CN111643606B

CN111643606B - Gel plaster for treating insomnia and preparation method thereof

Info

Publication number: CN111643606B
Application number: CN202010446545.0A
Authority: CN
Inventors: 焦玥; 杜茂波; 刘兵
Original assignee: INSTITUTE OF ACUPUNCTURE AND MOXIBUSTION CHINA ACADEMY OF CHINESE MEDICAL SCIENCES
Current assignee: INSTITUTE OF ACUPUNCTURE AND MOXIBUSTION CHINA ACADEMY OF CHINESE MEDICAL SCIENCES
Priority date: 2020-05-25
Filing date: 2020-05-25
Publication date: 2021-12-03
Anticipated expiration: 2040-05-25
Also published as: CN111643606A

Abstract

The invention belongs to the technical field of traditional Chinese medicine, and discloses a gel patch for treating insomnia and a preparation method thereof. The gel patch for treating insomnia includes Yintang gel patch and Yongquan gel patch; The Shuyintang gel paste is prepared from raw Pinellia, glutinous rice, raw keel, raw oyster, raw iron, white peony and raw jujube; Prepared from peppers. The gel patch for treating insomnia provided by the present invention is an external patch composed of hydrophilic polymer materials. Compared with oral dosage forms, it has no liver first-pass effect, no harm to the spleen and stomach, and no liver and kidney toxicity. Side effects, not affected by gastrointestinal degradation, high bioavailability; compared with injection, easy to use, non-invasive, no pain; compared with ointment, the dosage is accurate, and the absorption area is fixed; compared with rubber ointment, no The sensitization effect that may be caused by tackifiers such as rosin is less irritating to the skin.

Description

Gel plaster for treating insomnia and preparation method thereof

Technical Field

The invention belongs to the technical field of traditional Chinese medicines, and particularly relates to a gel plaster for treating insomnia and a preparation method thereof.

Background

Insomnia disorder is a common clinical condition. According to statistics, about 30-35% of people worldwide have the symptoms of sleep difficulty, and more than about 10% of people have chronic insomnia. Recent statistics in China show that the incidence rate of insomnia disorders is up to more than 40%, and the insomnia disorders tend to be younger. Besides causing dysfunction of multiple organs and reduction of immune function, the medicine is also a high-risk factor of mental disorder. The long-term insomnia is harmful to the physical and mental health of human bodies, and the life quality is seriously influenced.

The insomnia intervention mainly takes western medicine treatment as main treatment. The western medicines are mainly divided into: benzodiazepine receptor agonists, melatonin receptor agonists, orexin receptor antagonists, antidepressants with a hypnotic effect, and the like. Although the variety of drugs available for insomnia is abundant at present, drug therapy is mainly suitable for patients with acute insomnia, and for patients with chronic insomnia, drug therapy should be used as an adjuvant therapy for cognitive behavioral therapy. The drug evidence for insomnia management is weak in efficacy, and almost all studies are low-quality evidence, for example, due to the fact that a drug enterprise sponsors, the sample size is too small, the follow-up time is too short, the clinical significance is limited, and the like, finding a safer, more effective and convenient-to-use supplementary replacement therapy is an urgent need for the clinical work reality of insomnia.

The traditional Chinese medicine for insomnia considers that the basic pathogenesis of the insomnia lies in 'loss of nutrient and defensive system and disharmony between yin and yang', and relates to three levels of essence, qi and spirit of a human body, namely, the insomnia is closely related to viscera and psychology. The three levels are interrelated and affect each other, and one of them is disordered, which can cause insomnia. Such as: dysfunction of the zang-fu organs; ying-wei-defensive disturbance, dysfunction of qi and blood circulation; or mental dysfunction.

The traditional Chinese medicine has long history and various methods for treating insomnia. The acupoint pasting therapy is a unique method for treating internal diseases externally in traditional Chinese medicine, is also an organic combination of the acupoints and traditional Chinese medicines, is a compound therapy integrating channels, collaterals, acupoints and medicines, and has the advantages of quick curative effect, medicine source saving, less toxic and side effects and the like. The acupoint application method for treating insomnia can stimulate related acupoints, stimulate qi of channels and collaterals, regulate qi and blood circulation of channels and collaterals through the conduction and regulation of channels and collaterals, play a role similar to acupuncture and moxibustion, promote yang to enter yin at night, and circulate yin to exhaust yang at full time in daytime, and communicate yin and yang and coordinate ying and weiqi. Can also play the role of medicine: can directly act on body surface acupuncture points to expand or contract local blood vessels, accelerate or inhibit blood circulation, promote qi circulation and blood circulation, or clear heat and cool blood; also can make the medicine pass through skin and hair striae from exterior to interior and transmit to viscera along meridians, or calm and tranquilize the mind, or nourish yin and clear heat, or soothe liver and relieve depression, balance yin and yang, improve qi and blood circulation, coordinate viscera functions, correct preponderance and decline of yin and yang of viscera, and make the five viscera safe and naturally tranquilize; and the multiple superposition effect is exerted by the amplification effect of the acupuncture points on the medicine functions. The therapy does not take medicine through stomach and intestine, has no harm to spleen and stomach, and has no toxic and side effect of liver and kidney; it is also non-invasive, especially suitable for insomnia patients who are afraid of acupuncture or old and young weakness, and patients who are difficult to apply tonics and purgation or inconvenient to take medicine.

