Use of gossypol in the treatment of pain

Abstract

The present application relates to the technical field of medicine, in particular to the application of gushangamine alcohol in treating pain. The present application first discovers that gushangamine alcohol has significant analgesic activity through pharmacodynamics experiment. In the hot plate method and acetic acid writhing method mouse pain model, gushangamine alcohol shows good analgesic effect, and the analgesic effect is better than that of gushangmethyl, gushangheptane and gushangnonose, etc. C 20 type diterpene alkaloid in the same class of gushangbai, and has good dose dependence, and can be used for treating various painful diseases such as acute pain, chronic pain, inflammatory pain, neuropathic pain, cancer pain, postoperative pain and traumatic pain, and has good drug development and clinical application prospect.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to the application of guanosine in the treatment of pain. Background Technology

[0002] Pain is one of the most common chronic and intractable symptoms worldwide, with main clinical manifestations including spontaneous pain, hyperalgesia, and anomalous pain, often accompanied by comorbidities such as anxiety, depression, and sleep disorders. Its core pathological mechanism is the abnormal amplification of sensory signals caused by damage or dysfunction of the peripheral or central nervous system, manifesting as peripheral and central sensitization. This involves abnormal discharge of nociceptors, plasticity changes in pain transmission pathways in the spinal cord and brain, and dysfunction of the descending inhibitory system. Currently, clinical treatment of pain primarily relies on nonsteroidal anti-inflammatory drugs (NSAIDs), calcium channel modulators (pregabalin, gabapentin), and opioids. However, long-term use of opioids can lead to serious adverse reactions such as tolerance, dependence, and respiratory depression, while NSAIDs also have gastrointestinal and nephrotoxicity. Existing drugs can only relieve symptoms and cannot reverse neuroplasticity damage, and about half of patients do not respond well to treatment, indicating that clinical needs are far from being met.

[0003] Guan-Fu aminol alcohol (GFAA) is a C-type compound derived from Guan Bai Fu. 20 Type diterpenoid alkaloids. Existing technologies mainly focus on the identification, analysis, and detection of the chemical components of diterpenoid alkaloids and related research. Summary of the Invention

[0004] This invention covers the following technical solutions: One aspect of the present invention relates to the use of guanine alcohols in the preparation of medicaments for the treatment of pain, wherein the guanine alcohols are selected from compounds of formula (I), or pharmaceutically acceptable salts, stereoisomers, solvates, or hydrates thereof: .

[0005] In some embodiments, the pain includes one or more of acute pain, chronic pain, inflammatory pain, neuropathic pain, cancer pain, postoperative pain, and traumatic pain.

[0006] In some embodiments, the medicament is a pharmaceutical composition comprising guanine alcohol and pharmaceutically acceptable excipients.

[0007] In some embodiments, the pharmaceutical composition is an oral formulation, an injectable formulation, a transdermal formulation, a mucosal formulation, or a rectal formulation.

[0008] In some preferred embodiments, the other analgesic active ingredient is selected from one or more of nonsteroidal anti-inflammatory drugs, opioid analgesics, calcium ion channel α2δ ligands, antidepressants, and pharmaceutically acceptable salts thereof.

[0009] In some implementations, the subject is a mammal.

[0010] This invention, through pharmacodynamic experiments, first discovered that guanfuminol possesses significant analgesic activity. In mouse pain models using both the hot plate test and the acetic acid writhing test, guanfuminol exhibited good analgesic effects, surpassing similar guanfumin diterpenoid alkaloids such as guanfumin A, guanfumin G, and guanfumin Ren, and demonstrating good dose-dependency. It can be used to treat various pain conditions, including acute pain, chronic pain, inflammatory pain, neuropathic pain, cancer pain, postoperative pain, and traumatic pain, showing promising prospects for drug development and clinical application. Detailed Implementation

[0011] The embodiments of the present invention will now be described in detail. The following examples are only used to explain the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. After reading this specification, those skilled in the art can make various modifications, substitutions or variations to the technical solutions of the present invention without departing from the concept and technical principles of the present invention, and all such modifications, substitutions or variations should fall within the scope of protection of the present invention.

[0012] Unless otherwise stated, the technical and scientific terms used herein shall have the meanings commonly understood by one of ordinary skill in the art. Unless otherwise specified, the experimental methods described herein shall be performed under standard experimental conditions, in accordance with relevant laboratory manuals, or as recommended by the manufacturers of reagents or instruments, or using other equivalent methods known in the art.

