A male external use delaying traditional Chinese medicine composition, essence and its preparation method and application

Abstract

The application discloses a male external use delaying traditional Chinese medicine composition, essence liquid and a preparation method and application thereof. The traditional Chinese medicine composition is composed of the following components in parts by weight: traditional Chinese medicine small molecule active ingredient 0.8-1.2 parts; borneol 0.08-0.12 parts; the traditional Chinese medicine small molecule active ingredient is prepared from the following components in parts by weight: radix ginseng 30-40 parts, shuangshen grass 20-30 parts, milk vetch 20-30 parts, radix salviae miltiorrhizae 5-15 parts, gold cherry 10-20 parts, and sophora flavescens 5-15 parts; small molecule active ingredients with a molecular weight less than 1000 Da are enriched through grouping extraction, purification and ultrafiltration membrane technology, and the transdermal efficiency is significantly improved; the traditional Chinese medicine composition can significantly prolong the ejaculation latency and improve the sexual satisfaction through the multi-target synergistic effect of inhibiting nerve sensitivity, improving microcirculation, repairing the barrier and cooling penetration, and there is no risk of burning, numbness and mucosal damage caused by chemical anesthetics.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of traditional Chinese medicine preparations, and specifically relates to a male external use time-extended traditional Chinese medicine composition, a serum, and a preparation method and application thereof. BACKGROUND

[0002] In the study of modern male health needs, prolonging the effective sexual life time has become an important demand to improve the quality of sexual life. The Twenty-First National Academic Conference of Chinese Medical Society reported that the prolongation of ejaculation latency is significantly related to the improvement of sexual satisfaction. A surgical treatment study on premature ejaculation patients showed that when the postoperative ejaculation latency is prolonged to more than 6 minutes, the sexual satisfaction is improved by more than 40% (P<0.01). The American Men's Health magazine reported in 2010 that 71% of adult men believe that moderately prolonging the ejaculation latency can significantly improve the sexual experience, and hope to prolong the sexual life time to improve the satisfaction of both parties. This demand has led to the rapid development of local external use time-extended products. Therefore, developing effective male external use time-extended products to meet market demand has important social and economic significance. However, the contradiction between safety and use experience of existing products has not been effectively balanced, making product development face technical bottlenecks.

[0003] In the prior art field, chemical synthesis products have long occupied the market mainstream. Local anesthetics with lidocaine and benzocaine as core components achieve the effect of prolonging time by inhibiting the sensitivity of nerve endings. Studies have shown that 7.5% benzocaine spray can produce anesthetic effect in about 2-5 minutes when applied locally to the genital organ (British Journal of Clinical Pharmacology, 2018), and its onset time can be shortened to 5-10 minutes. However, such products have significant limitations. In terms of safety, according to the data of Journal of Sexual Medicine (2019), 18.7% of benzocaine users reported local burning sensation or erythema, and the adverse reaction rate of high-frequency users (more than 3 times a week) increased to 27.3%. Sensitive groups may also develop contact dermatitis, and repeated use can damage the skin barrier function. Long-term use may cause adaptive increase in the tactile threshold, forcing the dose to be increased, and even causing damage to the mucosal barrier. In terms of use experience, many users lose the sense of pleasure due to excessive numbness in the local area, and the problem of numbness caused by anesthesia leading to the dulling of pleasure makes the user satisfaction significantly decrease, which is contrary to the core demand of users to improve the experience. In addition, such products only rely on a single nerve block mechanism to work, and cannot improve the blood circulation or promote tissue repair in the local genital area, making it difficult to meet the needs of users for "natural experience".

[0004] Although there are traditional Chinese medicines for external use for men to prolong ejaculation, the traditional Chinese medicine extract (such as the crude extract obtained by water extraction and alcohol precipitation) often contains a large amount of high molecular weight impurities (such as polysaccharides, proteins, tannin polymers, etc.), and the molecular weight of the active ingredients is generally large (usually >1000 Da). The stratum corneum of human skin is a natural physical barrier, and the transdermal absorption rate of substances with a molecular weight exceeding 500 Da decreases sharply. These macromolecular substances are difficult to effectively penetrate the skin barrier to reach the target site (such as the dorsal penile nerve endings, the endothelium of the cavernous body, etc.), resulting in low transdermal absorption efficiency. In terms of extraction and purification process, the crude extract obtained by traditional water extraction and alcohol precipitation has many impurities, not only slow onset, but also easy to irritate the skin; the problem of low transdermal absorption rate is particularly prominent, animal experiments show that the relevant products need to be continuously applied for more than 40 minutes to reach the effective blood concentration, and the delayed effect and fluctuation during use seriously affect the user experience. In addition, most traditional Chinese medicine preparations use greasy ointment forms, which have poor air permeability and are easy to stain clothes, which does not meet the needs of contemporary men who pursue freshness. SUMMARY

[0005] The purpose of the present application is to overcome the problems of existing chemical anesthetics, such as strong irritation, blunt pleasure, and poor transdermal absorption of traditional Chinese medicine preparations, and to provide an external use traditional Chinese medicine composition, which is composed of seven kinds of traditional Chinese medicines, i.e. ginseng, Herba Isatidis, Millettia speciosa, Chamaerops fruticosa, Salvia miltiorrhiza, Sophora flavescens and borneol. The small molecule active ingredients with a molecular weight of less than 1000 Da are extracted and purified by grouping, which significantly improves the transdermal efficiency. The traditional Chinese medicine composition can significantly prolong the ejaculation latency and improve the sexual satisfaction through the multi-target synergistic effect of inhibiting nerve sensitivity, improving microcirculation, repairing the barrier and cooling penetration, and has no risk of burning, numbness and mucosal damage caused by chemical anesthetics.

[0006] The second purpose of the present application is to provide the use of the external use traditional Chinese medicine composition in the preparation of male external use prolong ejaculation products.

[0007] The third purpose of the present application is to overcome the problems of traditional ointments, such as greasiness, poor air permeability and poor user experience, and to provide a male external use prolong ejaculation serum, which replaces the greasy ointment with the above-mentioned enriched small molecule active ingredients to prepare a refreshing and easily absorbed serum dosage form, thereby optimizing the air permeability and use comfort.

[0008] The fourth purpose of the present application is to provide a preparation method of the serum.

[0009] The above purposes of the present application are achieved by the following technical solutions:

[0010] An external use traditional Chinese medicine composition, which is composed of the following components in parts by weight: traditional Chinese medicine small molecule active ingredient 0.8-1.2 parts, borneol 0.08-0.12 parts; the traditional Chinese medicine small molecule active ingredient is prepared from the following components in parts by weight: ginseng 30-40 parts, shizonepeta 20-30 parts, milk vetch 20-30 parts, red sage root 5-15 parts, gold cherry 10-20 parts, and sophora flavescens 5-15 parts; the preparation method of the traditional Chinese medicine small molecule active ingredient is as follows: the ginseng, shizonepeta, milk vetch and red sage root in the corresponding parts by weight are uniformly mixed, and then extracted by reflux extraction with 65-75% ethanol; the extract is eluted by gradient elution with non-polar adsorption resin using 50% ethanol and 70% ethanol, and then concentrated to obtain a ginseng / shizonepeta / milk vetch / red sage root purified liquid; the gold cherry in the corresponding parts by weight is extracted by reflux extraction with 55-65% ethanol, and then eluted with medium-polar adsorption resin using 65-75% ethanol, and then concentrated to obtain a gold cherry extraction and purification liquid; the sophora flavescens in the corresponding parts by weight is extracted by acid water extraction method, and then the extract is adsorbed by strong acid cation exchange resin, the resin is treated with alkali solution, and the total alkaloids are eluted and concentrated to obtain a sophora flavescens extraction and purification liquid; the ginseng / shizonepeta / milk vetch / red sage root group extraction and purification liquid, the gold cherry extraction and purification liquid, and the sophora flavescens extraction and purification liquid are combined, purified, and enriched with active ingredients with a molecular weight of less than 1000 Da.

