Pharmaceutical composition for treating pain

Abstract

The present invention belongs to the technical field of biopharmaceutics, and specifically relates to a pharmaceutical composition for treating pain. It has been found that TSA and GSK343, when administered alone in vivo, exhibit a certain therapeutic effect on neuropathic pain, while the combined administration of low-concentration TSA and GSK343 in vivo exhibits a significant therapeutic effect on neuropathic pain, showing good therapeutic effects at different phases. The combined administration regimen can manage acute NP, prevent transitional pain states and progression, and prevent the conversion of acute NP to chronic NP. In addition, the analgesic regimen has a high safety profile, and its therapeutic effect remains well‑maintained after drug withdrawal during the conversion phase and the chronic phase, solving the clinical problem that the persistence or recurrence of NP causes great suffering and functional impairment in patients.

Description

A pharmaceutical composition for treating pain Technical Field

[0001] This invention belongs to the field of biomedical technology, and specifically relates to a pharmaceutical composition for treating pain. Background Technology

[0002] The International Association for the Study of Pain (IASP) updated its definition of pain in 2020: Pain is an unpleasant sensory and emotional experience, or a similar experience, associated with actual or potential tissue damage. Pain can be classified by duration into acute and chronic pain; and by cause into nociceptive pain, neuropathic pain (NP) (or a mixture of both), and nociplastic pain (Trouvin AP, Perrot S. New concepts of pain[J]. Best Pract Res Clin Rheumatol. 2019 Jun; 33(3):101415.). Chronic neuropathic pain (CNP) is a common and difficult-to-treat type of chronic pain in clinical practice.

[0003] The International Association for the Study of Pain defines neuropathic pain (NP) as pain caused by damage or disease of the somatosensory system. Persistent or intermittent pain lasting more than 3 months is considered chronic neuropathic pain, characterized by spontaneous pain, touch-induced pain, hyperalgesia, and paresthesia (Finnerup NB, Kuner R, Jensen TS. Neuropathic pain: from mechanisms to treatment[J]. Physiol Rev, 2021, 101(1):259-301.). Based on the initial site of involvement, this specific type of pain is divided into central and peripheral neuropathic pain. Central pain is chronic pain caused by lesions or diseases of the central somatosensory nervous system. Common clinical examples include post-stroke pain (such as thalamic pain), multiple sclerosis-related pain, Parkinson's disease-related pain, and spinal cord injury pain. Peripheral pain is caused by lesions affecting the peripheral nervous system. Common types of pain include trigeminal neuralgia, glossopharyngeal neuralgia, alcoholic polyneuropathy, drug-induced polyneuropathy (such as chemotherapy drugs), complex regional pain syndrome, diabetic neuropathy, phantom limb pain, and postherpetic neuralgia (Nicholas M, Vlaeyen JWS, Rief W, et al. The IASP classification of chronic pain for ICD-11: chronic primary pain[J]. Pain. 2019 Jan; 160(1):28-37.). Peripheral pain (NP) is also one of the most difficult neurological diseases to treat, with a prevalence of 3.0% to 17.0% in the general population. NP is usually chronic, with persistent or recurrent pain, and is often accompanied by sleep disorders, anxiety, depression and other diseases. It not only brings a great economic burden to patients' families and society, but also causes great suffering and functional impairment to patients (Tian Sheng, Wu Wei. Research progress on pyroptosis and its role in neuropathic pain [J]. Chinese Journal of Pain Medicine, 2024, 30(4):290-295.).

[0004] The mechanism of neuropathic pain (NP) is complex and not yet fully understood. Recent studies have found that the possible mechanisms of NP mainly include changes in ion channels, central and peripheral sensitization, neuroinflammatory response, and imbalance between central excitatory and inhibitory signal transduction. When nerve fibers are damaged, the expression of voltage-gated sodium and calcium channels in the dorsal root ganglion is enhanced, which lowers the threshold of nerve fibers and neurons and can also enhance the release of neurotransmitters, promote ectopic discharge of excitatory and peripheral sensory neurons, and lead to spontaneous pain (Meacham K, Shepherd A, Mohapatra DP, et al. Neuropathic pain: central vs. peripheral mechanisms[J]. Curr Pain Headache Rep, 2017, 21(6):28; Alles SRA, Smith PA. Etiology and pharmacology of neuropathic pain[J]. Pharmacol Rev, 2018, 70(2):315-347.). Studies have shown that after nerve injury, chloride ion imbalance in the dorsal horn of the spinal cord leads to a shift from descending inhibition to descending facilitation of the endogenous serotonergic (5-HT) system, thereby inducing NP (Aby F, Lorenzo LE, Grivet Z, et al. Switch of serotonergic descending inhibition into facilitation by a spinal chloride imbalance in neuropathic pain[J]. Sci Adv, 2022, 8(30): eabo0689.). When inflammatory reactions or injuries occur, a series of neuropathological changes occur in the peripheral and central nervous systems. Peripheral sensitization and central sensitization are the main causes of pain hypersensitivity in NP patients. In neuroinflammation, neuroinflammatory response has been considered a potential common driver (Zhang LQ, Gao SJ, Sun J, et al. DKK3 ameliorates neuropathic pain via inhibiting ASK-1 / JNK / p-38-mediated microglia polarization and neuroinflammation[J]. J Neuroinflammation, 2022, 19(1): 129.).Neuroinflammatory reactions can increase Langerhans cells, leading to the loss of intraepidermal nerve fibers, enhancing synaptic transmission and central sensitization of spinal dorsal horn neurons, and ultimately causing abnormal pain (Zambusi A, Ninkovic J. Regeneration of the central nervous system-principles from brain regeneration in adult zebrafish[J].World J Stem Cells,2020,12(1):8-24.).

