CN114470145A - Warm moxibustion type gel plaster for relieving pain of bone diseases and preparation method thereof - Google Patents
Warm moxibustion type gel plaster for relieving pain of bone diseases and preparation method thereof Download PDFInfo
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- CN114470145A CN114470145A CN202210084932.3A CN202210084932A CN114470145A CN 114470145 A CN114470145 A CN 114470145A CN 202210084932 A CN202210084932 A CN 202210084932A CN 114470145 A CN114470145 A CN 114470145A
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Abstract
The invention relates to the technical field of traditional Chinese medicines, and discloses a warm moxibustion type gel plaster for relieving pain caused by bone diseases, a preparation method and a quality consistency evaluation method, wherein the warm moxibustion type gel plaster for relieving pain caused by bone diseases is externally used and comprises a gel plaster and a self-heating bag; the gel plaster is prepared from an external traditional Chinese medicine composition, a hydrophilic polymer matrix and a far infrared material; the self-heating bag is prepared from a self-heating material. The warm moxibustion type gel plaster provided by the invention takes the traditional Chinese medicines with the effects of warming channels, dispelling cold, promoting blood circulation, relieving pain, dispelling wind and removing dampness as raw materials, is convenient to apply, high in transdermal absorption rate, capable of promoting medicine permeation to generate a warm moxibustion curative effect, convenient to use, free of damage to skin, not prone to getting inflamed and low in cost. The invention establishes an integral quality control mode and a method of the gel plaster, controls the amplitude range and the quality consistency of the total effective substances of the gel plaster by using macro-quantitative similarity, and has accurate administration dosage.
Description
Technical Field
The invention relates to the technical field of traditional Chinese medicines, in particular to a warm moxibustion type gel plaster for relieving pain of bone diseases, a preparation method and a quality consistency evaluation method.
Background
Bone diseases such as cervical spondylosis, lumbar disc herniation, scapulohumeral periarthritis, arthritis and the like are frequently encountered and common diseases, and particularly the incidence rate is higher in cold areas in the north. In recent years, with the improvement of living standard and the acceleration of work rhythm, the disease has a tendency to spread to young people, and more people often have symptoms such as waist pain, numbness and pain of legs and feet, stiff neck, dizziness, hand numbness and the like. At present, the clinical treatment methods comprise oral or external drug treatment, operation treatment and physical therapy (including traction, massage, acupuncture and moxibustion and the like). Because intervertebral discs, bone joints and the like are vascular tissues, the oral medicament is not easy to reach focuses, and adverse reactions such as gastrointestinal tract and the like are easy to cause after long-term administration; the operation treatment cost is high, the risk is high, and the operation treatment is not suitable for mild and moderate patients; the treatments such as physical therapy for relieving pain and medicament fumigation and washing, which need to be carried out in hospitals or clinics, have long consumption time and high cost, are not noticed slightly and are easy to relapse, some hospitals and clinics adopt an ion introduction method to promote medicament absorption when medicament fumigation and washing is carried out, although the curative effect is good, the medicament has large stimulation to the skin, pores begin to scab or partially ulcerate after several days of treatment, and the compliance of patients is seriously influenced. In contrast, many patients often purchase various patches on their own for pain relief. The common plasters on the market at present comprise traditional black plasters, traditional Chinese medicine plasters prepared by modern preparation technology, various far infrared plasters, warm plasters, hot compress plasters, hot moxibustion plasters and the like. The products are registered according to medicines, medical equipment products and cosmetics, and also have marks of national standard characters, mechanical character numbers and makeup character numbers which cannot be seen. The black plaster is easy to damage and injure effective components when being refined at high temperature, needs to be heated and softened before being used, is easy to pollute clothes, is inconvenient to use and has the hidden trouble of lead allergy; common emplastrum generally uses rubber, hot melt adhesive and the like, has small drug-loading rate, and is easy to cause skin allergy or damage after long-term use; the far infrared plaster generally consists of far infrared cloth and a self-heating bag, and some common plasters contain far infrared powder; the warm patch, the hot application patch and the hot moxibustion patch adopt a graphene power-on heating or iron powder self-heating technology, some of the warm patches only use a heating bag, some of the warm patches only use a layer of medicine powder bag on the heating bag or add medicine powder into the heating bag, only use a heating method to only temporarily relieve cold pain, and because most of products have higher heating temperature (50-60 ℃), the skin loses temperature sensitivity after long-time use, and is easy to cause skin burning pain or low-temperature scald; many patients have meridian obstruction and deficiency of qi and blood, and the hot patches with higher temperature are used on the waist, the back and the cervical vertebra, so that the phenomena of upper heat and lower cold are aggravated, and dry mouth and tongue, toothache, red and swollen throat, oral ulcer and the like are caused by upper fire; the application of the medicinal powder which is not extracted and is separated by the non-woven fabric can not fully exert the curative effect of the medicament.
Through the above analysis, the problems and defects of the prior art are as follows: at present, the treatment time of bone diseases such as cervical spondylosis, lumbar disc herniation, arthritis and the like is long, the effect is slow, the cost is high, various external products for relieving bone disease pain in the market are complicated, the existing products lack a standardized quality standard system to ensure the product quality, and products and reports that gel plasters are prepared by extracting different traditional Chinese medicine prescriptions and are matched with far infrared materials and self-heating bags to achieve the warm moxibustion effect are not available.