[0011] The application deeply integrates traditional Chinese medicine theory and modern pharmacological mechanism, scientifically combines ginseng, shizonepeta, milk vetch, gold cherry, red sage root, sophora flavescens and borneol based on the compatibility principle of Chinese medicine "jun, chen, za and shi", forms an external use delayed compound system with the action of "multi-target point synergistic intervention" (inhibiting nerve sensitivity, improving local microcirculation, repairing mucosal barrier, and regulating hormone level), and realizes the design of the compound.

[0012] Ginseng, as the principal herb, plays a core role in replenishing qi, strengthening the body's foundation, and invigorating the reproductive system. Its saponin components not only promote the release of nitric oxide to improve blood flow in the corpora cavernosa but also regulate sex hormone levels and enhance sexual endurance. *Smilax glabra* and *Smilax china* serve as assistant herbs, synergistically tonifying kidney yang. By regulating the hypothalamus-pituitary-gonadal axis and immune pathways, they promote testosterone secretion and alleviate symptoms of kidney yang deficiency. Their active ingredients also possess antioxidant and anti-inflammatory activities, indirectly improving erectile quality. *Rosa laevigata*, *Salvia miltiorrhiza*, and *Sophora flavescens* are adjuvant herbs. *Rosa laevigata* is primarily used for astringency and consolidation; its tannins can reduce sensitivity and prolong ejaculation latency. *Salvia miltiorrhiza* invigorates blood circulation and removes blood stasis; through tanshinone IIA and salvianolic acid B, it improves penile microcirculation, promotes angiogenesis, and significantly enhances transdermal efficiency when combined with borneol. *Sophora flavescens* clears heat and dries dampness; its alkaloid components relieve damp heat and local irritation through antibacterial, anti-inflammatory, and TRPV1 blocking effects, ensuring safety for external use. Borneol is used as a penetration enhancer to increase the penetration of active ingredients by widening the intercellular spaces of epidermal cells. Its cooling properties can immediately reduce local temperature and nerve sensitivity, improving user comfort. The specific mechanisms of action of each medicinal material are as follows:

[0013] Ginseng is the plant ginseng of the Araliaceae family. Panax ginseng The dried roots and rhizomes of CA Mey. Ginseng is the principal ingredient in this traditional Chinese medicine formula, possessing the effects of tonifying qi, strengthening the body's foundation, and invigorating the reproductive organs. In external application for men, ginseng enhances the circulation of qi and blood in the reproductive organs by tonifying kidney yang and heart qi, thereby improving erectile function and sexual endurance. Its foundation-strengthening and vital-nourishing effects can regulate essence, qi, and spirit, alleviating premature ejaculation and decreased libido caused by kidney yang deficiency. Modern pharmacological studies have shown that its core active ingredient, ginsenosides (such as Rg1 and Rb1), can promote the release of nitric oxide (NO), dilate local blood vessels, and improve microcirculation in the penile corpora cavernosa; its antioxidant components scavenge free radicals, protect nerve and vascular endothelial cells, and delay the decline of sexual function. Animal experiments have also confirmed that ginsenosides can significantly prolong the mating latency period and increase the mounting frequency in male mice, with its mechanism of action involving PDE5 inhibition (IC5). 50 =12.47 nmol / L) and antioxidant protection. Clinical data show that continuous use for 8 weeks can improve erectile rigidity score by 42%, without the cardiovascular risks associated with sildenafil-like drugs. In addition, ginseng extract can regulate the hypothalamus-pituitary-gonadal axis, increase testosterone levels, and indirectly prolong the duration of sexual intercourse.

[0014] Double kidney grass is a monocotyledonous medicinal plant, orchid of the Orchidaceae family, *Hylocereus scoparia* (also known as *Hylocereus scoparia*). Herminium bulleyi(Rolfe)Tanget Wang. Oxytropis is a traditional medicine of the Miao nationality and is the ministerial drug of the traditional Chinese medicine compound, which is used with Millettia pinnata to tonify kidney yang. Oxytropis exhibits significant effects on improving male sexual function. Experiments show that Oxytropis extract can significantly increase the indexes of male accessory organs (seminal vesicle and prostate) of male mice, shorten the capture latency and increase the frequency of sexual behavior, suggesting that it has sex hormone-like activity. Its active ingredients (such as bibenzyl compounds, palmitic acid, and β-sitosterol) may promote testosterone secretion by activating the hypothalamic-pituitary-gonadal axis, while antioxidant ingredients (such as bibenzyls) can scavenge free radicals and improve the oxidative stress state of testicular tissue, indirectly improving erectile function. The terpenes in Oxytropis may enhance the cavernosal blood flow through the NO-cGMP pathway. In addition, phytosterols such as β-sitosterol can competitively bind to sex hormone receptors, synergistically enhance androgenic effects, and thus improve symptoms of kidney yang deficiency such as impotence and spermatorrhea.

[0015] Millettia pinnata is a leguminous liana, Sophora tonkinensis Gapn. Millettia speciosa The dried root of Millettia pinnata Champ. is a traditional medicine in the Lingnan region and is the ministerial drug of the traditional Chinese medicine compound, which is used with Oxytropis to tonify kidney yang. Research suggests that flavonoids and polysaccharides in Millettia pinnata may indirectly improve sexual function by regulating immunity, antioxidant activity, and affecting vasodilation pathways. Polysaccharides may enhance macrophage activity, regulate immune signaling pathways such as TLR4, and reduce the impact of reproductive system inflammation on sexual function; flavonoids may reduce oxidative stress damage through antioxidant activity and inhibition of the NF-κB inflammatory pathway. In terms of improving erectile dysfunction, active ingredients may activate the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway by promoting NO synthesis and inhibiting phosphodiesterase 5 (PDE5) degradation of cGMP, thereby relaxing the cavernosal smooth muscle of the penis and increasing blood flow.

[0016] Rosa laevigata, Salvia miltiorrhiza, and Sophora flavescens are used as the auxiliary drugs of the traditional Chinese medicine compound.

[0017] Rosa laevigata is the dried mature fruit of Rosa laevigata Rosa laevigata Champ. is the dried mature fruit of Rosa laevigata. Rosa laevigata has the effects of astringing and reducing urine and stopping diarrhea. As a classic astringent and reducing urine drug, it can effectively restrain the essence by its astringent nature, reducing premature ejaculation through astringent and astringent effects. Modern pharmacological research shows that tannins in Rosa laevigata can reduce the sensitivity of the glans penis. Animal experiments have confirmed that the alcohol extract can significantly prolong the ejaculation latency of rats, and has no obvious central inhibition. In addition, the root extract of Rosa laevigata has an inhibitory effect on urinary system inflammation such as prostatitis, indirectly improving sexual function by relieving inflammation.

[0018] Salvia miltiorrhiza is a plant of the Lamiaceae family Salvia miltiorrhizaThe dried root and rhizome of *B. ge.*. *Salvia miltiorrhiza* is known for its blood-activating, stasis-removing, blood-cooling, and swelling-reducing properties. In this formula, it primarily functions to "unblock," improving penile hemodynamics, reducing microcirculation stagnation in the corpora cavernosa, and enhancing erectile quality. Its blood-cooling properties balance local damp-heat, preventing redness and swelling caused by topical medications. Tanshinone IIA, contained in *Salvia miltiorrhiza*, inhibits platelet aggregation, promotes penile arterial blood flow, enhances tissue plasminogen activator (t-PA) activity, and dissolves fibrin deposits. Tanshinone B promotes penile angiogenesis by upregulating vascular endothelial growth factor (VEGF) and protects vascular endothelium by activating the PI3K / Akt signaling pathway, thus maintaining erectile function. Studies have shown that its combination with borneol significantly improves skin permeability, allowing the active ingredients to reach the dorsal nerve region of the penis more quickly.

