Application of Cyclovirobuxine D in Pharmaceutical Manufacturing

Abstract

The present invention provides an application of Cyclovirobuxinum D (CVB-D) in pharmaceutical preparation, belonging to the technical field of medical drugs. CVB-D has a significant inhibitory effect on Ca v 3.2 Activity of low voltage-gated calcium channels, different ion channels involved in pain transmission in peripheral nociceptors, such as Na v 1.7 Na v 1.8, TRPV1, TPRA1, TRPM8, ASIC3, P 2 X 2 and P 2 X 4 In addition, CVB-D can significantly relieve inflammatory pain induced by carlean gum and complete Freund's adjuvant and neuropathic pain induced by paclitaxel, and its effect is comparable to that of the positive control Z944. v 3.2 Low voltage-gated calcium channel inhibitors.

Description

Technical Field

[0001] The present invention belongs to the field of medical drug technology. It relates to the application of cyclovirobuxinum D in pharmaceutical preparation, and specifically to the application of a drug combination with cyclovirobuxinum D (CVB-D) as an active ingredient in the preparation of a drug for treating inflammatory pain and neuropathic pain. Background Art

[0002] Cyclovirobuxine D (CVB-D) is an active triterpene alkaloid extracted and separated from Buxus microphylla and plants of the same genus in the Buxaceae Dumort. family. From the discovery of the Huang Buxus prescription in 1969 to the successful development of Huang Buxus Ning tablets with CVB-D as the main ingredient, it has become the first new drug in China to treat ischemic cardiovascular and cerebrovascular diseases. It can be said that CVB-D is another major discovery in the treasure house of traditional Chinese medicine after artemisinin and ephedrine. The drug has been included in the 2010 Pharmacopoeia. CVB-D is mainly used clinically to treat ischemic heart disease (coronary heart disease, angina pectoris), various arrhythmias, and heart failure. In addition to its functions of dilating blood vessels, increasing coronary flow, reducing myocardial oxygen consumption, exerting positive inotropic effects, and prolonging myocardial action potential and effective refractory period, in recent years it has also been found to have a series of physiological functions such as anti-malignant glioma, neuroprotection, and immunosuppression, indicating that CVB-D has extremely strong vitality and deserves further study.

[0003] Ion channels are the second largest target for current drug development. v 3.2 belongs to low voltage-gated calcium channels (LVGCC), which can open and inactivate rapidly when stimulated close to the resting potential (about -60mV), and can quickly deactivate under hyperpolarization stimulation. Its important physiological function is to participate in the formation of low threshold calcium spikes and generate "window currents" at resting membrane potential. These play an important regulatory role in important life activities such as the transmission of action potentials of neuronal cells, regulation of synaptic plasticity, release of low threshold neurotransmitters, and maintenance of normal vibration (discharge) of rhythmic tissues such as thalamocortical circuits. Ca v 3.2 Functional disorders or gene mutations can induce a variety of serious diseases, such as neuropathic pain, absence epilepsy, cerebellar ataxia, Parkinson's tremor and depression. In recent years, well-known foreign pharmaceutical companies such as Zalicus, MERK, Actelion, Idorsia and Cavion have begun to use it as a target for innovative drug research and development, and a series of pain relief active molecules represented by Z944 have also entered clinical research. v3.2 has become one of the important targets for pain drug development, and it is worthwhile to carry out in-depth research and development of related drugs.

[0004] So far, CVB-D has not been found in the prior art as a new type of Ca v 3.2 Report on the use of low voltage-gated calcium channel inhibitors and drug combinations as main active molecules in the preparation of drugs for the treatment of inflammatory pain and neuropathic pain. Summary of the invention

[0005] The purpose of the present invention is to provide CVB-D as a new type of Ca v 3.2 Low voltage-gated calcium channel inhibitors and their use as drug combinations with the main active molecules in the preparation of drugs for the treatment of inflammatory pain and neuropathic pain.

[0006] In order to achieve the above-mentioned object of the present invention, the present invention provides the following technical solutions:

[0007] Compound CVB-D is used in the preparation of Ca v 3.2 Application of low voltage-gated calcium channel inhibitors.

[0008] Compound CVB-D is used in the preparation of Ca-inhibiting v 3.2 Application of drugs in diseases with low voltage-gated calcium channel activity.

[0009] Application of the compound CVB-D in preparing medicines for treating inflammatory pain and neuropathic pain.