The difficulty in solving the above problems and defects is: the extraction process of the traditional Chinese medicine composition needs to be optimized and screened, and effective substances are fully reserved. The prepared external preparation has the advantages of large drug-loading rate, good skin-friendly property, quick transdermal absorption, and certain effect of locally heating to a small extent to promote blood circulation and drug absorption, so the ointment forming effect of various water-soluble high polymer materials, traditional Chinese medicine compositions and far infrared ceramic powder needs to be examined. Because the traditional Chinese medicine components are complex, the common method for measuring single chemical components or simple thin-layer identification can not well identify and ensure the quality of products, a modern instrument analysis means is required to be applied, a new quality control method and a standard fingerprint control mode of a standard preparation are established, and index components capable of reflecting the quality can be controlled in a key quantitative mode.
The significance of solving the problems and the defects is as follows: the invention belongs to a novel external preparation prepared by organically combining traditional Chinese medicine paste and modern gel paste, not only retains the advantages and characteristics of the traditional Chinese medicine paste, but also overcomes the defects of poor transdermal property, clothes pollution, inconvenient use and the like of the traditional paste, and has the advantages of convenient and comfortable use, quick transdermal absorption, large drug loading amount, high drug release efficiency, good air permeability, no sweaty hair drawing and repeated pasting. The invention uses far infrared material, which can promote percutaneous absorption of medicine, enhance drug effect, help to remove pathogenic cold and dampness, and achieve the purpose of warming and dredging channels. In addition, the self-heating material is used, power is not needed, a patient can select whether to add the self-heating bag after applying the gel plaster according to the self requirement, the effect of warm moxibustion and hot compress can be further achieved by adding the self-heating bag, the cost is low, the use is convenient, the internal heat is not easy to generate, and the pain and the economic burden of the majority of patients can be relieved. The new quality control method and the standard fingerprint control mode of the standard preparation established by the invention can be used as the internal control standard of the product, not only can ensure the quality of the product, but also can be a tool for preventing the infringement of counterfeit and shoddy products.
Disclosure of Invention
The prescription of the invention is a hereditary prescription, and two methods are provided for clinical application, wherein firstly, the prescription is fumigated and washed after being decocted in water, secondly, a towel soaked with hot medicine soup is applied to an affected part, and simultaneously, a cloth bag filled with iron sand is added on the towel, vinegar is poured on the iron sand bag immediately after the towel is ready, and the medicine absorption is promoted by the heat generated by the iron sand. Although the curative effect is good, the medicine dosage and the heating temperature of the iron sand are not easy to control, the use is inconvenient, clothes are easy to pollute, the skin irritation is large, and partial skin ulceration is easy to occur.
Aiming at the problems in the prior art, the invention provides a warm moxibustion type gel plaster for relieving pain of bone diseases, a preparation method and application.
The warm moxibustion type gel plaster for relieving the pain of the bone disease comprises an external traditional Chinese medicine composition for relieving the pain of the bone disease, a matrix, a far infrared material and a self-heating material.
Further, the external traditional Chinese medicine composition for relieving the pain of the bone diseases consists of 30-50 parts of folium artemisiae argyi, 5-10 parts of safflower, 10-30 parts of lycopodium clavatum, 10-30 parts of garden balsam stem, 5-10 parts of cassia twig, 5-10 parts of angelica, 5-10 parts of radix angelicae pubescentis and 1-5 parts of rhizoma zingiberis, and has the effects of warming channels, dispelling cold, promoting blood circulation, relieving pain, dispelling wind and removing dampness.
Further, the matrix is made of polypropylene10-40 parts of sodium, 1-10 parts of dihydroxyaluminium glycinate, 1-5 parts of polyvidone, 1-5 parts of tartaric acid, 60-100 parts of glycerol and 3-10 parts of kaolin, wherein the penetration enhancer is composed of lauryl nitrogen
The ketone and the propylene glycol are 1:1, and the dosage of the total penetration enhancer is 2-5%.
Further, the far infrared material is: superfine powder far infrared ceramic powder.
Further, the self-heating material is: 4-6 parts of reduced iron powder, 1-2 parts of vermiculite powder, 1-2 parts of activated carbon, 1-2 parts of sodium chloride, 1-2 parts of resin and 1-2 parts of water.
Another object of the present invention is to provide a method for preparing a warming moxibustion type gel patch for relieving pain of bone disease, which comprises the steps of:
taking prescription decoction pieces (four fifths) to prepare prescription extract; pulverizing decoction pieces (one fifth of the decoction pieces) into superfine powder (300 mesh);
step two, taking a proper amount of folium artemisiae argyi to prepare folium artemisiae argyi essential oil;
and step three, preparing the Aitong gel plaster.
And step four, preparing the self-heating bag.
Further, in the step one, the preparation of the prescription extract comprises:
crushing the decoction pieces of the medicinal materials in the prescription into coarse powder, soaking the coarse powder in 50% ethanol for 30 minutes, extracting the coarse powder twice in a reflux extraction mode by 8 times of 50% ethanol for 2 hours for the first time and 1.5 hours for the second time, filtering, combining the extracting solutions, and concentrating the extracting solutions under reduced pressure to obtain an extract (the relative density is 1.20-1.25).