[0019] Sophora flavescens is a legume plant. Sophora flavescens The dried root of Ait. Sophora flavescens. Sophora flavescens has the effects of clearing heat and drying dampness, killing parasites and relieving itching. It can solve the accompanying symptoms such as scrotal dampness and itching caused by damp heat. It can indirectly prolong the duration of sexual intercourse by improving the local environment. The matrine and oxymatrine contained in it are the main active ingredients. They not only have significant antibacterial (such as Staphylococcus aureus and Candida albicans) and anti-inflammatory effects, but also reduce the release of inflammatory factors (such as TNF-α and IL-6). They can also block the transient receptor potential channel (TRPV1) and block the action potential conduction of the dorsal nerve of the penis, thereby reducing skin sensitivity and burning sensation. Its effect of inhibiting the release of histamine from mast cells further reduces skin irritation and ensures the safety of external use.

[0020] Natural borneol is derived from the camphor tree (Cinnamomum camphora), a plant belonging to the Lauraceae family. Cinnamomum camphora Borneol is a white crystalline powder or flaky crystal made from the fresh branches and leaves of *L.* Presl. It is pungent and aromatic, cool in nature and bitter in taste, and has the effects of opening the orifices, refreshing the mind, clearing heat and relieving pain. As the guiding herb in this traditional Chinese medicine compound, borneol acts as a meridian guide and penetration enhancer; its pungent and aromatic properties can carry the active ingredients through the stratum corneum barrier. Modern research has confirmed that borneol can expand the intercellular spaces of epidermal cells by 3-5 times, increasing the transdermal absorption rate of drugs. Simultaneously, the cooling sensation produced by activating the transient receptor potential M8 (TRPM8) cold receptor can immediately relieve the burning sensation of sexual arousal, reduce local temperature and nerve sensitivity, and significantly improve user comfort.

[0021] The innovative point of the traditional Chinese medicine composition in the present application is that the traditional efficacy is deeply integrated with the modern mechanism analysis. Through scientific compounding of seven traditional Chinese medicines such as ginseng and double kidney grass, multi-pathway synergistic intervention (sensitivity inhibition, blood flow improvement, barrier repair, hormone regulation) is realized. On the one hand, the sensitivity is reduced by using prunus mume tannin and matrine (inhibiting TRPV1 channel), and the cool touch is provided by using borneol to significantly reduce the numbness, thereby avoiding the common problems of chemical anesthetics (such as benzocaine) such as burning, erythema and numbness. On the other hand, the erectile hardness and durability are enhanced by using ginsenosides to promote NO release, tanshinone to improve microcirculation and promote angiogenesis, and flavonoids in Caulis Bauhiniae to activate the NO-cGMP pathway. At the same time, the skin mucosa barrier is protected by the synergistic effect of the anti-inflammatory and antibacterial effect of sophora and the antioxidant effect of ginseng, thereby reducing the irritation. Animal experiments prove that the ejaculation latency period can be prolonged to more than 6 minutes (3.2 minutes for the control group), and the sexual satisfaction is improved by more than 40%. This comprehensive mechanism not only significantly prolongs the ejaculation latency period, but also improves the reproductive health environment, provides more natural, comprehensive and long-lasting delay effect and sexual function support, has high long-term use safety, and has no risk of mucosa damage. In addition, by grouping extraction and purification, resin purification and molecular sieve technology, small molecule active ingredients are enriched, and the problems of poor transdermal absorption and slow effect of traditional Chinese medicine are solved, thereby significantly improving the transdermal absorption efficiency. The onset time is shortened to less than 15 minutes from more than 40 minutes of traditional Chinese medicine preparations, which is close to the level of chemical anesthetics (5-10 minutes), thereby meeting the actual use requirements.

[0022] Further, the ginseng, double kidney grass, Caulis Bauhiniae and Danshen are mixed and then subjected to cellulase pretreatment and 65-75% ethanol reflux extraction. The cellulase assisted extraction hydrolyzes cellulose and hemicellulose in the plant cell wall, destroys the cell structure, and is beneficial to the release of the effective components wrapped in the cells.

[0023] Preferably, the cellulase is used in an amount of 0.4-0.6% w / w.

[0024] Further, the non-polar adsorption resin is D101 macroporous adsorption resin.

[0025] Further, the medium-polar adsorption resin is HPD-400 macroporous adsorption resin.

[0026] Further, the acid water extraction method is reflux extraction using 0.8-1.2% dilute hydrochloric acid solution.

[0027] Further, the strong acid cation exchange resin is type 001×7.

[0028] Further, the concentration is concentrated to a volume of about 10g crude drug / mL.

[0029] Further, the purification is filtration using an ultrafiltration membrane with a molecular weight cut-off of 1000 Da to remove macromolecular components such as polysaccharides / proteins with a molecular weight > 1000 Da, thereby retaining the active ingredients with a molecular weight < 1000 Da.

[0030] As a preferred embodiment, the preparation method of the ginseng / Herba Rubus Suavissimi / Herba Desmodii Styracifolii / Herba Salviae Miltiorrhizae purified extract is as follows: crude powder of ginseng, Herba Rubus Suavissimi, Herba Desmodii Styracifolii, and Herba Salviae Miltiorrhizae is taken in parts by mass, soaked in a small amount of water, and pretreated for 0.5-2 hours by adding cellulase 0.4-0.6% w / w to destroy the cell wall structure. The pretreated material is extracted twice by refluxing with 65-75% ethanol, with a solid-liquid ratio of 1:9-11 w / v for the first extraction and 1:7-9 w / v for the second extraction. The filtrates are combined, ethanol is recovered until no alcohol smell is left, and distilled water is added to dilute the solution to a volume of about 0.2 g crude drug / mL. The solution is purified by D101 macroporous adsorption resin, the sample solution is passed through the resin column at a flow rate of 2 BV / h (the sample amount is about 2-3 g crude drug / g resin), and after adsorption, the resin is eluted with 1.5 BV distilled water, 3 BV 50% ethanol (2 BV / h), and 2 BV 70% ethanol (1 BV / h) in gradient. The 50% and 70% ethanol eluates are collected, combined, and concentrated to a volume of about 10 g crude drug / mL to obtain the extract / purified extract of this group.

[0031] As a preferred embodiment, the preparation method of the Rosa laevigata Michx. extract / purified extract is as follows: crude powder of Rosa laevigata Michx. is taken in parts by mass, extracted twice by refluxing with 55-65% ethanol, with a solid-liquid ratio of 1:9-11 w / v for the first extraction and 1:7-9 w / v for the second extraction. The filtrates are combined, ethanol is recovered under reduced pressure, and water is added to dilute the solution to a volume of about 0.2 g crude drug / mL. The solution is purified by HPD-400 macroporous adsorption resin: the sample solution is passed through the resin column at a flow rate of 2 BV / h (the sample amount is about 2-3 g crude drug / g resin), and after adsorption, the resin is eluted with 3 BV distilled water and 2 BV 70% ethanol (2 BV / h). The whole process is monitored by ferric chloride colorimetry. The 70% ethanol eluate is collected and concentrated to a volume of about 10 g crude drug / mL to obtain the Rosa laevigata Michx. extract / purified extract.

[0032] As a preferred implementation manner, the preparation method of the Sophora flavescens extract and purified liquid is as follows: taking Sophora flavescens crude powder by mass fraction, using 0.8-1.2% dilute hydrochloric acid solution to reflux extract twice at 75-85°C, each time for 1-3 hours, the first time with a solid-liquid ratio of 1:9-11, w / v, and the second time with a solid-liquid ratio of 1:7-9, w / v. The filtrates are combined, and the solvent is recovered to a volume of about 0.2 g of crude drug / mL. The strong acid cation exchange resin (001x7 type) is used for purification, and the loading liquid is passed through the resin column at a flow rate of 1 BV / h. After adsorption, the impurities are washed with 3 BV of pure water, and then the target total alkaloids are eluted with 5 BV of 70% ethanol solution containing 5% ammonia water at a flow rate of 0.5 BV / h. The eluate is collected, and the ethanol is recovered under reduced pressure to concentrate to a volume of about 10 g of crude drug / mL, to obtain the Sophora flavescens extract and purified liquid.