[0010] The invention discloses an application of the compound CVB-D in preparing medicines for treating pain, absence epilepsy, tremor, sleep disorder and depression.

[0011] According to the application, wherein the Ca v 3.2 Low voltage-gated calcium channel activity diseases are one or more of inflammatory pain and neuropathic pain.

[0012] According to the application, the dosage of the compound CVB-D is 0.1 mg / kg to 30 mg / kg.

[0013] According to the application, the compound CVB-D exists in the form of a racemate, a mixture of stereoisomers or a stereoisomer.

[0014] According to the application, the compound CVB-D exists in the form of a salt.

[0015] According to the application, the compound CVB-D exists in the form of a solvate.

[0016] The present invention also provides a Ca v 3.2 Low voltage-gated calcium channel inhibitor, which has compound CVB-D as the active ingredient.

[0017] Preferably, the CVB-D dose is 1 mg / kg to 30 mg / kg body weight.

[0018] Preferably, the specific dosage of CVB-D can be adjusted within the above dosage range according to the actual symptoms and administration methods.

[0019] Preferably, CVB-D is present in the form of a racemate, a mixture of stereoisomers or stereoisomers.

[0020] Preferably, the CVB-D is in the form of a salt.

[0021] Preferably, the CVB-D exists in the form of a solvate.

[0022] Preferably, the pharmaceutical composition is an oral preparation or an external preparation.

[0023] Preferably, the oral preparations include oral solid preparations and oral liquid preparations, the oral solid preparations are tablets, enteric-coated tablets, sustained-release tablets, granules or hard capsules, and the oral liquid preparations are oral solutions or syrups.

[0024] Preferably, the external preparation is an ointment, a transdermal patch, a suppository, an aerosol, a liniment, a gel or an injection.

[0025] The auxiliary materials and / or additives that can be used in the pharmaceutical preparations involved in the present invention can be selected from carrier materials, excipients, stent materials, glidants, fillers, solvents, cosolvents, diluents, colorants, flavoring agents, antioxidants, adhesives, transdermal enhancers, surfactants, propellants, pill bases, suppository bases, and / or ointment bases, and the selection of the types and amounts of these auxiliary materials and / or additives depends on the method of making and using the product. These oral or external preparations can be applied.

[0026] The pharmaceutical salts in the present invention refer to pharmaceutically acceptable salts, including salts formed with organic acids and inorganic acids. The organic acids are tartaric acid, citric acid, formic acid, acetic acid, oxalic acid, butyric acid, oxalic acid, maleic acid, succinic acid, oxalic acid, alginic acid, aspartic acid, benzenesulfonic acid, camphoric acid, camphorsulfonic acid, digluconic acid, cyclopentanepropionic acid, dodecylsulfonic acid, ethanesulfonic acid, glucoheptonic acid, glycerophosphoric acid, hemisulfuric acid, heptanoic acid, hexanoic acid, fumaric acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, methanesulfonic acid, nicotinic acid, 2-naphthalenesulfonic acid, pamoic acid, pectinic acid, 3-phenylpropionic acid, picric acid, pivalic acid, propionic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonate and undecanoate. The inorganic acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid or phosphoric acid.

[0027] CVB-D has a significant inhibitory effect on Ca v 3.2 Activity of low voltage-gated calcium channels, different ion channels involved in pain transmission in peripheral nociceptors, such as Na v 1.7 Na v The selectivity of CVD-B in 1.8, TRPV1, TPRA1, TRPM8, ASIC3, P2X2 and P2X4 is outstanding. The inventor's previous studies have shown that CVD-B has a good effect on relieving various pain symptoms. Combined with its long-term clinical use, it shows that it is a Ca v 3.2 Low voltage-gated calcium channel inhibitors have potential medicinal value in the treatment of inflammatory pain and neuropathic pain.

[0028] The present invention provides a Ca-based v 3.2 A pharmaceutical composition having low voltage-gated calcium channel inhibitory activity, consisting of an active ingredient and a pharmaceutically acceptable excipient.

[0029] The present invention has no particular limitation on the pharmaceutically acceptable excipients. Specifically, the pharmaceutically acceptable excipients preferably include one or more of a drug carrier, a surfactant, a buffer substance, a disintegrant, a binder, a filler, a lubricant, an excipient, a solubilizer, a flavoring agent, and a coloring agent. The present invention has no particular limitation on the specific types of the above excipients, and they can be selected according to actual needs.

