CN115025145B - Method and composition for improving pharmaceutical performance of traditional Chinese medicine composition and application thereof - Google Patents
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Abstract
The invention relates to a method for improving the pharmaceutical performance of a traditional Chinese medicine composition, the composition and application thereof. In particular to a throat-opening sword spray which is prepared from cinnabar root, subprostrate sophora, cicada slough, menthol and the like. The preparation method of the spray comprises the following steps: decocting radix Ardisiae Crenatae, radix Sophorae Tonkinensis, and periostracum Cicadae in water twice, mixing decoctions, concentrating into fluid extract, adding ethanol, standing, filtering, recovering ethanol under reduced pressure, concentrating into fluid extract, adding Mentholum, essence, citric acid, sodium benzoate, ethanol, etc., and adding water to total amount. The composition of the present invention has excellent antiviral effect, especially against coronavirus and the like. The compositions of the present invention exhibit excellent properties.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to a traditional Chinese medicine composition for treating stomatitis, which is a traditional Chinese medicine preparation of a Miao medicine's Kaihoujian spray and has the effects of clearing heat, detoxicating, reducing swelling and relieving pain; can be used for treating acute and chronic pharyngolaryngitis, tonsillitis, laryngopharynx swelling and pain, stomatitis, and gingival swelling and pain in clinic; for example, it can be used for treating throat swelling and pain, dry mouth, bitter taste, gum swelling and pain, oral ulcer, recurrent aphtha caused by lung and stomach heat. The traditional Chinese medicine composition provided by the invention can be especially used for treating children's oral pharyngitis. In particular, the present invention relates to methods of improving the pharmaceutical properties of open throat sword spray compositions, as well as the resulting compositions and uses thereof.
Background
The children are young, the viscera are tender and tender, the body is of the type of 'young yin and young yang', the skin striae and sweat pores are not filled, the skin striae are often sparse, the children are susceptible to exogenous evil, in addition, the children are curious and vigorous to the outside, and the children can easily grasp the articles at hand and put the articles into the mouth. Along with the influence of external factors such as climate change, environmental pollution and the like, families are easy to make children 'enter from the mouth' without paying attention to the influence of the external factors, and the 'baby raising' is described as: the infant viscera are tender, spleen is often deficient, and the infant viscera are easy to attack due to dysfunction of transportation and transformation. The epidemic toxin is caused by the invasion of the lung and spleen through the mouth and nose, and is sent to hands and feet, fumigated up the mouth and throat, and externally penetrated through the skin to form herpes. The clinical pediatric oral ulcer belongs to a common disease with higher incidence rate, and is characterized in that superficial ulcers occur on the surface of oral mucosa, the incidence causes are Coxsackie virus, bacterial infection, hand-foot-mouth disease, recurrent aphtha and the like, the infants often show symptoms such as salivation, fever, crying and the like [ Zhang Fubo, and the like ], the analysis of the curative effect of the combination of montmorillonite powder, open throat sword and borneol boron powder for treating the pediatric oral ulcer [ J ]. Chinese women and young health research, 2017,28 (S1): 495], wherein the hand-foot-mouth disease is an acute fever eruptive infectious disease caused by enterovirus and is mainly manifested by red maculopapules and small herpes on hands and feet, buttocks skin, the oral mucosa is scattered on the small ulcers and the small herpes, fever, hypo accompanying and even vomiting after refusing eating or eating, and the infant can be transmitted through the approaches such as close contact, respiratory tract and digestive tract. In addition, the tonsillitis and acute pharyngitis of the children are common respiratory tract infectious diseases, the infants are taken as main morbidity groups, the children have the characteristics of urgent onset, rapid disease progress and the like, and the clinical symptoms such as pharyngalgia, fever, cough, expectoration, hoarseness and dysphagia are mainly presented; the infant acute pharyngolaryngitis is frequently seen in infants from 6 months to 3 years old, the infant can be ill all year round, the early stage is manifested by glowing and dryness of the throat, the illness state is prolonged with pain, the pain is aggravated when cough and swallowing are caused, and the infant acute pharyngolaryngitis is easy to progress to chronic pharyngolaryngitis [ Sun Jing ], etc., the usage amount of the open throat sword spray (children) for treating the infant acute pharyngitis and acute tonsillitis is discussed [ J ]. Chinese experimental journal of prescriptions, 2019,25 (10): 33-40; guan Xiaojuan A.C. throat opening and relieving spray and a clinical analysis of children acute tonsillitis [ J ]. New Chinese medicine 2016,48 (03): 158-160] by combining the oral liquid for treating children acute tonsillitis.
The traditional Chinese medicine throat opening sword spray is a Miao medicine compound preparation produced by Guizhou Sanli company, the content of the Miao medicine compound preparation is light brown to brown liquid, the taste is sweet, slightly bitter and slightly tingling, the cool feeling of mint is achieved, and the prescription is as follows: radix Ardisiae Crispae, radix Sophorae Tonkinensis, periostracum Cicadae, and Mentholum. The spray for opening throat has the effects of clearing heat, detoxicating, detumescence and relieving pain, and is clinically used for treating acute and chronic pharyngolaryngitis, tonsillitis, sore throat, stomatitis, gingival swelling and pain, etc. Wherein, the radix Ardisiae Crispae is collected in quality standard of Chinese medicinal materials and national medicinal materials of Guizhou province (2003 edition), and comprises three basic sources: the cinnabar root, the bailiangjin and the red parachute are loaded into 2015 and 2020 edition of Chinese pharmacopoeia, so that the octopus macrophylla in 2019 edition of Guizhou Chinese herbal medicine quality standard is only loaded with the bailiangjin and the red parachute, and the octopus macrophylla in the throat-opening sword spray formula is named as the cinnabar root.
The oral cavity mucosa spray is directly acted on the oral cavity mucosa in a spray administration mode, the maximum medicine concentration is easy to form at the focus part, the oral cavity mucosa spray has the advantages of high bioavailability, quick response, strong action and the like, and the spray has the cool feeling of mint after spraying, thereby avoiding the pain of children patients caused by methods such as smearing and the like, improving the compliance of children patients [ Peng, and the like.
The research shows that the spray has better clinical curative effects on bacillus proteus, staphylococcus aureus, candida albicans and the like [ high storage jiao ], the analysis of the curative effects of the spray for treating children acute sphagitis [ J ]. Chinese medical abstract (ear, nose and throat science), 2022,37 (01): 72-73], the spray for treating children herpetic angina [ leaf ice and the like ] can be combined with other medicaments or treatment methods, can also be used for treating children herpetic angina besides enhancing anti-inflammatory effect, and can also be used for treating the clinical curative effects of the spray for treating children herpetic angina and the safety thereof [ J ]. Clinical rational medicine journal, 2021,14 (21): 51-54], laryngeal cough [ Song Xiao and the like [ J ]. Acupoint application is matched with the spray for treating children laryngeal cough, 2015,31 (08): 775-776] and the like.
CN104758348B (application No. 201510187892.5, three force) discloses the use of a Chinese medicinal composition for treating stomatocace, which is prepared from active ingredients including radix Ardisiae Crispae, radix Sophorae Tonkinensis, periostracum Cicadae, and Mentholum, wherein the weight ratio of the active ingredients is: radix Sophorae Tonkinensis: cicada slough: menthol=200-350: 200-350:150-280:0.8-1.2, wherein the canker sore is canker sore caused by tumor chemoradiotherapy.