[0033] The above natural extracted traditional Chinese medicine compound ingredients of the present application inhibit nerve sensitivity, improve microcirculation and repair mucosal barrier through multi-target synergistic effect, thereby prolonging ejaculation latency and improving sexual life quality. Therefore, the present application also provides application of the above any described external traditional Chinese medicine composition in preparation of male external time-delay products.

[0034] Further, the product is a serum, an aqueous agent, a gel or a spray.

[0035] The present application also provides a serum containing the above any described external traditional Chinese medicine composition.

[0036] Further, the mass percentage content of the external traditional Chinese medicine composition in the serum is 0.8-1.3%.

[0037] Further, the serum comprises the following components by mass percentage: 0.8-1.2 parts of traditional Chinese medicine small molecule active ingredient, 0.08-0.12 parts of borneol, 0.4-0.6 parts of sodium hyaluronate, 4-6 parts of glycerol, 4-6 parts of butanediol, 2-4 parts of 1,3-propanediol, 1-3 parts of trehalose, 0.05-0.2 parts of allantoin, 0.2-0.4 parts of carbomer, 0.04-0.06 parts of disodium EDTA, deionized water added to 100 parts, and pH is 6.0-6.5.

[0038] The present application discards the greasy and heavy feeling of traditional Chinese medicine ointments, and uses an aqueous serum. The addition of sodium hyaluronate, glycerol, butanediol and other components has a refreshing and easy-to-absorb texture, good air permeability and no staining of clothes. The pH value (6.0-6.5) is close to the skin environment, borneol brings a cooling feeling, and the use comfort is significantly improved.

[0039] Further, it also comprises 0.4-0.6 parts of phenoxyethanol as a preservative for the serum.

[0040] The application further provides a preparation method of the above-mentioned essence, which comprises the following steps: pre-swelling a carbomer matrix, dissolving traditional Chinese medicine small-molecule active ingredients, borneol, sodium hyaluronate, glycerol, butylene glycol, 1,3-propanediol, trehalose, allantoin and disodium EDTA in an aqueous phase, mixing the carbomer matrix and the aqueous phase to thicken, adjusting the pH value to 6.0-6.5, homogenizing and filling.

[0041] As a preferred implementation manner, the preparation method of the above-mentioned essence comprises the following steps:

[0042] S1. Preparation of the carbomer matrix: disperse the carbomer in part of deionized water, uniformly stir to fully swell, and heat to about 70 DEG C to promote dissolution.

[0043] S2. Preparation of the aqueous phase: in another clean and sterile container, add deionized water (part of which is reserved for dissolving the carbomer). Add the traditional Chinese medicine small-molecule active ingredients, borneol, sodium hyaluronate, glycerol, butylene glycol, 1,3-propanediol, trehalose, allantoin and disodium EDTA in sequence. Heat to about 75 DEG C, and stir while heating until all the ingredients are completely dissolved and uniformly distributed.

[0044] S3. Mixing and thickening: when the temperature of the aqueous phase decreases to about 70 DEG C, slowly add the pre-prepared carbomer solution under continuous stirring to avoid generating a large amount of foam. Continue stirring until the carbomer is completely dissolved to form a uniform and viscous matrix.

[0045] S4. pH adjustment: use triethanolamine to slowly titrate and adjust the pH value of the mixed solution to 6.0-6.5.

[0046] S5. Cooling and adding preservatives: cool the solution to near room temperature (about 25-30 DEG C). Add phenoxyethanol and stir uniformly.

[0047] S6. Homogenization: use a homogenizer to homogenize the solution to improve the uniformity and stability of the product.

[0048] S7. Quality detection and filling: detect the appearance, odor, pH value, viscosity and other quality indicators of the obtained essence, and ensure that the requirements meet the standard requirements before filling, so that the male external use delay essence based on traditional Chinese medicine small-molecule active ingredients is obtained.

[0049] The traditional Chinese medicine composition in the present application realizes comprehensive intervention through "multi-target point regulation", and meanwhile, with the aid of modern extraction and purification technologies (such as enzyme-assisted extraction, macroporous resin purification, ultrafiltration membrane separation, etc.), macromolecular impurities can be effectively removed, small molecular active ingredients (molecular weight <1000 Da) can be enriched, and the transdermal absorption efficiency can be significantly improved, so as to solve the contradiction between safety, speed of taking effect and experience comfort. This technical integration meets the core needs of users for "natural, long-acting and non-sensory intervention" through the synergistic effect of multiple pathways, and provides a scientific and feasible technical path for upgrading the male external use delay product. Thus, the contradiction between safety, speed of taking effect and experience comfort is solved. This technical integration meets the core needs of users for "natural, long-acting and non-sensory intervention" through the synergistic effect of multiple pathways, and provides a scientific and feasible technical path for upgrading the male external use delay product.

[0050] Compared with the prior art, the present application has the following beneficial effects:

[0051] The present application provides a kind of male external use delay traditional Chinese medicine composition, it is by following weight fraction Each component consisting of: Traditional Chinese medicine small molecule active ingredient: 0.8~1.2 parts;Borneol: 0.08~0.12 parts;The traditional Chinese medicine small molecule active ingredient is prepared by following weight fraction Each component: Ginseng 30~40 parts, double kidney grass 20~30 parts, cow strength 20~30 parts, Salvia miltiorrhiza 5~15 parts, cherry 10~20 parts, Sophora flavescens 5~15 parts;The traditional Chinese medicine composition can significantly prolong the ejaculation latency, improve the sexual satisfaction (can prolong the ejaculation latency to 6 minutes or more (3.2 minutes of control group), the sexual satisfaction is improved by 40% or more) by the multi-target point synergistic effect of inhibiting nerve sensitivity, improving microcirculation, repairing barrier and cooling penetration, provide more natural, comprehensive and lasting delay effect and sexual function support, and there is no risk of burning, numbness and mucosal damage caused by chemical anesthetics, and the long-term use safety is high.In addition, by grouping extraction and purification and enrichment of small molecular active ingredients with molecular weight <1000 Da, the transdermal efficiency is significantly improved, the onset time is shortened to 15 minutes or less from more than 40 minutes of traditional Chinese medicine preparation, close to the level of chemical anesthetics (5~10 minutes). Meet the core needs of users for "natural, long-acting and non-sensory intervention", and provide a scientific and feasible technical path for upgrading the male external use delay product. DETAILED DESCRIPTION

[0052] The present application is further illustrated by specific examples, but the examples do not limit the present application in any form. Unless otherwise specified, the reagents, methods and equipment used in the present application are conventional reagents, methods and equipment in the technical field.

[0053] Unless otherwise specified, the reagents and materials used in the following examples are commercially available.

[0054] The ginseng, bi-shen grass, milk vetch, salvia, and bitter apricot kernel medicinal materials were pretreated, and then ground to pass through a 24 mesh sieve (pore size 850 pm), and the fine powder of 65 mesh sieve (pore size 250 pm) accounted for less than or equal to 40%, to obtain the coarse powder meeting the pharmacopoeia.

[0055] Borneol was purchased from Fujian Nanping Qing Song Chemical Co., Ltd., CAS No.: 507-70-0.

[0056] Cellulase was purchased from Shanghai Yuan Ye Biotechnology Co., Ltd., product No.: S10041, CAS No.: 9012-54-8, BR, 50 U / mg.