[0005] NP treatment can be divided into pharmacological and non-pharmacological treatments. Pharmacological treatments include first-line, second-line, and third-line drugs; non-pharmacological treatments include interventional therapy, physical therapy, and psychotherapy. First-line drugs include tricyclic antidepressants (TCAs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and anticonvulsants; second-line drugs include lidocaine, capsaicin, and tramadol; third-line treatments include certain potent opioids. Less than 50% of patients with neuropathic pain respond to existing drug treatments, 40% are undertreated, and 30% do not respond (van Hecke O, Austin SK, Khan RA, et al. Neuropathic pain in the general population: a systematic review of epidemiological studies[J]. Pain. 2014 Apr; 155(4):654-662.). Most drugs currently available for treating acute pain are ineffective in preventing pain. Opioids are often overused, especially during chronic pain. Postoperative severe pain is almost ubiquitous. For some patients, acute postoperative pain persists beyond the normal time for tissue healing and transitions into a chronic pain state. Chronic postoperative pain occurs in approximately 10% of surgical patients, typically beginning with uncontrollable acute postoperative pain but quickly transitioning to a persistent pain condition characterized by neuropathy that is unresponsive to opioids. However, the effective dose for postoperative pain is usually higher than the dose used for acute or non-neuropathy-related chronic pain. In addition to the typical side effects of tramadol, potent opioids can cause respiratory depression, and more importantly, the risk of drug abuse and overdose death is high (Benyamin R, Trescot AM, Datta S, et al. Opioid complications and side effects. Pain Physician. 2008 Mar; 11(2Suppl):S105-20.). Furthermore, other common analgesics also have varying degrees of adverse reactions. Some medications, such as gabapentin, pregabalin, duloxetine, and venlafaxine, may cause dizziness, drowsiness, peripheral edema, and gait disturbances (Thouaye M, Yalcin I. Neuropathic pain: From actual pharmacological treatments to new therapeutic horizons[J]. Pharmacol Ther. 2023 Nov; 251:108546.).Selective serotonin reuptake inhibitors (SSRIs) are ineffective or poorly effective when used alone for the treatment of neuropathic pain (Otto M, Bach FW, Jensen TS, et al. Escitalopram in painful polyneuropathy: a randomized, placebo-controlled, cross-over trial[J]. Pain. 2008 Oct 15; 139(2):275-283.). Mild side effects such as dizziness, sedation, dry mouth, constipation, and headache may occur when using TCAs (Saarto T, Wiffen PJ. Antidepressants for neuropathic pain[J]. Cochrane Database Syst Rev. 2007 Oct 17; 2007(4):CD005454.). SNRI use may cause side effects such as sedation or insomnia, headache and / or decreased appetite or libido (Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis[J]. Lancet Neurol. 2015 Feb;14(2):162-73.).Tramadol and tapentadol are second-line drugs for the treatment of neuropathic pain. They are weak opioid peptide agonists with low affinity only for MOR. Both have a variety of side effects, including nausea, vomiting, constipation, dizziness, drowsiness, and abuse risk (Thouaye M, Yalcin I. Neuropathic pain: From actual pharmacological treatments to new therapeutic horizons[J]. Pharmacol Ther. 2023 Nov; 251:108546.). Tramadol is metabolized by the liver and excreted by the kidneys. The clearance rate is low in patients with renal insufficiency (Silvasti M, Tarkkila P, Tuominen M, et al. Efficacy and side effects of tramadol versus oxycodone for patient-controlled analgesia after maxillofacial surgery[J]. Eur J Anaesthesiol. 1999 Dec; 16(12):834-9.). Therefore, there is an urgent need for effective and well-tolerated drug treatment.