CN103040927a (application No. 201110309375.2, three forces) discloses a spray for treating throat diseases and its preparation method, which relates to a medicine with the functions of clearing heat and detoxicating, detumescence and relieving pain, which is used for treating acute and chronic sphagitis, tonsillitis, sore throat, stomatitis, stomatocace, dry mouth and bitter taste, gum swelling and pain, recurrent aphtha and other diseases. The throat opening sword spray takes radix Ardisiae Crispae, radix Sophorae Tonkinensis, periostracum Cicadae and Mentholum as medicinal materials, and also contains Borneolum Syntheticum, essence, citric acid, steviosin, tween-80, glycerol, sodium benzoate and ethanol as adjuvants; in one example, the prescription of the throat sword spray is: 313g of radix Ardisiae Crispae (i.e. radix Ardisiae Crenatae), 313g of radix Sophorae Tonkinensis, 250g of periostracum Cicadae and 1g of menthol are used as medicinal materials, and the auxiliary materials comprise 0.09g of borneol, 5.5ml of waxberry essence, 1g of citric acid, 2.5g of sodium benzoate, 2.0g of steviosin, 10ml of Tween-80, 4ml of glycerol, 20ml of ethanol and 1000ml of water; in one example, the throat opening sword spray is prepared by: decocting the raw materials of the ardisia crenata, the subprostrate sophora and the cicada slough with water of which the amount is 8 times that of the raw materials for 2 times, each time for 1.5 hours, merging decoction, filtering, concentrating filtrate to obtain fluid extract with the relative density of 1.05-1.10 at 50 ℃, adding ethanol to ensure that the alcohol content reaches 75%, standing for 24 hours, filtering, recovering ethanol from the filtrate under reduced pressure, and concentrating the filtrate to obtain fluid extract with the relative density of 1.10-1.35 at 80 ℃; then taking menthol, borneol, essence, citric acid, sodium benzoate, steviosin, tween-80, glycerin and ethanol, stirring and dissolving, adding into the fluid extract, adding water to 1000ml, stirring uniformly, filtering, and filling to obtain the throat opening sword spray preparation.
However, there remains a need in the art for new open-throat sword sprays in an effort to improve their pharmaceutical properties.
Disclosure of Invention
The invention aims to provide a throat-opening sword spray, or aims to provide a use of a throat-opening sword spray. It has been unexpectedly found that the open throat sword spray prepared by the method of the present invention exhibits an improved pharmaceutical performance. The present invention has been completed based on such findings.
To this end, the first aspect of the present invention provides a throat-opening sword spray, which is formulated as follows: 220 to 330g of cinnabar root, 220 to 330g of subprostrate sophora, 180 to 270g of cicada slough, 0.8 to 1.2g of menthol, 5.5ml of essence, 1g of citric acid, 1 to 2.5g of sodium benzoate, 20ml of ethanol and a proper amount of water are prepared into 1000ml.
According to the first aspect of the invention, the throat opening sword spray comprises the following components: 250g of cinnabar root, 250g of subprostrate sophora, 200g of cicada slough, 1g of menthol, 5.5ml of pineapple essence, 1g of citric acid, 1g of sodium benzoate, 20ml of ethanol and a proper amount of water to prepare 1000ml.
According to the first aspect of the invention, the throat opening sword spray comprises the following components: 313g of cinnabar root, 313g of subprostrate sophora, 250g of cicada slough, 1g of menthol, 5.5ml of waxberry essence, 1g of citric acid, 2.5g of sodium benzoate, 20ml of ethanol and a proper amount of water, and is prepared into 1000ml.
The throat opening sword spray according to the first aspect of the invention is prepared by the following steps: decocting radix Ardisiae Crenatae, radix Sophorae Tonkinensis and periostracum Cicadae in water twice for 2 hr and 1 hr respectively, mixing decoctions, filtering, concentrating the filtrate to obtain fluid extract with relative density of 1.05-1.10 (50deg.C), adding ethanol to 80%, standing for 24 hr, filtering, recovering ethanol from the filtrate under reduced pressure, concentrating to obtain fluid extract with relative density of 1.10-1.20 (80deg.C), mixing and dissolving Mentholum, sodium benzoate, citric acid, essence and ethanol 20ml, adding water to the above extract, stirring, filtering, and packaging.
The open throat sword spray according to the first aspect of the present invention further comprises 2 to 4ml polysorbate 80 per 1000ml, for example 3ml polysorbate 80; for example polysorbate 80 is added during the menthol addition stage.
The open throat sword spray according to the first aspect of the present invention further comprises 1.0 to 1.2g, e.g. 1.0 to 1.1g, e.g. 1.04g or 1.1g steviosin per 1000 ml; for example steviosin is added during the menthol addition stage.
The open throat sword spray according to the first aspect of the present invention does not comprise glycerol.
The throat opening sword spray according to the first aspect of the present invention does not contain borneol.
According to the first aspect of the invention, the throat opening sword spray comprises the following components: 220 to 330g of cinnabar root, 220 to 330g of subprostrate sophora, 180 to 270g of cicada slough, 0.8 to 1.2g of menthol, 5.5ml of essence, 1g of citric acid, 1 to 2.5g of sodium benzoate, 2 to 4ml of polysorbate 80, 1.0 to 1.2g of steviosin, 20ml of ethanol and a proper amount of water, and is prepared into 1000ml.
According to the first aspect of the invention, the throat opening sword spray comprises the following components: 250g of cinnabar root, 250g of subprostrate sophora, 200g of cicada slough, 1g of menthol, 5.5ml of pineapple essence, 1g of citric acid, 1g of sodium benzoate, 3ml of polysorbate 80, 1.1g of steviosin, 20ml of ethanol and a proper amount of water to prepare 1000ml.
According to the first aspect of the invention, the throat opening sword spray comprises the following components: 313g of cinnabar root, 313g of subprostrate sophora, 250g of cicada slough, 1g of menthol, 5.5ml of waxberry essence, 1g of citric acid, 2.5g of sodium benzoate, 3ml of polysorbate 80, 1.04g of steviosin, 20ml of ethanol and a proper amount of water to prepare 1000ml.
The throat opening sword spray according to the first aspect of the invention is prepared by the following steps: decocting radix Ardisiae Crenatae, radix Sophorae Tonkinensis and periostracum Cicadae in water twice for 2 hr for 1 hr, mixing decoctions, filtering, concentrating the filtrate to obtain fluid extract with relative density of 1.05-1.10 (50deg.C), adding ethanol to make alcohol content reach 80%, standing for 24 hr, filtering, recovering ethanol from the filtrate under reduced pressure, concentrating to obtain fluid extract with relative density of 1.10-1.20 (80deg.C), mixing Mentholum, essence, citric acid, sodium benzoate, optional polysorbate 80, optional steviosin and ethanol, stirring to dissolve, adding water to prescribed amount, stirring, filtering, and packaging.
Further, a second aspect of the present invention provides a method for preparing the open throat sword spray of any one of the first aspect of the present invention, comprising the steps of: decocting radix Ardisiae Crenatae, radix Sophorae Tonkinensis and periostracum Cicadae in water twice for 2 hr for 1 hr, mixing decoctions, filtering, concentrating the filtrate to obtain fluid extract with relative density of 1.05-1.10 (50deg.C), adding ethanol to make alcohol content reach 80%, standing for 24 hr, filtering, recovering ethanol from the filtrate under reduced pressure, concentrating to obtain fluid extract with relative density of 1.10-1.20 (80deg.C), mixing Mentholum, essence, citric acid, sodium benzoate, optional polysorbate 80, optional steviosin and ethanol, stirring to dissolve, adding water to prescribed amount, stirring, filtering, and packaging.
Further, the third aspect of the invention provides the use of the open throat sword spray according to any one of the first aspect of the invention in the preparation of a medicament for antiviral treatment.
The use according to the third aspect of the invention, wherein the virus is selected from: coronavirus.
The use according to the third aspect of the invention, wherein the virus is selected from: human coronavirus HCoV-229E.
Further, the fourth aspect of the invention provides the use of the throat-opening sword spray according to any one of the first aspect of the invention in the preparation of a medicament for treating acute pharyngitis.
The use according to the fourth aspect of the invention, wherein the acute pharyngitis is caused by coronavirus.
The use according to the fourth aspect of the invention, wherein the acute pharyngitis is caused by the human coronavirus HCoV-229E.