[0013] The terms "comprising," "including," and "containing" as used herein are open-ended expressions, and unless explicitly specified, they do not exclude the presence of other components, steps, or structures not explicitly listed. The terms "preferred," "optional," and "optional" as used herein are only for illustrating some embodiments and do not constitute a limitation on the scope of protection of this invention.

[0014] Unless otherwise specified, the numerical ranges mentioned in this article include any integers, fractions, decimals, and their upper and lower limits within that range.

[0015] Unless otherwise specified, the singular expressions such as "a," "a kind," and "the" used in this article also include the plural forms; "multiple" usually refers to two or more.

[0016] As used in this document, the term "and / or" refers to any one or any combination of the relevant objects.

[0017] Where there is no contradiction, the technical features of the various embodiments and examples in this specification can be combined with each other. Any conventional adjustments, substitutions, or equivalent modifications made by those skilled in the art based on the content of this specification should be considered part of the disclosure herein.

[0018] The references cited in this invention are only used to illustrate the background technology or related technical content of this invention, and their disclosures may be used for reference only if they do not conflict with the technical solutions of this invention.

[0019] In this article, "guanfuminol" refers to the compound with the structure shown in formula (I), or its pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate; .

[0020] In this document, "pharmaceutically acceptable salt" refers to a salt formed by the compounds of this invention with a pharmaceutically acceptable acid or base, while maintaining the bioactivity and pharmacological activity of the amino alcohols of this invention. This salt is suitable for administration to animals, especially mammals, and more particularly to humans. Exemplary pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochlorides, hydrobroms, sulfates, nitrates, phosphates, methanesulfonates, ethanesulfonates, p-toluenesulfonates, acetates, lactates, citrates, malates, tartrates, fumarates, maleates, succinates, and benzoates. In some embodiments, the pharmaceutically acceptable alkali metal salts or organic base salts include, but are not limited to, sodium salts, potassium salts, calcium salts, magnesium salts, ammonium salts, triethylamine salts, diisopropylamine salts, diethanolamine salts, and triethanolamine salts.

[0021] In this article, "stereoisomers" refers to compounds that have the same molecular composition and linkage sequence but different spatial arrangements, including but not limited to optical isomers, enantiomers, diastereomers, racemates and mixtures thereof, as well as cis, trans, E / Z isomers, etc. The related amino alcohols described in this invention include all possible stereoisomers and mixtures thereof in any proportion.

[0022] In this document, "solvent" refers to an associative compound formed by the compound of the present invention and one or more solvent molecules through non-covalent interactions. Exemplary solvents include, but are not limited to, methanol, ethanol, isopropanol, acetonitrile, acetone, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, and combinations thereof.

[0023] In this article, "hydrate" refers to a solvate formed by the compound of the present invention and water molecules, including monohydrate, dihydrate, polyhydrate, and aqueous forms without a fixed stoichiometric ratio.

[0024] In this article, "pharmaceutically acceptable" means substances or materials that, within reasonable medical judgment, are suitable for contact with the tissues of subjects such as humans or other mammals without causing excessive toxicity, irritation, allergic reactions or other problems, and have a commensurate benefit / risk ratio.

[0025] In this article, "therapeutic effective dose" refers to the dose of analgesic alcohol that produces the desired therapeutic effect on the subject, such as reducing or eliminating pain, increasing the pain threshold, lowering pain scores, improving pain-related symptoms, improving the patient's quality of life, or reducing the use of other analgesics, or one or more of these effects. Those skilled in the art can determine the appropriate therapeutic effective dose based on the subject's specific circumstances, pain type, disease severity, route of administration, and clinical response.

[0026] In this article, "pain" refers to unpleasant sensory and emotional experiences caused by, or related to, actual or potential tissue damage.

[0027] In this article, "treatment" refers to intervention on the existing disease or pathological state of the subjects in order to achieve one or more of the following: cure, alleviate, improve, control, delay disease progression, reduce or eliminate disease symptoms, improve pathological state, improve physiological function, improve quality of life, reduce the risk of disease recurrence and / or reduce the risk of disease-related death.

[0028] In this article, "analgesic active ingredient" refers to a pharmaceutical active ingredient that has the effect of relieving, reducing or eliminating pain and can be used alone or in combination to treat pain.

