pain response in the schisandrin group was significantly longer compared to the oxaliplatin model group. See Table 4 and the attached diagram in the instruction manual for the results. Figure 3 .

[0055] Table 4. Results of cold pain sensitivity test in rats of each group in Example 3.

[0056]

[0057]

[0058] Example 4: Therapeutic administration of schisandrin can reduce paclitaxel-induced mechanical hyperalgesia in rats.

[0059] Experimental methods: Male SD rats weighing 180-220g were randomly divided into two groups: a paclitaxel model group (n=8) and a schisandrin B 100mg / kg group (n=9).

[0060] Before the experiment, mechanical pain baseline values ​​were measured in all rats. Subsequently, all rats were injected intraperitoneally with 2 mg / kg paclitaxel every other day for a total of 4 times to establish the CIPN model.

[0061] Schisandrin B was prepared into a suspension with a concentration of 10 mg / ml using 0.5% CMC-Na solution. After modeling, the mechanical withdrawal thresholds of rats were measured using an electronic analgesic device. Once the mechanical withdrawal thresholds of rats significantly decreased, the schisandrin B suspension was administered by gavage to achieve a final dosage of 100 mg / kg. The mechanical withdrawal thresholds of rats in each group were measured again at 1 h, 2 h, and 4 h after administration.

[0062] Experimental Results: Intraperitoneal injection of paclitaxel was used to establish the mechanical pain model. Results from D23-D29 (D0 being the day of the first paclitaxel injection) before administration showed a significant decrease in the mechanical pain threshold in all groups, with statistically significant differences compared to pre-modeling levels. Gavage administration of 100 mg / kg schisandrin resulted in relief of mechanical pain sensitivity in rats 1 hour after administration, with a statistically significant difference compared to pre-administration levels. Two hours after administration, the schisandrin group showed a statistically significant difference compared to the paclitaxel model group. See Table 5 and the attached diagram in the instruction manual for the results. Figure 4 .

[0063] Table 5. Results of mechanical pain sensitivity testing in rats of each group in Example 4.

[0064]

[0065] Example 5: Therapeutic administration of schisandrin can alleviate paclitaxel-induced cold pain in rats.

[0066] Experimental methods: Twelve male SD rats weighing 180-220g were randomly divided into two groups: a paclitaxel model group and a schisandrin B 100mg / kg group, with six rats in each group.

[0067] Before the experiment, the cold pain baseline value of all rats was measured. Subsequently, all rats were injected intraperitoneally with 2 mg / kg paclitaxel every other day for a total of 4 times to establish the CIPN model.

[0068] Schisandrin B was prepared into a suspension with a concentration of 10 mg / ml using 0.5% CMC-Na solution. After modeling, the response latency of rats to cold pain was measured using dry ice. Once the response latency of rats to cold pain was significantly reduced, the schisandrin B suspension was administered by gavage to achieve a final dosage of 100 mg / kg. The response latency of rats to cold pain was further measured at 1 h, 2 h, and 4 h after administration.

[0069] Experimental Results: Paclitaxel was administered intraperitoneally to establish the cold pain model. Results from D16-D20 (D0 being the day of the first paclitaxel injection) before administration showed a significantly shortened latency period for cold pain response in all groups of rats. While no significant difference was observed between the paclitaxel model group and the 100 mg / kg schisandrin group at any time point after gavage administration, cold pain sensitivity was alleviated at 1 h and 4 h after administration, and the latency period for cold pain response was significantly prolonged compared to before administration (P < 0.01). See Table 6 and the attached diagram in the instruction manual for the results. Figure 5 .

[0070] Table 6. Results of cold pain sensitivity test in rats of Example 5.

[0071]

[0072] Example 6: Preparation of Schisandrin B Tablets

[0073] The prescription is as follows: Schisandrin B 5g

[0074] Povidone K90 15g

[0075] Microcrystalline cellulose MCC102 15g

[0076] 15g of cross-linked carboxymethyl cellulose sodium (CCNa)

[0077] Micronized silica gel 15g

[0078] Preparation process: Measure 500ml of ethanol, add 15g of povidone K90, shake thoroughly to dissolve, then add 5g of schisandrin B, place in a rotary evaporator, concentrate until the solvent is basically evaporated, cool rapidly, dry, and pulverize the resulting solid through an 80-mesh sieve to obtain a schisandrin B solid dispersion. Then, 15g of microcrystalline cellulose MCC102, 15g of croscarmellose sodium CCNa, and 15g of micronized silica gel are each sieved through an 80-mesh sieve, and then mixed evenly with the schisandrin B solid dispersion. Compress directly into tablets of 50mg schisandrin B per tablet to obtain schisandrin B tablets.

