A cream effective against pain

Abstract

This invention belongs to the field of biomedical technology, specifically relating to an ointment and its application. The toad oil used in this invention differs significantly in composition from toad venom, and its ointment is effective for various acute and chronic pain conditions. Animal experiments have confirmed that the toad oil ointment significantly reduces the frequency and delays the onset of acetic acid-induced writhing responses, demonstrating a clear analgesic effect. Clinical studies have shown that this ointment is rapidly effective and has a definite therapeutic effect on acute gout attacks, postherpetic neuralgia, and arthritis-related pain and swelling. The formulation effectively improves drug retention and user comfort, and no skin irritation has been observed. This development achieves comprehensive utilization of toad resources, providing an example for the sustainable development of traditional Chinese medicine and the efficient utilization of biological resources.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202610201379.5 (22) Application Date 2026.02.11 (71) Applicant: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences Address: No. 16, Nanxiaojie, Dongzhimennei, Dongcheng District, Beijing 100700 (72) Inventors: Si Nan, Yan Xinwei, Peng Jiahui, Chen Yin, Lu Zitong, Gao Wenya, Feng Shuyi (74) Patent Agency: Beijing Xianghe Intellectual Property Agency (General Partnership) 11893 Patent Attorney: Feng Mingyan (51) Int.Cl. A61K 35 / 65 (2015.01) A61K 9 / 06 (2006.01) A61K 47 / 10 (2017.01) A61K 47 / 14 (2017.01) A61K 47 / 06(2006.01) A61K 47 / 24(2006.01) A61K 47 / 32(2006.01) A61K 47 / 36(2006.01) A61K 47 / 18(2017.01) A61P 29 / 00(2006.01) A61P 25 / 00(2006.01) A61P 25 / 06(2006.01) A61P 19 / 06(2006.01) A61P 25 / 02(2006.01) A61P 19 / 02(2006.01) (54) Invention Title: A Cream Effective for Pain (57) Abstract: This invention belongs to the field of biomedical technology, specifically relating to a cream and its application. The toad oil used in this invention differs significantly from toad venom in its composition, and its cream is effective for various acute and chronic pain conditions. Animal experiments have confirmed that the toad oil cream significantly reduces the frequency and delays the onset of acetic acid-induced writhing responses, demonstrating a clear analgesic effect. Clinical studies have shown that this cream is rapidly effective and has a definite therapeutic effect on acute gout attacks, postherpetic neuralgia, and arthritis-related pain and swelling. The formulation effectively improves drug retention and user comfort, and no skin irritation has been observed. This development achieves the comprehensive utilization of toad resources, providing a model for the sustainable development of traditional Chinese medicine and the efficient utilization of biological resources. Claims 1 page, Description 9 pages, Drawings 2 pages, CN 122075549 A 2026.05.26 CN 1 22 07 55 49 A 1. The application of toad oil cream in the preparation of pain-relieving products, characterized in that the toad oil cream is composed of toad oil and a matrix; the toad oil is obtained by crushing toad viscera, heating the toad viscera paste, and then centrifuging; the matrix consists of cetearyl alcohol, glyceryl monostearate, liquid paraffin, dimethyl silicone oil, propylparaben, carbomer, glycerin, and methylparaben.The product comprises potassium cinnamyl phosphate, hyaluronic acid, methylparaben, triethanolamine, and water. 2. The product of claim 1, wherein the toad oil constitutes 1%-20% by mass in the toad oil cream. 3. The product of claim 1, wherein the pain includes acute pain and chronic pain. 4. The product of claim 1, wherein the acute pain includes, but is not limited to, traumatic pain, postoperative pain, acute visceral pain, infectious pain, and gout; and the chronic pain includes, but is not limited to, neuropathic pain, musculoskeletal chronic pain, headache and facial pain, cancer pain, primary / unexplained chronic pain, and gout. 5. The product of claim 1, wherein the product comprises a pharmaceutical product or a non-pharmaceutical product. 6. The use of toad oil cream in the preparation of a medicament for treating pain, wherein the toad oil cream comprises toad oil and a matrix; the toad oil is obtained by crushing toad viscera, heating the toad viscera paste, and then centrifuging; the matrix comprises cetearyl alcohol, glyceryl monostearate, liquid paraffin, dimethyl silicone oil, propylparaben, carbomer, glycerin, potassium lauryl phosphate, hyaluronic acid, methylparaben, triethanolamine, and water. 7. The application of claim 6, wherein the toad oil constitutes 1%-20% by mass in the toad oil cream. 8. The application of claim 6, wherein one or more pharmaceutically acceptable carriers may be added to the medicament. 9. The application of claim 6, wherein the pain includes acute pain and chronic pain. 10. The application as described in claim 6, characterized in that the acute pain includes, but is not limited to, traumatic pain, postoperative pain, visceral acute pain, infectious pain, and gout; the chronic pain includes, but is not limited to, neuropathic pain, musculoskeletal chronic pain, headache and facial pain, cancer pain, primary / unexplained chronic pain, and gout. Claims 1 / 1 page 2 CN 122075549 A Cream Effective for Pain Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to a cream and its application. Background Art