[0029] This invention relates to the use of guanine alcohol in the preparation of medicaments for treating pain; The guanine alcohol is selected from compounds with the structure shown in formula (I), as well as their pharmaceutically acceptable salts, stereoisomers, solvates, and hydrates; .

[0030] Through pharmacodynamic studies, the inventors discovered that guanoamine alcohol possesses significant analgesic activity. In both the hot plate test and acetic acid writhing test mouse pain models, it significantly increased the pain threshold and reduced the number of writhing movements, demonstrating a good analgesic effect, suggesting that guanoamine alcohol can be used for pain treatment. Therefore, this invention provides the application of guanoamine alcohol in the preparation of drugs for treating pain.

[0031] In some embodiments, the pain includes one or more of the following: acute pain, chronic pain, inflammatory pain, neuropathic pain, cancer pain, postoperative pain, and traumatic pain.

[0032] The acute pain described in this article generally refers to pain of relatively short duration caused by factors such as tissue damage, inflammatory stimulation, or surgical trauma, including but not limited to postoperative pain, traumatic pain, burn pain, and acute inflammatory pain.

[0033] Chronic pain, as described in this article, generally refers to pain that lasts for more than three months or exceeds the normal tissue healing time, including but not limited to chronic musculoskeletal pain, chronic low back pain, osteoarthritis pain, and chronic cancer pain.

[0034] The inflammatory pain discussed in this article generally refers to pain caused by the release of inflammatory mediators, including but not limited to pain caused by rheumatoid arthritis, osteoarthritis, gout, inflammatory bowel disease, and other inflammatory-related diseases.

[0035] The neuropathic pain described in this article generally refers to pain caused by damage or disease of the central or peripheral nervous system, including but not limited to diabetic peripheral neuropathy, postherpetic neuralgia, trigeminal neuralgia, sciatica, spinal cord injury-related pain, and chemotherapy-induced neuropathic pain.

[0036] The cancer pain discussed in this article usually refers to pain caused by the malignant tumor itself, tumor metastasis, or tumor treatment.

[0037] Postoperative pain, as described in this article, usually refers to acute or persistent pain after surgery.

[0038] The traumatic pain discussed in this article usually refers to pain caused by fractures, soft tissue injuries, burns, crush injuries, and other external injuries.

[0039] In some embodiments, the medicament is a pharmaceutical composition comprising guanine alcohol and pharmaceutically acceptable excipients.

[0040] The pharmaceutically acceptable excipients described herein include commonly used excipients, diluents, binders, disintegrants, lubricants, glidants, suspending agents, emulsifiers, stabilizers, preservatives, antioxidants, flavoring agents, colorants, buffers, isotonic modifiers, solubilizers, cosolvents, and combinations thereof. Those skilled in the art can select one or more suitable pharmaceutically acceptable excipients to formulate a pharmaceutical preparation based on the chosen dosage form and route of administration.

[0041] In some embodiments, the pharmaceutical composition can be prepared as an oral formulation, an injectable formulation, a transdermal formulation, a mucosal formulation, or a rectal formulation. Preferred dosage forms are oral formulations, injectable formulations, and transdermal formulations.

[0042] In some embodiments, the oral formulation includes tablets, capsules, granules, powders, oral liquids, and suspensions. Oral administration has advantages such as convenience, high patient compliance, and suitability for long-term treatment, and is applicable to diseases requiring long-term or repeated administration, such as chronic pain, inflammatory pain, and neuropathic pain. In some more preferred embodiments, the oral formulation is a capsule. Capsules can effectively encapsulate guanosine, reducing direct contact between the drug and the external environment, which is beneficial for improving formulation stability, masking any unpleasant odors or bitterness of the drug, and improving patient compliance; therefore, it is a preferred oral dosage form of this invention. In other preferred embodiments, the oral formulation is a tablet. Tablets have advantages such as mature manufacturing processes, easy quality control, and convenient transportation and storage, making them suitable for industrial production.

[0043] In some embodiments, the injectable formulation includes an injection solution and a lyophilized powder for injection. Lyophilized powder for injection can improve the stability of some active ingredients of natural products during storage, facilitates long-term preservation, and can be reconstituted before use, thus making it a preferred injectable dosage form of this invention. The injection solution has a rapid onset of action, quickly reaching an effective blood drug concentration, and is suitable for clinical situations requiring rapid analgesia, such as acute pain, postoperative pain, and cancer pain.