In summary, the problems of the prior art are as follows: in the prior art, no gel plaster for treating insomnia by taking Yintang and Yongquan as acupoint combinations and matching with different traditional Chinese medicine prescriptions is reported.

The industry standard 'evidence-based acupuncture clinical practice guideline: insomnia' issued by the Chinese acupuncture society brings the method for treating insomnia by acupoint application into the guideline. The prior literature reports also indicate that the acupoint application therapy can be used alone or together for intervening insomnia or treating insomnia caused by or accompanied by other diseases. The traditional Chinese medicines for treating insomnia are usually selected for application to acupuncture points, and the medicines mainly enter heart, lung, liver and kidney meridians while focusing on the functions of nourishing the heart, soothing the nerves and relieving depression of the medicines, so that acupuncture points are usually selected from Yongquan and Shenque. The Yongquan point is located on the sole of the foot, is the key point for the ascending and descending of qi activity of a human body, can excite kidney water and make the kidney water coordinate heart fire to achieve the effect of communicating yin and yang, and can coordinate water and fire, clear heart, purge fire, calm heart, calm nerves and help sleep. In addition, Yongquan is the well point of kidney meridian, where yin and yang meridians meet each other, and is the root node, recorded in Ling Shu: the well of the zang-organs can also regulate and treat visceral mental diseases, and improve insomnia caused by dysfunction of the zang-organs in spirit.

Clinical observation shows that the Yintang acupoint is red and has heat sensation or has depression or even wrinkles when the insomnia patients are observed, which indicates that the patients often have vigorous heart fire and serious thinking and have muscle shrinkage without relaxation. The acupuncture applied on Yintang acupoint has good immediate tranquilizing effect. The Yintang acupoint is located on the governor vessel circulation route, the governor vessel enters the brain, and the governor vessel enters the heart, so that the Yintang acupoint can calm the brain spirit and nourish the heart spirit, the Yintang acupoint is located at the 'que position' of the human body, corresponds to the heart, and the deep part of the Yintang acupoint is the pine fruit body of the human brain, can regulate the secretion and synthesis of the human melatonin, and is favorable for falling asleep.

In many traditional prescriptions for insomnia, the ban Xia jowar soup from Huangdi's Nei Jing is praised as the first prescription for insomnia, because ban Xia can pass yin and yang, jowar can pass spleen and stomach, yin and yang pass through, and spleen and stomach are harmonized, people can sleep well. Ban Xia is warm in nature and sweet in flavor and can activate yang, check adverse rise of qi and purge defensive qi. Modern pharmacological studies also prove that rhizoma pinellinae praeparata has good nerve center calming effect; husked sorghum is sweet and cool in nature and can nourish ying and nourish yin to promote diuresis of large intestine, recorded in compendium of materia Medica, "husked sorghum treats exuberance of yang and yin deficiency and insomnia at night, and is used in ban Xia Tang (i.e. husked sorghum soup with pinellia) to tonify yin and promote diuresis of large intestine, while large intestine is good at yang deficiency . It is horizontal to the right when it has the actions of purging and tonifying, tonifying deficiency and discharging excess, communicating yin and yang, regulating ying and wei, and removing the pathogenic factors by dredging its channel. All kinds of insomnia can be treated by the formula as the basic formula. In addition, the above-mentioned materials can be modified as appropriate according to the specific conditions of the patients.

The difficulty of solving the technical problems is as follows: the invention firstly determines the selected acupuncture points of the insomnia treatment gel plaster according to the acupuncture theory: yintang and Yongquan; and simultaneously stimulate the Yintang and Yongquan acupoints to generate a synergistic effect so as to communicate the heart spirit, enable the heart fire to dive and the kidney water to rise to form qi circulation, and greatly enhance the treatment effect; the gel plaster preparation is adopted to stimulate acupuncture points, can be continuously administered, has no irritation to skin, and has good patient compliance. The difficulties of the present invention are mainly two: (1) the selection of the acupuncture points for treating insomnia and the prescription of the traditional Chinese medicine are as follows: according to the theory of traditional Chinese medicine and clinical observation; (2) gel plaster preparation: the active ingredients in the Yintang plaster medicine mainly have hydrophilicity and are polarized, and the active ingredients in the Yongquan plaster medicine mainly have lipid solubility and are nonpolar; the preparation of different coagulation plasters of two pharmaceutical properties is a challenge for the present invention.

The significance of solving the technical problems is as follows: the invention realizes the perfect combination of the traditional Chinese medicine clinic and the modern preparation technology, and the modern preparation technology is used for serving the clinic, so that the clinical effect is realized to the maximum extent, and the invention has important clinical value; the invention realizes a needle-medicine combination mode, changes the acupuncture point stimulation mode from needle to gel plaster, changes short acupuncture stimulation to continuous medicine stimulation, and is a new acupuncture stimulation mode; the invention realizes the simultaneous stimulation of two acupuncture points, one is at the upper part (Yintang acupuncture point) and the other is at the lower part (Yongquan acupuncture point), and can play the synergistic effect of the two acupuncture points and enhance the clinical curative effect.