Further, in the second step, the preparation of the artemisia argyi essential oil comprises the following steps:
cutting folium Artemisiae Argyi with scissors, weighing appropriate amount, placing in round bottom flask, adding 3% (g/mL) NaCl solution, soaking for 20min, performing ultrasonic treatment at power of 150W for 20min, and performing steam distillation. The experimental conditions of steam distillation are that the liquid-material ratio is 15:1 and the distillation time is 2 h. Separating the oil-water mixture after distillation, and adding a dehydrating agent into the oil phase to dehydrate to obtain the folium artemisiae argyi essential oil.
Further, in the third step, the preparation of the Aitong gel plaster comprises:
extracting folium Artemisiae Argyi essential oil and laurel nitrogen
Mixing ketone, propylene glycol and polysorbate 80, and making into phase I; dissolving tartaric acid in appropriate amount of water, and mixing to obtain phase II; adding sodium polyacrylate, dihydroxyaluminum glycolate and polyvidone into glycerol according to the proportion of the prescription, uniformly mixing, adding the prescription extract, the medicinal material ultrafine powder, the ultrafine powder far infrared ceramic powder, kaolin and the I-phase mixed solution, and uniformly mixing to obtain a III phase; slowly dripping the phase II into the phase III, and uniformly stirring to obtain a viscous and elastic paste. And (3) after the paste is prepared, immediately coating, covering a film, standing for 24h until the paste is solidified and formed, and sealing and storing. Can be cut into common type, knee joint type, cervical vertebra type, shoulder type and back protecting type according to the using position.
Further, in the fourth step, the preparing the self-heating pack comprises:
weighing 4-6 parts of reduced iron powder, 1-2 parts of vermiculite powder, 1-2 parts of activated carbon, 1-2 parts of sodium chloride, 1-2 parts of resin and 1-2 parts of water. Firstly, mixing water and resin to expand the resin into slurry; then uniformly mixing the reduced iron powder, the vermiculite powder, the activated carbon and the sodium chloride; and (3) rapidly mixing the prepared slurry with the mixture, and then sealing and bagging. It can be classified into common type, knee joint type, cervical vertebra type, shoulder type and back protection type according to the use position.
Another object of the present invention is to provide a moxibustion type gel plaster for relieving pain of bone disease prepared by the method for preparing the moxibustion type gel plaster for relieving pain of bone disease.
The invention also aims to provide application of the warm moxibustion type gel plaster for relieving pain of bone diseases in preparing medicines for treating and relieving pain of bone diseases.
The invention also aims to provide application of the warm moxibustion type gel plaster for relieving pain of bone diseases in preparing a medicament for preventing pain of bone diseases.
The invention also aims to provide a standard fingerprint spectrum and a quality consistency evaluation method of a standard preparation mode of the moxibustion type gel plaster prepared by the preparation method of the moxibustion type gel plaster for relieving pain of bone diseases, wherein the standard fingerprint spectrum and the quality consistency evaluation method of the standard preparation mode of the moxibustion type gel plaster comprise the following steps:
step one, preparing a test solution
Taking 1 piece of gel plaster, equally dividing into 12 parts according to the size, taking one of the gel plaster, placing in a conical flask with a plug, precisely adding 50% (V/V) ethanol 50mL, weighing, carrying out ultrasonic treatment for 30min, cooling, weighing again, supplementing the loss weight with 50% (V/V) ethanol, shaking up, centrifuging at 3000rpm for 15min, precisely absorbing 5mL of supernatant, placing in a 50mL measuring flask, adding 50% (V/V) ethanol to dilute to scale, shaking up, and obtaining the gel plaster, wherein a 0.45 mu m filter membrane is used for filtering before sample injection;
step two, preparing a mixed reference substance solution
Preparing a mixed reference solution, wherein the mixed reference solution comprises the following components in concentration: 0.22mg/ml of chlorogenic acid, 0.40mg/ml of isochlorogenic acid A, 0.24mg/ml of isochlorogenic acid B, 0.40mg/ml of isochlorogenic acid C, 0.22mg/ml of rutin, 0.07mg/ml of eupatilin and 0.08mg/ml of hydroxysafflor yellow A;
step three, chromatographic conditions
The chromatographic column takes octadecylsilane chemically bonded silica as a bonding phase, the length of the chromatographic column is 15-25cm, the inner diameter is 4.6mm, and the particle size is 5 mu m; the flow rate is 0.8-1.2 mL/min; setting ultraviolet detection wavelengths to be 237nm, 250nm, 280nm, 300nm and 326nm, and simultaneously collecting a 190-400 nm three-dimensional chromatogram by using DAD; the column temperature is 25-40 ℃; the sample amount is 1-50 mul; mobile phase composition and gradient elution procedure were as follows:
step four, fingerprint spectrum checking method
The number of common fingerprint peaks of a test sample under the fusion of detection wavelengths of 237nm and five wavelengths of 237nm, 250nm, 280nm, 300nm and 326nm is 26, wherein isochlorogenic acid A is used as a reference peak for identification and recognition of the common fingerprint peaks, and the macro qualitative similarity of the fingerprint of the test sample is not less than 0.90 and is between 80 and 120 percent respectively calculated according to the peak area and the retention time of the common fingerprint peaks;
step five, index component quantitative method
The standard curve method can be used for quantitative determination of 7 compound components in the test sample, and the linearity, range, detection limit and quantitative limit of the 7 compound components in the test sample are as follows:
the method comprises the following steps of quantitatively measuring 7 compound components in a test sample by using a first-line multiple evaluation method, wherein the S compound is any one of chlorogenic acid, isochlorogenic acid A, isochlorogenic acid B and isochlorogenic acid C, and the concentrations of other 6 compounds can be obtained by measuring the peak area of the S compound with a known concentration during analysis, and the calculation formula is as follows:
wherein A issIs a measurement of the peak area of the compound, CsTo determine the concentration of the compound, AiPeak area of compound to be evaluated, CiThe concentration of the multi-evaluation compound to be tested; relative correction factor values f for seven of the compoundssiThe following were used:
by combining all the technical schemes, the invention has the advantages and positive effects that: the invention discloses a warm moxibustion type gel plaster which contains self-heating materials and far infrared materials and is externally used for relieving pain of bone diseases, wherein a traditional Chinese medicine composition with the functions of warming channels and dispelling cold, promoting blood circulation and relieving pain, and dispelling wind and removing dampness is used as a raw material, a hydrophilic material is used as a matrix, the plaster is convenient to apply, high in transdermal absorption rate, capable of promoting local blood circulation and medicine permeation through the far infrared effect and further assisting in anti-inflammation, detumescence and pain relief, if a warm moxibustion curative effect can be generated by adding a self-heating bag, the cost is low, the use is convenient, time and labor are saved, and the pain and economic burden of patients can be relieved. The standard fingerprint spectrum of the standard preparation is formed on the basis of the quantitative fingerprint spectrum research of the self-made 24 batches of products, and can be used for comprehensively controlling the product quality; the invention is different from any multi-index quantitative quality control method and a fingerprint spectrum inspection method in Chinese pharmacopoeia, and uses macro quantitative similarity to control the amplitude range and the quality consistency of the total drug effect substances of the product.
Drawings
Fig. 1 is a flow chart of a method for preparing a warming moxibustion type gel patch for relieving pain of bone diseases according to an embodiment of the present invention.
FIG. 2 is a standard fingerprint of a standard preparation detected at 237nm according to an embodiment of the present invention.
FIG. 3 is a graph showing 7 fingerprint peaks identified at 237nm according to an embodiment of the present invention.
FIG. 4 is a standard fingerprint of a five-wavelength full-fusion assay standard preparation at 237nm, 250nm, 280nm, 300nm and 326nm, provided by an 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.
In view of the problems in the prior art, the present invention provides a warming moxibustion type gel patch for alleviating pain of bone diseases and a method for preparing the same, and the present invention will be described in detail with reference to the accompanying drawings.
The warm moxibustion type gel plaster for relieving bone disease pain provided by the embodiment of the invention comprises an external traditional Chinese medicine composition for relieving bone disease pain, a substrate, a far infrared material and a self-heating material.
The external traditional Chinese medicine composition for relieving bone pain provided by the embodiment of the invention is composed of 30-50 parts of folium artemisiae argyi, 5-10 parts of safflower, 10-30 parts of lycopodium clavatum, 10-30 parts of garden balsam stem, 5-10 parts of cassia twig, 5-10 parts of angelica sinensis, 5-10 parts of radix angelicae pubescentis and 1-5 parts of rhizoma zingiberis.
The matrix provided by the embodiment of the invention comprises 10-40 parts of sodium polyacrylate, 1-10 parts of dihydroxyaluminium aminoacetate, 1-5 parts of povidone, 1-5 parts of tartaric acid, 60-100 parts of glycerol and 3-10 parts of kaolin, and the penetration enhancer is composed of laurocapram
The ketone and the propylene glycol are 1:1, and the dosage of the total penetration enhancer is 2-5%.
The far infrared material provided by the embodiment of the invention is as follows: superfine powder far infrared ceramic powder.
The self-heating material provided by the embodiment of the invention is as follows: 4-6 parts of reduced iron powder, 1-2 parts of vermiculite powder, 1-2 parts of activated carbon, 1-2 parts of sodium chloride, 1-2 parts of resin and 1-2 parts of water.
As shown in fig. 1, a method for preparing a warming moxibustion type gel patch for relieving pain of bone diseases according to an embodiment of the present invention includes: the preparation method comprises the steps of preparation of a prescription extract, preparation of medicinal material ultrafine powder, preparation of folium artemisiae argyi essential oil, preparation of gel plaster and preparation of a self-heating bag.
The preparation of the prescription extract provided by the embodiment of the invention comprises the following steps:
crushing the decoction pieces of the medicinal materials in the prescription into coarse powder, soaking the coarse powder in 50% ethanol for 30 minutes, extracting the coarse powder twice in a reflux extraction mode by 8 times of 50% ethanol for 2 hours for the first time and 1.5 hours for the second time, filtering, combining the extracting solutions, and concentrating the extracting solutions under reduced pressure to obtain an extract (the relative density is 1.20-1.25).
The preparation of the folium artemisiae argyi essential oil provided by the embodiment of the invention comprises the following steps:
cutting folium Artemisiae Argyi with scissors, weighing appropriate amount, placing in round bottom flask, adding 3% (g/mL) NaCl solution, soaking for 20min, performing ultrasonic treatment at power of 150W for 20min, and performing steam distillation. The experimental conditions of steam distillation are that the liquid-material ratio is 15:1 and the distillation time is 2 h. And separating the oil-water mixture after the distillation is finished to obtain the argy wormwood leaf essential oil.