[0044] In some embodiments, the transdermal formulation includes patches, gels, creams, and ointments. In some preferred embodiments, the transdermal formulation is a patch. Patches can continuously release guanosine, maintain a relatively stable blood drug concentration, reduce the frequency of administration, and improve patient compliance, making them particularly suitable for patients requiring long-term analgesic treatment, such as those with chronic pain, cancer pain, and neuropathic pain.

[0045] In some embodiments, the mucosal preparation includes sublingual tablets, oral films, sublingual membranes, nasal sprays, and oral sprays.

[0046] In some embodiments, the rectal administration formulation includes suppositories, etc.

[0047] The drug of this invention can be used alone or in combination with other analgesic active ingredients.

[0048] In some embodiments, the other analgesic active ingredients include one or more of nonsteroidal anti-inflammatory drugs, opioid analgesics, calcium channel α2δ ligands, antidepressants, and pharmaceutically acceptable salts thereof.

[0049] In some embodiments, the nonsteroidal anti-inflammatory drug includes one or more of aspirin, ibuprofen, diclofenac, celecoxib, etoricoxib, loxoprofen, naproxen, meloxicam, indomethacin, ketorolac, flurbiprofen ester, and pharmaceutically acceptable salts thereof.

[0050] In some embodiments, the opioid analgesics include one or more of morphine, fentanyl, sufentanil, remifentanil, oxycodone, hydromorphone, pethidine, tramadol, bupirocin, buprenorphine, and pharmaceutically acceptable salts thereof.

[0051] In some embodiments, the calcium ion channel α2δ ligand includes pregabalin, gabapentin, and pharmaceutically acceptable salts thereof.

[0052] In some embodiments, the antidepressant includes amitriptyline, duloxetine, venlafaxine, and pharmaceutically acceptable salts thereof.

[0053] In some embodiments, the guanoamine can be administered simultaneously, separately, sequentially, or in combination with other analgesic active ingredients to form the same pharmaceutical composition. Those skilled in the art can select an appropriate combination dosing regimen based on the patient's condition, pain type, and treatment needs.

[0054] In some embodiments, the drug can be administered orally, by injection, transdermally, nasally, through the oral mucosa, rectally, or by other suitable routes.

[0055] In some embodiments, the subject of the drug is a mammal, preferably a human.

[0056] The present invention also provides a method for treating pain, comprising administering a therapeutically effective amount of guanosine to a subject in need, said guanosine being selected from compounds with the structure shown in formula (I), or pharmaceutically acceptable salts, stereoisomers, solvates, or hydrates thereof, to treat or relieve pain; .

[0057] In some embodiments, the pain includes one or more of the following: acute pain, chronic pain, inflammatory pain, neuropathic pain, cancer pain, postoperative pain, and traumatic pain.

[0058] In some embodiments, the guanoamine can be administered alone or in combination with one or more other analgesic active ingredients. The combined administration can be simultaneous, sequential, sequential, or spaced out. The guanoamine and the other analgesic active ingredients can be prepared into the same pharmaceutical composition or separately into different pharmaceutical compositions for combined use.

[0059] In some embodiments, the guanoamine can be administered orally, by injection, transdermal, mucosal, or rectal routes. Preferably, the guanoamine is administered orally; more preferably, it is administered in capsules, tablets, or granules. For patients requiring rapid onset of action, injection is preferred; for patients requiring long-term maintenance of analgesia, transdermal administration, especially patch administration, is preferred.

[0060] In some embodiments, the administration frequency of guanfubase can be once a day, twice a day, three times a day, or adjusted according to clinical needs. Those skilled in the art can determine the appropriate administration dosage, administration frequency and treatment course based on the subject's age, body weight, severity of the condition, pain type, administration route, concomitant diseases and tolerance, so as to obtain the optimal therapeutic effect.

[0061] In some embodiments, the subject is a mammal, preferably a human; the treatment can be implemented as a single therapeutic regimen, or as a part of a comprehensive therapeutic regimen, and can be implemented in combination with surgical treatment, radiation therapy, physical therapy or other drug therapies, so as to further improve the pain symptoms and quality of life of the patient.

