A natural ingredient-containing external use time delay spray and a method for preparing the same

Abstract

The application belongs to the field of traditional Chinese medicine, and particularly relates to a time-delay spray containing dry toad extract and toad oil and a preparation method thereof. The time-delay spray provided by the application can significantly treat male erectile dysfunction. The time-delay spray prepared by the application has the advantages of direct action, quantitative drug delivery, and no contact to avoid drug pollution. The application realizes the transformation of waste into treasure of toad oil, fully excavates the medicinal value of toad oil, further improves the rational utilization system of toad resources, and provides a practical scheme for efficient development of toad medicinal resources.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine, specifically relating to the preparation of a traditional Chinese medicine external delay spray. Background Technology

[0002] Toads are a general term for the Chinese giant toad (Bufo bufogargarizans Cantor) or the black-rimmed toad (Bufo melanostictus Schneider) belonging to the Bufonidae family. As a traditional Chinese medicine, its medicinal history is long, first recorded in the *Shennong Bencao Jing* (Shennong's Classic of Materia Medica), which describes it as having a "pungent taste, cool nature, and entering the heart, liver, spleen, and lung meridians. It treats pathogenic factors, breaks up blood stasis, dispels heat, promotes urination, and kills parasites." It can be used to treat carbuncles, boils, sores, ulcers, infantile malnutrition, oral ulcers, hemorrhoids, ascites, boils, and other ailments. Currently, the main medicinal toads in my country are the Chinese giant toad and the black-rimmed toad, widely distributed in Jiangsu, Shandong, Zhejiang, and other regions. The entire toad has medicinal value, with toad venom, dried toad, and toad skin being the most widely used core ingredients clinically. Their core medicinal effects include anti-tumor, local anesthesia, analgesia, and anti-inflammation.

[0003] Dried toad is an important category of toad-derived medicinal materials, second only to toad venom and toad skin. However, the current local standards and processing specifications for medicinal materials do not uniformly include the medicinal parts of dried toad, toad skin, and dried toad skin. For example, the dried toad included in the "Shanghai Municipal Standard for Processing Traditional Chinese Medicine Pieces" and the "Zhejiang Provincial Standard for Processing Traditional Chinese Medicine" are also known as dried toad skin and / or toad skin, respectively.

[0004] Due to factors such as changes in the ecological environment, excessive use of pesticides and fertilizers, and fragmentation by road networks, the habitat range of toads has shrunk significantly. Coupled with human overhunting and killing, wild toad resources are continuously declining and are nearing depletion, leading to a year-on-year increase in the price of medicinal materials made from toads (such as toad skin and toad venom). Toad venom meeting the standards of the Chinese Pharmacopoeia sells for up to 85,000 yuan per kilogram, while toad venom with higher content sells for over 100,000 yuan per kilogram. In contrast, dried toads sell for only 50-80 yuan per kilogram. Therefore, large-scale toad farming has broad market prospects. Currently, the mortality rate of toad farming is over 70%. Utilizing dead toads to produce dried toads can effectively improve resource utilization. Currently, toads are mainly used in medicine for dried toads, toad skin, and toad venom. The bones, meat, and internal organs of toads after collecting venom and skin are mostly discarded as waste, resulting in a huge waste of resources. If these wastes are used as raw materials to extract and process toad oil, waste can be turned into treasure. As a new resource for traditional Chinese medicine, toad oil has unique development potential. It can transform livestock waste into high-value-added products, thereby improving the efficiency of resource reuse.

[0005] Premature ejaculation (PE) is the most common ejaculatory dysfunction in men, with an incidence rate as high as 35%-50%. Epidemiological studies show that 75% of men will experience PE symptoms at some point in their lives. With the development of domestic society and the improvement of residents' living standards, people's demand for sexual health is increasing. In the past 30 years, women's sexual awareness has gradually increased, and more men are actively seeking medical help for ejaculation problems. However, the current clinical diagnostic system for premature ejaculation is still relatively backward.

[0006] Erectile dysfunction (ED) refers to a man's persistent inability to achieve or maintain an erection sufficient for satisfactory sexual intercourse for more than three months. This condition significantly impacts the quality of life for both the patient and their partner, and is most common in men over 40, although it has shown a trend towards affecting younger men in recent years. Traditional Chinese medicine classifies ED as "yangwei," "yinwei," or "yangshibuji," clinically manifesting as weak or unsustainable penile erection, or complete loss of erection. These symptoms may occur alone or alternately. Traditional Chinese medicine considers its etiology and pathogenesis to be complex, often involving factors such as deficiency of internal organs, emotional imbalance, congenital insufficiency, blood stasis, and excessive sexual activity.