[0002] The World Health Organization (WHO) and the International Association for the Study of Pain (IASP) define pain as: "an unpleasant sensory and emotional experience associated with actual or potential tissue damage." Pain is not only an accessory symptom of disease, but also a direct signal of tissue damage; it is a disease in itself. According to the revised definition of the International Association for the Study of Pain (IASP) in 2020, pain encompasses multiple dimensions including sensory, emotional, cognitive, and social aspects. It is not only an important physiological warning signal, but also evolves into a unique form of pain when it persists.This definition breaks through the traditional single-physiological understanding and provides a foundation for a comprehensive understanding and management of pain. According to the World Health Organization (WHO) classification of pain, clinical classification is generally based on anatomy, etiology, course of disease, and pathophysiology. The anatomical classification system describes pain experienced in a specific area of ​​the body and is usually the first-level classification system for identifying pain. The etiological classification of pain can be further subdivided into malignant and non-malignant, referencing the cancerous and non-cancerous causes of pain. Etiological pain factors include acute injury or underlying diseases and / or conditions. If classified by duration, pain can generally be divided into acute pain and chronic pain, further subdivided into three categories: acute, chronic, and occasional. The pathophysiological pain classification system is based on the pathophysiological mechanisms by which bodily injury leads to pain. Pain reflexes mainly involve two physiological pathways: the sensory pathway and the neural pathway. Sensory pain is a normal bodily response to injury, possibly caused by damage to internal organs, muscles, and / or bones. Pain remains an unexplained problem. To study pain, people often differentiate it from different angles, but there are no clear boundaries for its classification.

[0003] Based on location, cause, duration, and nature, this study classifies pain into nociceptive pain and pathological pain, namely acute pain and chronic pain. Acute pain refers to pain caused by brief nociceptive stimulation of peripheral nociceptors, also known as "physiological pain." Acute pain is not persistent; for example, needle pricks or burns cause only minor or small tissue damage, and the pain is instantaneous. Some surgeries, although causing severe damage and intense pain, disappear after wound healing and tissue repair. Chronic pain refers to pain lasting more than 3 months, or even a lifetime. Based on its cause, it can be divided into neuropathic pain, inflammatory pain, and functional pain. Neuropathic pain is caused by damage to peripheral or central nerves, such as spinal cord injury, diabetes, multiple sclerosis, and stroke. Inflammatory pain refers to pain caused by local tissue inflammation due to trauma, chemicals, infection, and surgery. Functional pain, such as migraine, refers to pain caused by abnormal nervous system function without obvious neurological lesions or peripheral abnormalities.

[0004] Modern pain management emphasizes a comprehensive principle of multimodal and individualized approaches. Drug therapy is the cornerstone, including nonsteroidal anti-inflammatory drugs (NSAIDs) for mild to moderate inflammatory pain, opioids for moderate to severe acute pain and cancer pain, and first-line drugs for neuropathic pain such as calcium channel modulators (gabapentin, pregabalin) and certain antidepressants (duloxetine, amitriptyline). For patients with poor drug response, interventional therapies (such as nerve blocks, radiofrequency ablation) and neuromodulation techniques are used.Techniques such as spinal cord stimulation provide important options. In addition, physical therapy, rehabilitation training, and psychological interventions such as cognitive behavioral therapy are all indispensable parts of the comprehensive management of chronic pain. However, the existing treatment system still faces serious challenges and significant defects, with approximately 30%–50% of chronic pain patients unable to achieve satisfactory control. The primary problem is the limited efficacy and low response rate. Existing drugs can only achieve partial relief for many chronic pain conditions, especially neuropathic pain. Secondly, the side effects of drugs are prominent: for example, after treatment with antidepressants, antiepileptic drugs, opioids, and local anesthetics, there are side effects such as dry mouth, confusion, cardiotoxicity, and blurred vision (Gao C, Zhao Y, Yang T, et al. Duhuo Jisheng decoction alleviates neuroinflammation and neuropathic pain by suppressing microglial M1 polarization: a network pharmacology research[J]. JOrthop Surg Res,2023;18 (1):629–42.). Interventional and neuromodulation techniques have limitations such as being invasive, costly, and having unclear patient selection criteria. Therefore, there is an urgent need for effective and well-tolerated drug treatments.