[0062] The embodiments of the present invention will be described in detail below with reference to examples. It should be understood that these examples are only used to illustrate the technical content of the present invention, rather than to limit the protection scope of the present invention. If no specific experimental conditions are explicitly defined in the following examples, reference is preferably made to the guidelines given in the specification of the present invention, and the implementation can also be carried out in accordance with generally accepted experimental manuals or conventional experimental conditions in the art, or with reference to other experimental methods known in the art, or in accordance with the conditions suggested by the relevant reagent or instrument manufacturers. In the specific examples, for the measurement parameters related to raw material components, unless otherwise specified, slight deviations within the range of weighing accuracy are allowed; for parameters such as temperature and time, reasonable deviations caused by instrument detection accuracy or operational accuracy are also allowed.

[0063] Example 1 This example discloses a C 20 analgesic effect of type diterpenoid alkaloid guanfubase in hot plate test, which is specifically verified by the following procedure: 1. Experimental materials and instruments Guanfu G, Guanfu A, Guanfu I and guanfubase were all isolated and purified in our laboratory in the early stage, with a purity of not less than 98%; bulleyaconitine A was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.; Electronic balance (Beijing Sartorius Scientific Instruments Co., Ltd.); hot and cold analgesia instrument (IITCINC, USA).

[0064] 2. Experimental animals Eight-week-old male C57BL / 6J mice, weighing 18-20 g, SPF grade, were purchased from Beijing Vital River Laboratory Animal Technology, with license number: SYXK (Jing) 2023-0001. Feeding environment: temperature 23±2 ℃, humidity 50% ± 10%, 12 h / 12 h light-dark cycle, free access to food and water. The experiment was started after 3 days of adaptive feeding, with free access to water.

[0065] 3. Experimental Grouping Seventy-two mice were randomly divided into nine groups (n = 8) according to their body weight: ① Control group (physiological saline) ② Morphine group ( i.p. 1 mg / kg ③ Aconitum carmichaelii group ( i.g. 1 mg / kg ④ Guan Fu Geng Su Group ( i.g. 1 mg / kg ⑤ Guanfujiasu group ( i.g. 1 mg / kg ⑥ Guan Fu Ren Su Group ( i.g. 1 mg / kg ⑦ Low-dose group of Guanfuminol ( i.g. 0.3 mg / kg ⑧ Guanfumin medium-dose group ( i.g. 1 mg / kg ⑨ High-dose group of Guanfu amino alcohol ( i.g. 3 mg / kg 4. Hot plate experiment Before the formal experiment, each mouse was placed on a 30 ℃ hot plate for 5 minutes for three consecutive days to acclimatize. On the fourth day, baseline pain threshold was measured and basic pain threshold screening was performed. Mice were gently placed on a 55 ℃ hot plate surface, and the pain threshold was measured by whether the mouse lifted its paw, licked its hind paw, or jumped. Mice with a pain threshold <5 s, ≥20 s, or those that liked to jump were excluded.

[0066] Forty qualified mice were randomly assigned to groups based on their baseline pain threshold. Mice were fasted and deprived of water before the test. After acclimatizing to the laboratory environment for 1 hour, the hot plate temperature was maintained at 55 ± 0.5 ℃. The latency of the thermal response was measured and recorded 1 hour after drug administration. To prevent tissue damage, the experimental cutoff time was set at 20 seconds. If no pain response was observed within 20 seconds, the latency of the thermal response was recorded as 20 seconds.

[0067] 5. Statistical processing Data are presented as mean ± standard error (Mean ± SEM). Experimental results were analyzed using Graphpad Prism 9.4.1 software. One-way ANOVA was performed first among multiple groups, followed by statistical testing using Tukey's multiple comparisons test. P A value <0.05 is considered statistically significant.

[0068] 6. Experimental Results As shown in Table 1, compared with the control group, the low-, medium-, and high-dose groups of Guanfu amine alcohol (0.3, 1, 3 mg / kg) can significantly prolong the heat response latency of mice in the hot plate test. At the medium dose (1 mg / kg), Guanfu amine alcohol exhibits better analgesic effect than Guanfu gengsu (1 mg / kg), Guanfu jiasu (1 mg / kg) and Guanfu wensu (1 mg / kg); at the high dose (3 mg / kg), the analgesic effect of Guanfu amine alcohol is superior to that of the positive drug bulleyaconitine A (1 mg / kg, a clinical non-addictive analgesic), and its analgesic effect is comparable to that of the positive drug morphine (1 mg / kg, a classic opioid analgesic).