[0007] The high stress, fast pace, and unhealthy lifestyles of contemporary society can easily lead to a decline in male sexual function and a shortened ejaculation time. Current oral medications suffer from long treatment courses and limited efficacy, while traditional Chinese medicine preparations also have drawbacks such as prolonged treatment duration, slow onset of action, and unsatisfactory results. Western medicine believes that premature ejaculation is mostly caused by psychological factors, with a few cases stemming from organic lesions. Existing medications for premature ejaculation caused by nervous sensitivity are mostly anesthetics, which reduce the sensitivity of the central nervous system by locally anesthetizing the male genitalia to achieve a delaying effect. However, these drugs can easily cause side effects such as burning sensation and numbness in the genital area, and long-term use may also lead to decreased libido and affect the health of the nervous system (CN 110151828 A). Although there are various treatment methods for premature ejaculation, including psychotherapy, behavioral training, antidepressant medication, and surgery, topical penile medications remain the mainstream clinical treatment due to their advantages of rapid onset of action, ease of use, high safety, and low cost. Studies have shown that topical penile medications can reduce local sensitivity, prolong ejaculation latency, and improve the quality of sexual life.

[0008] Sprays refer to a local drug delivery method based on a closed container system. They are mainly used in clinical scenarios such as respiratory inhalation therapy, intracavitary mucosal surface drug delivery, and skin local drug delivery. They can improve the efficiency of local drug delivery. Sprays deliver drugs in the form of fine droplets, which act directly on the lesion site. The unique drug delivery form greatly facilitates the use of drugs in sensitive areas such as the mouth. They also have high local concentrations and rapid onset of action. In addition, most sprays are lightweight, portable, and easy to use. Therefore, they have broad application potential in clinical treatment (Mu Hong. Study on the application effect of hawthorn spray on thirst in maintenance hemodialysis patients [D]. Dali University, 2025.000243.). Summary of the Invention

[0009] This invention addresses the problems existing in the prior art by providing a delay spray containing dried toad extract and toad oil. This delay spray is effective in treating premature ejaculation and erectile dysfunction. The technical solution of this invention transforms toad oil from waste into a valuable resource, while simultaneously improving the toad resource utilization system. This not only reduces the economic burden of drug production and clinical application but also revitalizes idle resources in traditional processes. Based on this, this invention was completed.

[0010] In a first aspect, the present invention provides a delay spray containing the following raw materials in parts by weight: 1 part of ultrafine powdered dried toad extract, 3-8 parts of toad oil, and an appropriate amount of the base required for the spray.

[0011] Preferably, the delay spray contains the following raw materials in parts by weight: 1 part of ultrafine powdered dried toad extract, 4-7 parts of toad oil, and an appropriate amount of the base required for the spray.

[0012] More preferably, the delay spray contains the following raw materials in parts by weight: 1 part of ultrafine powdered dried toad extract, 5 parts of toad oil, and an appropriate amount of the base required for the spray.

[0013] The extraction process of the ultrafine powdered dried toad extract is as follows: S01 Add 95% ethanol to dried toad powder and extract 1-3 times at a material-to-liquid ratio of 1:10, each extraction lasting 1-2 hours; S02 is heated and refluxed through a reflux condenser, and the extract is collected. The residue is then extracted twice more, and the extracts are combined. S03 The obtained extract was concentrated under reduced pressure to obtain a dried toad extract.

[0014] S04 The above-mentioned dried toad extract is mixed with water at a material-liquid ratio of 1:1, soaked for 30 minutes, and continuously dried in a drying oven at 60°C until the water content is less than 5%. The dried toad extract is then pulverized through an 80-mesh pharmacopoeia sieve and pulverized through an air jet mill to obtain an ultrafine powder of dried toad extract with a mesh size of 800-2000.

[0015] Furthermore, in step S01, the preparation of the dried toad powder involves placing dried toads in a drying oven for continuous drying until the moisture content is less than 5%, pulverizing them with a pulverizer, and passing them through a 120-mesh pharmacopoeia sieve to obtain dried toad powder.

[0016] The toad oil is made from toad viscera, which are crushed, heated, and centrifuged. The resulting oil is then filtered to obtain toad oil.

[0017] The matrix comprises Labrasol, Plurol Oleique CC497, and water.

[0018] Furthermore, the matrix contains the following components in parts by weight: 100-300 parts of Labrasol, 50-100 parts of Plurol Oleique CC497, and 400-500 parts of water.

[0019] Preferably, the matrix contains the following components in parts by weight: 200 parts Labrasol, 60 parts Plurol Oleique CC497, and 450 parts water.