[0006] Trichostatin A (TSA) is a non-selective histone deacetylase inhibitor (HDACi) that promotes cellular acetylation and regulates cellular function through epigenetic modifications (Ho TCS, Chan AHY, Ganesan A. Thirty Years of HDAC Inhibitors: 2020 Insight and Hindsight[J]. J Med Chem. 2020 Nov 12; 63(21):12460-12484.). Studies have shown that the combination therapy of TSA and 5-aza-20-deoxycytidine is more effective than single-agent therapy and significantly inhibits cell viability, migration, and tumor formation and growth. Cisplatin (1 mg / kg) and TSA (0.3 mg / kg, intraperitoneal injection) significantly inhibited the tumorigenicity of HEY xenografts by suppressing EMT and reducing the pluripotency of ovarian cancer cells (Meng F, Sun G, Zhong M, et al. Anticancer efficacy of cisplatin and trichostatin A or 5-aza-2'-deoxycytidine on ovarian cancer[J]. Br J Cancer. 2013 Feb 19; 108(3):579-86.). In a randomized controlled efficacy study of a rat model of breast cancer induced by the carcinogen N-methyl-N-nitrosourea, TSA showed significant antitumor activity in vivo when animals were subcutaneously injected daily at a dose of 500 μg / kg. Furthermore, TSA did not cause any measurable toxicity at subcutaneous injection doses up to 5 mg / kg. (Vigushin DM, Ali S, Pace PE, et al. Trichostatin A is a histone deacetylase inhibitor with potent antitumor activity against breast cancer in vivo[J]. Clin Cancer Res. 2001 Apr; 7(4):971-6.). Currently, there are clinical studies on the tolerability of trichostatin A in patients with relapsed or refractory hematologic malignancies.

[0007] GSK343 ​​is a selective, SAM-competitive inhibitor of histone lysine methyltransferase EZH2. GSK343 ​​inhibits the activity of this enzyme by competing with the cofactor SAM (Erma SK, Tian X, LaFrance LV, et al. Identification of potent, selective, cell-active inhibitors of the histone lysine methyltransferase EZH2[J].ACS medicinal chemistry letters,2012,3(12):1091-1096; Ferraro A, Boni T, Pintzas A. EZH2 Regulates Cofilin Activity and Colon Cancer Cell Migration by Targeting ITGA2 Gene[J]. PloS one,2014,9(12):e115276.). Studies have shown that GSK343 ​​treatment can reverse the reduction of Paneth cells caused by cecal ligation and perforation, and GSK343 ​​can protect the intestine from in vivo damage caused by sepsis (Yue D, Wang Z, Yang Y, et al. EZH2 inhibitor GSK343 ​​inhibits sepsis-induced intestinal disorders[J]. Exp Ther Med. 2021 May; 21(5):437.). Mouse models were administered GSK343 ​​intraperitoneally from day 5 to day 22. Then, weaned mice were orally administered low-dose (100 μM) or high-dose (400 μM) GSK343 ​​via water bottle. GSK343 ​​enhanced autophagy in the treatment of calcific arterial disease (Lino Cardenas CL, Jiang W, Kajuluri LP, et al. Treatment of calcific arterial disease via enhancement of autophagy using GSK343[J]. iScience. 2023 Oct 29; 26(11):108360.). Yu et al. found that GSK343 ​​could inhibit cancer stem cell-like phenotype and reverse mesenchymal transition in glioma cells, reduce the proliferation of U87 and LN229 glioma cells, weaken cell motility, and reverse epithelial-mesenchymal transition.Studies by Rondeaux et al. have shown that the pharmacological inhibition of EZH2 by GSK-343 resolves H3K27 methylation of the bivalent gene promoter, thereby enhancing their expression and promoting the repair function of human monocytes. Based on this protective effect, GSK-343 treatment accelerated the resolution of cardiac inflammation after MI in female mice, preventing infarct enlargement and subsequent cardiac dysfunction. (Rondeaux J, Groussard D, Renet S, et al. Ezh2 emerges as an epigenetic checkpoint regulator during monocyte differentiation limiting cardiac dysfunction post-MI[J]. Nat Commun. 2023 Jul 25;14(1):4461.) Furthermore, GSK343 ​​can effectively inhibit the progression and development of subcutaneous xenograft and primary CCA (cholangiocarcinoma) mouse models (Wu G, Wang Q, Wang D, et al. Targeting polycomb repressor complex 2-mediated bivalent promoter epigenetic silencing of secreted frizzled-related protein 1 inhibits cholangiocarcinoma progression[J]. Clin Transl Med. 2023 Dec;13(12):e1502.). Currently, no clinical trial records for GSK343 ​​have been found. Summary of the Invention

[0008] This invention discovers that TSA and GSK343 ​​can manage acute NP, prevent the progression of pain during the transition phase, promote safer analgesia regimens, prevent the conversion of acute NP to chronic NP, and have good therapeutic effects on chronic NP. Based on this, this invention was completed.