Disclosure of Invention

Aiming at the problems in the prior art, the invention provides a gel plaster for treating insomnia and a preparation method thereof.

The invention is realized in such a way that the gel plaster for treating insomnia comprises Yintang gel plaster and Yongquan gel plaster. The dosage of the Yintang gel plaster and the Yongquan gel plaster is 1: 2.

Further, the Yintang gel plaster is prepared from raw pinellia ternate, jowar (sorghum rice), raw keel, raw oyster, pig iron, white peony root and raw jujube kernel in a ratio of 2:4:2:2:1:2: 1. The pinellia ternate is warm and dry in nature, the sorghum is cool and moist, and the pinellia ternate and the sorghum are mutually matched to eliminate dampness and reduce phlegm, harmonize stomach and descend adverse qi; the raw keel, the raw oyster and the pig iron complex have the effects of stabilizing the diving and absorbing yang qi; the white peony root and the jujube kernel nourish liver blood; the medicines are combined to play the effects of nourishing blood and tranquillizing, harmonizing stomach and lowering adverse qi, and suppressing yang and entering yin.

Furthermore, the Yongquan gel plaster is prepared from raw fructus evodiae, raw folium artemisiae argyi and raw pericarpium zanthoxyli at a ratio of 1:1: 1. The raw fructus evodiae, the raw folium artemisiae argyi and the raw pericarpium zanthoxyli are warm in nature, enter kidney channels, can warm and dredge channels, act on Yongquan acupoints, and can stimulate kidney water, nourish yin and induce fire to return to original origin.

The invention also aims to provide a preparation method of the gel plaster for treating insomnia, which comprises a preparation method of a Yintang gel plaster and a preparation method of a Yongquan gel plaster.

Further, the preparation method of the Indonesia gel plaster comprises the following steps:

step one, extraction and refining: weighing 10 prescription medicinal materials, carrying out water extraction for 2 times, wherein the amount of water is 10 times that of the first time, the amount of water is 8 times that of the second time, and the time of the two times of extraction is 1 hour.

Step two, merging the two water extracts, and concentrating in water bath until the medicinal materials: precipitating with 2 times of 95% ethanol at 1:1, standing at 4 deg.C for 16 hr, and collecting supernatant to obtain fluid extract.

And step three, recovering ethanol from the supernatant obtained in the step two until no alcohol smell exists, and concentrating the supernatant in a water bath at 50 ℃ until the relative density of the supernatant is 1.18-1.20 for later use.

Step four, preparing the Yintang gel paste: and (4) adding the fluid extract prepared in the step two into the matrix of the gel plaster prepared in the step three, and fully and uniformly stirring.

And step five, coating the Yintang gel paste prepared in the step four, covering a polyethylene film, and cutting into circular paste with the diameter of 2cm, namely the Yintang gel paste.

Further, the preparation method of the Yongquan gel plaster comprises the following steps:

firstly, extraction and refining: weighing 10 prescription dose medicinal materials, extracting with 7 times of 80% ethanol for 2 times, each time for 1.5 hours. And combining the alcohol extract, recovering ethanol until no alcohol smell exists, and concentrating in a water bath at 50 ℃ until the relative density is 1.18-1.20 for later use.

Secondly, preparing Yongquan gel plaster: adding the prepared fluid extract into the matrix of the prepared gel plaster, stirring, coating, covering with polyethylene film, and cutting into circular plaster with diameter of 3cm to obtain YONGQUAN gel plaster.

In summary, the advantages and positive effects of the invention are: the gel plaster for treating insomnia provided by the invention is an external plaster consisting of hydrophilic high polymer materials, and the Yintang gel plaster and the Yongquan gel plaster are both gel plasters for treating acupuncture points, and can effectively treat insomnia disorders by combining the gel plasters. Compared with oral dosage forms, the preparation has no first pass action of liver, no damage to spleen and stomach, no toxic and side effects of liver and kidney, no influence of gastrointestinal degradation, and high bioavailability; compared with injection, the injection is convenient to use, has no wound and no pain; compared with ointment, the ointment has accurate administration dosage and fixed absorption area; compared with rubber paste, the emulsion has no sensitization caused by tackifier such as rosin, and has less irritation to skin.

Drawings

Fig. 1 is a flow chart of a method for preparing a yin tang gel plaster according to an embodiment of the present invention.

Fig. 2 is a flow chart of a preparation method of the yongquan gel plaster provided by the embodiment of the invention.

Fig. 3 is a graph illustrating the trend of the score decrease for each treatment time point of 2 sets of PSQI scores according to the present invention.

Fig. 4 is a graph of the decreasing trend of each treatment time point score for 2 groups of sleep quality scores provided by the embodiment of the present invention.

Fig. 5 is a graph of the decreasing trend of each treatment time point score for the 2 groups of sleep onset time scores provided by the embodiment of the present invention.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

Aiming at the problems in the prior art, the invention provides a gel plaster for treating insomnia and a preparation method thereof, and the invention is described in detail with reference to the accompanying drawings.