[0005] Toads, also known as frogs, toads, and leper toads, mainly refer to the Chinese giant toad (Bufo gargarizans Cantor), an animal of the Bufonidae family. Toads were first recorded in the "Shennong's Classic of Materia Medica". They are pungent and cool in nature, and enter the heart, liver, spleen, and lung meridians. They have the effects of breaking up blood stasis, removing hard masses, dispelling evil and heat, promoting diuresis and killing parasites. They can treat carbuncles, boils, genital sores, malignant sores, genital erosion, infantile malnutrition, oral ulcers, hemorrhoids, ascites, boils, etc. (Mingyi Bielu. Lower Grade, Volume 3 [M]. Beijing: China Traditional Chinese Medicine Press, 2013.). Studies have shown that toad fatty oil (hereinafter referred to as toad oil) extracted from the waste of toad internal organs after the collection of toad venom and toad skin exhibits significant pharmacological effects in the treatment of atopic dermatitis (AD) model mice. Research indicates that toad oil is rich in various active ingredients, including bufotalene, fatty acids, and alkaloids. Bufotalene has attracted much attention due to its diverse pharmacological activities, including anti-inflammatory, analgesic, immunomodulatory, antitumor, antiviral, antiradiation, antibacterial, and diuretic effects, demonstrating broad application potential (Liu Yuyang, Feng Shuyi, Wang Wei, et al. Optimization of toad oil extraction process and cream preparation [J / OL]. China Oils and Fats, 1-14 [2026-01-28].). The discovery of toad oil, a new toad resource.This invention is a beneficial supplement to the comprehensive and full utilization of toad resources, providing a model for the sustainable development of traditional Chinese medicine and the full utilization of biological resources, and offering a useful reference for the future development of traditional Chinese medicine and the rational utilization of traditional biological resources. Currently, there are no scientific research or clinical trial records of toad oil used for pain treatment.

[0006] The toad oil used in this invention differs significantly in composition from toad venom. Its cream is effective for acute and chronic pain such as gout, herpes zoster, and arthritis, and animal experiments have confirmed its analgesic effect. This cream shows no skin irritation, possesses both safety and ease of use, and the development of toad oil also provides a useful reference for the comprehensive and rational utilization of traditional Chinese medicine and biological resources. Based on this, this invention was completed.

[0007] In a first aspect, the present invention provides the application of toad oil cream in the preparation of pain-relieving products, wherein the toad oil cream is composed of toad oil and a matrix; the matrix is ​​composed of cetearyl alcohol, glyceryl monostearate, liquid paraffin, dimethyl silicone oil, propylparaben, carbomer, glycerin, potassium lauryl phosphate, hyaluronic acid, methylparaben, triethanolamine and water.

[0008] Further, the toad oil preparation method includes the following steps: S1: crushing toad viscera to obtain toad viscera slurry; S2: heating the toad viscera slurry obtained in step S1 and centrifuging to obtain toad oil.

[0009] Further, in step S2, the heating method includes heating the toad viscera slurry in a water bath, heating with water, and heating with a dilute alkali; the heating temperature is ≤95℃, preferably 80℃; the heating time is ≤60 min, preferably 45 min.

[0010] Further, the toad oil cream base, by weight, comprises: 2 parts cetearyl alcohol, 1 part glyceryl monostearate, 8 parts liquid paraffin, 2 parts dimethyl silicone oil, 0.1 parts propylparaben, 0.1 parts carbomer, 7 parts glycerin, 2 parts potassium lauryl phosphate, 1 part hyaluronic acid, 0.2 parts methylparaben, 57 parts water, and 0.1 parts triethanolamine. (Instructions for Use, Page 2 / 9, CN 122075549 A) ​​

[0011] Further, the toad oil in the toad oil cream has a mass fraction of 1%-20%.