[0079] Example 7: Preparation of Schisandrin B Tablets

[0080] The prescription is as follows: Schisandrin B 5g

[0081] Povidone K90 20g

[0082] Microcrystalline cellulose MCC102 10g

[0083] 10g of croscarmellose sodium (CCNa)

[0084] 10g of micronized silica

[0085] Preparation process: Measure 500ml of ethanol, add 20g of povidone K90, and shake thoroughly to dissolve. Then add 5g of schisandrin B, add to a rotary evaporator, concentrate until the solvent is basically evaporated, cool rapidly, dry, and pulverize the resulting solid through an 80-mesh sieve to obtain a schisandrin B solid dispersion. Then, 10g of microcrystalline cellulose MCC102, 10g of croscarmellose sodium CCNa, and 10g of micronized silica gel are each sieved through an 80-mesh sieve, and then mixed evenly with the schisandrin B solid dispersion. Compress directly into tablets of 50mg schisandrin B per tablet to obtain schisandrin B tablets.

[0086] Example 8: Preparation of Schisandrin B Capsules

[0087] The prescription is as follows: Schisandrin B 330g

[0088] 250g of microcrystalline cellulose

[0089] 16g of croscarmellose sodium cellulose

[0090] Micronized silica gel 60g

[0091] 4g magnesium stearate

[0092] Appropriate amount of 5% polyvinylpyrrolidone aqueous solution

[0093] Preparation process of the prescription: The microcrystalline cellulose and excipients in the prescription are passed through an 80-mesh sieve. The amount of schisandrin B in the prescription is weighed and mixed evenly with each excipient. Then, 5% polyvinylpyrrolidone aqueous solution is added to make a soft material, which is then granulated, dried, sized, talc powder is added, mixed evenly, and filled into capsules to obtain 1000 capsules.

[0094] Example 9: Preparation of Schisandrin B Capsules

[0095] The prescription is as follows: Schisandrin B 160g

[0096] 250g of microcrystalline cellulose

[0097] 16g of croscarmellose sodium cellulose

[0098] Micronized silica gel 60g

[0099] 4g magnesium stearate

[0100] Appropriate amount of 5% polyvinylpyrrolidone aqueous solution

[0101] Preparation process of the prescription: The microcrystalline cellulose and excipients in the prescription are passed through an 80-mesh sieve. The amount of schisandrin B in the prescription is weighed and mixed evenly with each excipient. Then, 5% polyvinylpyrrolidone aqueous solution is added to make a soft material, which is then granulated, dried, sized, talc powder is added, mixed evenly, and filled into capsules to obtain 1000 capsules.

[0102] The above description is merely a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. The use of schisandrin B or a pharmaceutically usable salt of schisandrin B in the preparation of analgesic drugs; wherein the analgesia is for the treatment and / or prevention of chemotherapy-induced neuropathic pain; wherein the neuropathic pain is caused by a chemotherapy drug selected from platinum-based drugs, taxane-based drugs, or combinations thereof.

2. The application according to claim 1, wherein the analgesia can alleviate neuropathic pain caused by chemotherapy.

3. The application according to claim 1, wherein the platinum group is selected from cisplatin, carboplatin, or oxaliplatin; and the taxane group is paclitaxel or docetaxel.

4. The application according to claim 1 or 2, wherein the drug is a pharmaceutical composition containing schisandrin B or a pharmaceutically usable salt of schisandrin B.

5. The application according to claim 4, wherein the pharmaceutical composition may further contain a pharmaceutically acceptable carrier.

6. The application according to claim 5, wherein the pharmaceutical composition is formulated into any pharmaceutically acceptable dosage form.

7. The application according to claim 6, wherein the pharmaceutically acceptable dosage form is selected from tablets, capsules, solutions, granules, powders, ointments, pills, suspensions, suppositories, emulsions, patches, or sprays.

8. The application according to claim 6, wherein the pharmaceutically acceptable dosage form is selected from liniments.

9. The application according to claim 6, wherein the pharmaceutically acceptable dosage form is selected from topical formulations.

10. The application according to claim 7, wherein the dosage form is in unit dose form, each unit dose containing schisandrin B or a pharmaceutically acceptable salt of schisandrin B: 1-10 mg, or 10-100 mg, or 100-1000 mg, or 1000-10000 mg.

Images