[0020] In a second aspect, the present invention provides a method for preparing the spray described in the first aspect, the method comprising the following steps: Preparation of S1 ultrafine powdered dried toad extract: S11 involves continuously drying the dried toad, pulverizing it, and then passing it through a 120-mesh pharmacopoeia sieve to obtain dried toad powder. S12 dried toad powder was added to 95% ethanol, heated under reflux using a reflux condenser, and the extract was collected. The residue was then extracted twice more, and the extracts were combined. S13 The extract obtained in the above steps is concentrated under reduced pressure to obtain dried toad extract; S14 The above-mentioned dried toad extract is soaked in water, continuously dried, pulverized and sieved, and the sieved dried toad extract is pulverized by an air jet mill to obtain ultrafine powdered dried toad extract.

[0021] S2 Toad Oil Preparation: Toad viscera are used as raw material. After crushing, heating and centrifuging, the resulting oil is filtered to obtain toad oil.

[0022] Preparation of S3 Delay Spray: S31 Add ultrafine powdered dried toad extract to Transcutol P solvent, and dissolve by shaking at room temperature to obtain dried toad extract solution; S32 adds toad oil, Labrasol, Plurol Oleique CC497 and water to a homogenization tank to obtain a toad oil dispersion; S33. Add the ultrafine powdered dried toad extract solution to the toad oil dispersion and mix thoroughly. The product is filtered through S34 and aseptically filled into a spray bottle, resulting in the delay spray of this invention.

[0023] Furthermore, in step S11, the final water content of the dried toad is less than 5%; Furthermore, in step S12, the ratio of the dried toad powder to 95% ethanol is 1:10, and the extraction is performed 1-3 times, with each extraction lasting 1-2 hours.

[0024] Further, in step S14, the ratio of the dried toad extract to water is 1:1, the mixture is soaked for 30 minutes, continuously dried in a drying oven at 60°C until the water content is less than 5%, pulverized through an 80-mesh pharmacopoeia sieve, and then pulverized by an air jet mill to obtain an 800-2000 mesh ultrafine powder of dried toad extract.

[0025] Further, in step S32, the weight parts of Labrasol, Plurol Oleique CC497 and water are 100-300 parts of Labrasol, 50-100 parts of Plurol Oleique CC497 and 400-500 parts of water; the homogenizing tank is set at 50°C, homogenized at 2000 r / min for 5 min, and cooled to below 30°C to obtain toad oil dispersion.

[0026] Thirdly, the present invention provides the application of the delay spray of the first aspect in the preparation of a treatment for premature ejaculation and erectile dysfunction in men; the delay spray contains the following raw materials in parts by weight: 1 part of ultrafine powdered dried toad extract, 3-8 parts of toad oil and an appropriate amount of the base required for the spray.

[0027] Furthermore, the premature ejaculation includes primary premature ejaculation, secondary premature ejaculation, naturally occurring variant premature ejaculation, and subjective premature ejaculation.

[0028] Furthermore, primary premature ejaculation refers to a condition that has persisted since the first sexual experience and with all sexual partners, with IELT typically being extremely short (<1 minute).

[0029] Furthermore, the aforementioned secondary premature ejaculation refers to a condition in which the patient previously had normal ejaculatory control, but which subsequently develops due to some reason, with IELT significantly shortened to less than 3 minutes.

[0030] Furthermore, the aforementioned natural variant premature ejaculation refers to irregular, occasional premature ejaculation, which is not true premature ejaculation but a normal fluctuation in sexual function.

[0031] Furthermore, subjective premature ejaculation refers to a patient's subjective belief that they have premature ejaculation, but their actual ejaculation time is within the normal or even longer range, and they are dissatisfied with their ejaculation time.

[0032] Furthermore, erectile dysfunction refers to a man's inability to maintain or achieve a sufficient penile erection to complete a satisfactory sexual intercourse.

[0033] The medicinal properties and effects of the Chinese medicinal materials used in this invention are as follows: Dried toad: pungent, cool; poisonous. Enters the spleen, liver, and lung meridians. Breaks up lumps, eliminates infantile malnutrition, promotes urination, detoxifies, kills parasites, and relieves pain. Used for boils, carbuncles, edema, and infantile malnutrition.

[0034] Toad oil: pungent, warm; enters the heart and spleen meridians. It tonifies the kidneys and replenishes essence, nourishes yin and moistens the lungs, and is mainly used for physical weakness, post-illness recovery, fatigue, palpitations, and insomnia.