[0009] In a first aspect, the present invention provides a pharmaceutical composition for treating pain, the pharmaceutical composition comprising TSA and / or GSK343; wherein the TSA has the chemical formula C 17 H 22 N2O3, the chemical formula of GSK343 ​​is C 31 H 39 N7O2.

[0010] Furthermore, the pharmaceutical composition may also contain other analgesic active ingredients.

[0011] Furthermore, the other analgesic active ingredients include calcium ion channel drugs, sodium ion channel drugs, tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors, opioids, botulinum toxin type A and novel anti-inflammatory drugs such as tetrandrine, platelet-rich plasma and / or other active ingredients of drugs.

[0012] Furthermore, the calcium ion channel drug is selected from one or more of pregabalin, gabapentin, crisaggabalin, and / or mirogabalin.

[0013] Furthermore, the sodium ion channel drug is selected from one or more of carbamazepine, oxcarbazepine, lidocaine, and / or bulleyaconitine A.

[0014] Furthermore, the tricyclic antidepressant is selected from one or more of amitriptyline, imipramine, desipramine, and / or desitriptyline.

[0015] Furthermore, the selected serotonin and norepinephrine reuptake inhibitors (SNRIs) are selected from one or more of duloxetine and / or venlafaxine.

[0016] Furthermore, the opioid drug is selected from one or more of morphine, oxycodone, fentanyl, buprenorphine, tapentadol, methadone, and / or hydromorphone.

[0017] Furthermore, the other drugs are selected from one or more of tramadol, capsaicin patches, NMDA receptor antagonists, cannabinoids, antiepileptic drugs, traditional Chinese medicines, glucocorticoids, vitamins and / or muscle relaxants.

[0018] Furthermore, one or more pharmaceutically acceptable carriers may be added to the pharmaceutical composition.

[0019] Furthermore, the carrier material includes, but is not limited to, one or more of water-soluble carrier materials, poorly soluble carrier materials, and / or enteric carrier materials.

[0020] Furthermore, the water-soluble carrier material includes, but is not limited to, one or more of polyethylene glycol, polyvinylpyrrolidone, and / or organic acids.

[0021] Furthermore, the poorly soluble carrier material includes, but is not limited to, one or more of ethyl cellulose and / or cholesterol stearate.

[0022] Furthermore, the enteric carrier material includes, but is not limited to, one or more of cellulose acetate phthalate and / or carboxymethyl ethyl cellulose.

[0023] Furthermore, the pharmaceutical composition can be formulated into various dosage forms, including but not limited to one or more of tablets, capsules, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal preparations, and / or suppositories.

[0024] Furthermore, the formulation may be one or more of a conventional formulation, a sustained-release formulation, and / or a controlled-release formulation.

[0025] Furthermore, the tablets can widely utilize a variety of carriers known in the art, including one or more of diluents and absorbents, humectants and binders, disintegrants, disintegration inhibitors, absorption promoters and / or lubricants.

[0026] Furthermore, the diluent and absorbent include, but are not limited to, one or more of starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, and / or aluminum silicate.

[0027] Furthermore, the wetting agent and adhesive include, but are not limited to, one or more of water, glycerin, polyethylene glycol, ethanol, propanol, starch paste, dextrin, syrup, honey, glucose solution, gum arabic paste, gelatin paste, sodium carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate and / or polyvinylpyrrolidone.

[0028] Furthermore, the disintegrant includes, but is not limited to, one or more of the following: dried starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene, sorbitol fatty acid ester, sodium dodecyl sulfonate, methylcellulose and / or ethylcellulose.

[0029] Furthermore, the disintegration inhibitors include, but are not limited to, sucrose, tristearate, cocoa butter, and / or hydrogenated oils.

[0030] Furthermore, the absorption enhancer includes, but is not limited to, one or more of quaternary ammonium salts and / or sodium dodecyl sulfate.

[0031] Furthermore, the lubricant includes, but is not limited to, one or more of talc, silica, corn starch, stearate, boric acid, liquid paraffin, and / or polyethylene glycol.

[0032] Furthermore, the tablets can be further formulated into coated tablets, including sugar-coated tablets, film-coated tablets, enteric-coated tablets, bilayer tablets, and multilayer tablets.

[0033] Furthermore, the pills can utilize a wide range of carriers known in the art, including diluents and absorbents, binders and / or disintegrants.