Among the steps of the above-described preparation method of the present invention, although the specific steps described therein are distinguished in some details or language description from the steps described in the preparation examples of the following detailed description, the above-described method steps can be fully summarized by one skilled in the art based on the detailed disclosure of the present invention as a whole.
Any of the embodiments of any of the aspects of the invention may be combined with other embodiments, provided that they do not contradict. Furthermore, in any of the embodiments of any of the aspects of the present invention, any technical feature may be applied to the technical feature in other embodiments as long as they do not contradict. The present invention is further described below.
All documents cited herein are incorporated by reference in their entirety and are incorporated by reference herein to the extent they are not inconsistent with this invention. Furthermore, various terms and phrases used herein have a common meaning known to those skilled in the art, and even though they are still intended to be described and explained in greater detail herein, the terms and phrases used herein should not be construed to be inconsistent with the ordinary meaning in the sense of the present invention.
The open throat sword spray is a product of Guizhou Sanli pharmacy. The Miao medicine function main indications of the children type throat opening sword spray are as follows: xuegakahi scab, an Dangmeng; steep: nano, meng Ninggong, meng Gagong on, jiang Gangfang, shui Gaguo west; the indications of the traditional Chinese medicine are as follows: clearing away heat and toxic materials, and relieving swelling and pain. Can be used for treating acute and chronic pharyngolaryngitis, tonsillitis, laryngopharynx swelling and pain, stomatitis, and gingival swelling and pain. The seedling medicine function main indications of the adult throat opening sword spray are as follows: raising a mask Song Gongzheng; meng Gagong, luo Lami; the indications of the traditional Chinese medicine are as follows: clearing away heat and toxic materials, and relieving swelling and pain. Can be used for treating sore throat, dry mouth, bitter taste, gingival swelling and pain, oral ulcer, and recurrent aphtha caused by lung and stomach heat.
The radix Ardisiae Crenatae is dry root of Ardisiae Crenatae Ardisia crenata Sims of Philippine. Collected in autumn and winter, washed and dried in the sun. Cinnabar root is cool in nature, bitter and pungent in taste, enters lung and stomach meridians, has the effects of clearing heat and detoxicating, relieving swelling and removing stasis, activating blood and relieving pain, dispelling wind and removing dampness, is clinically used for treating symptoms such as acute pharyngitis, tonsillitis, sore throat, rheumatalgia and traumatic injury, and is called as a good medicine of the laryngeal family by Miao nationality. The radix Ardisiae Crenatae mainly contains triterpene saponins, coumarin and other substances; wherein the structural type of the saponin is mainly pentacyclic triterpene oleanane derivatives, and the aglycone comprises 2 types: epoxy ethers and 12-ene; coumarin is mainly bergenin; also contains some other components: viol, friedelane, beta-sitosterol, and daucosterol.
The Sophora tonkinensis root is the dried root and rhizome of Sophora tonkinensis Sophora tonkinensis Gagnep. The radix sophorae tonkinensis has bitter and cold property and toxic property, enters lung and stomach channels, has the effects of clearing heat and detoxicating, and relieving swelling and sore throat, is used for treating symptoms such as fire toxin accumulation, sore throat, cough due to lung heat, throat obstruction of the tonsillitis, sore mouth and tongue and the like [ national formulary committee, pharmacopoeia of people' S republic of China, one part of [ S ]. Beijing: chinese medical science and technology Press, 2020], "Kaibao Bencao" describes that "main drugs are detoxified, analgesic, anti-vesicular and anti-tumor", "Bencao Jingshu" is a drug for detoxification and heat clearing; the "first key medicine for relieving sore throat" is carried in Ben Cao Qizhen ". The radix Sophorae Tonkinensis contains chemical components such as alkaloid, saponin, flavonoids and polysaccharide, etc., and its main medicinal components are alkaloid such as matrine, oxymatrine, and flavonoid component such as pterocarpan-side.
Cicada slough has sweet and cold nature, enters lung and liver channels, has the effects of dispelling wind-heat, improving eyesight, removing nebula, relieving sore throat, promoting eruption and the like, and is clinically used for treating wind-heat type common cold, sore throat, hoarseness, febrile convulsion, itching throat, frequent cough and other symptoms [ Meng Xianlan ], and the like. The description of Ben Cao gang mu is: cicada is mainly used for treating all wind-heat syndromes, old people use the cicada body, later people use the slough to treat the channels and collaterals of the zang-fu organs, and when the cicada body is used; for skin sores and ulcers due to wind-heat, it is indicated for periostracum Cicadae. Record in "materia medica derivative: "treating dizziness and nebula". But also decocting the shell juice in water can treat infantile sore and rash. The drug theory is also written: it is indicated for infantile convulsive epilepsy due to heat-strengthening of whole body and combined with thirst quenching.
Menthol, also known as menthol, has pharmacological actions such as pain relieving, anticancer, anti-inflammatory etc. [ Du Jian. Neuroprotection of menthol on LPS-induced parkinsonism model and its mechanism [ D ]. Jilin university, 2021.DOI:10.27162/d.cnki.gjlin.2021.005422].
The throat-opening sword spray prepared by the invention has excellent effects, such as excellent biological activity.
Drawings
Fig. 1: in vitro antiviral effect of the spray.
Fig. 2: lesions of mucosal tissue of the animal pharynx (HE 10 x 10); a normal group A, a model group B, a group C ribavirin positive drug group, a group D with low dosage of open throat sword, a group E with medium dosage of open throat sword, and a group F with high dosage of open throat sword.
Detailed Description
The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. Those skilled in the art will appreciate that various changes and modifications can be made to the invention without departing from the spirit and scope thereof. The present invention generally and/or specifically describes the materials used in the test as well as the test methods. Although many materials and methods of operation are known in the art for accomplishing the objectives of the present invention, the present invention will be described in as much detail herein. In the invention, all medicinal materials are dry medicinal materials and meet pharmacopoeia regulations unless specified otherwise.
When the traditional Chinese medicine composition is prepared in the following way, the raw medicinal materials, the auxiliary materials and the packaging material spray bottle are all in the same batch unless specified. When the traditional Chinese medicine composition is prepared, the prepared liquid medicine is filled in a 30ml spray medicinal high-density polyethylene bottle (B20190004717, wantong).
Example 1: preparation of open throat sword spray (Children type)
This example refers to the prescription and process of the national pharmaceutical standard WS-10132 (ZD-0132) -2002 for the preparation of a throat-opening sword spray (children).
Prescription: 250g of cinnabar root, 250g of subprostrate sophora, 200g of cicada slough, 1g of menthol, 5.5ml of pineapple essence serving as an auxiliary material, 1g of citric acid, 1g of sodium benzoate, 20ml of ethanol and a proper amount of water to prepare 1000ml.
The preparation method comprises the following steps: adding water with the amount of 8 times of medicinal materials into three ingredients of cinnabar root, subprostrate sophora and cicada slough, decocting for 2 times, 2 hours for the first time and 1 hour for the second time, mixing decoctions, filtering, concentrating the filtrate into clear paste with the relative density of 1.05-1.10 (50 ℃), adding ethanol to ensure that the ethanol content reaches 80%, standing for 24 hours, filtering, recovering the ethanol from the filtrate under reduced pressure, and concentrating the filtrate into clear paste with the relative density of 1.10-1.20 (80 ℃); mixing menthol, sodium benzoate, citric acid and essence with ethanol 20ml, adding into the above extract, adding water to specified amount, stirring, filtering, and packaging.
Example 2: preparation of spray for opening throat and sword
This example refers to the prescription and process of the national pharmaceutical standard WS-11017 (ZD-1017) -2002 for the preparation of a throat-opening sword spray, which may be referred to as adult type.
Prescription: 313g of cinnabar root, 313g of subprostrate sophora, 250g of cicada slough, 1g of menthol, 5.5ml of waxberry essence serving as an auxiliary material, 1g of citric acid, 2.5g of sodium benzoate, 20ml of ethanol and a proper amount of water, and preparing 1000ml.