The gel plaster for treating insomnia provided by the embodiment of the invention comprises Yintang gel plaster and Yongquan gel plaster. The dosage of the Yintang gel plaster and the Yongquan gel plaster is 1: 2.

The Yintang gel plaster provided by the embodiment of the invention is prepared from raw pinellia ternate, sorghum rice, raw keel, raw oyster, pig iron, white paeony root and raw jujube kernel according to the mass ratio of 2:4:2:2:1:2: 1.

The Yongquan gel plaster provided by the embodiment of the invention is prepared from raw fructus evodiae, raw folium artemisiae argyi and raw pericarpium zanthoxyli according to the mass ratio of 1:1: 1.

The preparation method of the gel plaster for treating insomnia provided by the embodiment of the invention comprises a preparation method of a Yintang gel plaster and a preparation method of a Yongquan gel plaster.

As shown in fig. 1, the preparation method of the yin tang gel plaster provided by the embodiment of the invention comprises the following steps:

s101, extraction and purification: weighing 10 prescription medicinal materials, carrying out water extraction for 2 times, wherein the amount of water is 10 times that of the first time, the amount of water is 8 times that of the second time, and the time of the two times of extraction is 1 hour.

S102, combining the two water extracts, and concentrating in a water bath until the medicinal materials: precipitating with 2 times of 95% ethanol at 1:1, standing at 4 deg.C for 16 hr, and collecting supernatant to obtain fluid extract.

S103, recovering ethanol from the supernatant obtained in the step S102 until no alcohol smell exists, and concentrating the supernatant in a water bath at 50 ℃ until the relative density of the supernatant is 1.18-1.20 for later use.

S104, preparing the Indonesia gel paste: and (4) adding the fluid extract prepared in the step (S102) into the matrix of the gel plaster prepared in the step (S103), and fully and uniformly stirring.

And S105, coating the Yintang gel paste prepared in the S104, covering a polyethylene film, and cutting into circular paste with the diameter of 2cm, namely the Yintang gel paste.

As shown in fig. 2, the preparation method of the yongquan gel plaster provided by the embodiment of the invention comprises the following steps:

s201, extraction and purification: weighing 10 prescription dose medicinal materials, extracting with 7 times of 80% ethanol for 2 times, each time for 1.5 hours. And combining the alcohol extract, recovering ethanol until no alcohol smell exists, and concentrating in a water bath at 50 ℃ until the relative density is 1.18-1.20 for later use.

S202, preparing Yongquan gel plaster: adding the prepared fluid extract into the matrix of the prepared gel plaster, stirring, coating, covering with polyethylene film, and cutting into circular plaster with diameter of 2cm to obtain YONGQUAN gel plaster.

The invention is further described with reference to specific examples.

Example 1: yintang gel plaster

1. Indonesia gel plaster matrix formula

1-8 g of hydroxypropyl methyl cellulose, 1-18 g of bone gelatin B, 1-20 g of refined peach gum, 1-15 g of sodium carboxymethylcellulose, 9402-20 g of carbomer, NP-7002-20 g of sodium polyacrylate, 20-150 g of glycerol, 0.1-0.4 g of iron powder, 0.01-0.1 g of tartaric acid, 30-270 g of water and 5-15 g of propylene glycol.

2. Preparation process of Yintang gel plaster

2.1 extraction of the drug

Weighing 200g of raw pinellia ternate, sorghum rice, raw dragon bones, raw oysters, pig iron, white paeony roots and raw jujube kernels (2:4:2:2:1:2:1), and carrying out water extraction for 2 times, wherein the water extraction time is 10 times that of the first time and 8 times that of the second time, and the extraction time is 1 hour; combining the two water extracts, and concentrating in water bath until the medicinal materials: precipitating with 2 times (weight ratio) of 95% ethanol when the liquid medicine is 1:1, standing at 4 ℃ for 16 hours, pouring out supernatant, recovering ethanol from the supernatant until no alcohol smell exists, concentrating in a water bath at 50 ℃ until the relative density is 1.18-1.20, and freeze-drying for later use.

2.2 preparation of the substrate

(1) 9403g of carbomer, 3g of bone gelatin B1g, 3g of refined peach gum, 3g of hydroxypropyl methylcellulose and 3g of sodium carboxymethylcellulose, 50g of glycerol and 100g of water are used, and the materials are stirred at room temperature, swelled and uniformly mixed;

(2) sodium polyacrylate NP7003g was dispersed with 6g of propylene glycol;

(3) 0.1g of iron powder, 0.05g of tartaric acid and 5g of water are added and mixed uniformly;

(4) adding the (2) into the (1), stirring for 10-30 minutes, and uniformly mixing;

(5) and (3) adding the mixture into the mixture (4) for a plurality of times in a small amount, stirring for 10-60 minutes, and uniformly mixing to obtain a matrix part.

3. Yintang gel plaster

(1) Dispersing the Indonesia freeze-dried powder with 2 times of water

(2) And (2) adding the (1) into the prepared substrate for a plurality of times in a small amount, stirring for 10-60 minutes, uniformly mixing, coating, drying, and cutting into a patch with the diameter of 2cm to obtain the adhesive.