[0034] Furthermore, the diluent and absorbent include, but are not limited to, one or more of glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin and / or talc.

[0035] Furthermore, the adhesive includes, but is not limited to, one or more of gum arabic, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste, and / or flour paste.

[0036] Furthermore, the disintegrant includes, but is not limited to, one or more of agar powder, dried starch, alginate, sodium dodecyl sulfonate, methylcellulose and / or ethylcellulose.

[0037] Furthermore, the suppository can widely use various carriers known in the art, including but not limited to one or more of polyethylene glycol, lecithin, cocoa butter, higher alcohols, esters of higher alcohols, gelatin and / or semi-synthetic glycerides.

[0038] Furthermore, the injectable formulation includes, but is not limited to, one or more of the following: solutions, emulsions, lyophilized powder for injection, and / or suspensions.

[0039] Furthermore, the injectable formulation may use all diluents commonly used in the art, including but not limited to one or more of water, ethanol, polyethylene glycol, 1,3-propanediol, ethoxylated isostearyl alcohol, polyoxyethylene isostearyl alcohol, and / or polyoxyethylene sorbitan fatty acid esters.

[0040] Furthermore, in order to prepare an isotonic injection solution, appropriate amounts of one or more of sodium chloride, glucose, glycerol, conventional solubilizers, buffers, and / or pH adjusters may be added to the injectable formulation.

[0041] Furthermore, colorants, preservatives, flavorings, tasters, sweeteners, or other materials may be added to the pharmaceutical preparations if necessary.

[0042] Furthermore, the pharmaceutical composition can be administered by injection, cavity administration, or inhalation.

[0043] Furthermore, the injection administration includes intrathecal injection, subcutaneous injection, intravenous injection, intramuscular injection, and intracavitary injection; the cavity administration includes rectal or vaginal administration; and the respiratory administration includes nasal administration.

[0044] Furthermore, the pain described is neuropathic pain.

[0045] Furthermore, the neuropathic pain is divided into acute phase, transformation phase, and chronic phase.

[0046] Furthermore, the neuropathic pain symptoms include hyperalgesia or hyperalgesia, spontaneous pain, and paresthesia.

[0047] Secondly, the present invention provides the application of TSA in the preparation of medicaments for treating pain; the chemical formula of the TSA is C 17 H 22 N2O3.

[0048] Furthermore, one or more pharmaceutically acceptable carriers may be added to the drug.

[0049] Furthermore, the drug can be formulated into various dosage forms, including but not limited to one or more of tablets, capsules, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal preparations, and / or suppositories.

[0050] Furthermore, the formulation may be one or more of a conventional formulation, a sustained-release formulation, and / or a controlled-release formulation.

[0051] Furthermore, colorants, preservatives, flavorings, tasters, sweeteners, or other materials may be added to the pharmaceutical preparations if necessary.

[0052] Furthermore, the drug can be administered by injection, cavity, or respiratory tract.

[0053] Furthermore, the injection administration includes intrathecal injection, subcutaneous injection, intravenous injection, intramuscular injection, and intracavitary injection; the cavity administration includes rectal or vaginal administration; and the respiratory administration includes nasal administration.

[0054] Furthermore, the pain described is neuropathic pain.

[0055] Furthermore, the neuropathic pain is divided into acute phase, transformation phase, and chronic phase.

[0056] Furthermore, the neuropathic pain symptoms include hyperalgesia or hyperalgesia, spontaneous pain, and paresthesia.

[0057] Thirdly, the present invention provides the use of GSK343 ​​in the preparation of a medicament for treating pain; the chemical formula of GSK343 ​​is C 31 H 39 N7O2.

[0058] Furthermore, one or more pharmaceutically acceptable carriers may be added to the drug.

[0059] Furthermore, the drug can be formulated into various dosage forms, including but not limited to one or more of tablets, capsules, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal preparations, and / or suppositories.

[0060] Furthermore, the formulation may be one or more of a conventional formulation, a sustained-release formulation, and / or a controlled-release formulation.

[0061] Furthermore, colorants, preservatives, flavorings, tasters, sweeteners, or other materials may be added to the pharmaceutical preparations if necessary.

[0062] Furthermore, the drug can be administered by injection, cavity, or respiratory tract.

[0063] Furthermore, the injection administration includes intrathecal injection, subcutaneous injection, intravenous injection, intramuscular injection, and intracavitary injection; the cavity administration includes rectal or vaginal administration; and the respiratory administration includes nasal administration.

[0064] Furthermore, the pain described is neuropathic pain.

[0065] Furthermore, the neuropathic pain is divided into acute phase, transformation phase, and chronic phase.