[0069] Table 1 Effect of each group on heat response latency of mice in hot plate test

[0070] (mean ± standard error of the mean, compared with the control group, P <0.05, P <0.01, P <0.001) Example 2 This example discloses a C 20 -type diterpenoid alkaloid Guanfu amine alcohol in acetic acid writhing test, and its analgesic effect is specifically verified by the following process: 1. Experimental materials and instruments Guanfu amine alcohol is self-made in the laboratory; 2. Experimental animals Eight-week-old male C57BL / 6J mice, weighing 18-20 g, SPF grade, were purchased from Beijing Vital River Laboratory Animal Technology, license No.: SYXK (Beijing) 2023-0001. Feeding environment: temperature 23±2 °C, humidity 50% ± 10%, 12 h / 12 h light-dark cycle, free access to food and water. The experiment was started after 3 days of adaptive feeding, with free access to water.

[0071] 3. Experimental grouping Seventy-two mice were randomly divided into 9 groups according to body weight (n = 8): ① Control group (normal saline) ② Morphine group ( i.p. 1 mg / kg) ③ Bulleyaconitine A group ( i.g. 1 mg / kg) ④ Guanfu gengsu group ( i.g. 1 mg / kg) ⑤ Guanfu jiasu group ( i.g. 1 mg / kg ⑥ Guan Fu Ren Su Group ( i.g. 1 mg / kg ⑦ Low-dose group of Guanfuminol ( i.g. 0.3 mg / kg ⑧ Guanfumin medium-dose group ( i.g. 1 mg / kg ⑨ High-dose group of Guanfu amino alcohol ( i.g. 3 mg / kg 4. Acetic acid writhing test One hour after administration, mice were intraperitoneally injected with 1% glacial acetic acid solution (0.1 mL / 10 g). The number of writhing responses in mice within 15 minutes after injection was recorded, and the writhing inhibition rate was calculated. Writhing inhibition rate (%) = [(number of writhing responses in the model group - number of writhing responses in the drug-treated group) / number of writhing responses in the model group] × 100.

[0072] 5. Statistical processing Data are presented as mean ± standard error (Mean ± SEM). Experimental results were analyzed using Graphpad Prism 9.4.1 software. One-way ANOVA was performed first among multiple groups, followed by statistical testing using Tukey's multiple comparisons test. P A value <0.05 is considered statistically significant.

[0073] Experimental results As shown in Table 2, compared with the control group, the medium and high dose groups of Guanfuminol (1, 3 mg / kg) showed a greater than 50% inhibition rate of writhing number in mice during the acetic acid writhing test. At the medium dose (1 mg / kg), Guanfuminol showed superior analgesic effects compared with Guanfugen (1 mg / kg), Guanfujia (1 mg / kg), and Guanfuren (1 mg / kg); at the high dose (3 mg / kg), Guanfuminol showed superior analgesic effects compared with the positive drug, aconitine (1 mg / kg, a clinical non-addictive analgesic), and comparable to the positive drug, morphine (1 mg / kg, a classic opioid analgesic).

[0074] Table 2. Effects of each group on the inhibition rate of writhing frequency in mice during the acetic acid writhing test.

[0075] (mean ± standard error, compared with the aconitine group) # P <0.05) Application Example 1 This invention discloses a capsule formulation using guanine alcohol as a raw material, the components of which are as follows: Guanfuminol 30.0mg 6.0g of starch Sodium metabisulfite 0.2g Magnesium stearate 0.2g Anhydrous ethanol appropriate amount Make 100 pills.

[0076] The specific preparation process is as follows: Take the guanine alcohol, starch, and sodium metabisulfite, mix them evenly, add anhydrous ethanol to make a soft material, pass it through a 24-mesh sieve to make granules, dry it, add magnesium stearate, mix well, and fill it into capsules.

[0077] Application Example 2 This invention discloses a granule formulation using the compound guanine alcohol as a raw material, the components of which are as follows: Guanfuminol 25.0mg 6.0g of starch Sodium bisulfite 0.2g Magnesium stearate 0.2g Anhydrous ethanol appropriate amount Make 100 bags.

[0078] The specific preparation process is as follows: After mixing the guanamine alcohol with starch and sodium bisulfite, anhydrous ethanol is added to form a soft material. The material is then passed through a 24-mesh sieve to form granules, dried, and then magnesium stearate is added. The mixture is then mixed and packaged.