[0030] The present invention provides the use of the compound described in the above technical solution and the pharmaceutical composition thereof in the preparation of a drug for treating pain, absence epilepsy, tremor, sleep disorder and depression.

[0031] The present invention has no particular limitation on the dosage form of the drug for treating inflammatory pain and neuropathic pain, and can be selected according to actual needs, and can specifically be tablets, capsules, granules, granules, pills, oral liquid preparations, ointments, transdermal patches and suppositories, etc. The present invention has no particular limitation on the preparation method of drugs in different dosage forms, and can be prepared by methods well known to those skilled in the art.

[0032] In the present invention, the dosage of the drug for treating inflammatory pain and neuropathic pain will vary with the compound used, the mode of administration, the desired treatment and the disorder indicated. For example, for topical administration, the daily dosage of CVB-D or a pharmaceutically acceptable salt thereof can be in the range of 1 mg / kg to 30 mg / kg of body weight. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 The CVB-D (30 μM) of the present invention is effective for Na v 1.7 Na v 1.8, inhibition of TRPV1, TPRA1, TRPM8, ASIC3, P2X2, and P2X4. Mock: HEK293 cells that do not express any channel.

[0034] Figure 2 .The effect of CVB-D of the present invention on relieving inflammatory pain. In the figure, A: the relieving effect of CVB-D (plantar injection) on mechanical sensitivity induced by carleish gum; BC: the relieving effect of CVB-D (plantar injection) on thermal sensitivity induced by carleish gum and the dose-effect relationship; D: the relieving effect of CVB-D (intraperitoneal injection) on mechanical sensitivity induced by carleish gum; EF: the relieving effect of CVB-D (plantar injection) on thermal and mechanical sensitivity induced by complete Freund's adjuvant; GH: the relieving effect of Z944 (plantar injection) on mechanical and thermal sensitivity induced by carleish gum; I: the relieving effect of Z944 (intraperitoneal injection) on mechanical sensitivity induced by complete Freund's adjuvant; JL: comparison of the relieving effects of CVB-D and Z944 on inflammatory pain.

[0035] Figure 3 .The effect of CVB-D of the present invention on relieving paclitaxel-induced neuropathic pain. In the figure, A: the relieving effect of CVB-D (plantar injection) on paclitaxel-induced neuropathic hyperthermia; B: the relieving effect of Z944 (plantar injection) on paclitaxel-induced neuropathic hyperthermia; D: the relieving effect of CVB-D (intraperitoneal injection) on carlesite-induced mechanical sensitivity; C: comparison of the relieving effects of CVB-D and Z944 on neuropathic pain. DETAILED DESCRIPTION

[0036] The following will be combined with the accompanying drawings and the embodiments of the present invention to clearly and completely describe the technical solutions of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0037] Example 1

[0038] Compound CVB-D (HY-N0107), purity: 99.36%, purchased from MedChemExpress Biotechnology Company

[0039] CVB-D inhibits Ca v Function of 3.2.

[0040] The CVB-D of the present invention has a great influence on the Ca v 3.2 The experimental methods and results of calcium channel inhibition activity are as follows:

[0041] 1. Cell preparation and expression

[0042] Human embryonic kidney (HEK) 293 cells were cultured in DMEM (HyClone) supplemented with 10% fetal calf serum (Gibco) and penicillin (100 units / ml) and streptomycin (0.1 mg / ml) (Biological Industries). 293 cells in logarithmic growth phase were stained with LipoD293 TM (SignaGen Laboratories) transfection reagent transfected human pCDNA3.1-TRPA1, TRPV1, TRPM8, P2X2, P2X4, ASIC3, Na v 1.7 Na v 1.8 Ca v Transfected human embryonic kidney (HEK) 293 cells should be used within 48 hours.

[0043] 2. Electrophysiology Experiment

[0044] All experiments were performed at room temperature (22-25°C). Borosilicate glass pipettes (World Precision Instruments) were prepared as glass electrodes with an impedance of 2-4 MΩ using a microelectrode puller (P-1000, Sutter Instrument) and heated polishing and used for whole-cell current recording. The current was amplified by Axopatch 200B, and then the data was converted by Digidata 1440A (Molecular Devices). The current was passed through a low-energy filter at 2 kHz and then sampled at 10 kHz. pCLAMP 10 (Molecular Devices) was used for data acquisition and analysis.