[0066] Furthermore, the neuropathic pain symptoms include hyperalgesia or hyperalgesia, spontaneous pain, and paresthesia.

[0067] Fourthly, this invention provides the application of TSA and GSK343 ​​in combination in the preparation of a medicament for treating pain; wherein the chemical formula of TSA is C 17 H 22 N2O3, the chemical formula of GSK343 ​​is C 31 H 39 N7O2.

[0068] Furthermore, one or more pharmaceutically acceptable carriers may be added to the drug.

[0069] Furthermore, the active ingredients TSA and GSK343 ​​in the drug can be in the same carrier or in two different carriers.

[0070] Furthermore, the drug can be formulated into various dosage forms, including but not limited to one or more of tablets, capsules, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal preparations, and / or suppositories.

[0071] Furthermore, the formulation may be one or more of a conventional formulation, a sustained-release formulation, and / or a controlled-release formulation.

[0072] Furthermore, colorants, preservatives, flavorings, tasters, sweeteners, or other materials may be added to the pharmaceutical preparations if necessary.

[0073] Furthermore, the drug can be administered by injection, cavity, or respiratory tract.

[0074] Furthermore, the injection administration includes intrathecal injection, subcutaneous injection, intravenous injection, intramuscular injection, and intracavitary injection; the cavity administration includes rectal or vaginal administration; and the respiratory administration includes nasal administration.

[0075] Furthermore, the pain described is neuropathic pain.

[0076] Furthermore, the neuropathic pain is divided into acute phase, transformation phase, and chronic phase.

[0077] Furthermore, the neuropathic pain symptoms include hyperalgesia or hyperalgesia, spontaneous pain, and paresthesia. Beneficial effects

[0078] 1. The present invention shows that TSA and GSK343, when administered alone in vivo, have a certain therapeutic effect on neuropathic pain, and that low concentrations of TSA and GSK343, when administered in vivo in combination, have a significant therapeutic effect on neuropathic pain, indicating that the analgesic regimen has a high safety factor.

[0079] 2. The combined administration of TSA and GSK343 ​​in vivo showed good therapeutic effects on acute (1-7 days), transition (8-14 days), and chronic (15-28 days) neuropathic pain. This combined administration regimen can manage acute NP, prevent the progression of transitional pain states, and prevent the transformation of acute NP into chronic NP.

[0080] 3. The therapeutic effect of this invention remains good even after drug withdrawal during the transformation or chronic phase. It solves the clinical problem of persistent or recurrent NP pain, which causes great suffering and functional impairment to patients. Attached Figure Description

[0081] Figure 1. Animal model of neuropathic pain caused by spinal nerve ligation (SNL) of L5 and L6.

[0082] Figure 2. Mechanical pain foot withdrawal threshold detection and behavioral testing equipment.

[0083] Figure 3. Mechanical pain foot withdrawal threshold detection and behavioral testing tools.

[0084] Figure 4. Results of mechanical pain withdrawal threshold detection after SNL surgery.

[0085] Figure 5 shows the effects of TSA and GSK343 ​​on the treatment of neuropathic pain model rats by independent administration.

[0086] Figure 6 shows the therapeutic effect of combined administration of TSA and GSK343 ​​on rats with neuropathic pain. Detailed Implementation

[0087] The specific embodiments of the present invention will be further described below. It should be noted that these descriptions are for the purpose of aiding understanding the present invention, but do not constitute a limitation thereof. Furthermore, the technical features involved in the embodiments described below can be combined with each other as long as they do not conflict with each other.

[0088] Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods, and the experimental materials used in the following embodiments are all available through conventional commercial channels.

[0089] Terminology Explanation

[0090] Nociceptive pain is a physiological response caused by the activation of specific peripheral sensory neurons (nociceptors) by noxious stimuli. It can elicit reflexes and corresponding behavioral responses to minimize tissue damage. Nociceptive pain is often considered "normal" pain, such as sprains, fractures, burns, contusions, inflammation, and myofascial pain. Once the injury heals, the pain usually disappears. However, in some cases, the underlying cause of the pain is difficult to remove, leading to chronic pain. Some nociceptive pain may eventually transform into neuropathic pain due to persistent nerve damage.

[0091] Nociplastic pain: a type of pain that does not involve the activation of nociceptors or lesions or diseases of the nervous system. It is pain that persists despite the absence of clear evidence that actual or potential tissue damage leads to the activation of peripheral nociceptors and thus causes pain, such as increased connectivity of the insular cortex due to long-term chronic pain.

[0092] Ectopic discharge refers to spontaneous discharge in the dorsal root ganglion and nerve injury sites. It is the electrophysiological basis of pain abnormalities and is related to the activity of various ion channels.