The preparation of the gel plaster provided by the embodiment of the invention comprises the following steps:
extracting folium Artemisiae Argyi essential oil and laurel nitrogen
Mixing ketone, propylene glycol and polysorbate 80, and making into phase I; dissolving tartaric acid in appropriate amount of water, and mixing to obtain phase II; taking sodium polyacrylate, dihydroxyaluminum aminoacetate and polyvidone according to the proportion of the prescription, adding into glycerol, mixing uniformly, then adding the prescription extract, the medicinal material ultra-fine powder, the ultra-fine powder far infrared ceramic powder, kaolin and the I-phase mixed solution, and mixing uniformly to obtain a III phase; slowly dripping the phase II into the phase III, and uniformly stirring to obtain a viscous and elastic paste. And (3) after the paste is prepared, immediately coating, covering a film, standing for 24h until the paste is solidified and formed, and sealing and storing. Can be cut into common type, knee joint type, cervical vertebra type, shoulder type and back protecting type according to the using position.
The preparation of the self-heating bag provided by the embodiment of the invention comprises the following steps:
weighing 4-6 parts of reduced iron powder, 1-2 parts of vermiculite, 1-2 parts of activated carbon, 1-2 parts of sodium chloride, 1-2 parts of resin and 1-2 parts of water. Firstly, mixing water and resin to expand the resin into slurry; then uniformly mixing the reduced iron powder, the vermiculite powder, the activated carbon and the sodium chloride; and (3) rapidly mixing the prepared slurry with the mixture, and then sealing and bagging. It can be classified into common type, knee joint type, cervical vertebra type, shoulder type and back protection type according to the use position.
The technical solution of the present invention is further described with reference to the following specific embodiments.
Example 1: extraction process of prescription extract
1. Method for preparing test solution
The prescription of the invention is a hereditary prescription, and is decocted with water when in use. In order to compare the difference of different solvents and better extract effective components, different solvents are adopted for reflux extraction, filtrates are combined, reduced pressure concentration is carried out to about 70mL, residual liquid is dissolved by 50% (V/V) ethanol and constant volume is carried out to 100mL, 4mL is precisely measured, dissolved by 50% (V/V) ethanol and constant volume is carried out to 50mL, and the preparation method is obtained by shaking up. Before injection, the mixture was filtered through a 0.45 μm filter membrane.
2. Fingerprint determination
Octadecylsilane chemically bonded silica is used as a chromatographic column filler, the column length is 15-25cm, the inner diameter is 4.6mm, and the particle size is 5 mu m; the flow rate is 0.8-1.2 mL/min; setting ultraviolet detection wavelengths to be 237nm, 250nm, 280nm, 300nm and 326nm, and simultaneously collecting a 190-400 nm three-dimensional chromatogram by using DAD; the column temperature is 25-40 ℃; the sample amount is 1-50 μ l (the sample amount is determined with the maximum chromatographic peak absorbance not more than 1); mobile phase composition and gradient elution procedure were as follows:
3. orthogonal experimental design and results
Before orthogonal testing, single factor testing is performed. Taking the medicinal materials according to the prescription amount, and respectively extracting by taking water, 25 percent (V/V) ethanol, 50 percent (V/V) ethanol, 75 percent (V/V) ethanol, 95 percent (V/V) ethanol, absolute ethanol and ethyl acetate as solvents. Sample 10 μ L of the test solution is injected, and chromatogram is recorded. As a result, the number of peaks was the largest in the chromatogram of the sample prepared using 50% (V/V) ethanol as an extraction solvent, and the separation amount index RF was the largest. Because the water and the ethanol are cheap and easy to obtain, and the main effective components of the traditional Chinese medicinal materials in the prescription have better solubility in the water and the ethanol, the ethanol with a certain concentration is used as an extraction solvent, and the effective components can be fully extracted.
Further taking ethanol concentration, solvent dosage, extraction time and reflux frequency as investigation factors, and taking chromatographic fingerprint spectrum separation quantity index RF as an index. According to L9(34) Is justCross-table the experiments were performed and the factors and level schedules are shown in the following table.
The results of the experiments are shown in the following table.
The analysis of variance results show that the influence of each factor on the extraction process is as follows: the concentration of ethanol (A) > the extraction times (D) > the extraction time (C) > the solvent dosage (B), and the factor A has significant influence. Combining the range analysis results, the optimal extraction process is A2B2C3D3Namely, the ethanol concentration is 50%, the solvent dosage is 8 times, the extraction time is 2 hours, and the extraction times are 3 times as the optimal extraction process conditions. Considering multiple factors such as energy conservation and time, the extraction process is determined as follows: adding 8 times of 50% ethanol, extracting twice, the first extraction for 2 hr, and the second extraction for 1.5 hr. The process is adopted for extraction for three times, the measured RF value is stable, the average value is 211.5, and the selected process is reasonable.
Example 2: extraction process of folium artemisiae argyi essential oil
1. The extraction method comprises collecting appropriate amount of pulverized or cut folium Artemisiae Argyi, placing in a round-bottom flask, adding inorganic salt water solution, soaking, placing in an ultrasonic cleaner, and performing ultrasonic enhancement at certain power. And after the ultrasonic strengthening is finished, performing steam distillation. And finally, separating the oil-water mixture, and adding a dehydrating agent into the oil phase to dehydrate to obtain the argy wormwood leaf essential oil.