[0012] Even further, the toad oil in the toad oil cream has a mass fraction of 5%-10%.

[0013] Further, the pain includes acute pain and chronic pain.

[0014] Further, the acute pain includes, but is not limited to, traumatic pain, postoperative pain, acute visceral pain, infectious pain, and gout.

[0015] Furthermore, the traumatic pain refers to pain caused by fractures, sprains, cuts, burns, falls, etc.

[0016] Furthermore, the acute visceral pain refers to pain caused by acute appendicitis, gallstones / kidney stones, myocardial infarction, intestinal obstruction, etc.

[0017] Furthermore, the chronic pain includes, but is not limited to, neuropathic pain, musculoskeletal chronic pain, headache and facial pain, cancer pain, primary / unexplained chronic pain, and gout.

[0018] Further, the neuropathic pain includes, but is not limited to, postherpetic neuralgia, diabetic peripheral neuropathy, phantom limb pain, and trigeminal neuralgia.

[0019] Further, the musculoskeletal chronic pain includes, but is not limited to, chronic low back pain, osteoarthritis, chronic joint pain such as rheumatoid arthritis, fibromyalgia, and chronic neck and shoulder pain.

[0020] Further, the headache and facial pain includes, but is not limited to, chronic migraine and tension headache.

[0021] Further, the product includes pharmaceutical products or non-pharmaceutical products.

[0022] Further, the pharmaceutical product is a drug.

[0023] In a second aspect, the present invention provides the application of toad oil cream in the preparation of a medicament for treating pain, wherein the toad oil cream is composed of toad oil and a matrix; the matrix is ​​composed of cetearyl alcohol, glyceryl monostearate, liquid paraffin, dimethyl silicone oil, propylparaben, carbomer, glycerin, potassium lauryl phosphate, hyaluronic acid, methylparaben, triethanolamine and water.

[0024] Further, the method for preparing toad oil includes the following steps: S1: crushing toad viscera to obtain toad viscera slurry; S2: heating the toad viscera slurry obtained in step S1 and centrifuging to obtain toad oil; further, in step S2, the heating method includes heating the toad viscera slurry in a water bath, heating with water, and heating with a dilute alkali; the heating temperature is ≤95℃, preferably 80℃; the heating time is ≤60 min, preferably 45 min.

[0025] Further, the toad oil cream base comprises, by weight, 2 parts cetearyl alcohol, 1 part glyceryl monostearate, 8 parts liquid paraffin, 2 parts dimethyl silicone oil, 0.1 parts propylparaben, 0.1 parts carbomer, 7 parts glycerin, 2 parts potassium lauryl phosphate, 1 part hyaluronic acid, 0.2 parts methylparaben, 57 parts water, and 0.1 parts triethanolamine.

[0026] Further, the toad oil in the toad oil cream has a mass fraction of 1%-20%.

[0027] Even further, the toad oil in the toad oil cream has a mass fraction of 5%-10%.

[0028] Further, one or more pharmaceutically acceptable carriers may be added to the drug.

[0029] Further, the drug dosage form includes, but is not limited to, one or more of tablets, capsules, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal preparations, and / or suppositories.

[0030] Further, the formulation may be one or more of ordinary formulations, sustained-release formulations, and / or controlled-release formulations.

[0031] Further, colorants, preservatives, flavorings, tasters, sweeteners, or other materials may be added to the various formulations if necessary.

[0032] Further, the drug can be administered transdermally, by injection, or through a cavity.

[0033] Further, the pain includes acute pain and chronic pain.

[0034] Further, the acute pain includes, but is not limited to, traumatic pain, postoperative pain, acute visceral pain, infectious pain, and gout.

[0035] Further, the traumatic pain refers to pain caused by fractures, sprains, cuts, burns, falls, etc.

[0036] Further, the acute visceral pain refers to pain caused by acute appendicitis, gallstones / kidney stones, myocardial infarction, intestinal obstruction, etc.

[0037] Further, the chronic pain includes, but is not limited to, neuropathic pain, musculoskeletal chronic pain, headache and facial pain, cancer pain, primary / unexplained chronic pain, and gout.

[0038] Furthermore, the neuropathic pain includes, but is not limited to, postherpetic neuralgia, diabetic peripheral neuropathy, phantom limb pain, and trigeminal neuralgia.

[0039] Furthermore, the musculoskeletal chronic pain includes, but is not limited to, chronic low back pain, osteoarthritis, chronic joint pain such as rheumatoid arthritis, fibromyalgia, and chronic neck and shoulder pain.