[0035] Beneficial effects: This invention relates to a topical delay spray prepared by quantitatively controlling the dosage of dried toad extract and toad oil, for the treatment of premature ejaculation and erectile dysfunction in men. Toad resources are relatively scarce, and the mortality rate during breeding is high. Furthermore, the entire toad plant has medicinal value; therefore, fully utilizing toad raw materials to exert their local anesthetic and analgesic effects is of great significance for reducing drug production costs and promoting clinical application. This method not only revitalizes resources that are not fully utilized in traditional processes, turning toad oil from waste into treasure, but also promotes the efficient integration of resources across the entire toad industry chain. This formulation has advantages such as direct action, controllable dosage, and non-contact administration to avoid contamination. Furthermore, by using toads that die during breeding as raw materials, the preparation cost is further reduced. Attached Figure Description

[0036] Figure 1 High-performance liquid chromatography (HPLC) spectrum of alcohol-extracted toad extract Figure 2 High-performance liquid chromatography (HPLC) spectrum of toad venom extract extracted with alcohol Figure 3 High-performance liquid chromatography (HPLC) spectrum of toad venom extracted with alcohol Detailed Implementation

[0037] 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.

[0038] 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.

[0039] Example 1: Preparation of a delay spray based on dried toad extract and toad oil 1. Raw material preparation (1) Preparation of ultrafine powdered dried toad extract: a. The dried toad is continuously dried until its final moisture content is less than 5%, then pulverized and passed through a 120-mesh pharmacopoeia sieve to obtain dried toad powder; b. Add 95% ethanol to dried toad powder and extract 1-3 times at a material-to-liquid ratio of 1:10, each extraction lasting 1-2 hours; c. Heat the extract under reflux using a reflux condenser, collect the extract, extract the residue twice more, and combine the extracts. d. Concentrate the extract obtained in step (c) under reduced pressure to obtain dried toad extract. Weigh 5g of the dried toad extract for high-performance liquid chromatography (HPLC) analysis to determine its components. Figure 1 Chromatogram; e. Mix the dried toad extract obtained in step (d) with water at a ratio of 1:1, soak for 30 minutes, dry continuously, pulverize through an 80-mesh pharmacopoeia sieve, and pulverize the sieved dried toad extract through an air jet mill to obtain 800-2000 mesh ultrafine powder dried toad extract. (2) Preparation of toad oil: Toad viscera are used as raw material. After crushing, heating and centrifuging, the resulting oil is filtered to obtain toad oil.

[0040] 2. Preparation of delay spray (1) Add 20g of ultrafine powdered dried toad extract to 180mL of Transcutol P solvent and shake at room temperature to dissolve, thus obtaining a dried toad extract solution.

[0041] (2) Add 100 mL toad oil, 200 mL Labrasol, 60 mL Plurol Oleique CC497 and 440 mL water to a homogenizing tank, heat to 50 °C, homogenize at 2000 r / min for 5 min, and cool to below 30 °C to obtain toad oil dispersion.

[0042] (3) Add the dried toad extract solution obtained in step (1) to the toad oil dispersion obtained in step (2) and mix well.

[0043] (4) Filter and fill into a spray bottle under sterile conditions to obtain the delay spray of the present invention.

[0044] Example 2: Preparation of Toad Venom Delay Spray 1. Preparation of toad venom extract: (1) Take 1000g of toad venom and dry it at a temperature of 60℃ for 12-24 hours to make the final moisture content of the toad venom less than 5%, and obtain 920g of dried toad venom. (2) Crush the dried toad venom and pass it through an 80-mesh pharmacopoeia sieve; (3) The dried toad venom powder and 95% ethanol were placed in a reaction vessel at a ratio of 1:20 and heated to 75°C. The reaction was carried out for 1 hour to obtain toad venom extract. (4) The toad venom extract obtained in step (3) was concentrated under reduced pressure to obtain 376.25g of toad venom extract. 5g of the obtained toad venom extract and 5g of toad venom were respectively analyzed by high performance liquid chromatography to determine their components. Figure 2 and Figure 3 Chromatogram.

[0045] 2. Determination of the content of toad venom and toad venom extract (1) Chromatographic conditions and system suitability test: Octadecylsilane-bonded silica gel was used as the packing material; acetonitrile was used as mobile phase A, and 0.3% acetic acid solution was used as mobile phase B, with gradient elution performed according to the specifications in the table below; the column temperature was 30℃; the flow rate was 0.6 mL per minute; and the detection wavelength was 296 nm. The theoretical plate number, calculated based on the bufotoxin base peak, should not be less than 10,000. (2) Preparation of reference solution: Take an appropriate amount of bufotoxin reference standard, accurately weigh it, add methanol to prepare a solution containing 100 μg per ml; (3) Preparation of test solution: Take 25 mg each of dried toad extract, toad venom powder and toad venom extract, weigh accurately, place in a stoppered conical flask, add 20 ml of methanol accurately, weigh, heat under reflux for 1 hour, cool, weigh again, make up the lost weight with methanol, shake well, filter, and take the filtrate to obtain the test solution. (4) Determination method: Accurately pipette 10 μl of the above reference solution and 10-20 μl of the test solution, respectively, and inject them into the liquid chromatograph for determination.