Example 2: yongquan gel plaster

1. Yongquan gel plaster matrix formula

1-8 g of hydroxypropyl methyl cellulose, 2-8 g of stearic acid, 1-18 g of bone gelatin B, 1-20 g of refined peach gum, 1-15 g of sodium carboxymethylcellulose, 9402-20 g of carbomer, 802-5 g of tween, 2-20 g of sodium polyacrylate NP-8002, 50-200 g of glycerol, 0.1-0.4 g of potassium aluminum sulfate, 0.01-0.1 g of citric acid, 30-270 g of water and 5-15 g of polyethylene glycol 4005-15 g of polyethylene glycol

2. Preparation process of Yongquan gel plaster

2.1 extraction of the drug

Weighing raw fructus evodiae, raw folium artemisiae argyi and raw pericarpium zanthoxyli with the ratio of 1:1:1200g, and extracting for 2 times with 7 times of 80% ethanol, wherein each time lasts for 1.5 hours. And combining the alcohol extract, recovering ethanol until no alcohol smell exists, and concentrating in a water bath at 50 ℃ until the relative density is 1.18-1.20 for later use.

2.2 preparation of the substrate

(1) 9402.5g of carbomer, B1.5g of bone gelatin, 3.5g of refined peach gum, 3.5g of hydroxypropyl methylcellulose, 3.5g of sodium carboxymethylcellulose and 3g of stearic acid, wherein 100g of glycerol and 150g of water are used for stirring at room temperature, swelling and uniformly mixing;

(2) dispersing sodium polyacrylate NP7004g with 2g Tween 80 and 8g polyglycol 400;

(3) 0.12g of aluminum potassium sulfate, 0.05g of citric acid and 6g of water are added and mixed uniformly;

(5) adding the (3) into the (4) for a plurality of times in small amount, stirring for 10-60 minutes, and uniformly mixing to obtain a matrix part

3. Yongquan gel plaster

And adding the prepared Yongquan fluid extract into the prepared matrix for multiple times in a small amount, stirring for 10-60 minutes, uniformly mixing, coating, drying, and cutting into a patch with the diameter of 3cm to obtain the Yongquan gel plaster.

Example 3: transdermal permeability study of Yintang plaster

1. Materials and instruments

Waters1515-717 autosampler, 2487 Detector, Empower2 data processing System. TK-12B transdermal diffusion tester (Shanghai Kai science and technology trade, Inc.); Z92-BD multifunction stirrer (Tianjin Lihua Instrument factory); balance AEL-200 (Shimazu Japan)

The paeoniflorin reference (110736-201943) is purchased from China pharmaceutical biological product institute; acetonitrile is chromatographically pure, the rest are analytically pure.

The cataplasma matrix is edible or medicinal.

Animal skin: mouse skin was provided by the laboratory animal center of the Chinese institute for drug assay.

2. Experimental methods and results

2.1 chromatographic conditions

A chromatographic column: kromasil C185 μ (4.6 mm. times.250 mm)

Mobile phase: acetonitrile-0.1% phosphoric acid solution (14: 86);

detection wavelength: 230 nm; column temperature: 25 ℃; flow rate: 1 ml/min.

2.2 preparation of Indonesia cream

Accurately weighing the extract and the matrix of the gel plaster according to the prescription amount, uniformly mixing, preparing into paste, uniformly coating the paste on a lining cloth, and covering a polyethylene film to obtain a cataplasm sample. The paeoniflorin content in YULIAN cataplasma is 3.59mg g^-1。

2.3 preparation of in vitro rat skin

After a healthy mouse with a proper age is killed, the hair of the mouse is carefully removed by using a depilatory, the mouse is washed clean, the skin is cut off, the fat is carefully stripped, the whole skin is selected, and the mouse is washed clean by using normal saline for later use.

2.4 Experimental methods and devices

The experiment used a vertical Franz diffusion cell with PEG 400-95% ethanol-water (1:3:6) as the receiving solution. The experimental process comprises the following steps: adhering the seal to the treated mouse skin, discharging air bubbles, fixing between the diffusion chamber and the receiving chamber of the diffusion device, allowing the back lining layer of the seal paste to face the diffusion chamber, filling the receiving chamber with receiving liquid, and discharging air bubbles. The magnetic stirrer rotation speed was set to: 400rpm, water bath temperature of 32 ℃, diffusion cell volume of 18mL, effective diffusion area of 2.834cm². Sampling for 1, 2, 4, 8, 14 and 24 hours respectively, pouring out all liquid in the receiving chamber during sampling, and simultaneously adding fresh receiving liquid with the same volume; and (4) after the poured liquid passes through a microporous filter membrane, measuring the content of paeoniflorin in the liquid, and calculating the permeability.

2.5 transdermal experiments and results

In vitro transdermal experiment of corni cataplasma was performed according to the above method, and the average transmittance of 6 samples of paeoniflorin was 11.2%.

The average cumulative transmittance of paeoniflorin in the Indonesia paste is 11.2%.