[0057] Example 1

[0058] According to the following weight parts, 30 parts of ginseng medicinal material coarse powder, 20 parts of bi-shen grass medicinal material coarse powder, 20 parts of milk vetch medicinal material coarse powder, and 5 parts of salvia medicinal material coarse powder were mixed uniformly, soaked with a small amount of water, and pretreated with cellulase (0.4% w / w) for 1 hour to destroy the cell wall structure. 65% ethanol was used for reflux extraction twice, the first time with a solid-liquid ratio of 1:10, w / v, and the second time with a solid-liquid ratio of 1:8, w / v. The filtrate was combined, ethanol was recovered until no alcohol taste was left, and distilled water was added to dilute to a volume of about 0.2 g of crude drug / mL. D101 macroporous adsorption resin was used for purification, the sample solution was passed through the resin column at a flow rate of 2 BV / h (the sample amount was about 2-3 g of crude drug / g of resin), and after adsorption, gradient elution was performed with 1.5 BV of distilled water, 3 BV of 45% ethanol (2 BV / h), and 2 BV of 70% ethanol (1 BV / h) in sequence. The 45% and 65% ethanol eluates were collected, combined, and concentrated to a volume of about 10 g of crude drug / mL to obtain the extraction and purification liquid of this group.

[0059] 10 parts of coarse powder of Chinese apricot kernel medicinal material were taken, and 55% ethanol was used for reflux extraction twice, the first time with a solid-liquid ratio of 1:10, w / v, and the second time with a solid-liquid ratio of 1:8, w / v. The filtrate was combined, ethanol was recovered under reduced pressure, and water was added to dilute to a volume of about 0.2 g of crude drug / mL. HPD-400 macroporous adsorption resin was used for purification: the sample solution was passed through the resin column at a flow rate of 2 BV / h (the sample amount was about 2-3 g of crude drug / g of resin), and after adsorption, elution was performed with 3 BV of distilled water and 2 BV of 65% ethanol (2 BV / h) in sequence. The whole process was monitored by ferric chloride colorimetry. The 65% ethanol eluate was collected and concentrated to a volume of about 10 g of crude drug / mL to obtain the extraction and purification liquid of Chinese apricot kernel.

[0060] Take 5 parts of crude powder of Sophora flavescens medicinal material, and extract twice at 80°C using 0.8% dilute hydrochloric acid solution (1:10, w / v) by refluxing. The first time is 1:10, w / v, and the second time is 1:8, w / v. Combine the filtrate, and recover the solvent to about 0.2g crude drug / mL. Purify using strong acid cation exchange resin (001x7 type), and pass the sample solution through the resin column at a flow rate of 1 BV / h. After adsorption, wash the impurities with 3 BV of pure water, and then elute the target total alkaloids with 5 BV of 65% ethanol solution containing 4.5% ammonia water at 0.5 BV / h. Collect the eluate, and concentrate under reduced pressure to about 10g crude drug / mL. Thus, the Sophora flavescens extract purification liquid is obtained.

[0061] Combine the above-mentioned ginseng / Herba Dispori / Herba Millettiae / Herba Salviae miltiorrhizae group extract purification liquid, Rosa laevigata extract purification liquid, and Sophora flavescens extract purification liquid. Filter the combined liquid through an ultrafiltration membrane with a molecular weight cutoff of 1000 Da to completely remove macromolecular impurities (such as polysaccharides, proteins, etc.), and retain small molecular active ingredients such as target saponins, flavones, and alkaloids. Concentrate and freeze-dry the filtrate. Thus, the traditional Chinese medicine active substance rich in small molecular active ingredients (molecular weight <1000 Da) is obtained.

[0062] Disperse 0.3 parts of carbomer in part of deionized water, and stir until it is fully swollen. The solution can be heated to about 70°C to promote dissolution. In another clean and sterilized container, add an appropriate amount of deionized water, and then sequentially add 0.8 parts of traditional Chinese medicine small molecular active ingredients, 0.08 parts of borneol, 0.5 parts of sodium hyaluronate, 5 parts of glycerol, 5 parts of butanediol, 3 parts of 1,3-propanediol, 2 parts of trehalose, 0.1 part of allantoin, and 0.05 parts of disodium EDTA. Finally, add deionized water to 100 parts (including the part of the solution in which the carbomer is dissolved). Heat to about 75°C, and stir while heating until all the ingredients are completely dissolved and uniform. When the temperature of the aqueous phase decreases to about 70°C, slowly add the previously prepared carbomer solution under continuous stirring to avoid the generation of a large amount of foam. Continue stirring until the carbomer is completely dissolved, and a uniform and viscous matrix is formed. Slowly titrate an appropriate amount of triethanolamine to adjust the pH of the mixed solution to between 6.0 and 6.5. Cool the solution to near room temperature (about 25-30°C). Add 0.5 parts of phenoxyethanol, and stir until uniform. Use a homogenizer to homogenize the solution to improve the uniformity and stability of the product. Detect the quality indicators such as appearance, odor, pH, and viscosity of the obtained serum, and ensure that the product meets the standard requirements. Then, fill the serum into containers. Thus, the male external use delay serum based on traditional Chinese medicine small molecular active ingredients is obtained.

[0063] Example 2

[0064] Take the crude powder of ginseng 35 parts, the crude powder of double kidney herb 25 parts, the crude powder of milk vetch 25 parts, and the crude powder of salvia miltiorrhiza 10 parts, mix them evenly, soak them in a small amount of water, and add cellulase (0.5% w / w) for pretreatment for 1 hour to destroy the cell wall structure. Extract them twice with 70% ethanol by refluxing, with a solid-liquid ratio of 1:10, w / v, for the first time, and a solid-liquid ratio of 1:8, w / v, for the second time. Combine the filtrates, recover the ethanol, and dilute them with distilled water to a volume of about 0.2 g of crude drug / mL. Purify them using D101 macroporous adsorption resin, with a flow rate of 2 BV / h for the sample solution through the resin column (about 2-3 g of crude drug / g of resin for the sample amount), and then elute them with 1.5 BV of distilled water, 3 BV of 50% ethanol (2 BV / h), and 2 BV of 70% ethanol (1 BV / h) in sequence after adsorption. Collect the 50% and 70% ethanol eluates, combine them, and concentrate them to a volume of about 10 g of crude drug / mL to obtain the extraction and purification liquid of this group.

[0065] Take the crude powder of rose hips 15 parts, extract it twice with 60% ethanol by refluxing, with a solid-liquid ratio of 1:10, w / v, for the first time, and a solid-liquid ratio of 1:8, w / v, for the second time. Combine the filtrates, recover the ethanol under reduced pressure, and dilute them with water to a volume of about 0.2 g of crude drug / mL. Purify them using HPD-400 macroporous adsorption resin: pass the sample solution through the resin column at a flow rate of 2 BV / h (about 2-3 g of crude drug / g of resin for the sample amount), and then elute them with 3 BV of distilled water and 2 BV of 70% ethanol (2 BV / h) in sequence after adsorption. Monitor the tannins throughout the process using the ferric chloride colorimetric method. Collect the 70% ethanol eluate, concentrate it to a volume of about 10 g of crude drug / mL, and obtain the extraction and purification liquid of rose hips.

[0066] Take the crude powder of sophora flavescens 10 parts, extract it twice with 1% dilute hydrochloric acid solution (with a solid-liquid ratio of 1:10, w / v) by refluxing at 80°C, with a solid-liquid ratio of 1:10, w / v, for the first time, and a solid-liquid ratio of 1:8, w / v, for the second time, for 2 hours each time. Combine the filtrates, recover the solvent to a volume of about 0.2 g of crude drug / mL. Purify them using strong acid cation exchange resin (type 001x7), pass the sample solution through the resin column at a flow rate of 1 BV / h. After adsorption, wash the impurities with 3 BV of pure water, and then elute the target total alkaloids with 5 BV of 70% ethanol solution containing 5% ammonia water at a flow rate of 0.5 BV / h. Collect the eluate, recover the ethanol under reduced pressure, and concentrate it to a volume of about 10 g of crude drug / mL to obtain the extraction and purification liquid of sophora flavescens.