[0046] (5) The results are shown in the table below. Table 1. Content Determination Results 3. Preparation of delay spray (1) Weigh 20g of the toad venom extract obtained in step 1 (4) and add it to 3775mL of Transcutol P solvent. Dissolve by shaking at room temperature to obtain toad venom extract solution.

[0047] (2) Add 4190mL Labrasol, 1258mL Plurol Oleique CC497 and 11315mL water to a homogenizing tank, heat to 50℃, homogenize at 2000r / min for 5min, and cool to below 30℃ to obtain an aqueous dispersion.

[0048] (3) Add the toad venom extract solution obtained in step (1) to the aqueous dispersion obtained in step (2) and mix well.

[0049] (4) Filter and fill into a spray bottle under sterile conditions to obtain toad venom delay spray.

[0050] Example 3 Preparation of matrix delay spray (1) Add 180mL Transcutol P, 200mL Labrasol, 60mL Plurol Oleique CC497 and 560mL water to a homogenizing tank, heat to 50℃, homogenize at 2000r / min for 5min, cool to below 30℃ to obtain a matrix dispersion, and filter.

[0051] (2) Fill the spray bottle under aseptic conditions to obtain the matrix delay spray. Example 4 Clinical Study

[0052] 1. Method A randomized, double-blind study design was used to conduct standardized clinical efficacy verification of premature ejaculation and erectile dysfunction in men.

[0053] 2. Research Subjects This study selected 92 patients with premature ejaculation and 102 patients with erectile dysfunction recommended by the Chinese Sexology Association and the First Affiliated Hospital of Sun Yat-sen University. Based on the diagnostic criteria of both traditional Chinese and Western medicine, and the inclusion and exclusion criteria, 90 patients with premature ejaculation and 102 patients with erectile dysfunction were screened. They were randomly divided into a premature ejaculation control group and a medication group (Medication Group 1: toad venom group; Medication Group 2: dried toad extract + toad oil group), with 30 patients in each group; and an erectile dysfunction control group and a medication group (Medication Group 1: toad venom group; Medication Group 2: dried toad extract + toad oil group), with 34 patients in each group.

[0054] 3. Instructions for use (1) Preparation before use: Wash the penis, foreskin and coronal sulcus with warm water before use, and dry them to ensure that the skin is dry, undamaged and free of inflammation, so as to avoid the drug irritating the damaged skin; (2) Usage and dosage: The blank group patients used the matrix delay spray, the drug group 1 patients used the toad venom delay spray, and the drug group 2 patients used the dried toad extract and toad oil delay spray. The above three groups of patients each sprayed one pump of the prepared spray evenly on the coronal sulcus, avoiding the application to non-sensitive areas such as the urethral opening and scrotum to reduce irritation. (3) Onset time: After spraying, wait 15 minutes for the drug to be fully absorbed, wipe off any residue on the surface, and avoid contact with the mucous membrane of the partner. (4) Frequency of use: Use before sexual intercourse, avoid frequent use.

[0055] 4. Diagnostic criteria 4.1 Western Medicine Diagnostic Criteria Premature ejaculation is diagnosed according to the standard diagnosis in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders.

[0056] Primary premature ejaculation (IELT): This condition persists from the first sexual experience and with all sexual partners; the IELT is typically very short, less than 1 minute. It is often more related to physiological and neurobiological factors, and is relatively difficult to treat.

[0057] Secondary premature ejaculation: Previously, there was normal ejaculatory control, but it developed later for some reason, with IELT significantly shortened to less than 3 minutes. It may be caused by hyperthyroidism, prostatitis, psychological stress, poor marital relationship, etc.

[0058] Natural variant premature ejaculation: Irregular, occasional premature ejaculation is not true premature ejaculation, but a normal fluctuation in sexual function, and usually does not require medical intervention.

[0059] Subjective premature ejaculation: The patient subjectively believes they have premature ejaculation, but their actual ejaculation time (IELT) is within the normal or even longer range, and they are dissatisfied with the ejaculation time. This is mainly related to psychological factors, erroneous perceptions, or a mismatch between the expectations of the partner.

[0060] For erectile dysfunction, please refer to the 2018 edition of the "AUA Guidelines for the Diagnosis and Treatment of Erectile Dysfunction".

[0061] 1. The penis is unable to achieve or maintain a sufficient erection to complete satisfactory sexual intercourse under adequate sexual stimulation, with a course of illness ≥3 months.