2. Determination of extraction ratio of essential oil%
3. Single factor test
Firstly, single-factor tests are carried out to respectively investigate different soaksSoaking time (0min, 10min, 20min, 30min, 60min), pulverizing degree (cutting folium Artemisiae Argyi into 5mm pieces, 10 mesh, 20 mesh), and inorganic salt and dosage (blank control, NaCl, MgSO)4、Na2SO4KCl), different ultrasonic powers (90W, 120W, 150W, 180W and 210W), liquid-material ratios (5:1, 10:1, 15:1, 20:1, 25:1 and 30:1), ultrasonic strengthening time (0min, 10min, 30min, 50min and 70min) and distillation extraction time (0.5h, 1h, 2h, 3h and 4h) on the extraction rate of essential oil. The results show that: soaking for 10-30min is favorable for improving the extraction rate, and the soaking for 20min is best; proper crushing is helpful for improving the extraction rate, but the crushing is too fine, but the extraction rate is reduced to about 5mm, so that the volatile oil is proper in volatilization speed and is not easy to generate bumping; adding NaCl can improve the extraction rate, and the influence of NaCl solutions with different concentrations (1%, 3%, 5% and 8%) is examined, preferably adding 3% NaCl solution; fourthly, when the ultrasonic power is too low or too high, the extraction rate cannot be obviously increased, and the effect is most obvious by 150W; when the liquid-material ratio is lower than 15:1, the extraction rate is increased to a certain extent along with the increase of the liquid-material ratio, and when the liquid-material ratio is higher than 15:1, the extraction rate is slightly reduced; sixthly, after the ultrasonic time exceeds 30min, the extraction rate is reduced; after the distillation extraction time exceeds 2 hours, the extraction rate is reduced to a certain degree.
3. Orthogonal experimental design and process verification
On the basis of the single-factor test, the liquid-material ratio, the ultrasonic strengthening time and the distillation extraction time are further taken as investigation factors, the extraction rate of essential oil is taken as an index, and the L is the ratio9(34) Orthogonal tables the experiments were performed, the factors and the horizontal arrangement are shown in the following table.
The results of the experiments are shown in the following table.
From the results of the anova, various factors can be seenThe influence on the extraction process is: the liquid-material ratio (A) > the ultrasonic strengthening time (B) > the distillation extraction time (C), and the factor A has significant influence. Combining the range analysis results, the optimal extraction process is A2B2C3Namely, the liquid-material ratio is 15:1, ultrasonic strengthening for 20min, and distilling and extracting for 2 hours to obtain the optimal extraction process condition.
The three batches of samples are prepared by respectively adopting the optimal process, the extraction rate of the essential oil is relatively stable, and the average extraction rate is 0.68 percent.
Example 3: gel plaster matrix prescription
1. Preparation process of gel plaster
Uniformly mixing a penetration enhancer to serve as a phase I for later use; dissolving the crosslinking regulator in a proper amount of distilled water, and uniformly mixing to obtain phase II for later use; adding the cross-linked skeleton, cross-linking agent and tackifier into glycerol, mixing, adding the formula extract, medicinal material superfine powder, far infrared ceramic powder, kaolin and the I-phase mixed solution, and mixing to obtain phase III; slowly dripping the phase II into the phase III, and uniformly stirring to obtain a viscous and elastic paste.
2. Evaluation index
The method for measuring the excipient performance refers to a method for measuring the excipient performance of 0122 emplastrum under the general regulation of 2020 edition Chinese pharmacopoeia, 1 piece of gel emplastrum sample is taken and placed in a constant humidity box with the temperature of 37 ℃ and the relative humidity of 64 percent for 30 minutes, the gel emplastrum sample is taken out, the gel emplastrum sample is fixed on a flat steel plate by a clamp, the inclination angle of the steel plate and the horizontal plane is 60 degrees, the gel emplastrum sample is placed for 24 hours, and whether the plaster surface has the phenomenon of flowing or not is observed. If the flow phenomenon does not occur, the flow phenomenon is counted as 10 minutes, the serious flow phenomenon is counted as 0 minutes, and the flow phenomenon is counted as 0, 2,4, 6, 8 and 10 minutes.
The adhesiveness is determined by referring to adhesive force determination method (0952 first method) of 'Chinese pharmacopoeia' 2020 edition, taking 1 piece of gel plaster sample, removing back lining layer, placing in the center of an inclined plate with an angle of 30 degrees with the horizontal plane, making the plaster surface upward, covering the upper 10cm and lower 15cm of the inclined plane with terylene film, leaving a plaster surface of 5cm in the middle, freely rolling down steel balls with different specifications from the top end of the inclined plane, and recording the maximum steel ball number capable of being adhered. 3, 2 or more than 2 steel balls can be stuck on the test section, if 1 steel ball can not be stuck, a smaller steel ball I is taken for test; if only one sheet can stick the steel ball, and the other 2 sheets can stick the smaller steel ball, another 3 sheets should be taken to retest, and the 3 sheets should stick the steel ball to meet the regulation. Scoring according to the number of steel balls which can be stuck, and dividing the total score into 10. The number of the steel balls is 27 or more, and 10 points are counted; the number of the steel balls is 24, and 8 points are counted; the number of the steel balls is 21, and 6 points are counted; the number of the steel balls is 18, and 4 points are counted; the number of the steel balls is 15, and 2 points are counted; the steel ball number is between the specified grades, and an intermediate score can be given, for example, the steel ball number is 22 or 23, and can be counted for 7; no. 15 or less, and 0 point is counted.