[0040] Furthermore, the headache and facial pain includes, but is not limited to, chronic migraine and tension headache.

[0041] Beneficial Effects The present invention conducted a systematic analysis of the full composition and characteristic components of toad oil and found that bufotalene is a characteristic component of toad oil, while fatty acids are its main components. Further, referring to the content determination method specified under the section on toad venom in the Pharmacopoeia of the People's Republic of China, the content of the legally limited components of toad venom in different batches of toad oil samples was detected. The results showed that there are essential differences in the main chemical composition and content levels between toad venom and the toad oil used in the present invention.

[0042] Animal experiments showed that toad oil cream can reduce the number of acetic acid writhing episodes in animals, with 5% toad oil cream showing significant effects. Simultaneously, the cream can prolong the time before the first writhing episode in animals, indicating that toad oil cream has a certain inhibitory effect on pain response caused by acetic acid writhing.

[0043] Clinical research results show that the toad oil cream of this invention, as a topical preparation, has a rapid onset and synergistic effect through multiple mechanisms in relieving acute symptoms of gout, postherpetic neuralgia, and arthritis-related pain and swelling. Furthermore, the development and utilization of toad oil is a beneficial supplement to the comprehensive and full utilization of toad resources, providing a model for the sustainable development of traditional Chinese medicine and the efficient utilization of biological resources, and also providing a useful reference for the future development of traditional Chinese medicine and the rational utilization of traditional biological resources. Neither the toad oil nor its cream of this invention showed skin irritation. Preparing toad oil as a cream effectively solves the problem of low drug retention rate when toad oil is directly administered, enabling the toad oil cream to treat various acute and chronic pains while also providing additional benefits.It has good safety and user comfort.

[0044] Figure 1 shows the acute skin irritation of guinea pig skin.

[0045] Figure 2 shows the repeated skin irritation of guinea pig skin.

[0046] Figure 3 shows the number of writhing movements in each group.

[0047] Figure 4 shows the time when the animals in each group exhibited their first writhing movement. Detailed Description

[0048] The specific embodiments of the present invention will be further described below. It should be noted that these descriptions are for the purpose of helping to understand the present invention, but do not constitute a limitation of the present invention. 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.

[0049] Unless otherwise specified, the experimental methods in the following embodiments are conventional methods, and the experimental materials used in the following embodiments are all obtainable through conventional commercial channels unless otherwise specified.

[0050] The acetic acid writhing test is used to study peritoneal nociceptors and measure spontaneous pain. Experimental animals are injected intraperitoneally with 0.6% acetic acid to stimulate the visceral and parietal peritoneum, producing pain over a large area and lasting for a long time. Researchers can observe and record the number of pain behaviors (stretching, curling up, abdomen touching the ground) in the animals. This method is simple, easy to perform, and has good reproducibility, and is often used in the study of central and peripheral analgesics (Zhang Meng, Luo Yanli. Overview of animal models of pain-related diseases [J]. Western Medicine, 2014, 26(06): 814-817.).

[0051] The toad oil cream of the present invention is prepared according to the method of Chinese invention patent application CN 118477039 B. The specific steps are as shown in Example 1. Example 1 Preparation method of toad oil cream 1. Preparation of toad oil S1: Put toad viscera into a meat grinder and grind it into toad viscera paste with a particle size ≤5 mm; S2: Take 30 g of toad viscera paste and put it into an Erlenmeyer flask, place it in an 80℃ constant temperature water bath and heat it for 45 min, take it out and place it at room temperature, centrifuge at 6000 r / min for 15 min, and separate toad oil.

[0052] 2. Preparation of the toad oil cream matrix: The components by weight are: 2 parts cetearyl alcohol, 1 part glyceryl monostearate, 8 parts liquid paraffin, 2 parts dimethyl silicone oil, 0.1 parts propylparaben, 0.1 parts carbomer, 7 parts glycerin, 2 parts potassium lauryl phosphate, 1 part hyaluronic acid, 0.2 parts methylparaben, 57 parts water, and 0.1 parts triethanolamine.