Example 4: transdermal permeability research of Yongquan plaster

1. Materials and instruments

Waters1515-Empower2 data processing system; chromatographic column Kromasil-C₁₈(4.6mm × 250mm, 5 μm), detection wavelength: 290 nm; column temperature: 30 ℃; flow rate: 1mL/min^-1(ii) a Mobile phase methanol-acetonitrile-15 mmol/L sodium dodecyl sulfate solution (20:36:44)

TK-12B transdermal diffusion tester (Shanghai Kai science and technology trade, Inc.); Z92-BD multifunction stirrer (Tianjin Lihua Instrument factory); balance AEL-200 (Shimazu Japan)

Evodiamine (China food and drug testing institute, batch No. 110802-200504), rutaecarpine (China food and drug testing institute, batch No. 0801-9702) acetonitrile are chromatographically pure, and the rest are analytically pure. The cataplasma matrix is edible or medicinal.

Animal skin: mouse skins were provided by the institute for food and drug testing laboratory animal center.

2. Experimental methods and results

2.1 chromatographic conditions

Chromatograph: waters15152487 detector, Empower2 data processing system column: rainbow 5. mu. Kromisal-C₁₈(250X 4.6mm) detection wavelength: 225nm, mobile phase: methanol-acetonitrile-15 mmol/L aqueous sodium dodecyl sulfate solution (20:36:44), column temperature: 25 ℃, flow rate: 1ml/min

2.2 preparation of Yuliangba ointment

Accurately weighing the extract and the cataplasm matrix according to the prescription amount, uniformly mixing, preparing into paste, uniformly coating on a lining cloth, and covering with a polyethylene film to obtain the cataplasm sample. The content of evodiamine and rutaecarpine in the cornus and coptis cataplasm is 1.61mg and 0.67mg respectively.

2.3 preparation of in vitro rat skin

2.4 Experimental methods and devices

The experiment used a vertical Franz diffusion cell with PEG 400-95% ethanol-water (1:3:6) as the receiving solution. The experimental process comprises the following steps: closely adhering and treating cornus officinalis and copaiba ointmentThe air bubbles were removed from the skin of the mouse and then fixed between the diffusion chamber and the receiving chamber of the diffusion device with the backing layer of the cataplasm facing the diffusion chamber and the receiving chamber filled with the receiving liquid to remove the air bubbles. The magnetic stirrer rotation speed was set to: 400rpm, water bath temperature of 32 ℃, diffusion cell volume of 18mL, effective diffusion area of 2.834cm². Sampling at 0.5, 1, 2, 4, 8, 14 and 24 hours respectively, pouring out all liquid in the receiving chamber during sampling, and simultaneously supplementing fresh receiving liquid with the same volume; and (4) after the poured liquid passes through a microporous filter membrane, measuring the evodiamine and the rutaecarpine, and calculating the permeability.

2.5 transdermal experiments and results

According to the method, an in-vitro transdermal experiment of the corni and coptis cataplasm is carried out, and the average penetration rate of 2 index components of 6 samples is as follows: 10.9 percent of evodiamine and 21.3 percent of rutaecarpine.

The external transdermal penetration of the Yongquan plaster is a precondition for evaluating whether the Yongquan plaster is effective, and the fact that the medicine is released from a matrix and can penetrate through the skin to meet the requirement of the transdermal penetration is very important. The cumulative transmittance of the evodiamine and the rutaecarpine in the Yongquan patch is 10.9 percent of the rutaecarpine and 21.3 percent of the rutaecarpine.

Example 5: clinical effectiveness and safety research of gel plaster for treating insomnia

The clinical effectiveness and safety of the gel plaster for treating insomnia by externally treating the insomnia by acupuncture points are examined. By adopting a random control test design, 63 patients are actually enrolled in acupuncture hospitals of Chinese academy of sciences and community health service stations of the rich age in 2 research centers during the period of 9-2019 and 12 months of 2019, and the patients are randomly divided into a gel plaster treatment group and a placebo plaster control group, wherein the treatment group comprises 32 patients and a control group comprises 31 patients. The treatment was actually completed in 62 cases, and the treatment group was dropped in 1 case. For a total of 4 weeks, 5 days per week, 2 days at rest. Baseline information is shown in table 1, with no statistical difference between groups (see table 1) (P > 0.05).

1. Baseline data

TABLE 12 comparison of baseline data

1. Baseline information is expressed in terms of instances unless otherwise noted

2. The main therapeutic index

2.1 Pittsburgh sleep index Scale (PSQI) Total score

After week 4 treatment, the PSQI score was significantly reduced in all 2 groups compared to baseline (P <0.01), and the improvement in PSQI score was significantly different in the gel patch treated group compared to the placebo patch group at the end of week 4 (after treatment) (P <0.05) (table 2, fig. 3). Compared with the other time points, the other time points have no significant difference (P > 0.05).

Table 22 sets of PSQI scores for each treatment time point score

Fig. 32 sets of PSQI scores each treatment time point score declined.

2.2PSQI7 factor score

(1) Scoring the sleep quality: the gel patch treatment groups showed significant differences in improvement in sleep quality scores (P <0.05) over the end of

treatment weeks

2, 3, 4, 6 compared to the placebo patch group (table 3, figure 4). There was no significant difference between the two at the end of treatment week 1 (P > 0.05).