[0062] 2. Disease grading criteria: The patient's condition is assessed according to the International Erectile Dysfunction Scale (IIEF-5): 22-25 points is normal, 17-21 points is mild dysfunction, 12-16 points is mild to moderate dysfunction, 8-11 points is moderate dysfunction, and 5-7 points is severe dysfunction.

[0063] 4.2 Traditional Chinese Medicine Diagnostic Criteria The TCM diagnostic criteria for premature ejaculation conform to the relevant diagnostic criteria in "Xu Fusong's Practical TCM Andrology" and "Clinical Guidelines for Andrology", and information is collected based on "inspection, auscultation, inquiry, and palpation".

[0064] Damp-heat in the Liver Meridian: Damp-heat in the Liver Meridian disturbs the seminal vesicle. Systemic symptoms: dizziness, bitter taste in the mouth, dry throat, irritability, dampness in the scrotum, and dark yellow urine. Tongue and pulse: red tongue, yellow and greasy coating, and wiry and rapid pulse.

[0065] Yin deficiency with exuberant fire: Kidney yin deficiency, internal disturbance of deficient fire, and scorching of the seminal vesicles. Systemic symptoms: Five-center heat (palms, soles, and chest), tidal fever and night sweats, soreness and weakness of the lower back and knees, dizziness and tinnitus. Tongue and pulse: Red tongue with little coating, thready and rapid pulse.

[0066] Kidney Qi Deficiency: Kidney Qi is deficient, its function of consolidating and retaining essence is impaired, and the seminal gate is not secure. Systemic Symptoms: Lower back and knee weakness, lethargy, pale complexion, frequent or clear urination. Tongue and Pulse: Pale tongue with white coating, deep and weak pulse.

[0067] Heart and Spleen Deficiency: This condition involves depletion of heart blood, impaired spleen function, qi deficiency leading to sinking, and inability to retain essence. Systemic symptoms include insomnia with excessive dreaming, fatigue, pale complexion, poor appetite, abdominal distension, and loose stools. Tongue and pulse characteristics: Pale, swollen tongue with teeth marks, thin white coating, and weak, thready pulse.

[0068] Heart-Kidney Disharmony: Insufficient kidney water fails to nourish heart fire, leading to excessive heart fire that fails to warm kidney water. Systemic symptoms: Palpitations, dizziness, tinnitus, dry throat and mouth, lower back and knee weakness, night sweats, and hot flashes. Tongue and pulse: Red tongue with little coating, thready and rapid pulse.

[0069] The TCM diagnostic criteria for erectile dysfunction were formulated with reference to the "Guiding Principles for Clinical Research of New Traditional Chinese Medicine (Trial Implementation)," "Traditional Chinese Medicine Andrology," and "Traditional Chinese Medicine Internal Medicine," combined with relevant content from this study, to establish the diagnostic criteria for kidney yang deficiency syndrome. Main symptom: Inability to maintain an erection during sexual intercourse.

[0070] Secondary symptoms: soreness and weakness in the lower back and knees, dizziness and tinnitus, aversion to cold and cold limbs.

[0071] Tongue and pulse: The tongue is pale with a white coating, and the pulse is deep and thready.

[0072] If two or more of the primary and secondary symptoms are present, and the tongue and pulse are also considered, the diagnosis is confirmed as this syndrome type.

[0073] 4.3 Severity classification of the disease ① Mild: Ejaculation occurs within 2 minutes of penile insertion into the vagina; ② Moderate: Ejaculation occurs within one minute of penile insertion into the vagina; ③ Severe: Ejaculation occurs before or immediately after penetration.

[0074] 5. Inclusion and exclusion criteria: 5.1 Inclusion Criteria 1. Patients must be male, aged ≥18 years and ≤50 years. 2. Maintaining a single, stable sexual relationship with the same woman for at least 6 months; 3. Intravaginal ejaculation latency time: The time from penile insertion into the vagina to ejaculation, whether continuous or repeated, is less than 3 minutes; 4. Ejaculatory control: Always or almost always unable to delay ejaculation; 5. Negative consequences: Premature ejaculation can lead to negative personal consequences such as distress, anxiety, frustration, or avoidance of sexual intimacy. 6. Duration and frequency of symptoms: Symptoms persist for 6 months or more and occur in almost (75%-100%) or almost all sexual activities; 7. Meets the diagnostic criteria of both traditional Chinese medicine and Western medicine.