[0053] The preparation process is as follows: 1) Cetearyl alcohol, glyceryl monostearate, liquid paraffin, dimethyl silicone oil and propylparaben are mixed and stirred for 12 min to obtain phase A emulsion; 2) Carbomer, glycerin, potassium lauryl phosphate, hyaluronic acid, methylparaben and water are mixed and stirred for 15 min to obtain phase B emulsion; 3) Phase A is added to phase B, heated to 85°C until completely dissolved, and homogenized for 3 minutes.min, keep warm for 25 min, add triethanolamine, homogenize for 3 min, and obtain the toad oil cream matrix.

[0054] 3. Preparation of toad oil cream Low-dose group of toad oil cream: Take 5 parts by weight of toad oil and add it to 95 parts of toad oil cream matrix, homogenize for 3 min, and obtain toad oil cream with a toad oil mass fraction of 5%.

[0055] High-dose group of toad oil cream: Take 10 parts by weight of toad oil and add it to 90 parts of toad oil cream matrix, homogenize for 3 min, and obtain toad oil cream with a toad oil mass fraction of 10%.

[0056] Example 2 Chemical composition and content of toad oil The toad oil was analyzed by LC-MS and GC-MS, and the characteristic components were analyzed by HPLC. The results showed that bufotalene is the characteristic component of toad oil, while fatty acids are the main components of toad oil.

[0057] Following the content determination method specified in the Toad Venom medicinal material section of the Pharmacopoeia of the People's Republic of China, the content of legally limited components of toad venom in different batches of toad oil samples was tested. The Pharmacopoeia of the People's Republic of China clearly stipulates that, calculated on a dried basis, toad venom must contain a total of not less than 7.0% of bufotoxin (C24H34O4), bufotoxin (C26H34O6), and bufotoxin ligand (C24H32O4). However, the toad oil used in this invention has extremely low contents of the aforementioned characteristic components of toad venom as defined in the Pharmacopoeia, with the total content of all three components less than 1.0‰ (Table 1). Combined with the above content determination results, it is evident that there are fundamental differences in the main chemical composition and content levels between the toad venom medicinal material and the toad oil used in this study.

[0058] Table 1 Detection instructions for the content of legally limited components of toad venom in different batches of toad oil samples 5 / 9 pages 7 CN 122075549 A The content of linoleic acid and oleic acid in toad oil was detected by high performance liquid chromatography of fatty acids, and compared with that of stone frog oil. The results showed that the content of oleic acid and linoleic acid in toad oil was relatively high (Table 2).

[0059] Table 2 Detection of linoleic acid and oleic acid content in different batches of toad oil samples Example 3 Skin irritation test of toad oil and toad oil cream 1. Animals Adult white guinea pigs were purchased from the Vital River Laboratory Animal Center. The animal husbandry work of this study was completed in the standardized animal experimental facility of the Medical Experimental Center of China Academy of Chinese Medical Sciences. The research protocol has been approved by the ethics committee of the center (approval number: ERCCACMS21-2405-03).

[0060] 2. Method 2.1 Acute skin irritation test The day before the experiment, the hair on the back of the guinea pig was removed using depilatory cream and a razor, covering an area of ​​2 cm × 2 cm. On the first day of the experiment, about 2 g of toad oil, toad oil cream base, toad oil diluted with olive oil, and toad oil cream were applied.The hair was removed from the back of the guinea pig, and a medical PU film and medical tape were applied to the back of the mouse for 24 hours. After 24 hours, the film was washed off with warm water. After the experiment, the skin condition of each group of guinea pigs was recorded, and the irritation was judged according to the guinea pig skin allergy reaction standard. See Table 3.

[0061] Table 3 Guinea Pig Skin Allergy Reaction Standard Instructions 6 / 9 pages 8 CN 122075549 A 2.2 Repeated Skin Irritation Experiment The day before the experiment, the hair on the back of the guinea pig was removed with hair removal cream and a razor. The area was 2 cm × 2 cm. Olive oil, toad oil cream base, toad oil diluted with olive oil, and toad oil cream were applied to the hair removal area on the back of the guinea pig. The film and medical tape were applied to the back of the mouse for 6 hours. The film was applied for a total of 7 days. After 6 hours each day, the film was washed off with warm water. After the experiment, the skin condition of each group of guinea pigs was recorded, and the irritation was judged according to the guinea pig skin allergy reaction standard.

[0062] 3. Experimental Results 3.1 Acute Skin Irritation Test The results of the acute skin irritation test showed that after each drug stimulation, no erythema or swelling appeared on the skin of the guinea pigs after the hair was removed from their backs, according to the guinea pig skin allergy reaction criteria and records. See Figure 2 and Table 4. According to the guinea pig skin allergy reaction criteria.