The preparation method comprises the following steps: adding water with the amount of 8 times of medicinal materials into three ingredients of cinnabar root, subprostrate sophora and cicada slough, decocting for 2 times, 2 hours for the first time and 1 hour for the second time, mixing decoctions, filtering, concentrating the filtrate into clear paste with the relative density of 1.05-1.10 (50 ℃), adding ethanol to ensure that the ethanol content reaches 80%, standing for 24 hours, filtering, recovering the ethanol from the filtrate under reduced pressure, and concentrating the filtrate into clear paste with the relative density of 1.10-1.20 (80 ℃); mixing menthol, sodium benzoate, citric acid and essence with ethanol 20ml, adding into the above extract, adding water to specified amount, stirring, filtering, and packaging.
Example 3: preparation of a spray for opening throat and sword with reference to CN103040927A
This example refers to the prescription and preparation examples described in the specification [0067] of CN103040927A (Chinese patent application No. 201110309375.2) and prepares a throat-opening sword spray.
Prescription: 313g of cinnabar root, 313g of subprostrate sophora, 250g of cicada slough, 1g of menthol, 5.5ml of waxberry essence serving as auxiliary materials, 1g of citric acid, 2.5g of sodium benzoate, 10ml of tween-80, 2.0g of steviosin, 0.09g of borneol, 4ml of glycerin, 20ml of ethanol and a proper amount of water, and preparing 1000ml.
The preparation method comprises the following steps: adding water with the amount of 8 times of medicinal materials into three ingredients of cinnabar root, subprostrate sophora and cicada slough, decocting for 2 times, each time for 1.5 hours, merging decoction, filtering, concentrating filtrate into clear paste with the relative density of 1.05-1.10 (50 ℃), adding ethanol to ensure that the ethanol content reaches 75%, standing for 24 hours, filtering, recovering ethanol from the filtrate under reduced pressure, and concentrating the filtrate into clear paste with the relative density of 1.10-1.20 (80 ℃); mixing menthol, sodium benzoate, citric acid, essence, tween-80, steviosin, borneolum Syntheticum and glycerol with ethanol 20ml, stirring, adding into the above fluid extract, adding water to 1000ml, stirring, filtering, and packaging.
Example 4: preparation of spray for opening throat and sword
A throat-opening sword spray was prepared with reference to example 3 of the present invention, but without the addition of borneol.
Prescription: 313g of cinnabar root, 313g of subprostrate sophora, 250g of cicada slough, 1g of menthol, 5.5ml of waxberry essence serving as auxiliary materials, 1g of citric acid, 2.5g of sodium benzoate, 10ml of tween-80, 2.0g of steviosin, 4ml of glycerin, 20ml of ethanol and a proper amount of water, and preparing 1000ml.
The preparation method comprises the following steps: adding water with the amount of 8 times of medicinal materials into three ingredients of cinnabar root, subprostrate sophora and cicada slough, decocting for 2 times, each time for 1.5 hours, merging decoction, filtering, concentrating filtrate into clear paste with the relative density of 1.05-1.10 (50 ℃), adding ethanol to ensure that the ethanol content reaches 75%, standing for 24 hours, filtering, recovering ethanol from the filtrate under reduced pressure, and concentrating the filtrate into clear paste with the relative density of 1.10-1.20 (80 ℃); mixing menthol, sodium benzoate, citric acid, essence, tween-80, steviosin and glycerol with ethanol 20ml, dissolving, adding into the above fluid extract, adding water to 1000ml, stirring, filtering, and packaging.
Example 5: preparation of spray for opening throat and sword
An open throat sword spray was prepared with reference to inventive example 3, but without glycerol.
Prescription: 313g of cinnabar root, 313g of subprostrate sophora, 250g of cicada slough, 1g of menthol, 5.5ml of waxberry essence serving as auxiliary materials, 1g of citric acid, 2.5g of sodium benzoate, 10ml of tween-80, 2.0g of steviosin, 0.09g of borneol, 20ml of ethanol and a proper amount of water, and is prepared into 1000ml.
The preparation method comprises the following steps: adding water with the amount of 8 times of medicinal materials into three ingredients of cinnabar root, subprostrate sophora and cicada slough, decocting for 2 times, each time for 1.5 hours, merging decoction, filtering, concentrating filtrate into clear paste with the relative density of 1.05-1.10 (50 ℃), adding ethanol to ensure that the ethanol content reaches 75%, standing for 24 hours, filtering, recovering ethanol from the filtrate under reduced pressure, and concentrating the filtrate into clear paste with the relative density of 1.10-1.20 (80 ℃); mixing Mentholum, sodium benzoate, citric acid, essence, tween-80, steviosin, and Borneolum Syntheticum with ethanol 20ml, stirring, adding into the above fluid extract, adding water to 1000ml, stirring, filtering, and packaging.
Example 6: preparation of spray for opening throat and sword
An open throat sword spray was prepared with reference to example 12 of the present invention, but the addition of Polyshan-li ester 80 was 10ml.
Prescription: 313g of cinnabar root, 313g of subprostrate sophora, 250g of cicada slough, 1g of menthol, 5.5ml of waxberry essence serving as auxiliary materials, 1g of citric acid, 2.5g of sodium benzoate, 1.04g of steviosin, 80 of 10ml of polidocanol, 20ml of ethanol and a proper amount of water to prepare 1000ml.
The preparation method comprises the following steps: adding water with the amount of 8 times of medicinal materials into three ingredients of cinnabar root, subprostrate sophora and cicada slough, decocting for 2 times, 2 hours for the first time and 1 hour for the second time, mixing decoctions, filtering, concentrating the filtrate into clear paste with the relative density of 1.05-1.10 (50 ℃), adding ethanol to ensure that the ethanol content reaches 80%, standing for 24 hours, filtering, recovering the ethanol from the filtrate under reduced pressure, and concentrating the filtrate into clear paste with the relative density of 1.10-1.20 (80 ℃); mixing menthol, sodium benzoate, citric acid, essence, steviosin and Polymountain ester 80 with ethanol 20ml, dissolving, adding into above extract, adding water to specified amount, stirring, filtering, and packaging.
Example 11: preparation of open throat sword spray (Children type)
In the embodiment, proper amounts of steviosin and polysorbate 80 are added in the prescription process of the children type throat opening sword spray.
Prescription: 250g of cinnabar root, 250g of subprostrate sophora, 200g of cicada slough, 1g of menthol, 5.5ml of pineapple essence, 1g of citric acid, 1g of sodium benzoate, 1.1g of steviosin, 80 of 3ml of polidocanol, 20ml of ethanol and a proper amount of water, and is prepared into 1000ml.
The preparation method comprises the following steps: adding water with the amount of 8 times of medicinal materials into three ingredients of cinnabar root, subprostrate sophora and cicada slough, decocting for 2 times, 2 hours for the first time and 1 hour for the second time, mixing decoctions, filtering, concentrating the filtrate into clear paste with the relative density of 1.05-1.10 (50 ℃), adding ethanol to ensure that the ethanol content reaches 80%, standing for 24 hours, filtering, recovering the ethanol from the filtrate under reduced pressure, and concentrating the filtrate into clear paste with the relative density of 1.10-1.20 (80 ℃); mixing menthol, sodium benzoate, citric acid, essence, steviosin and Polymountain ester 80 with ethanol 20ml, dissolving, adding into above extract, adding water to specified amount, stirring, filtering, and packaging.
Example 12: preparation of spray for opening throat and sword
In the embodiment, a proper amount of steviosin and polysorbate 80 are added in the prescription process of the adult throat-opening sword spray
Prescription: 313g of cinnabar root, 313g of subprostrate sophora, 250g of cicada slough, 1g of menthol, 5.5ml of waxberry essence serving as auxiliary materials, 1g of citric acid, 2.5g of sodium benzoate, 1.04g of steviosin, 80 of 3ml of polidocanol, 20ml of ethanol and a proper amount of water to prepare 1000ml.