[0045] Record Ca v 3.2 During the current recording, the extracellular solution contained (in mM) 142CsCl, 1MgCl2, 2CaCl2, 10Glucose and 10HEPES (pH = 7.4, adjusted with CsOH). The intracellular solution contained (in mM) 127Cs-methanesulphonate, 2MgCl2, 2Na2ATP, 10HEPES and 11EGTA (pH = 7.4, adjusted with CsOH). The current recording procedure was as follows: the cell membrane was clamped at -100mV potential, and the cell was stimulated with a 150ms -30mV depolarizing voltage, with a 4s interval between each stimulation.

[0046] When recording TRPA1, TRPV1 and TRPM8 currents, the extracellular solution contained (in mM) 150 NaCl, 1 MgCl2 and 10 HEPES (pH = 7.4, adjusted with NaOH). The intracellular solution contained (in mM) 150 NaCl, 1 MgCl2, 1 EGTA and 10 HEPES (pH = 7.4, adjusted with NaOH). The current recording procedure was as follows: the cell membrane was clamped at 0 mV potential, and the cell was stimulated with a ramp voltage from -100 mV to +100 mV for 500 ms, with an interval of 2 s between each stimulation.

[0047] When recording ASIC3, P2X2 and P2X4 currents, the extracellular solution contained (in mM) 150 NaCl, 1 MgCl2 and 10 HEPES (pH = 7.4, adjusted with NaOH). The intracellular solution contained (in mM) 140 KCl, 5 EGTA and 10 HEPES (pH = 7.4, adjusted with NaOH). The current recording procedure was: the cell membrane was clamped at -60 mV potential and the current was recorded in gap-free mode.

[0048] Record Na v 1.7 and Na vThe extracellular solution contained (in mM) 135K-gluconate, 5KCl, 5Mg-ATP, 0.5Na2GTP, 5HEPES, 2MgCl2, 5EGTA and 0.5CaCl2 (pH = 7.4, adjusted with KOH) at 1.8 current. The intracellular solution contained (in mM) 140NaCl, 5KCl, 2CaCl2, 2MgCl2, 10HEPES and 10glucose (pH = 7.4, adjusted with NaOH). The current recording procedure was: the cell membrane was clamped at a potential of -110mV, and the cell was stimulated with a 10ms depolarizing voltage of -30mV, with an interval of 5s between each stimulation.

[0049] 3. Data analysis and statistics

[0050] Data collection and statistical analysis were performed using GraphPad 8.0.1 (GraphPad Software, San Diego, CA USA). 50 The Hill coefficient is calculated by the Hill equation Y = I Min +(I Max -IC Min ) / [1+10(LogEC 50 -C)×Hillslope] is calculated using the collected data. Here IC 50 is the concentration at which the channel current is inhibited by half, C is the concentration of the compound, and I Min is the minimum inhibition rate, I Max is the maximum inhibition rate, Hillslope is the Hill coefficient. All data are mean ± standard deviation.

[0051] 4. CVB-D for Ca v 3.2 Calcium channel inhibitory activity experiment, as shown in Table-1.

[0052] The experimental results showed that under the above experimental conditions, mibefradil (a classic low voltage-gated calcium 2+ Channel inhibitors, once used clinically to treat hypertension, are effective in treating Ca v The inhibitory activity of 3.2 was significant, and the IC 50 =2.0μM, and the Hill coefficient was 1.1. CVB-D also showed a significant Ca v 3.2 Calcium flux inhibition activity, IC 50 The Hill coefficient of CVB-D was 2.28 μM and 1.4. v The inhibitory effect of 3.2 is basically at the same order of magnitude as that of the positive control mibefradil, and the activity is similar.

[0053] Table-1. Effects of CVB-D and mibefradil on Ca v 3.2 Dose-effect relationship of inhibition

[0054]

[0055] 5. Effects of CVB-D on different ion channels involved in pain transmission in peripheral nociceptors

[0056] like Figure 1 As shown, high concentration of CVB-D (30 μM) Na v 1.7 Na v 1.8, TRPV1, TPRA1, TRPM8, ASIC3, P2X2 and P2X4, a series of ion channels involved in pain transduction in peripheral nociceptors, have no obvious effect and are highly selective.

[0057] In order to demonstrate that the CVB-D drug combination has a significant alleviating effect on inflammatory pain, the present invention conducted the following pharmacological experiments:

[0058] Experimental methods:

[0059] SPF grade C57BL / 6 experimental mice aged 8-10 weeks were adapted to the SPF barrier system environment for 3 days before the experiment.