[0063] Table 4 Results of Acute Skin Irritation Test 3.2 Repeated Skin Irritation Test The results of the repeated skin irritation test showed that after each drug stimulation, no erythema or swelling appeared on the skin of the guinea pigs after the hair was removed from their backs, according to the guinea pig skin allergy reaction criteria and records. See Figure 3 and Table 5. According to the guinea pig skin allergy reaction criteria.

[0064] Table 5 Results of Repeated Skin Irritation Test Guinea pig skin is highly similar to human skin in terms of tissue structure, biochemical characteristics and barrier function, especially in terms of chemical permeability and reaction patterns, showing significant analogy. This similarity makes guinea pigs an ideal model for simulating human skin's response to drugs in skin irritation experiments. Based on this characteristic, acute (single) and long-term (multiple) skin irritation experiments were conducted on guinea pigs using toad oil and its cream to evaluate its potential irritation and safety. The experimental results showed that neither acute exposure nor long-term contact with toad oil and its cream produced significant irritation to guinea pig skin, indicating that the drug has good safety and tolerability in skin application. This finding not only provides important safety evidence for further research on toad oil, but also eliminates potential interfering factors of skin irritation for subsequent experiments, providing important experimental evidence for its pharmacological mechanism research and clinical application transformation.

[0065] Example 4 Analgesic Experiment of Toad Oil Cream To explore the analgesic effect of toad oil cream on ICR mice, this invention selected 30 male ICR mice weighing 20-22 kg.Animals were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. Mice were randomly divided into three groups: a blank control group, a low-dose (5%) toad oil cream group, and a high-dose (10%) toad oil cream group, with 10 mice in each group. Animals were acclimatized for three days, and the abdomens of mice in each group were shaved and skinned the day before the end of the experiment. The corresponding doses of the drugs were applied to the groups, while the blank control group received a blank matrix. On the day of the experiment, one hour after the drug application, each group of animals was intraperitoneally injected with 0.6% glacial acetic acid solution at a dose of 0.1 mL / 10g, inducing a writhing response (signs of writhing response: the mouse abdomen concave, the abdomen contracting into an "S" shape, hind limbs extended, the buttocks raised, and crawling forward). Within 30 minutes after injection, the total number of writhing responses was recorded as a quantitative indicator of pain. The number of writhing responses in each group was statistically compared; the time of the first writhing response was recorded as the writhing latency period, and the differences in writhing latency periods between the groups were statistically compared.

[0066] The results showed (Figures 3-4) that toad oil ointment could reduce the number of acetic acid writhing in animals, with a significant difference between the 5% treatment group and the blank control group (P<0.05); toad oil ointment could also delay the time of the first writhing in animals, but there was no statistical significance. This indicates that the drug has a certain inhibitory effect on the pain response caused by acetic acid writhing. Example 5 Clinical Study

[0067] This example aims to study the clinical application effect of toad oil ointment in a variety of common painful diseases (acute gout attack, postherpetic neuralgia, arthritis). Through feedback from typical patients, the onset time, degree of symptom improvement and tolerance of this product after external application were observed.

[0068] Case 1 Evaluation of efficacy in gout patients Diagnosis and symptoms: The patient was a 52-year-old male with an acute gout attack in the first metatarsophalangeal joint of the left foot, manifested as severe pain, extensive redness and swelling of the dorsum of the foot, accompanied by movement disorders (difficulty walking). Instructions for use, pages 8 / 9, CN 122075549 A

[0069] Medication and observation: After applying 10% toad oil cream for 12 hours, significant reduction in redness and swelling was observed, skin color returned to normal, and pain was significantly reduced. Continued use for 1 day (total approximately 36 hours) resulted in basic recovery of joint function and normal walking.

[0070] Case 2: Evaluation of efficacy in patients with herpes zoster. Diagnosis and symptoms: The patient was a 78-year-old female with a history of 6 months of severe pain, which seriously affected her sleep at night and her mood during the day.

[0071] Medication and observation: One hour after applying 10% toad oil cream, the patient felt pain relief. Sleep quality improved that night. The next morning, the cream was used again, and no severe pain occurred during the treatment; only a slight warming sensation was felt locally.

[0072] Case 3: Evaluation of efficacy in patients with arthritis. Diagnosis and symptoms: The patient was a 72-year-old female who had long suffered from knee swelling and pain, with limited joint flexion.