[0093] Peripheral sensitization refers to the condition where nociceptors are activated and exhibit higher excitability and sensitivity, while the response threshold to harmful stimuli is lowered. When local inflammation or peripheral nerve damage occurs, the reactivity of peripheral pain neurons increases, resulting in pain hypersensitivity.

[0094] Central sensitization is a state in which repeated pain input increases spinal cord excitability. During this process, nociceptive neurons can generate or increase spontaneous activity, lower the peripheral stimulation threshold that can activate neurons, and increase the response to suprathreshold stimuli.

[0095] Hyperalgesia: refers to an excessive pain response to a suprathreshold stimulus. The stimulus-response pattern remains unchanged, meaning the pain sensation is amplified but its nature remains the same.

[0096] Hyperalgesia: This refers to pain perceived by stimuli that do not normally induce pain; that is, normal touch and temperature sensations are perceived as pain. It is a change in the nature of sensation. Patients may experience a more intense stinging sensation than normal people, and this sensitivity may be accompanied by a prolonged period of discomfort.

[0097] Spontaneous pain refers to pain without any external cause, and is usually related to a disease. Patients experience pain suddenly, and the location and nature of the pain are related to the disease.

[0098] Paresthesia: Paresthesia is generally used to describe abnormal sensations, regardless of whether the sensation is pleasant or unpleasant. When this abnormal sensation manifests as pain, it is called paresthesia. Patients may experience abnormal sensations such as pain, numbness, tingling, burning, etc.

[0099] EC99: This is the concentration at which a drug achieves a 99% maximal effect. This value can be used to compare the potency of different drugs and to assess drug sensitivity in different organisms or under different conditions. If a drug has a low EC99 value but a high maximal effect, then this drug may have high therapeutic potential.

[0100] Material

[0101] The chemical formula of TSA is C 17 H 22 N2O3, the structural formula is shown in formula (Ⅰ);

[0102] GSK343 ​​has the chemical formula C. 31 H 39 N7O2, the structural formula is shown in formula (Ⅱ);

[0103] Example 1: The therapeutic effects of TSA and GSK343 ​​administered independently in a rat model of neuropathic pain.

[0104] A neuropathic pain animal model was established using spinal nerve ligation (SNL). By ligating the L5 and L6 spinal nerves individually, many symptoms of human neuropathic pain, such as spontaneous pain, hyperalgesia, and sensitization, were simulated. The injury site is clearly defined; by blocking nerve signal transmission, local ischemia and damage to nerve fibers are caused, thereby inducing pain sensitization. This method has unique advantages for studying changes in the central nervous system after specific spinal nerve injuries. The SNL model shows significant changes in the mechanical pain threshold, good stability, reproducibility, and reliability. It is suitable for studying the mechanisms of the transition from acute to chronic pain after nerve injury and is often used to screen drugs effective for acute nerve injury pain and central sensitization-related pain, especially drugs targeting spinal cord-level nerve conduction and modulation pathways. After SNL, the mechanical pain withdrawal threshold in rats was assessed using the Von Frey Hairs test. The mechanical pain withdrawal threshold decreased significantly after SNL.

[0105] 1. Materials

[0106] Male Wistar rats aged 4-8 weeks, Von Frey Hairs, TSA, GSK343

[0107] 2. Method

[0108] (1) An animal model of SNL neuropathic pain was prepared by ligating the L5 and L6 spinal nerves separately, as shown in Figure 1;

[0109] (2) Simultaneously, intrathecal catheters were inserted into the rats after surgery. Subsequent intrathecal drug administration experiments were conducted. The control group was treated with physiological saline, while the experimental group was administered #1 (5μg / 100g TSA) and #2 (50ng / 100g GSK343) in vivo after surgery, respectively.

[0110] (3) Mechanical pain withdrawal threshold and behavioral tests were performed on rats at different time points before and after surgery. The testing equipment and tools are shown in Figure 2 and Figure 3.

[0111] 3. Results

[0112] As shown in Figure 4, the mechanical pain threshold for foot withdrawal significantly decreased after SNL surgery.

[0113] As shown in Figure 5a, in rats with neuropathic pain, compared with the control group, both drugs showed certain therapeutic effects in the acute phase (1-7 days), transition phase (8-14 days), and chronic phase (15-28 days) of neuropathic pain.

[0114] As shown in Figure 5b, the EC99 of TSA is 4.01 μg / 100g, and the EC99 of GSK343 ​​is 8.91 ng / 100g.

[0115] Example 2: The therapeutic effect of combined administration of TSA and GSK343 ​​on a rat model of neuropathic pain.