[0060] Experimental groups:

[0061] 1. Vehicle control group (n=6-12): The vehicle was injected subcutaneously into the plantar surface of the right hind limb of mice, with a volume of 20 μl.

[0062] 2. Inflammatory pain model group (n=10-12): 3% carbenicillin saline solution or 20 μl complete Freund's adjuvant saline solution was subcutaneously injected into the plantar of the right hind limb of mice.

[0063] 3. Test drug group (n=10-12): 10 μl of test drug was injected intraplantarly or intraperitoneally at a volume of 10 ml / kg.

[0064] 4. Test drug + inflammatory pain model group (n=10-12): The test drug was injected into the plantar or intraperitoneal cavity 30 minutes before modeling.

[0065] Note: When the number of animals is even, half are male and half are female. When the number is odd, there is one more male or female.

[0066] Drug dosage:

[0067] Carbenicillin: 50 μl.

[0068] Complete Freund's adjuvant: 20 μl.

[0069] CVB-D: 10 μL / paw, 0.4 to 10.07 μg, intraplantar injection; 5 mg / kg, intraperitoneal injection.

[0070] Z944: 10 μL / paw, 3.84 μg, intraplantar injection; 3 mg / kg, intraperitoneal injection.

[0071] Drug solvent:

[0072] Carbenicillin / Complete Freund's Adjuvant: Normal Saline

[0073] CVB-D: 5% alcohol saline solution

[0074] Z944: 1% DMSO in saline

[0075] Animal thermal stimulation pain sensitivity test: The mice were placed on a stainless steel hot plate (round plate with a diameter of 20 cm) at a temperature of 52°C, and the time of the first paw withdrawal or paw licking of the drug-administered paw was recorded.

[0076] Animal mechanical stimulation pain sensitivity test: The mice were placed in a plastic box with a circular grid (aperture 6mm) on the bottom (length: 45cm, width: 29cm). The paws were stimulated with 0.008-4g von Frey fibers. The appropriate fibers were determined according to the current threshold of the mice. If there was a reaction, a fiber with a smaller intensity was selected. If there was no reaction, a fiber with a larger intensity was selected. The paw retraction reaction of the mice under stimulation of different intensities was recorded. Each fiber of each intensity was stimulated 3 times, and the thresholds of 6 fibers with different intensities were recorded. The recorded data were then substituted into the Vonfrey threshold table to find the corresponding threshold.

[0077] T-test was used for the significant difference between the two groups, P>0.5, *P<0.05, **P<0.01, ***P<0.001. All data are mean ± standard error.

[0078] Example 2

[0079] The effect of CVB-D in alleviating inflammatory pain.

[0080] like Figure 2 As shown in Figures AC, the sensitivity of mice in the inflammatory model group induced by carbene glue to temperature (heat) and mechanical stimulation was greatly improved compared with the vehicle group and the test drug group, as shown by a significant shortening of the first paw withdrawal or licking time on a 52°C hot plate and a significant decrease in the threshold of paw withdrawal response to von Frey fiber stimulation. Intraplantar injection of CVB-D significantly alleviated the enhanced pain sensitivity caused by inflammation in mice, and the effect of alleviating heat sensitivity was dose-dependent, EC 50 The CVB-D intraperitoneal injection also showed a significant pain relief effect ( Figure 2Similar to the carbeneform-induced inflammatory model, CVB-D can significantly alleviate the hyperalgesia induced by complete Freund's adjuvant ( Figure 2 It is worth noting that a single dose of CVB-D showed a long-lasting analgesic effect in the above model, especially for heat sensitivity, which CVB-D could prevent. Z944 is currently being studied in clinical analgesic effects. v 3.2 inhibitors, which also have a prominent effect in alleviating pain in the above models ( Figure 2 It is worth noting that the mitigating effects of CVB-D on thermosensitivity and mechanosensitivity in the above models are comparable to those of Z944 ( Figure 2 (shown in JL).

[0081] In order to demonstrate that the CVB-D drug combination has a significant alleviating effect on neuropathic pain, the present invention conducted the following pharmacological experiments:

[0082] Experimental methods:

[0083] SPF grade C57BL / 6 experimental mice aged 8-10 weeks were adapted to the SPF barrier system environment for 3 days before the experiment.

[0084] Experimental groups:

[0085] 1. Vehicle control group (n=12): The vehicle was injected subcutaneously into the plantar surface of the right hind limb of mice, with a volume of 20 μl.