[0067] The ginseng / Herba Desmodii Styracifolii / Herba Millettiae / Herba Salviae Miltiorrhizae group extraction and purification liquid, the Rosa davurica extraction and purification liquid, and the Sophora flavescens extraction and purification liquid obtained above were combined. The combined liquid was filtered through an ultrafiltration membrane with a molecular weight cut-off of 1000 Da to completely remove macromolecular impurities (such as polysaccharides, proteins, etc.) and retain small-molecule active ingredients such as saponins, flavonoids, and alkaloids. The filtrate was concentrated and freeze-dried to obtain the traditional Chinese medicine active substance rich in small-molecule active ingredients (molecular weight < 1000 Da).

[0068] Carbomer 0.3 parts was dispersed in part of deionized water, and stirred uniformly to swell sufficiently. It can be heated to about 70°C to promote dissolution. In another clean and sterile container, add an appropriate amount of deionized water, then add the traditional Chinese medicine small-molecule active ingredients 1 part, borneol 0.1 part, sodium hyaluronate 0.5 part, glycerol 5 parts, butanediol 5 parts, 1,3-propanediol 3 parts, trehalose 2 parts, allantoin 0.1 part, disodium EDTA 0.05 part, and finally add deionized water to 100 parts (including part of the solution of carbomer). Heat to about 75°C, and stir while heating until all ingredients are completely dissolved and uniform. When the temperature of the aqueous phase drops to about 70°C, slowly add the previously prepared carbomer solution under continuous stirring to avoid generating a large amount of foam. Continue stirring until the carbomer is completely dissolved to form a uniform viscous matrix. Slowly titrate an appropriate amount of triethanolamine to adjust the pH of the mixed solution to between 6.0 and 6.5. Cool the solution to near room temperature (about 25-30°C). Add phenoxyethanol 0.5 parts and stir uniformly. Use a homogenizer to homogenize the solution to improve the uniformity and stability of the product. After detecting the appearance, odor, pH, and viscosity of the obtained serum to ensure that they meet the standard requirements, fill the serum into containers to obtain the male external use delay serum based on the traditional Chinese medicine small-molecule active ingredients.

[0069] Example 3

[0070] The crude powder of ginseng 40 parts, the crude powder of Herba Desmodii Styracifolii 30 parts, the crude powder of Herba Millettiae 30 parts, and the crude powder of Herba Salviae Miltiorrhizae 15 parts were mixed uniformly, soaked with a small amount of water, and pretreated with cellulase (0.6% w / w) for 1 hour to destroy the cell wall structure. 75% ethanol was used for reflux extraction twice, with a solid-liquid ratio of 1:10 w / v for the first time and a solid-liquid ratio of 1:8 w / v for the second time. The filtrates were combined, the ethanol was recovered until there was no alcohol smell, and distilled water was added to dilute to a volume of about 0.2 g crude drug / mL. D101 macroporous adsorption resin was used for purification, the sample solution was passed through the resin column at a flow rate of 2 BV / h (the sample amount was about 2-3 g crude drug / g resin), and after adsorption, gradient elution was performed with 1.5 BV of distilled water, 3 BV of 55% ethanol (2 BV / h), and 2 BV of 70% ethanol (1 BV / h) in sequence. The 55% and 75% ethanol eluates were collected, combined, and concentrated to a volume of about 10 g crude drug / mL to obtain the extraction and purification liquid of this group.

[0071] Take 20 parts of crude powder of Rosa laevigata Michx. medicinal material, and extract twice with 65% ethanol by reflux. The first time, the solid-liquid ratio is 1:10, w / v, and the second time, the solid-liquid ratio is 1:8, w / v. Combine the filtrates, recover ethanol under reduced pressure, and dilute with water to a volume of about 0.2 g of crude drug / mL. Purify using HPD-400 macroporous adsorption resin: flow the sample solution through the resin column at a flow rate of 2 BV / h (the sample amount is about 2-3 g of crude drug / g of resin), and then elute with 3 BV of distilled water and 2 BV of 75% ethanol (2 BV / h) in sequence after adsorption. Monitor the tannins throughout the process using the ferric chloride colorimetric method. Collect the 75% ethanol eluate, concentrate to a volume of about 10 g of crude drug / mL, and obtain the Rosa laevigata Michx. extraction and purification liquid.

[0072] Take 15 parts of crude powder of Sophora flavescens Ait. medicinal material, and extract twice with 1.2% dilute hydrochloric acid solution (solid-liquid ratio 1:10, w / v) at 80°C by reflux, 2 hours each time. The first time, the solid-liquid ratio is 1:10, w / v, and the second time, the solid-liquid ratio is 1:8, w / v. Combine the filtrates, recover the solvent to a volume of about 0.2 g of crude drug / mL. Purify using strong acid cation exchange resin (001x7 type), and flow the sample solution through the resin column at a flow rate of 1 BV / h. After adsorption, wash the impurities with 3 BV of pure water, and then elute the target total alkaloids with 5 BV of 75% ethanol solution containing 5.5% ammonia water at a flow rate of 0.5 BV / h. Collect the eluate, concentrate to a volume of about 10 g of crude drug / mL under reduced pressure, and obtain the Sophora flavescens Ait. extraction and purification liquid.

[0073] Combine the Sophora flavescens Ait. extraction and purification liquid, the Rosa laevigata Michx. extraction and purification liquid, and the above-mentioned ginseng / Rehmannia glutinosa Libosch / Millettia pinnata (L.) Panzer / Salvia miltiorrhiza Bunge group extraction and purification liquid. Filter the combined liquid through an ultrafiltration membrane with a molecular weight cutoff of 1000 Da to completely remove macromolecular impurities (such as polysaccharides and proteins) and retain small molecular active ingredients (such as saponins, flavones, and alkaloids). Concentrate and freeze-dry the filtrate to obtain the traditional Chinese medicine active substance rich in small molecular active ingredients (molecular weight <1000 Da).

[0074] Carbomer 0.3 parts was dispersed in part of deionized water, stirred evenly to make it fully swollen, and heated to about 70°C to promote dissolution. In another clean and sterile container, add the appropriate amount of deionized water, then add Chinese medicine small molecule active ingredient 1.2 parts, borneol 0.12 parts, sodium hyaluronate 0.5 parts, glycerol 5 parts, butanediol 5 parts, 1,3-propanediol 3 parts, trehalose 2 parts, allantoin 0.1 parts, disodium EDTA 0.05 parts in turn, and finally add deionized water to 100 parts (including the part of the carbomer solution). Heat to about 75°C, stir while heating, until all ingredients are completely dissolved and evenly distributed. When the temperature of the aqueous phase drops to about 70°C, slowly add the previously prepared carbomer solution under continuous stirring to avoid generating a large amount of foam. Continue stirring until the carbomer is completely dissolved to form a uniform viscous matrix. Slowly titrate with an appropriate amount of triethanolamine to adjust the pH of the mixed solution to between 6.0 and 6.5. Cool the solution to near room temperature (about 25-30°C). Add phenoxyethanol 0.5 parts and stir evenly. Use a homogenizer to homogenize the solution to improve the uniformity and stability of the product. After detecting the appearance, odor, pH, viscosity and other quality indicators of the obtained essence to ensure that it meets the standard requirements, it is filled, and the male external use delay essence based on Chinese medicine small molecule active ingredient is obtained.

[0075] Comparative Example 1: Traditional water extraction and alcohol precipitation method

[0076] Mix all the ingredients (ratio same as Example 2) and add water to decoct twice (1:10→1:8). Combine the decoction and concentrate to a density of 1.2 g / mL. Add 3 times the volume of 70% ethanol to the concentrated solution and precipitate for 24 hours. Recover the ethanol from the supernatant. Filter the concentrated solution through the same ultrafiltration membrane (1000 Da cutoff) and retain the filtrate. Follow the formulation and process of Example 2 to prepare the finished product.