[0073] Medication and observation: Apply 10% solution twice daily, morning and evening.After two days of continuous use, the swelling of the knee joint disappeared, the pain was reduced, and the flexibility of joint flexion was significantly improved.

[0074] Based on the above clinical observation, the toad oil cream of the present invention showed the following advantages in the management of three different types of pain: (1) Rapid onset of action: For acute inflammatory pain (gout) and neuralgia (PHN), significant improvement of symptoms was observed within a few hours to one day.

[0075] (2) Multidimensional efficacy: It not only relieves pain, but also has a positive effect on redness and swelling caused by acute inflammation, swelling caused by chronic arthritis, and sleep disorders caused by neuralgia.

[0076] (3) Wide range of applications: This product showed a certain degree of relief in inflammatory pain, neuropathic pain and degenerative joint pain, suggesting that its mechanism of action may have multiple targets.

[0077] (4) Good tolerability: In the observed cases, only one case reported a slight local warming sensation, and no other obvious irritation or discomfort was reported, suggesting that the topical application is safe. Instruction sheet 9 / 9 page 11 CN 122075549 A Figure 1 Figure 2 Figure 3 Instruction drawing 1 / 2 page 12 CN 122075549 A Figure 4 Instruction sheet drawing 2 / 2 page 13 CN 122075549 A Abstract A CREAM EFFECTIVE AGAINST PAIN The present invention belongs to the field of biomedicine, and specifically relates to a cream and an application thereof. The toad oil used therein. in the present invention has significantly different components from those of the toad venom medicinal material, and its cream is effective against various types of acute and chronic pain. Animal experiments have confirmed that the toad oil cream can significantly reduce the number of writhing responses induced by acetic acid and delay their onset,demonstrating a clear analgesic effect. Clinical studies indicate that the cream has a rapid onset of action and definite efficacy against acute gout attacks, postherpetic neuralgia, and arthritis-related pain and swelling. The formulation effectively improves drug retention rate and application comfort, with no skin irritation observed. This development achieves the comprehensive utilization of toad resources and provides an example for the sustainable development of traditional Chinese medicine and the efficient utilization of biological resources. Abstract

Claims

1. The application of toad oil cream in the preparation of pain-relieving products, characterized in that, The toad oil cream is composed of toad oil and a matrix; the toad oil is obtained by crushing toad viscera, heating the toad viscera paste, and then centrifuging; the matrix is ​​composed of cetearyl alcohol, glyceryl monostearate, liquid paraffin, dimethyl silicone oil, propylparaben, carbomer, glycerin, potassium lauryl phosphate, hyaluronic acid, methylparaben, triethanolamine, and water.

2. The product as described in claim 1, characterized in that, The toad oil has a mass fraction of 1%-20% in the toad oil cream.

3. The product as described in claim 1, characterized in that, The pain includes both acute and chronic pain.

4. The product as described in claim 1, characterized in that, The acute pain includes, but is not limited to, traumatic pain, postoperative pain, acute visceral pain, infectious pain, and gout; the chronic pain includes, but is not limited to, neuropathic pain, musculoskeletal chronic pain, headache and facial pain, cancer pain, primary / unexplained chronic pain, and gout.

5. The product as described in claim 1, characterized in that, The products include pharmaceutical products or non-pharmaceutical products.

6. The application of toad oil cream in the preparation of a pain-relieving drug, wherein the toad oil cream is composed of toad oil and a matrix; the toad oil is obtained by crushing toad viscera, heating the toad viscera paste, and then centrifuging; the matrix is ​​composed of cetearyl alcohol, glyceryl monostearate, liquid paraffin, dimethyl silicone oil, propylparaben, carbomer, glycerin, potassium lauryl phosphate, hyaluronic acid, methylparaben, triethanolamine, and water.

7. The application as described in claim 6, characterized in that, The toad oil has a mass fraction of 1%-20% in the toad oil cream.

8. The application as described in claim 6, characterized in that, The drug may also contain one or more pharmaceutically acceptable carriers.

9. The application as described in claim 6, characterized in that, The pain includes both acute and chronic pain.

10. The application as described in claim 6, characterized in that, The acute pain includes, but is not limited to, traumatic pain, postoperative pain, acute visceral pain, infectious pain, and gout; the chronic pain includes, but is not limited to, neuropathic pain, musculoskeletal chronic pain, headache and facial pain, cancer pain, primary / unexplained chronic pain, and gout.

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