TABLE 32 sleep quality scores for each treatment time point score

Figure 42 sets of sleep quality scores with decreasing trend for each treatment time point score.

(2) Time to sleep score

The gel-patch treated groups showed significant differences in improvement in time to sleep scores (P <0.05) over the 3 rd and 4 th week of treatment compared to the placebo-patch group (table 4, fig. 5). There was no significant difference between the two at the end of treatment week 1 (P > 0.05).

FIG. 52 group sleep time scores decrease trend of score at each treatment time point

(3) And (3) scoring the sleep time: the gel patch treatment group showed no significant difference in improvement in sleep time scores over the 1 st, 2 nd, 3 rd, 4 th, 6 th week of treatment compared to the placebo patch group (P > 0.05).

(4) Scoring the sleep efficiency: the gel patch treatment group showed no significant difference in improvement in sleep efficiency score compared to the placebo patch group at the 1 st, 2 nd, 3 rd, 4 th, and 6 th week of treatment (P > 0.05).

(5) Sleep disorder scoring: the gel patch treatment group showed no significant difference in the improvement in sleep disorder scores at the 1 st, 2 nd, 3 rd, 4 th, and 6 th weeks of treatment compared to the placebo patch group (P > 0.05).

(6) Scoring of hypnotic drugs: the gel patch treatment group showed no significant difference in improvement in hypnotic score compared to the placebo patch group at the 1 st, 2 nd, 3 rd, 4 th, and 6 th weeks of treatment (P > 0.05).

(7) Daytime dysfunction: the gel patch treatment group showed no significant difference in the improvement in the daytime dysfunction scores over the 1 st, 2 nd, 3 rd, 4 th, 6 th week of treatment compared to the placebo patch group (P > 0.05).

3. Secondary index of therapeutic effect

(1) Epworth Somnolence Scale (ESS) score: the gel patch treatment groups showed no significant difference in ESS score improvement compared to placebo patch groups at the end of

treatment weeks

1, 2, 3, 4, 6 (P > 0.05).

(2) Flinders Fatigue Scale (FFS) score: there was no significant difference in the improvement in FFS scores in the gel patch treated groups compared to the placebo patch group at the end of

treatment weeks

1, 2, 3, 4, 6 (P > 0.05).

(3) Scoring of traditional Chinese medicine symptoms: compared with the placebo patch group, the gel patch treatment group has no significant difference in the improvement of the Chinese medical symptom score on the 1 st, 2 nd, 3 rd, 4 th and 6 th weeks of treatment (P > 0.05).

(4) SF-36 score: the gel plaster treatment groups have no significant difference (P >0.05) in the treatment of 1 st, 2 nd, 3 th, 4 th and 6 th weekends compared with the placebo plaster group in the aspect of improving the physiological function, body pain, general health condition, energy, social function, affective disorder and mental health 8.

(5) Traditional Chinese medicine syndrome differentiation and typing:

the traditional Chinese medicine is characterized by comprising the following components in percentage by weight: treatment groups: 6 cases (19%) of liver depression transforming into fire, 2 cases (7%) of phlegm-heat disturbing internally, 14 cases (45%) of deficiency of both heart and spleen, and 9 cases (29%) of yin deficiency with effulgent fire. Control group: 7 cases (23%) of liver depression transforming into fire, 8 cases (26%) of phlegm-heat internal disturbance, 12 cases (39%) of heart-spleen deficiency and 4 cases (13%) of yin deficiency with effulgent fire. The number of people in two groups with the syndrome of heart-spleen deficiency is the most.

The gel plaster analyzes the curative effect of each syndrome type: after treatment, the treatment group of the gel plaster can obviously improve the total PSQI score for the three types of symptoms of liver depression transforming into fire, deficiency of both heart and spleen and yin deficiency and internal heat, and the improvement on phlegm-heat and internal heat is not obvious but can be caused by too few cases.

4. Evaluation of safety index

4.1 physiological and biochemical indexes

The physiological indexes (blood pressure, electrocardio, respiration and pulse) and safety inspection (blood routine, blood biochemistry and urine analysis) of patients in the treatment group and the control group have no significant difference before and after treatment.

4.2 incidence of adverse events

1 patient quits the study because of skin allergy of Yintang acupoint, and 7 patients complain that slight allergy (redness) appears on the skin of the Yintang acupoint, and the skin of the patients is gradually adapted without special treatment.

The comprehensive results are as follows: (1) after 4 weeks of treatment, the gel plaster treatment group and the placebo control group both significantly improved the sleep quality of patients with insomnia (P <0.01), and the treatment group was more significantly improved than the control group (P < 0.05). (2) The treatment group had better improvement in subjective evaluation of sleep quality patients than the control group from week 2 to week 6 of treatment with significance of difference (P <0.05) (3) the treatment group had better improvement in time to sleep than the control group from week 3 to week 4 of treatment with significance of difference (P < 0.05). (4) The gel plaster treatment group can obviously improve the sleep quality (P <0.05) of patients with three symptoms of liver depression transforming into fire, deficiency of both heart and spleen and yin deficiency and internal heat, wherein the improvement on the symptoms of deficiency of both heart and spleen is the most obvious (P < 0.002).