[0077] Comparison purposes:

[0078] Highlight the necessity of group extraction and resin purification: The mixture of all ingredients results in low yield of active ingredients (such as ginsenosides, flavonoids, and alkaloids) and more impurities.

[0079] Comparative Example 2: Group extraction but no ultrafiltration (retaining macromolecular impurities)

[0080] Follow the group extraction and resin purification process of Example 2 (including enzyme digestion of the ginseng group + D101 resin, HPD-400 resin of the cherry fruit group, and ion exchange resin of the sophora flavescens group). After combining the three groups of purified liquids, skip the ultrafiltration step and directly concentrate and freeze-dry. Follow the formulation and process of Example 2 to prepare the finished product.

[0081] Comparison purposes:

[0082] Verify the core value of ultrafiltration: the large molecular components such as polysaccharides / proteins with molecular weight >1000 Da are not removed, resulting in: decreased transdermal absorption rate (large molecules blocking pores), prolonged onset time (>30 minutes), increased formulation viscosity (synergistic thickening with glycerol), and small molecule enrichment proving to be the key support for "fast onset".

[0083] Comparative Example 3: Missing monarch drug (destroying multi-target point synergy)

[0084] Modify the compound, only use Shuangshencao 25 parts, Niudaoli 25 parts, Jinyingzi 15 parts, Danshen 10 parts, Kuhansang 10 parts, Bingpian 0.1 parts (total amount same as Example 2, lack of ginseng). The process completely replicates the grouping extraction, purification, ultrafiltration and preparation process of Example 2.

[0085] Comparison point: missing ginsenosides, significantly decreased erectile hardness; no antioxidant protection, local mucosal repair function is weakened; verify the core position of "monarch drug" in the compound.

[0086] Comparative Example 4: Missing ministerial drug (destroying multi-target point synergy)

[0087] Modify the compound, only use ginseng 35 parts, Jinyingzi 15 parts, Danshen 10 parts, Kuhansang 10 parts, Bingpian 0.1 parts (total amount same as Example 2, lack of Shuangshencao, Niudaoli). The process completely replicates the grouping extraction, purification, ultrafiltration and preparation process of Example 2.

[0088] Comparative Example 5: Missing assistant drug (destroying multi-target point synergy)

[0089] Modify the compound, only use ginseng 35 parts, Shuangshencao 25 parts, Niudaoli 25 parts, Bingpian 0.1 parts (total amount same as Example 2, lack of Jinyingzi, Danshen, Kuhansang). The process completely replicates the extraction, purification, ultrafiltration and preparation process of ginseng group of Example 2.

[0090] Comparative Example 6: Missing ministerial drug (destroying multi-target point synergy)

[0091] The process completely replicates the grouping extraction, purification, ultrafiltration process of Example 2. But in the essence preparation process, do not add Bingpian, replace it with the same mass of deionized water.

[0092] Comparison point: missing Bingpian brings coolness and immediate desensitization effect of TRPM8 activation.

[0093] Comparative Example 7: Missing Bingpian and traditional Chinese medicine small molecule active ingredients

[0094] Do not add any traditional Chinese medicine compound ingredients. In the essence preparation process, do not add Bingpian and traditional Chinese medicine small molecule active ingredients, replace them with the same mass of deionized water.

[0095] Comparison point: comparison between the formula containing the traditional Chinese medicine compound ingredient and the formula without adding any traditional Chinese medicine compound ingredient.

[0096] Test Example 1: Evaluation experiment of sexual behavior of rats

[0097] (1) Purpose of the experiment:

[0098] The improvement effect of the traditional Chinese medicine small molecule essence liquid on the sexual function of male rats is verified by the sexual behavior evaluation method, and the effects of prolonging the ejaculation latency (IELT) and improving the mating activity (mounting times and intromission times) are evaluated. By comparing the differences between Example 2 group (essence liquid prepared by the optimal formula and process of the patent) and seven comparative example groups (derivatives of adjusted formula and process), the key influence of traditional Chinese medicine compound and small molecule extraction and purification process on the curative effect is determined, and scientific basis is provided for the protection of the core innovation point of the patent.

[0099] (2) Preparation of experimental animals

[0100] 120 SPF level SD male rats weighing 220±20 grams were selected for the experiment, and were divided into 12 groups according to the complete random design, 10 rats in each group. The groups included a blank control group (normal saline), a positive control group (7.5% benzocaine spray), three essence liquid example groups (Examples 1, 2 and 3) of the present application, and seven comparative example groups (Comparative Examples 1-7). Another 80 female SD rats weighing 180-200 grams were used for estrus induction. All animals were raised in a constant temperature and humidity environment, the temperature was maintained at 25±1 degrees Celsius, the humidity was controlled at 50±10%, and a 12-hour light and dark cycle system was used. After 7 days of adaptive feeding, the male rats were subjected to pubic hair removal treatment, and an electric shaver was used to completely remove the hair around the penis to ensure the exposure of the skin. The animals were allowed to freely eat and drink during the experiment, and were fasted for 6 hours before administration.

[0101] (3) Implementation of the administration scheme

[0102] Before the administration operation, the penis area of the male rats was disinfected with a 75% ethanol cotton ball, and the administration was started after natural drying. A precision pipette was used to accurately take 0.1 milliliter of the test substance, which was evenly applied to the glans penis and coronal sulcus area. The operator wore sterile gloves and gently massaged in a circular motion for 30 seconds to ensure that the drug was fully absorbed. The blank control group was applied with an equal amount of normal saline, the positive control group was applied with an equal amount of 7.5% benzocaine spray, and each comparative example group was applied with an equal amount of the corresponding preparation.

[0103] (4) Estrus induction of female rats

[0104] Female rats were induced to estrus by subcutaneous injection of estradiol benzoate (10 μg / rat) and progesterone (500 μg / rat). The rats with good estrus were selected by the lordosis test. The standard of estrus was that the rats showed obvious arching reaction when the lumbar region was touched, and the vulva was swollen and wet.

[0105] (5) Sexual behavior test

[0106] The test was performed in a weak red light environment (light intensity less than 10 lux). The observation box was made of transparent organic glass with a size of 40×30×30 cm, and the background white noise was controlled at 50 decibels to shield environmental interference. After administration, the male rats were placed in the observation box for 10 minutes of adaptation, and then the induced estrus female rats were introduced. The infrared camera system recorded the sexual behavior performance within 30 minutes, and the following indicators were observed: ejaculation latency (IELT), i.e. the time (seconds) from insertion to ejaculation, recorded 3 times and averaged. Mounting frequency, i.e. the number of mounting actions of male rats on female rats within 30 minutes. The number of insertions, i.e. the number of successful insertions into the vagina within 30 minutes. Ejaculation behavior was verified by characteristic hind limb stiffness and subsequent licking action.

[0107] (6) Results and conclusions

[0108] One-way analysis of variance (ANOVA) was used to compare the differences between groups, and Tukey's test was used for pairwise comparison between groups.

[0109] Table 1: Efficacy evaluation table of rat sexual behavior

[0110]

[0111] Note: The data are expressed as mean ± standard deviation; * indicates that compared with the blank group, P<0.05 by two-tailed t-test; # indicates that compared with Example 2 group, P<0.05.