[0075] 5.2 Exclusion Criteria 1. Individuals with a history of significant comorbidities in various systems; 2. Those with other sexual dysfunctions, such as decreased libido, inhibited orgasm, or anejaculation; 3. The female partner has significant sexual dysfunction, such as sexual aversion, decreased libido, painful intercourse, orgasmic disorder, and others; 4. Penile deformity; 5. Acute and chronic inflammation of the reproductive system and sexually transmitted diseases; 6. Those allergic to alcohol or the selected traditional Chinese medicine; 7. Those with ulcers or other skin lesions on the foreskin and glans; 8. Homosexual patients; 9. Individuals with a history of drug abuse or drug use within the past year; 10. Non-human factors: Premature ejaculation caused by factors other than one's own body, such as alcohol or drug abuse or withdrawal; 11. Partner's sexual problems: Sexual dysfunction in the partner (such as painful intercourse, vaginal dryness) is a major cause of premature ejaculation; 12. Other sexual dysfunctions: Erectile dysfunction that is a coexisting and primary problem; 13. Non-vaginal sexual activity: The standard only applies to vaginal intercourse and does not include premature ejaculation in other forms of sexual activity.

[0076] 6. Observation Indicators 6.1 Therapeutic indicators The effects of the dried toad extract and toad oil of this invention on male premature ejaculation and erectile dysfunction were evaluated using the CISFPE score (Chinese Premature Ejaculation Sexual Function Evaluation Scale), the Sexual Satisfaction Score (SSS, using scores of 6, 7, and 8 from 0 to 15 in the CISFPE score), and the International Index of Erectile Function (IIEF-5).

[0077] 6.2 Safety Indicators Complete blood count, urinalysis, liver function tests, and kidney function tests.

[0078] 6.3 Adverse Events Observe for any redness, swelling, pain, itching, rash, burning sensation, or erectile dysfunction due to penile numbness in the glans penis; also observe for any decreased vaginal sensation or discomfort in the woman.

[0079] 7. Statistical Analysis and Content Statistical analysis will be performed using SPSS 22.0 statistical analysis software. All inter-group statistical tests will be two-tailed, and a p-value less than or equal to 0.05 will be considered statistically significant. Chi-square tests will be used for categorical data, and continuous data will be expressed as mean ± standard deviation (x ± s). Paired-samples t-tests will be used for within-group comparisons, and independent-samples t-tests will be used for between-group comparisons. The rank-sum test will be used for comparing ordinal data. Pearson's correlation test will be used for correlation analysis.

[0080] 8. Results 8.1 Evaluation of premature ejaculation in patients Table 2. Evaluation Scale for Sexual Function in Chinese Patients with Premature Ejaculation (CISFPE Score) Note: * Compared with the blank control group, P < 0.05 As shown in Table 2, the sexual function of male patients was evaluated from aspects such as intravaginal ejaculation latency time, control of ejaculation time, and sexual satisfaction. Among them, the blank group had a low CISFPE score, indicating that they could not have normal sexual intercourse. Compared with the blank group, the toad venom group and the dried toad extract + toad oil group could significantly improve male sexual dysfunction (P<0.05) and significantly improve female sexual satisfaction (P<0.05).

[0081] Table 3. Sexual Satisfaction Rating (SSS) Note: * Compared with the blank control group, P < 0.05 As shown in Table 3, the sexual function of male patients was evaluated based on both male and female sexual satisfaction and the frequency of female orgasm. The blank group had a low CISFPE score, indicating an inability to have normal sexual intercourse. The toad venom group and the toad extract + toad oil group of this invention showed significantly higher sexual satisfaction (P < 0.05), indicating a good improvement effect on male premature ejaculation.

[0082] 8.2 Evaluation of Erectile Function Table 4 International Index of Erectile Function (IIEF-5) Note: * Compared with the blank control group, P < 0.05 As shown in Table 4, the patients' erectile function was evaluated using the International Index of Erectile Function (IIEF-5). The control group had moderate erectile dysfunction. The scores of the dried toad extract + toad oil group and the toad venom group after treatment were greater than or equal to 22 points, which is considered normal. Compared with the control group, the dried toad extract + toad oil group and the toad venom group of this invention can significantly improve male erectile dysfunction (P < 0.05).

[0083] 8.3 Safety Index Measurement Results Blood routine, urine routine, liver function and kidney function were not significantly abnormal. The patient did not experience penile redness, swelling, pain, itching, rash, burning sensation, or erectile dysfunction due to penile numbness; the female patient did not experience decreased vaginal sensation or vaginal discomfort.

Claims

1. A delay spray, characterized in that, The delay spray contains the following raw materials in parts by weight: 1 part of ultrafine powdered dried toad extract, 3-8 parts of toad oil, and an appropriate amount of the base required for the spray.

2. The delay spray as described in claim 1, characterized in that, The delay towel contains the following raw materials in parts by weight: 1 part of ultrafine powdered dried toad extract, 4-7 parts of toad oil, and an appropriate amount of the base required for the spray.