The comprehensive sensory score was evaluated according to the peelability, uniformity, spreadability, and spreadability of the gel plaster test article, and was 20 points in total. Easily peeled off and no paste remained, and the peelability was 5 points; the color and luster is uniform, no granular sensation, no obvious bubbles and uniform thickness, and the uniformity is 5 minutes; the coating is very easy to coat, and the spreadability is 5 points; the cloth permeability is 5 points for the case without cloth permeability; the above items are divided into 6 grades according to specific degrees, and 0, 1, 2, 3, 4 and 5 grades are given in sequence.
Evaluation index comprehensive scoring method total score is excipient score + adhesiveness score + comprehensive sensory score.
3. Single factor test
And (4) scoring according to the evaluation index by adopting a single factor method, and determining the proper matrix type and dosage range.
(1) Crosslinked framework materials
And (3) taking the sodium polyacrylate NP-600, the sodium polyacrylate NP-700, the sodium polyacrylate NP-800 and the polyvinyl alcohol as cross-linked skeletons without changing other matrixes, respectively preparing blank matrixes, and investigating the influence of the blank matrixes on forming, so that the paste prepared from the sodium polyacrylate NP-700 has better forming property, and therefore the NP700 is taken as the cross-linked skeleton.
(2) Selection of crosslinking agent
Other matrixes are unchanged, aluminum glycollate, aluminum hydroxide and aluminum glycinate are taken as cross-linking agents to respectively prepare blank matrixes, and as a result, the paste prepared from the aluminum glycollate has better uniformity, so the aluminum glycollate is taken as the cross-linking agent.
(3) Crosslinking regulator
And other matrixes are unchanged, citric acid, tartaric acid and ethylenediamine tetraacetic acid are taken as crosslinking regulators to respectively prepare blank matrixes, and as a result, the paste prepared from the tartaric acid is appropriate in curing time and good in comprehensive appearance, so that the tartaric acid is taken as the crosslinking regulator.
(4) Moisture-retaining agent
And other matrixes are unchanged, glycerin and polyethylene glycol are taken as the moisturizing agents to respectively prepare blank matrixes, so that the ointment prepared from the glycerin has better indexes, and the glycerin has proper price and can be used as a good solvent for other materials, so the glycerin is taken as the moisturizing agent.
(5) Adhesion promoter
And other matrixes are unchanged, sodium carboxymethylcellulose, povidone and gelatin are taken as the viscosity increasing agents to respectively prepare blank matrixes, and as a result, all indexes of the paste prepared from the povidone are better, so that the povidone is taken as the viscosity increasing agent.
(6) Filler
Other matrixes are unchanged, kaolin, superfine medicine powder and a kaolin-superfine medicine powder-superfine powder far infrared ceramic powder mixture are taken as fillers to respectively prepare blank matrixes, so that the ointment prepared from the kaolin-superfine medicine powder-superfine powder far infrared ceramic powder mixture has better indexes and can increase the drug loading, and the kaolin-superfine medicine powder-superfine powder far infrared ceramic powder mixture is taken as the filler.
4. Preference for orthogonal tests
On the basis of single-factor test, the sodium polyacrylate NP-700, dihydroxyaluminum glycinate, tartaric acid and the amount of mixed fillers are used as investigation factors A, B, C, D, each factor test has 3 levels, comprehensive scores are used as indexes, and L is used as9(34) Orthogonal tables the experiments were performed and the results are shown in the following table.
From the analysis of variance results, the influence of each factor is as follows: sodium polyacrylate NP-700(A) > dihydroxyaluminium glycinate (B) > tartaric acid (C) > mixed filler (D), and factor A has a significant influence. Combining the results of range analysis, the optimum ratio is A2 B2C3D3. Three batches of samples are prepared according to the optimal proportion, and all indexes are stable.
Example 4: quality evaluation of gel plaster
1. Fingerprint spectrum inspection and index component quantification method
(1) Preparing test solution
Taking 1 piece of gel plaster, equally dividing into 12 parts according to the size, taking one of the gel plaster, placing in a conical flask with a plug, precisely adding 50% (V/V) ethanol 50mL, weighing, carrying out ultrasonic treatment for 30min, cooling, weighing again, supplementing the loss weight with 50% (V/V) ethanol, shaking up, centrifuging at 3000rpm for 15min, precisely absorbing 5mL of supernatant, placing in a 50mL measuring flask, adding 50% (V/V) ethanol to dilute to scale, shaking up, and obtaining the gel plaster, wherein a 0.45 mu m filter membrane is used for filtering before sample injection.
(2) Preparation of control solutions
Preparing a mixed reference solution, wherein the mixed reference solution comprises the following components in concentration: 0.22mg/ml of chlorogenic acid, 0.40mg/ml of isochlorogenic acid A, 0.24mg/ml of isochlorogenic acid B, 0.40mg/ml of isochlorogenic acid C, 0.22mg/ml of rutin, 0.07mg/ml of isoeupatilin and 0.08mg/ml of hydroxysafflor yellow A.