[0116] 1. Materials

[0117] Male Wistar rats aged 4-8 weeks, Von Frey Hairs, TSA, GSK343

[0118] 2. Method

[0119] (1) Prepare an animal model of SNL neuropathic pain by ligating the L5 and L6 spinal nerves, as shown in Figure 1;

[0120] (2) Simultaneously, intrathecal catheterization was performed on the rats post-surgery. Subsequent intrathecal drug administration experiments were conducted. The control group received saline treatment, while the treatment group received a combination of #1 (2 μg / 100g TSA) and #2 (4 ng / 100g GSK343) post-surgery. Specifically, 2 μg / 100g TSA was administered continuously from day 1 to day 28 post-surgery in treatment groups 1-3, with withdrawal after day 28; while 4 ng / 100g GSK343 ​​was administered in combination at different times in treatment groups 1-3.

[0121] Treatment group 1: medication was administered during the acute phase (1-7 days), and withdrawn after 7 days;

[0122] Treatment group 2, acute and transformation phase (1-14 days), medication was withdrawn after 14 days;

[0123] Treatment group 3 received medication during the acute, transformation, and chronic phases (1-21 days), and withdrew the medication after 28 days.

[0124] The dosage concentration was based on half the EC99 of TSA (4.01 μg / 100g) and GSK343 ​​(8.91 ng / 100g). Administration was via intrathecal administration through a pre-placed indwelling catheter (same as in Example 1).

[0125] (3) Behavioral tests were conducted on rats at different time points before and after surgery to detect mechanical pain withdrawal threshold. The testing equipment and tools are shown in Figures 2 and 3.

[0126] 3. Results

[0127] As shown in Figure 6, in rats with a neuropathic pain model, compared to the control saline group, both drugs showed good therapeutic effects during the acute phase (days 1-7), transition phase (days 8-14), and chronic phase (days 15-21) of neuropathic pain. Even after withdrawing GSK343 ​​on days 7, 14, and 21 post-surgery, and TSA on day 28 post-surgery, the therapeutic effect remained good.

[0128] Low concentrations of TSA combined with GSK343 ​​in vivo showed good therapeutic effects on neuropathic pain in the acute phase (1-7 days), transition phase (8-14 days), and chronic phase (15-28 days).

Claims

1. A pharmaceutical composition for treating pain, said pharmaceutical composition comprising TSA and / or GSK343; said TSA having the chemical formula C 17 H 22 N2O3, the chemical formula of GSK343 ​​is C 31 H 39 N7O2.

2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition may further contain other analgesic active ingredients; the other analgesic active ingredients include calcium ion channel drugs, sodium ion channel drugs, tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors, opioids, botulinum toxin type A and novel anti-inflammatory drugs tetrandrine, platelet-rich plasma and / or other active ingredients of drugs.

3. The pharmaceutical composition according to any one of claims 1 or 2, wherein one or more pharmaceutically acceptable carriers may be added to the pharmaceutical composition.

4. The pharmaceutical composition according to any one of claims 1-3, wherein the pharmaceutical composition can be formulated into a variety of dosage forms, including but not limited to one or more of tablets, capsules, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal preparations and / or suppositories.

5. The pharmaceutical composition according to any one of claims 1-4, wherein the pharmaceutical composition can be administered by injection, cavity administration, or respiratory administration; the injection administration includes intrathecal injection, subcutaneous injection, intravenous injection, intramuscular injection, and intracavitary injection, etc.; the cavity administration includes rectal or vaginal administration; and the respiratory administration includes nasal administration.

6. The pharmaceutical composition according to claims 1-5, wherein the pain is neuropathic pain; the neuropathic pain is divided into acute phase, transformation phase and chronic phase; the symptoms of neuropathic pain include hyperalgesia or hyperalgesia, spontaneous pain and paresthesia, etc.

7. Application of TSA in the preparation of drugs for treating pain; the chemical formula of the TSA is C 17 H 22 N2O3, the chemical formula of GSK343 ​​is C 31 H 39 N7O2; The pain described is neuropathic pain.

8. Application of GSK343 ​​in the preparation of drugs for treating pain; the chemical formula of the TSA is C 17 H 22 N2O3, the chemical formula of GSK343 ​​is C 31 H 39 N7O2; The pain described is neuropathic pain.

9. The application of TSA and GSK343 ​​in the preparation of a drug for treating pain; wherein the chemical formula of TSA is C 17 H 22 N2O3, the chemical formula of GSK343 ​​is C 31 H 39 N7O2; The pain described is neuropathic pain.

10. The application as described in claim 9, wherein one or more pharmaceutically acceptable carriers may be added to the medicament, and the active ingredients TSA and GSK343 ​​may be in the same carrier or in two different carriers.

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