3. The delay spray as described in claim 1, characterized in that, The delay towel contains the following raw materials in parts by weight: 1 part of ultrafine powdered dried toad extract, 5 parts of toad oil, and an appropriate amount of the base required for the spray.

4. The delay spray as described in claim 1, characterized in that, The extraction process of the ultrafine powdered dried toad extract is as follows: S01 Add 95% ethanol to dried toad powder and extract 1-3 times at a material-to-liquid ratio of 1:10, each extraction lasting 1-2 hours; S02 is heated and refluxed through a reflux condenser, and the extract is collected. The residue is then extracted twice more, and the extracts are combined. S03 The obtained extract was concentrated under reduced pressure to obtain a dried toad extract; S04 The above-mentioned dried toad extract is mixed with water at a material-liquid ratio of 1:1, soaked for 30 minutes, and continuously dried in a drying oven at 60°C until the water content is less than 5%. The dried toad extract is then pulverized through an 80-mesh pharmacopoeia sieve and pulverized through an air jet mill to obtain an ultrafine powder of dried toad extract with a mesh size of 800-2000.

5. The delay spray as described in claim 1, characterized in that, The preparation of dried toad powder in the ultrafine powdered toad extract extraction process involves placing dried toads in a drying oven for continuous drying until the moisture content is less than 5%, then pulverizing them with a pulverizer and passing them through a 120-mesh pharmacopoeia sieve to obtain dried toad powder.

6. The delay spray as described in claim 1, characterized in that, The toad oil is made from toad viscera, which are crushed, heated, and centrifuged. The resulting oil is then filtered to obtain toad oil.

7. The delay spray as described in claim 1, characterized in that, The matrix contains the following components in parts by weight: 100-300 parts Labrasol, 50-100 parts Plurol Oleique CC497, and 400-500 parts water.

8. A method for preparing the delay spray as described in claim 1, characterized in that, The preparation method of the delay spray includes the following steps: Preparation of S1 ultrafine powdered dried toad extract: S11 involves continuously drying the dried toad, pulverizing it, and then passing it through a 120-mesh pharmacopoeia sieve to obtain dried toad powder. S12 dried toad powder was added to 95% ethanol, heated under reflux using a reflux condenser, and the extract was collected. The residue was then extracted twice more, and the extracts were combined. S13 The extract obtained in the above steps is concentrated under reduced pressure to obtain dried toad extract; S14 Soak the above-mentioned dried toad extract in water, continuously dry it, pulverize and sieve it, and then pulverize the sieved dried toad extract through an air jet mill to obtain ultra-fine powdered dried toad extract. S2 Toad Oil Preparation: Toad viscera are used as raw material. After crushing, heating and centrifuging, the resulting oil is filtered to obtain toad oil. Preparation of S3 Delay Spray: S31 Add ultrafine powdered dried toad extract to Transcutol P solvent, and dissolve by shaking at room temperature to obtain dried toad extract solution; S32 adds toad oil, Labrasol, Plurol Oleique CC497 and water to a homogenization tank to obtain a toad oil dispersion; S33. Add the ultrafine powdered dried toad extract solution to the toad oil dispersion and mix thoroughly. The product is filtered through S34 and aseptically filled into a spray bottle, resulting in the delay spray of this invention.

9. The method for preparing the delay spray as described in claim 8, characterized in that, In step S11, the final water content of the dried toad is less than 5%; in step S12, the ratio of dried toad powder to 95% ethanol is 1:10, and extraction is performed 1-3 times, each extraction lasting 1-2 hours; in step S14, the ratio of dried toad extract to water is 1:1, soaking for 30 minutes, and continuously drying in a 60°C drying oven to reduce the water content to less than 5%, then pulverizing through an 80-mesh pharmacopoeia sieve and pulverizing using an air jet mill to obtain an 800-2000 mesh ultrafine powder of dried toad extract; in step S32, the weight proportions of Labrasol, Plurol Oleique CC497, and water are 100-300 parts of Labrasol, 50-100 parts of Plurol Oleique CC497, and 400-500 parts of water; the homogenizing tank is set at 50°C, homogenized at 2000 r / min for 5 minutes, and then cooled to below 30°C to obtain a toad oil dispersion.

10. The use of the delay spray as described in claim 1 in the preparation of a treatment for premature ejaculation and erectile dysfunction in men, characterized in that... The spray contains the following raw materials in parts by weight: 1 part of ultrafine powdered dried toad extract, 3-8 parts of toad oil, and an appropriate amount of the base required for the spray; the premature ejaculation includes primary premature ejaculation, secondary premature ejaculation, natural variant premature ejaculation, and subjective premature ejaculation; the erectile dysfunction refers to a man's inability to maintain or obtain a sufficient penile erection to complete satisfactory sexual intercourse.

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