[0086] 2. Neuropathic pain model group (n=12): Paclitaxel was intraperitoneally injected once every other day for a total of four times.

[0087] 3. Test drug group (n=12): 10 μl of test drug was injected into the plantar surface of the foot.

[0088] 4. Test drug + neuropathic pain model group (n=12): Paclitaxel was administered by intraplantar injection 30 minutes before the first intraperitoneal injection.

[0089] Note: When the number of animals is even, half are male and half are female. When the number is odd, there is one more male or female.

[0090] Drug dosage:

[0091] Paclitaxel: 4 mg / kg, intraperitoneal injection

[0092] CVB-D: 10 μL / paw, 10.07 μg, intraplantar injection.

[0093] Z944: 10 μL / paw, 3.84 μg, intraplantar injection.

[0094] Drug solvent:

[0095] Paclitaxel: normal saline

[0096] CVB-D: 5% alcohol saline solution

[0097] Z944: 1% DMSO in saline

[0098] T-test was used for the significant difference between the two groups, P>0.5, *P<0.05, **P<0.01, ***P<0.001. All data are mean ± SD

[0099] Example 3

[0100] Effect of CVB-D in relieving neuropathic pain.

[0101] like Figure 3 As shown in A, the sensitivity of the mice in the yew-induced neuropathic pain model group to thermal stimulation was greatly improved compared with the vehicle group and the test drug group, as shown by a significant shortening of the first paw retraction or paw licking time on a 52°C hot plate. Intraplantar injection of CVB-D significantly alleviated the enhanced thermal sensitivity caused by neurological damage in mice ( Figure 2 It is worth noting that a single dose of CVB-D can prevent the occurrence of heat sensitivity induced by nerve damage. Z944 is currently being studied in clinical pain relief. v 3.2 inhibitors, which also have a prominent effect in alleviating pain in the above models ( Figure 3 It is worth noting that the mitigating effect of CVB-D on thermosensitivity in the above model is comparable to that of Z944 ( Figure 3 (as shown in C).

[0102] Formulation Examples

[0103] 1 Tablets: Compound CVB-D and a salt made from an organic acid (tartaric acid, citric acid, formic acid, oxalic acid, etc.) or an inorganic acid (hydrochloric acid, sulfuric acid, phosphoric acid, etc.) are added to the excipients at a weight ratio of 1:5-1:10 to the excipients, and the mixture is granulated and tableted.

[0104] 2. Oral solution: Take compound CVB-D and a salt made from an organic acid (tartaric acid, citric acid, formic acid, oxalic acid, etc.) or an inorganic acid (hydrochloric acid, sulfuric acid, phosphoric acid, etc.), and prepare an oral solution according to a conventional oral solution preparation method.

[0105] 3. Capsules, granules or powders: Take compound CVB-D and a salt made from an organic acid (tartaric acid, citric acid, formic acid, oxalic acid, etc.) or an inorganic acid (hydrochloric acid, sulfuric acid, phosphoric acid, etc.), add an excipient at a weight ratio of 5:1 to the excipient to prepare capsules, granules or powders.

[0106] 4. Ointment: Take compound CVB-D and a salt made from an organic acid (tartaric acid, citric acid, formic acid, oxalic acid, etc.) or an inorganic acid (hydrochloric acid, sulfuric acid, phosphoric acid, etc.), add an excipient at a weight ratio of 5:1 to the excipient to prepare an ointment.

[0107] 5. After dissolving the compound CVB-D with DMSO, add water for injection according to the conventional method, filter finely, and fill and sterilize to prepare an injection solution, wherein the concentration of the injection solution is 0.5-5 mg / mL.

[0108] 6. Dissolve the compound CVB-D in DMSO and then dissolve it in sterile water for injection. Stir to dissolve it. Filter it with a sterile suction funnel, filter it with sterile fine filtration, and dispense it into ampoules. After low-temperature freeze-drying, aseptically seal it to obtain a powder injection.

[0109] 7. Compound CVB-D was added to the excipient at a mass ratio of 9:1 to the excipient to prepare a powder.

[0110] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. The use of the compound cyclovirobuxine D as the sole active ingredient in the preparation of drugs for the treatment of inflammatory pain and neuropathic pain.

2. The use according to claim 1, characterized in that: The dosage of the compound cyclovirobuxine D is 0.1 mg / kg to 30 mg / kg.

3. The use according to claim 1, characterized in that: The compound cyclovirobuxine D exists in the form of a salt.

Images