The preparation method comprises the following steps: adding water with the amount of 8 times of medicinal materials into three ingredients of cinnabar root, subprostrate sophora and cicada slough, decocting for 2 times, 2 hours for the first time and 1 hour for the second time, mixing decoctions, filtering, concentrating the filtrate into clear paste with the relative density of 1.05-1.10 (50 ℃), adding ethanol to ensure that the ethanol content reaches 80%, standing for 24 hours, filtering, recovering the ethanol from the filtrate under reduced pressure, and concentrating the filtrate into clear paste with the relative density of 1.10-1.20 (80 ℃); mixing menthol, sodium benzoate, citric acid, essence, steviosin and Polymountain ester 80 with ethanol 20ml, dissolving, adding into above extract, adding water to specified amount, stirring, filtering, and packaging.
Example 21: preparation of open throat sword spray (Children type)
In the embodiment, proper amounts of steviosin and polysorbate 80 are added in the prescription process of the children type throat opening sword spray.
Prescription: 250g of cinnabar root, 250g of subprostrate sophora, 200g of cicada slough, 1g of menthol, 5.5ml of pineapple essence, 1g of citric acid, 1g of sodium benzoate, 1.1g of steviosin, 80 g of 3ml of polidocanol, 6g of glycine, 20ml of ethanol and a proper amount of water, and is prepared into 1000ml.
The preparation method comprises the following steps: adding water with the amount of 8 times of medicinal materials into three ingredients of cinnabar root, subprostrate sophora and cicada slough, decocting for 2 times, 2 hours for the first time and 1 hour for the second time, mixing decoctions, filtering, concentrating the filtrate into clear paste with the relative density of 1.05-1.10 (50 ℃), adding ethanol to ensure that the ethanol content reaches 80%, standing for 24 hours, filtering, recovering the ethanol from the filtrate under reduced pressure, and concentrating the filtrate into clear paste with the relative density of 1.10-1.20 (80 ℃); mixing menthol, sodium benzoate, citric acid, essence, steviosin, polyshan ester 80 and glycine with ethanol 20ml, dissolving, adding into above extract, adding water to specified amount, stirring, filtering, and packaging.
Example 22: preparation of spray for opening throat and sword
In the embodiment, a proper amount of steviosin and polysorbate 80 are added in the prescription process of the adult throat-opening sword spray
Prescription: 313g of cinnabar root, 313g of subprostrate sophora, 250g of cicada slough, 1g of menthol, 5.5ml of waxberry essence serving as auxiliary materials, 1g of citric acid, 2.5g of sodium benzoate, 1.04g of steviosin, 80 g of 3ml of polidocanol, 8g of glycine, 20ml of ethanol and a proper amount of water, and preparing 1000ml of the waxberry essence.
The preparation method comprises the following steps: adding water with the amount of 8 times of medicinal materials into three ingredients of cinnabar root, subprostrate sophora and cicada slough, decocting for 2 times, 2 hours for the first time and 1 hour for the second time, mixing decoctions, filtering, concentrating the filtrate into clear paste with the relative density of 1.05-1.10 (50 ℃), adding ethanol to ensure that the ethanol content reaches 80%, standing for 24 hours, filtering, recovering the ethanol from the filtrate under reduced pressure, and concentrating the filtrate into clear paste with the relative density of 1.10-1.20 (80 ℃); mixing menthol, sodium benzoate, citric acid, essence, steviosin, polyshan ester 80 and glycine with ethanol 20ml, dissolving, adding into above extract, adding water to specified amount, stirring, filtering, and packaging.
Test example 1: spray Performance investigation
The spray prepared in the examples of the present invention and filled in the spray bottle was measured for each spray amount in 0 month (within 2 days after the preparation), then left to stand in the dark at 40℃and sampled for each spray amount in 2, 4, 6 months. The measurement method for each spray amount comprises the following steps: for a certain batch of samples to be tested at a certain time point, taking 6 bottles, continuously spraying 6 times after the initial 5-time spraying of each bottle, collecting the samples, measuring the sprayed liquid medicine amount of 36 total spraying of the 6 bottles, and calculating the average weight of each sprayed liquid medicine as each spraying amount. For a certain batch of samples, the percentage obtained by dividing the amount per shot at a certain time point by the amount per shot of 0 month and multiplying the amount per shot by 100% is taken as the relative amount per shot at the time point.
According to the measurement, when the polyethylene bottle is matched with an oral liquid medical spray pump (B20190003718, bona), the relative amount of each spray in 2, 4 and 6 months: the three month results of the spray of example 1 are 98.6%, 96.1% and 92.4% respectively, the three month results of the spray of example 2 are 98.3%, 95.7% and 91.6% respectively, the three month results of the spray of example 3-6, the three month results of the spray of examples 11-12 and examples 21-22 are 99.2-101.7%, 99.4-101.1% and 98.7-100.4% respectively, for example, the spray of example 11 is 99.6% and the spray of example 12 is 100.1% respectively; polyethylene bottles were used with pharmaceutical aerosol pumps Freepod (B20190000625, aptar Mezzovico) with relative amounts of each aerosol per spray for three months of 2, 4, 6 months: the three month results of the spray of example 1 are 97.8%, 95.3% and 91.2% respectively, the three month results of the spray of example 2 are 98.0%, 95.4% and 91.0% respectively, the three month results of the spray of examples 3-6, examples 11-12 and examples 21-22 are 99.3-101.1%, 99.6-100.8% and 98.9-100.6% respectively, for example, the spray of example 11 is 99.9% for 6 months and the spray of example 12 is 99.3% for 6 months; when the polyethylene bottle is matched with a medicinal spray pump (B20210000603, meijie), the relative amount of each spray in 2, 4 and 6 months: the three month results of the spray of example 1 are 98.1%, 95.7% and 92.0% respectively, the three month results of the spray of example 2 are 98.5%, 95.1% and 90.4% respectively, the three month results of the spray of example 3-6, the three month results of the spray of examples 11-12 and the spray of examples 21-22 are 99.5-101.3%, 99.1-100.7% and 98.5-100.5% respectively, for example, the spray of example 11 has a 6 month result of 100.2% and the spray of example 12 has a 6 month result of 99.2%; when the polyethylene bottle is matched with an oral liquid medicinal spray pump (B20190000977, shitong), the relative amount of each spray in each spray of 2, 4 and 6 months is as follows: the three month results of the spray of example 1 were 98.3%, 95.5% and 91.4% respectively, the three month results of the spray of example 2 were 97.8%, 94.8% and 90.7% respectively, the three month results of the spray of examples 3 to 6, the three month results of the spray of examples 11 to 12 and the spray of examples 21 to 22 were 99.4 to 101.2%, 99.6 to 100.6% and 98.9 to 101.1% respectively, for example, the spray of example 11 was 99.8% for 6 months and the spray of example 12 was 99.2% for 6 months. From this result, it was unexpectedly found that some of the tween and steviosin-added sprays had excellent spray stability, which concluded that the same results were presented when using multiple brands of spray pumps.