[0079] Application Example 3 This invention discloses an oral liquid using the compound guanine alcohol as a raw material, the components of which are as follows: Guanfuminol 20.0mg 3.0g sucrose Sodium bisulfite 0.2g Methylparaben 0.2g Sodium bicarbonate 0.5g 1000.0 mL of water for injection Make 100 pieces.

[0080] The specific preparation process is as follows: After the above components are mixed, they can be dispensed using conventional oral liquid preparation methods.

[0081] Application Example 4 This invention discloses an injectable preparation using the compound guanine alcohol as the active pharmaceutical ingredient, the components of which are as follows: Guanfuminol 25.0mg Vitamin C 0.2g Sodium chloride 6.0g Sodium bicarbonate 0.5g 1000.0 mL of water for injection Make 100 pieces.

[0082] The specific preparation process is as follows: After the above components are mixed, 100 vials can be obtained by using conventional injection preparation methods.

[0083] Application Example 5 This invention discloses a tablet using the compounds guanoamine alcohol and gabapentin as active pharmaceutical ingredients, the composition of which is as follows: Guanfuminol 20.0mg Gabapentin 60.0mg Hydroxypropyl methylcellulose 18.0g 0.4g of talc Lactose 0.2g Magnesium stearate 0.2g Anhydrous ethanol appropriate amount Make 100 pieces.

[0084] The specific preparation process is as follows: Take guanine alcohol, gabapentin, hydroxypropyl methylcellulose, talc, lactose, and magnesium stearate, mix them evenly, add anhydrous ethanol to make a soft mass, pass it through a 24-mesh sieve to make granules, dry it, add magnesium stearate, mix well, and compress into tablets.

[0085] Application Example 6 This invention discloses a capsule formulation using compounds guanosine and pregabalin as active pharmaceutical ingredients, the components of which are as follows: 3.5 mg of guanethidine Pregabalin 300.0mg 6.0g of starch Sodium metabisulfite 0.2g Magnesium stearate 0.2g Anhydrous ethanol appropriate amount Make 100 pills.

[0086] The specific preparation process is as follows: Take guanine alcohol, pregabalin, and sodium metabisulfite, mix them, add anhydrous ethanol to make a soft material, pass it through a 24-mesh sieve to make granules, dry it, add magnesium stearate, mix well, and fill it into capsules.

[0087] Application Example 7 This invention discloses an injection using compounds guanoamine alcohol and amitriptyline as active pharmaceutical ingredients, the components of which are as follows: 5.0 mg of guanethidine Amitriptyline 20.0 mg Vitamin C 0.2g Sodium chloride 6.0g Sodium bicarbonate 0.5g 1000.0 mL of water for injection Make 100 pieces.

[0088] The specific preparation process is as follows: After the above components are mixed, 100 vials can be obtained by using conventional injection preparation methods.

[0089] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of protection of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the scope of protection of the present invention. The scope of protection of the present invention should be determined by the appended claims, and the specification can be used to interpret the content of the claims.

Claims

1. The application of guanine in the preparation of drugs for treating pain; The guanine alcohol is selected from compounds with the structure shown in formula (I), as well as their pharmaceutically acceptable salts, stereoisomers, solvates, and hydrates; 。 2. The application according to claim 1, wherein the pain includes one or more of acute pain, chronic pain, inflammatory pain, neuropathic pain, cancer pain, postoperative pain, and traumatic pain.

3. The application according to claim 1, wherein the medicament is a pharmaceutical composition comprising guanine alcohol and pharmaceutically acceptable excipients.

4. The application according to claim 3, wherein the pharmaceutical composition is an oral formulation, an injectable formulation, a transdermal formulation, a mucosal formulation, or a rectal formulation.

5. The application according to claim 4, wherein the oral formulation is selected from tablets, capsules, granules, powders, oral liquids, and suspensions.

6. The application according to claim 4, wherein the injectable formulation is an injection solution or a lyophilized powder for injection.

7. The application according to claim 4, wherein the transdermal formulation is selected from patches, gels, creams, and ointments.

8. The application according to any one of claims 1 to 7, wherein the medicament further comprises one or more other analgesic active ingredients.

9. The application according to claim 8, wherein the other analgesic active ingredient is selected from one or more of nonsteroidal anti-inflammatory drugs, opioid analgesics, calcium ion channel α2δ ligands, antidepressants, and pharmaceutically acceptable salts thereof.

10. The application according to any one of claims 1 to 7, 9, wherein the subject of the drug is a mammal, preferably a human.

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