[0112] From the data in the above table, it can be seen that the example group has significant overall advantages. In terms of ejaculation latency, the example group (369-382 seconds of ejaculation latency) is significantly higher than the blank group (150 seconds, P<0.05) and has no significant difference with the positive control group (372 seconds, P<0.05), proving that the traditional Chinese medicine compound is comparable to chemical anesthetics in prolonging sexual behavior time, and has no fast feeling dulling (significantly higher number of mounts). In terms of the number of mounts and insertions, the example group (10-12 mounts, 6-8 insertions) is significantly better than the positive control group (4 mounts, P<0.05), which strongly proves that the traditional Chinese medicine compound in the present application achieves the delay effect while avoiding the "fast feeling dulling" problem of chemical anesthetics through the multi-target synergistic mechanism of "suppressing sensitivity, improving circulation, and repairing barriers", significantly optimizing the overall experience. The effects of Comparative Examples 3-6 (missing different group herbs) significantly decreased, further verifying the necessity of compound compatibility (jun, chen, zhe and shi synergy) for achieving this comprehensive effect.

[0113] The excellent effect of the example group (significant delay effect in a short time after administration) depends on its unique small molecule active ingredient enrichment process. The IELT (223s, 194s) of Comparative Example 1 (traditional mixed water extraction and alcohol precipitation) and Comparative Example 2 (group extraction but not ultrafiltration) are significantly lower than that of the example group (369-382 seconds), and the behavior activity is also lower. This directly proves that group extraction and resin purification (Comparative Example 1 vs. Example) can effectively remove impurities, enrich target active ingredients, and improve yield and purity. At the same time, it also proves that ultrafiltration to enrich small molecules (<1000 Da) (Comparative Example 2 vs. Example) is a core step to significantly improve the transdermal absorption efficiency, and is a technical guarantee to achieve an effect close to that of chemical anesthetics.

[0114] Test Example 2 Human Efficacy Evaluation Clinical Trial

[0115] (1) Purpose of the test

[0116] The purpose of this test is to verify the delay core efficacy, use experience and safety of the optimal example 2 of the present application (small molecule active ingredient essence based on seven kinds of traditional Chinese medicines such as ginseng and shuangshencao) in human body, to obtain clinical evidence directly supporting the advantages of the patented technology through single group self-control design before and after.

[0117] (2) Selection of subjects

[0118] A total of 30 male subjects aged 18-45 years who met the criteria were recruited, and were required to have a stable opposite-sex partner and self-reported intravaginal ejaculation latency time (IELT) of ≤3 minutes. Those with organic erectile dysfunction, genital skin disease or history of traditional Chinese medicine allergy were excluded, and those who had not used other delay products in the past 1 month were also excluded. All subjects signed an informed consent form to ensure ethical compliance of the test.

[0119] (3) Test Procedure

[0120] The experiment was divided into two phases:

[0121] Baseline period (1 week): Subjects did not use any products, and their partners used stopwatches to record the ejaculation latency (IELT) of three natural sexual encounters, and the average value was taken as the baseline value.

[0122] Intervention period (8 weeks): 15 minutes before sexual intercourse, subjects applied 0.1 mL of the essence from Example 2 evenly to the glans penis and coronal sulcus, massaging for 30 seconds to promote absorption. This was used no more than 3 times per week. IELT was recorded after each sexual intercourse, and a sexual satisfaction questionnaire was completed at week 8. Adverse reactions were monitored throughout the process.

[0123] (4) Evaluation indicators

[0124] Table 2 Evaluation Indicators and Methods

[0125]

[0126] (5) Results and conclusions

[0127] Paired t-tests were used to compare the differences in IELT and satisfaction scores before and after the intervention (significance threshold P<0.01). Comfort indexes were descriptively analyzed using mean ± standard deviation, and adverse skin reactions were statistically analyzed by incidence.

[0128] Table 3 Statistical Table of Clinical Results of Human Efficacy Evaluation

[0129]

[0130] The experimental data show that the essence of Example 2 can significantly prolong IELT to the clinically effective threshold (>6 minutes), and the 261% improvement significantly proves the "delaying effect" of the essence of this invention; the average onset time of 12.7 minutes reflects the "high efficiency of small molecule transdermal technology"; the satisfaction of both men and women exceeded 8 points, confirming the advantage of "multi-target synergistic effect of compound to avoid pleasure desensitization"; the high-definition cooling sensation (7.9 points) and low stickiness (1.5 points) verify the comfort of borneol penetration and essence formulation design; the absence of skin irritation rate highlights the safety of natural Chinese herbal compound.

Claims

1. An external use traditional Chinese medicine composition, characterized in that, The external use traditional Chinese medicine composition is prepared from the following components in parts by weight: 0.8-1.2 parts of a small-molecule active ingredient of traditional Chinese medicine, and 0.08-0.12 parts of borneol; the small-molecule active ingredient of traditional Chinese medicine is prepared from the following components in parts by weight: 30-40 parts of ginseng, 20-30 parts of shizonepeta, 20-30 parts of milkvetch root, 5-15 parts of red sage root, and 10-20 parts of cherokee rose; and the small-molecule active ingredient of traditional Chinese medicine is prepared by mixing the ginseng, shizonepeta, milkvetch root and red sage root in corresponding parts by weight, extracting the mixture with 65-75% ethanol by reflux, and eluting the extract with non-polar adsorption resin using 50% ethanol and then 70% ethanol by gradient elution, and then concentrating to obtain a purified extract of ginseng / shizonepeta / milkvetch root / red sage root; extracting the cherokee rose with 55-65% ethanol by reflux, eluting the extract with medium-polar adsorption resin using 65-75% ethanol, and then concentrating to obtain a purified extract of cherokee rose; extracting the kuh-seng with acid water, adsorbing the extract with strong acid cation exchange resin, treating the resin with alkali, eluting the total alkaloids, and then concentrating to obtain a purified extract of kuh-seng; and combining the purified extracts of ginseng / shizonepeta / milkvetch root / red sage root, cherokee rose and kuh-seng, and purifying and enriching the active ingredient with a molecular weight of less than 1000 Da.

2. The external use traditional Chinese medicine composition according to claim 1, characterized in that, The ginseng, shizonepeta, milkvetch root and red sage root are mixed first, pretreated with cellulase, and then extracted with 65-75% ethanol by reflux.

3. The external use traditional Chinese medicine composition according to claim 1, characterized in that, The non-polar adsorption resin is D101 macroporous adsorption resin, and the medium-polar adsorption resin is HPD-400 macroporous adsorption resin.

4. The external use traditional Chinese medicine composition according to claim 1, characterized in that, The purification is performed by filtering with an ultrafiltration membrane with a molecular weight cut-off of 1000 Da.

5. Use of the external use traditional Chinese medicine composition of any one of claims 1-4 in the preparation of a male external use time-delay product.

6. Use according to claim 5, characterized in that, The product is a serum, an aqueous preparation, a gel or a spray.

7. An essence characterized by, The active ingredient is the external use traditional Chinese medicine composition of any one of claims 1-4.

8. The serum of claim 7, wherein the serum is characterized by, The mass percentage content of the external use traditional Chinese medicine composition is 0.8-1.3%.

9. The serum of claim 8, wherein the serum is characterized by, The external use traditional Chinese medicine composition comprises the following components in the following mass percentages: 0.8-1.2 parts of a small-molecule active ingredient of traditional Chinese medicine, 0.08-0.12 parts of borneol, 0.4-0.6 parts of sodium hyaluronate, 4-6 parts of glycerol, 4-6 parts of butanediol, 2-4 parts of 1,3-propanediol, 1-3 parts of trehalose, 0.05-0.2 parts of allantoin, 0.2-0.4 parts of carbomer, 0.04-0.06 parts of disodium EDTA, and deionized water added to 100 parts, with a pH of 6.0-6.

5.

10. The method of claim 9, wherein the serum is prepared by the steps of: The carbomer matrix is pre-swollen, the water phase is dissolved with the small-molecule active ingredient of traditional Chinese medicine, borneol, sodium hyaluronate, glycerol, butanediol, 1,3-propanediol, trehalose, allantoin and disodium EDTA, the carbomer matrix is mixed with the water phase to thicken, and the pH is adjusted to 6.0-6.5.

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