Test example 2: viscous property investigation
The four kinds of spray pumps mentioned in test example 1 were respectively mixed with a polyethylene bottle, and the percentage of deviation of a certain spray pump when spraying a certain chemical liquid was calculated by the following formula by measuring the amount of water (average value of 36 sprays) for injection by the four kinds of spray pumps (corresponding to a liquid of standard viscosity) and measuring the amount of each spray of the spray liquid obtained in each example by the four kinds of spray pumps according to the method of test example 1:
deviation percentage = [ (water spray per spray amount-liquid spray per spray amount)/(water spray per spray amount ] ×100%)
Results: the deviation percentage of the liquid medicines of the four spray pumps spraying examples 1 to 2 was in the range of 0.9 to 1.3%, for example, the spray pump (B20190003718) spraying example 1 was 1.16%, the deviation percentage of the liquid medicines of the four spray pumps spraying examples 11 to 12 and examples 21 to 22 was in the range of 1.2 to 1.5%, for example, the spray pump (B20190003718) spraying example 11 was 1.33%, the deviation percentage of the liquid medicines of the four spray pumps spraying examples 5 to 6 was in the range of 4.5 to 5.4%, for example, the spray pump (B20190003718) spraying example 5 was 5.27%, and the deviation percentage of the liquid medicines of the four spray pumps spraying examples 3 to 4 was 8.6 to 11.3%, for example, the spray pump (B20190003718) spraying example 5 was 10.53%. From the results, it was found that the addition of tween 80 (and glycerol) at higher concentrations in the formulation may lead to a decrease in the amount of spray per spray due to an increase in viscosity, which is expected to be avoided. In addition, it was determined that the amount of water injected by the spray pump (B20190003718) per injection was 152.6mg, the amount of water injected by the spray pump Freepod (B20190000625) per injection was 127.1mg, the amount of water injected by the spray pump (B20210000603) per injection was 155.8mg, and the amount of water injected by the spray pump (B20190000977) per injection was 146.3mg, which indicated that the design spray amounts for the different brands of spray pumps were different, but that this difference did not affect the accuracy of other experiments of the present invention.
The above percentage of deviation is related to the performance of the liquid medicine and the spray pump, and is not related to the bottle filled with the liquid medicine, for example, is not related to the bottle of the high-density polyethylene for the medicinal aerosol.
Test example 3: determination of matrine
The test example provides a method for measuring matrine content in spray liquid medicine, and the measuring method comprises the following steps: determining according to specification of high performance liquid chromatography of four appendixes VID of Chinese pharmacopoeia 2020 edition; octadecylsilane chemically bonded silica was used as filler (Welch Ultimate Plus C, 4.6X105 mm,5 μm); using a non-nitrile absolute ethyl alcohol-0.3% phosphoric acid solution (80:10:10) as a mobile phase, wherein the detection wavelength is 220nm, and the theoretical plate number is not lower than 2010 according to matrine peaks; taking a proper amount of matrine reference substance, precisely weighing, adding acetonitrile-absolute ethyl alcohol (80:20) for dissolving, and preparing a solution containing 80 mug per 1ml to obtain a reference substance solution; taking a spray solution to be tested, shaking up, precisely measuring 5ml, adding water to dilute to 20ml, shaking up, adding 0.5ml of concentrated ammonia test solution, shaking up and extracting for 2 times by using chloroform, 20ml each time, combining the chloroform solutions, evaporating in a water bath, dissolving residues in absolute ethyl alcohol, transferring the residues into a 10ml measuring flask, adding absolute ethyl alcohol to scale, shaking up, filtering, and taking a subsequent filtrate to obtain a sample solution; precisely sucking 10 μl of control solution and 10 μl of sample solution, respectively, and injecting into liquid chromatograph to determine and calculate matrine amount in each 1ml of medicinal liquid to obtain matrine concentration (μg/ml) in spray medicinal liquid.
The spray prepared in the embodiment of the invention and filled in a spray bottle is subjected to matrine concentration measurement in the spray liquid medicine within 0 month (within 2 days after preparation), then is placed in a dark place at 40 ℃, and is sampled and measured for 3 months and 6 months respectively. For a certain batch of samples, the percent obtained by dividing the matrine concentration by the matrine concentration for 0 month and multiplying the matrine concentration by 100% is taken as the matrine relative content (%) at the sampling time point. According to measurement, the relative content of the matrine 3 months of each spray obtained in examples 1-2, examples 5-6, examples 11-12 and examples 21-22 is in the range of 99.1-100.4%, for example, the relative content of the matrine 3 months of the sprays in examples 11 and 12 is 99.8% and 99.4%, and the relative content of the matrine 3 months of the sprays in examples 3 and 4 is 93.6% and 94.2%, respectively; the comparative amounts of matrine in spray formulations 6 obtained in examples 1-2, examples 5-6, examples 11-12 and examples 21-22 were all in the range of 98.4-99.5%, for example, the comparative amounts of matrine in spray formulations 6 in examples 11 and 12 were 98.7% and 99.1%, respectively, and the comparative amounts of matrine in spray formulations 6 in examples 3 and 4 were 88.2% and 89.5%, respectively. Based on this result, it was unexpectedly found that the chemical stability of matrine in some sprays with added borneol was poor, although it is not clear whether this result is caused by borneol alone or by the action of borneol with other substances, and it is known to those skilled in the art that this tendency is not desirable. According to the results of the above test examples 1 to 3, the prescription processes of examples 11 to 12 and examples 21 to 22 are advantageous, which have not only excellent spray stability but also excellent chemical stability.
Test example 4: determination of bergenin
Bergenin is an important chemical component of the spray of the present invention, and it is necessary to determine it.
The invention refers to the specification of high performance liquid chromatography (general rule 0512) of four parts of Chinese pharmacopoeia 2020 edition, and the method for measuring the bergenin content in the spray comprises the following steps:
chromatographic conditions and system suitability test: octadecylsilane chemically bonded silica is used as a filler; methanol-water (25:75) as mobile phase; the detection wavelength is 275nm; the number of theoretical plates is not lower than 1500 according to bergenin peak calculation;
preparation of a control solution: taking a proper amount of bergenin reference substance, precisely weighing, adding methanol to prepare a solution containing 50 mug per 1 ml;
preparation of test solution: precisely sucking 5ml of spray solution, placing in 50ml measuring flask, adding methanol to scale, and shaking;
assay: respectively precisely sucking 20 μl of control solution and 20 μl of sample solution, injecting into liquid chromatograph, measuring, and calculating bergenin concentration in the liquid medicine according to external standard method by peak area.
The obtained spray solutions of the examples were directly sampled and measured by the HPLC method, and the results were: bergenin concentrations in the sprays of examples 1, 11 and 21 were 542.8. Mu.g/ml, 534.1. Mu.g/ml, 548.4. Mu.g/ml, bergenin concentrations in the sprays of examples 2, 12 and 22 were 674.2. Mu.g/ml, 682.6. Mu.g/ml, 663.4. Mu.g/ml, bergenin concentrations in the sprays of examples 3 to 6 were 658 to 686. Mu.g/ml, for example 677.5. Mu.g/ml in example 3. From the point of view of stability test, the result can be regarded as 0 month bergenin content of each spray. The spray liquid medicine of each example prepared herein was filled in a high-density polyethylene bottle (20 ml liquid medicine/bottle) for medical use, sealed, and left to stand in the dark at 40 ℃ for 6 months, the liquid medicine was directly sucked, and after dilution by the HPLC method, the bergenin concentration was measured, and the relative content (%) of each liquid medicine sample for 6 months relative to 0 month was calculated, as a result: examples 21 and 22 sprays 6 moon bergenin relative content was 98.7% and 98.3%, respectively, examples 1-6, examples 11-12 sprays 6 moon bergenin relative content was in the range of 90-92%, for example 3 spray 6 moon bergenin relative content was 91.6%. Accurately filling the spray liquor of each embodiment prepared herein into a medicinal high-density polyethylene bottle (20.0 ml liquor/bottle), sealing, standing in a dark place at 40 ℃ for 6 months, transferring the liquor to be tested into a 50ml measuring bottle, shaking for 3 times by using 25ml of methanol, cleaning the bottle, transferring the washing liquor into the measuring bottle, fixing the volume by using the methanol, accurately sucking 5ml of the washing liquor, placing into the 20ml measuring bottle, adding the methanol to a scale, shaking uniformly to obtain a test solution, measuring the bergenin concentration of the test solution by using the HPLC method, and calculating the relative content (%) of each liquor sample relative to 0 month for 6 months, thereby obtaining the result: the spray formulations of examples 1 to 6, examples 11 to 12 and examples 21 to 22 all have a relative content of 6-month bergenin in the range of 97.8 to 99.4%, for example, the spray formulation of example 3 has a relative content of 6-month bergenin of 98.2%. The spray liquid of each example prepared herein was filled into a medicinal glass bottle (20 ml liquid/bottle), sealed, left to stand in the dark at 40 ℃ for 6 months, the liquid was directly sucked and diluted by the HPLC method, the bergenin concentration was measured, and the relative content (%) of each liquid sample for 6 months relative to 0 month was calculated, as a result: the spray formulations of examples 1 to 6, examples 11 to 12 and examples 21 to 22 all have a relative content of 6-month bergenin in the range of 97.6 to 99.1%, for example, the spray formulation of example 3 has a relative content of 6-month bergenin of 98.5%. The results show that bergenin is not obviously lost after the liquid medicine is kept stand for a long time, but is possibly adhered to the inner wall of a medicinal high-density polyethylene bottle; it has surprisingly been found that the addition of glycine to the liquid medicine can avoid such adhesion. Thus in one embodiment of the spray of the present invention, it also comprises 6 to 8g, for example 6g or 8g, glycine per 1000ml of the liquid medicine, and furthermore glycine may be added together with the poly-shan-ester. In addition, bergenin does not adhere, and from the standpoint of drug storage, transportation and use, pharmaceutical high density polyethylene bottles are more suitable and more commonly used as spray bottles.