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.

Claims

1. A gel plaster for treating insomnia is characterized in that the gel plaster for treating insomnia consists of a Yintang gel plaster and a Yongquan gel plaster; the dosage of the Yintang gel plaster and the Yongquan gel plaster is 1: 2;

the YINTANG gel plaster is prepared from rhizoma Pinelliae, jowar, Os Draconis, Concha Ostreae, pig iron, radix Paeoniae alba and semen Ziziphi Spinosae;

raw pinellia ternate according to the mass ratio: husked sorghum: raw keel: raw oyster shells: and (3) pig iron complexing: white peony root: raw jujube kernel is 2:4:2:2:1:2: 1;

the YONGQUAN gel patch is prepared from fructus evodiae, folium Artemisiae Argyi, and fructus Zanthoxyli;

raw fructus evodiae according to the mass ratio: raw folium artemisiae argyi: raw zanthoxylum piperitum 1:1: 1.

2. The method for preparing the gel patch for treating insomnia according to claim 1, wherein the method for preparing the gel patch for treating insomnia comprises a method for preparing a Yintang gel patch and a method for preparing a Yongquan gel patch.

3. The method for preparing gel patch for treating insomnia as set forth in claim 2, wherein the method for preparing said auditorium gel patch comprises the steps of:

(1) extracting the medicine:

weighing 200g of raw pinellia ternate, sorghum, raw dragon bones, raw oysters, pig iron collaterals, white paeony roots and raw jujube kernels, wherein the raw pinellia ternate is prepared by the following raw materials in percentage by mass: husked sorghum: raw keel: raw oyster shells: and (3) pig iron complexing: white peony root: 2, carrying out water extraction for 2 times, namely 2:4:2:2:1:2:1, wherein the time for extracting the raw jujube kernel for the first time is 10 times that for the second time is 8 times that for the second time, and the time for extracting the raw jujube kernel for the second time is 1 hour; combining the two water extracts, and concentrating in water bath until the medicinal materials: when the liquid medicine is 1:1, performing alcohol precipitation by using 95% ethanol in an amount which is 2 times the weight of the liquid medicine, standing at 4 ℃ for 16 hours, pouring out supernatant, recovering ethanol from the supernatant until no alcohol smell exists, concentrating in a water bath at 50 ℃ until the relative density is 1.18-1.20, and performing freeze drying for later use;

(2) preparing a matrix:

1) 9403g of carbomer, 3g of bone gelatin B1g, 3g of refined peach gum, 3g of hydroxypropyl methylcellulose and 3g of sodium carboxymethylcellulose, 50g of glycerol and 100g of water are used, and the materials are stirred at room temperature, swelled and uniformly mixed;

2) sodium polyacrylate NP7003g was dispersed with 6g of propylene glycol;

3) 0.1g of iron powder, 0.05g of tartaric acid and 5g of water are added and mixed uniformly;

4) adding the mixture obtained in the step 2) into the mixture obtained in the step 1), stirring for 10-30 minutes, and uniformly mixing;

5) adding the 3) into the 4), stirring for 10-60 minutes, and uniformly mixing to obtain a matrix part;

(3) yintang gel plaster

1) Dispersing the Indonesia freeze-dried powder with 2 times of water

2) Adding the powder 1) into the prepared substrate, stirring for 10-60 minutes, uniformly mixing, coating, drying, and cutting into a patch with the diameter of 2cm to obtain the patch.

4. The method for preparing gel patch for treating insomnia as set forth in claim 2, wherein the method for preparing said Yongquan gel patch comprises the steps of: (1) extracting the medicine:

weighing 200g of raw fructus evodiae, raw folium artemisiae argyi and raw pericarpium zanthoxyli, wherein the raw fructus evodiae is weighed according to the mass ratio: raw folium artemisiae argyi: extracting raw pericarpium Zanthoxyli (1: 1: 1) with 7 times of 80% ethanol for 2 times, each for 1.5 hr; mixing the alcohol extract, recovering ethanol until no alcohol smell exists, and concentrating in a water bath at 50 ℃ until the relative density is 1.18-1.20 for later use;

(2) preparing a matrix:

1) 9402.5g of carbomer, B1.5g of bone gelatin, 3.5g of refined peach gum, 3.5g of hydroxypropyl methylcellulose, 3.5g of sodium carboxymethylcellulose and 3g of stearic acid, wherein 100g of glycerol and 150g of water are used for stirring at room temperature, swelling and uniformly mixing;

2) dispersing sodium polyacrylate NP7004g with 2g Tween 80 and 8g polyglycol 400;

3) 0.12g of aluminum potassium sulfate, 0.05g of citric acid and 6g of water are added and mixed uniformly;

(3) yongquan gel plaster:

adding the prepared Yongquan fluid extract into the prepared matrix, stirring for 10-60 minutes, uniformly mixing, coating, drying, and cutting into pieces with the diameter of 3cm to obtain Yongquan gel plaster.