Test example 5: pharmacodynamic research of in-vitro antiviral and in-vivo acute pharyngitis prevention and treatment spray of sword for opening throat
1. Reagent
Example 1 a throat opening sword spray,
ribavirin Lin Pen agent: jiangsu Tianji pharmaceutical Co., ltd., H20059502.
2. Experimental animal
Young ICR mice (SPF/VAF grade), weighing 13-15 g, 3-4 weeks old, supplied by beijing vernalia laboratory animal technology limited, animal license number: SCXK (jing) 2016-0011.
3. Viruses and cells
Virus strain: parainfluenza virus 3 (HPIV 3, available from ATCC), respiratory Syncytial Virus (RSV), coxsackie virus A6 (CoxA 6), human coronavirus (HCoV-229E), offered by the national academy of medical biotechnology institute, and stored in a refrigerator at-80℃for further use.
Cell lines: human laryngeal carcinoma epithelial cells Hep-2, human embryonic lung fibroblasts MRC-5; human lung epithelial cells A549 were purchased from Beijing North Innovative Biotechnology institute, and stored in liquid nitrogen for use.
4. Test reagent: nutrient broth medium was purchased from CORNING, rubbit IL-2 and other ELISA kits from Shanghai enzyme-linked, and the remaining conventional reagents were purchased from commercial sources.
5. Test instrument: a2 biosafety cabinet (ThroMSC 1.8, thromo corporation), multifunctional enzyme-labeled instrument (Enspirae, perkinelmer, germany), full-automatic cell counter (IC 1000, countstar corporation), inverted microscope (CKX 41, OLYMPUS corporation), fluorescence inverted microscope (IX 71, OLYMPUS corporation), full-automatic blood and body fluid integrated machine (XN-55, sysmex corporation), and the rest of the conventional test instruments are commercially available.
6. In vitro antiviral pharmacodynamic studies
6.1. Toxic effects of drug on cultured cells in vitro:
the open throat sword spray was diluted 2-fold with nutrient broth culture medium for a total of 8 dilutions, added to the monolayer-grown MRC5, A549 and Hep-2 cell culture plates at 100. Mu.L/well, 4 multiplex wells were made for each dilution, and normal cell controls were set. The culture plate was placed at 37℃with 5% CO 2 Culturing in incubator, observing cytopathy condition under daily inverted microscope for 72 hr, and determining minimum dilution multiple (maximum nontoxic concentration TC) of cells without obvious lesion 0 ) And 50% cytotoxicity concentration (TC) was calculated according to Reed-Muench method 50 ). The results are shown in Table 1.
Cytopathy is judged according to a grade 6 standard:
-: the cells grow normally without lesions;
and (3) the following steps: cytopathic effect is less than 10% of the whole monolayer;
+: cytopathy accounts for less than about 25% of the whole monolayer;
++: cytopathy accounts for less than about 50% of the whole monolayer;
+++: cytopathy accounts for less than 75% of the whole monolayer;
++++: cytopathy accounts for about 75% or more of the whole monolayer.
Table 1: toxic effects of the drug on in vitro cultured cells (original concentration 0.7g crude drug/ml)
Note that: "-" indicates that the cells are growing normally and no lesions are present; "1" represents "+", i.e., the cytopathy is less than about 25% of the whole monolayer of cells; "2" represents "++", i.e., the cytopathy is less than about 50% of the whole monolayer of cells; "3" represents "+". "+", i.e., cytopathy accounts for less than about 75% of the total monolayer of cells; "4" stands for "++", i.e., cytopathy accounts for about 75% or more of the whole monolayer of cells. The results are shown in Table 2.
Table 2: toxic effects of the drug on in vitro cultured cells (Unit: mg crude drug/ml)
| Index (I) | TC 50 | TC 0 |
| MRC-5 | 15.6 | 10.9 |
| A549 | 15.6 | 10.9 |
| Hep-2 | 7.8 | 5.5 |
6.2. Inhibition of virus by drugs on cells cultured in vitro
Taking a culture plate of MRC-5, A549 and Hep-2 grown into monolayer cells, pouring out the culture solution, flushing the cell surface with a cell maintenance solution for 3 times, and respectively inoculating HCoV-229E, RSV, coxA6, HPIV3 virus solution and 100TCID 50 100. Mu.L/well, and placed at 37℃in 5% CO 2 After 1h of adsorption in the incubator, each of 8 dilutions below the nontoxic concentration was added in sequence, 100 μl/well, with normal cell control and virus control. Placing at 37 ℃ 5% CO 2 Culturing in incubator, observing cytopathy condition under inverted microscope every day, after 72 hours the virus control group cytopathy is ++ to +++ to +++ test results were recorded at time. 50% Inhibition Concentration (IC) calculated as Reed-Muench 50 ) And Therapeutic Index (TI), ti=tc 50 /IC 50 . The results are shown in Table 3.
Table 3: inhibition of virus-infected in vitro cells by drugs
Note that: "-" indicates that the cells are growing normally and no lesions are present; and (3) the following steps: cytopathic effect is less than 10% of the whole monolayer; "1" represents "+", i.e., the cytopathy is less than about 25% of the whole monolayer of cells; "2" represents "++", i.e., the cytopathy is less than about 50% of the whole monolayer of cells; "3" represents "+". "+", i.e., cytopathy accounts for less than about 75% of the total monolayer of cells; "4" stands for "++", i.e., cytopathy accounts for about 75% or more of the whole monolayer of cells. The results are shown in Table 4 and FIG. 1.
Table 4: inhibition of virus by drugs on cells cultured in vitro
| Virus (virus) | IC 50 (mg crude drug/mL) | TI |
| HCoV-229E | 1.99 | 7.8 |
The effect of the drug on HCoV-229E, PR, RSV, ad3, coxA6, HPIV3 virus infection was observed by CPE method and MRC-5, A549 and Hep-2 cytopathic effects were cultured in vitro, the results of tables 1-4 and FIG. 1 show: the open throat sword spray of example 1 (childhood) showed significant inhibition of HCoV-229E induced cytopathy, IC 50 1.99mg crude drug/mL, while exhibiting no inhibitory effect on HPIV3, RSV, coxA 6-infected Hep-2 cells.
Referring to the above-mentioned "6. In vitro antiviral pharmacodynamics study", the four sprays of examples 11 to 12 and examples 21 to 22 of the present invention were tested for their inhibitory effect on viruses on cells cultured in vitro, and as a result, the four sprays showed significant inhibitory effect on cytopathy caused by HCoV-229E: EXAMPLE 11 IC of spray 50 IC of spray of example 12 at 1.56mg crude drug/mL 50 IC of spray of example 21 at 1.45mg crude drug/mL 50 IC of example 22 spray at 1.51mg crude drug/mL 50 1.39mg crude drug/mL, none of the four sprays of examples 11 to 12 and examples 21 to 22 showed inhibitory effect on HPIV3, RSV and CoxA 6-infected Hep-2 cells.
7. In vivo pharmacodynamics research-influence on acute pharyngitis model of young mice caused by coronavirus infection
The in vivo efficacy of the throat-opening sword spray is evaluated by using an acute pharyngitis model of young mice infected with HCoV-229E and by using pharyngeal lesion scoring and pathological detection.
The test method comprises the following steps: the throat of the young mice is infected by HCoV-229E virus liquid. The rest of the groups except the normal control group were each pharyngeal injected with 100TCID 50 The diluted HCoV-229E virus solution was 50. Mu.l/dose, 1 dose/dose daily for 2 consecutive days, resulting in an acute pharyngitis model. Throat spray administration of example 1 spray or ribavirin (100 μl/day) was started on day 3, and vehicle was sprayed under equivalent conditions for normal and model control groups for 3 consecutive days. Animals were dissected on day 6 and the mice were visually observed for pharyngeal mucosa.
Pharyngeal lesions scoring criteria:
"-": the pharyngeal tissue is light red, the surface is moist and glossy, no secretion is seen, and congestion and swelling are avoided;
"+": the pharyngeal mucosa has poor glossiness, small amount of secretion and slight acute congestion;
"++": poor gloss of pharyngeal tissues, dark red color, small amount of secretion, acute congestion with slight swelling;
"+++": the pharyngeal tissues are dark red and matt, and mucous secretions are increased, so that the pharyngeal tissues are in obvious acute hyperemia and swelling states.
Visual inspection shows that the pharyngeal tissues of the normal control group animals are light red, the surfaces of the animals are moist and glossy, no secretion is seen, and congestion and swelling are avoided; the animal pharyngeal tissue of the model control group has poor glossiness, dark red color, small amount of secretion, acute congestion with slight swelling; the pharyngeal lesions of the animals of each administration group are relieved to different degrees, which is manifested by congestion, obvious relief of swelling and no obvious inflammatory secretion. The results are shown in Table 5 below.
Table 5: effect of Kaihujian spray on acute pharyngitis model of young mice infected with coronavirus
Note that: p-values were compared to model control.
The results in the table show that the integration of pharyngeal lesions in the model control group is significantly different from that in the normal control group (P < 0.01); throat-opening sword spray (children) has different administration groups with reduced integral of pharyngeal lesions, and significant difference (P <0.05, P < 0.01) compared with model control group.
After the animals are sacrificed, pharyngeal mucosa tissues are taken for pathological examination, and the results are shown as figure 2, wherein three dose groups of the throat-opening sword spray show better treatment effect on acute pharyngitis models of young mice infected by coronaviruses.
In further experiments, referring to the "7. In vivo pharmacodynamic study-effect on acute pharyngitis model of young mice infected with coronavirus", four sprays of examples 11 to 12 and examples 21 to 22 of the present invention were tested for their effect on acute pharyngitis model of young mice infected with coronavirus, and the results of lesion mean values are shown in Table 5, showing that both sprays with 3ml of Tween and steviosin added or further glycine added exhibited excellent effects.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Claims (13)
1. A throat opening sword spray is prepared from the following components: 220-330 g of cinnabar root, 220-330 g of subprostrate sophora, 180-270 g of cicada slough, 0.8-1.2 g of menthol, 5.5ml of essence, 1g of citric acid, 1-2.5 g of sodium benzoate, 2-4 ml of polysorbate 80, 1.0-1.2 g of steviosin, 20ml of ethanol, 6-8 g of glycine and a proper amount of water to prepare 1000ml.
2. The open throat sword spray according to claim 1, which is made from the following components: 250g of cinnabar root, 250g of subprostrate sophora, 200g of cicada slough, 1g of menthol, 5.5ml of pineapple essence, 1g of citric acid, 1g of sodium benzoate, 3ml of polysorbate 80, 1.1g of steviosin, 6g of glycine, 20ml of ethanol and a proper amount of water to prepare 1000ml.
3. The open throat sword spray according to claim 1, which is made from the following components: 313g of cinnabar root, 313g of subprostrate sophora, 250g of cicada slough, 1g of menthol, 5.5ml of waxberry essence, 1g of citric acid, 2.5g of sodium benzoate, 3ml of polysorbate 80, 1.04g of steviosin, 8g of glycine, 20ml of ethanol and a proper amount of water to prepare 1000ml.
4. The throat opening sword spray according to any one of claims 1-3, which comprises the following steps: decocting radix Ardisiae Crenatae, radix Sophorae Tonkinensis and periostracum Cicadae in water twice for 2 hr for 1 hr, mixing decoctions, filtering, concentrating the filtrate to obtain fluid extract with relative density of 1.05-1.10 at 50deg.C, adding ethanol to make alcohol content reach 80%, standing for 24 hr, filtering, recovering ethanol from the filtrate under reduced pressure, concentrating to obtain fluid extract with relative density of 1.10-1.20 at 80deg.C, taking menthol, sodium benzoate, citric acid, essence, steviosin, polysorbate 80, glycine and ethanol, stirring for dissolving, adding water to specified amount, stirring, filtering, and packaging.
5. The open throat sword spray according to claim 1, which comprises 3ml polysorbate 80 per 1000ml.
6. The open throat sword spray according to claim 1, wherein polysorbate 80 is added during the menthol addition stage.
7. The throat opening sword spray according to claim 1, which comprises 1.0-1.1 g of steviosin per 1000 ml.
8. The open throat sword spray according to claim 1, which comprises 1.04g or 1.1g steviosin per 1000 ml.
9. The open-throat sword spray according to claim 1, wherein the steviosin is added during the menthol addition stage.
10. A method for preparing the open throat sword spray according to any one of claims 1-9, comprising the following steps: decocting radix Ardisiae Crenatae, radix Sophorae Tonkinensis and periostracum Cicadae in water twice for 2 hr for 1 hr, mixing decoctions, filtering, concentrating the filtrate to obtain fluid extract with relative density of 1.05-1.10 at 50deg.C, adding ethanol to make alcohol content reach 80%, standing for 24 hr, filtering, recovering ethanol from the filtrate under reduced pressure, concentrating to obtain fluid extract with relative density of 1.10-1.20 at 80deg.C, mixing and dissolving menthol, essence, citric acid, sodium benzoate, polysorbate 80, steviosin, glycine and ethanol, adding water to specified amount, stirring, filtering, and packaging.
11. Use of the open throat sword spray of any one of claims 1-9 in the manufacture of a medicament for antiviral use, said virus being human coronavirus HCoV-229E.
12. Use of the open throat sword spray of any one of claims 1-9 in the manufacture of a medicament for treating acute pharyngitis.
13. The use according to claim 12, wherein the acute pharyngitis is caused by the human coronavirus HCoV-229E.
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| CN1686185A (en) * | 2005-03-22 | 2005-10-26 | 贵州三力制药有限责任公司 | Traditional Chinese medicina preparation for treating oral cavity, throat disease and its preparation method |
| CN107998177A (en) * | 2017-12-26 | 2018-05-08 | 贵州三力制药股份有限公司 | Children open larynx sword spray and its prepare and the quality standard method of inspection |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1686185A (en) * | 2005-03-22 | 2005-10-26 | 贵州三力制药有限责任公司 | Traditional Chinese medicina preparation for treating oral cavity, throat disease and its preparation method |
| CN107998177A (en) * | 2017-12-26 | 2018-05-08 | 贵州三力制药股份有限公司 | Children open larynx sword spray and its prepare and the quality standard method of inspection |
Non-Patent Citations (1)
| Title |
|---|
| 中药抗冠状病毒活性和机理方法研究进展;李宁;钱秀玉;聂黎行;姚令文;戴忠;马双成;;药物分析杂志(第09期);1527-1535页 * |
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