(3) Chromatographic conditions
The chromatographic column takes octadecylsilane chemically bonded silica as a bonding phase, the length of the chromatographic column is 15-25cm, the inner diameter of the chromatographic column is 4.6mm, and the particle size of the chromatographic column is 5 mu m; the flow rate is 0.8-1.2 mL/min; setting ultraviolet detection wavelengths to be 237nm, 250nm, 280nm, 300nm and 326nm, and simultaneously collecting a 190-400 nm three-dimensional chromatogram by using DAD; the column temperature is 25-40 ℃; the sample amount is 1-50 μ l (the sample amount is determined with the maximum chromatographic peak absorbance not more than 1); mobile phase composition and gradient elution procedure were as follows:
(4) HPLC fingerprint spectrum checking method
And (4) respectively injecting sample into 24 self-made test solutions, and recording the chromatogram. Because the retention time of the isochlorogenic acid A peak is moderate and the isochlorogenic acid A peak is better separated from adjacent peaks, the isochlorogenic acid A peak (No. 15) is taken as a reference peak, the total fingerprint peaks are 26 according to the peak occurrence rate of 100 percent, a Reference Fingerprint (RFP) is generated according to an average value method, and the common peak label chart is shown in figure 2. Calculating according to the peak area and retention time of the common fingerprint peak respectively, wherein the macro qualitative similarity of the fingerprint of the sample is not lower than 0.90, and the macro quantitative similarity is between 80% and 120%; the detection wavelength of the embodiment includes but is not limited to 237nm, 250nm, 280nm, 300nm and 326nm, and any wavelength within 190-400 nm of DAD acquisition is used for fingerprint detection; the number of common fingerprint peaks in this embodiment includes, but is not limited to, 26 or more fingerprint peaks, and all fingerprint peaks whose signal is 5 times or more of noise can be regarded as valid fingerprint peaks.
The fingerprint data (obtained by measuring the sample solution at 10 mg/ml) of the standard preparation detected at 237nm in the example are as follows:
when the total fingerprint peaks detected at 237nm are 26, the identification peak is 7 fingerprint peaks (see figure 3), and the seven online ultraviolet spectrums are all the same as the online ultraviolet spectrum of the corresponding reference product. Wherein: 8. chlorogenic acid; 9. hydroxysafflor yellow a; 13. rutin; 14. isochlorogenic acid B; 15. isochlorogenic acid A; 16. isochlorogenic acid C; 26. eupatilin.
In this example, the fingerprint of the standard preparation obtained by performing five-wavelength total fusion detection at 237nm, 250nm, 280nm, 300nm and 326nm is shown in FIG. 4, and the fingerprint data (obtained by detecting 10mg/ml of test solution) is as follows:
| peak number | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 |
| Retention time/min | 2.8 | 3.5 | 3.7 | 7.8 | 8.0 | 9.0 | 10.2 | 10.6 | 11.1 | 11.5 | 12.5 | 13.6 | 15.6 |
| Peak area | 16.3 | 24.2 | 148.3 | 55.7 | 92.0 | 98.7 | 118.1 | 608.8 | 70.3 | 141.3 | 60.9 | 64.9 | 379.1 |
| Relative retention time | 0.17 | 0.21 | 0.22 | 0.47 | 0.48 | 0.54 | 0.61 | 0.64 | 0.67 | 0.69 | 0.75 | 0.82 | 0.94 |
| Relative peak area | 0.02 | 0.03 | 0.16 | 0.06 | 0.10 | 0.10 | 0.13 | 0.64 | 0.07 | 0.15 | 0.06 | 0.07 | 0.40 |
| Peak number | 14 | 15 | 16 | 17 | 18 | 19 | 20 | 21 | 22 | 23 | 24 | 25 | 26 |
| Retention time/min | 16.2 | 16.6 | 17.8 | 22.0 | 22.3 | 24.9 | 25.4 | 26.0 | 26.2 | 27.0 | 27.4 | 28.7 | 29.8 |
| Peak area | 342.0 | 945.7 | 573.1 | 72.6 | 1807.1 | 68.5 | 56.9 | 78.3 | 13.8 | 121.9 | 26.5 | 63.6 | 185.1 |
| Relative retention time | 0.98 | 1.00 | 1.07 | 1.32 | 1.34 | 1.50 | 1.53 | 1.57 | 1.58 | 1.62 | 1.65 | 1.73 | 1.79 |
| Relative peak area | 0.36 | 1.00 | 0.61 | 0.08 | 1.91 | 0.07 | 0.06 | 0.08 | 0.02 | 0.13 | 0.03 | 0.07 | 0.20 |
When the total fingerprint peaks are 26 in the above five-wavelength total fusion (237nm, 250nm, 280nm, 300nm and 326nm), the identification peaks are 7 fingerprint peaks, wherein: 8. chlorogenic acid; 9. hydroxysafflor yellow a; 13. rutin; 14. isochlorogenic acid B; 15. isochlorogenic acid A; 16. isochlorogenic acid C; 26. eupatilin.
(5) Index component quantitative method
The standard curve method can be used for quantitative determination of 7 compound components in the test sample, and the linearity, range, detection limit and quantitative limit of the 7 compound components in the test sample are as follows:
the method can also be used for quantitatively measuring 7 compound components in a test sample by utilizing a first-line multiple evaluation method, wherein the S compound is any one of chlorogenic acid, isochlorogenic acid A, isochlorogenic acid B and isochlorogenic acid C, the concentrations of other 6 compounds can be obtained by measuring the peak area of the S compound with a known concentration during analysis, and the calculation formula is as follows:
wherein A issIs a measurement of the peak area of the compound, CsTo determine the concentration of the compound, AiPeak area of compound to be evaluated, CiThe concentration of the multi-scored compound to be tested; relative correction factor values f for seven of the compoundssiThe following were used:
| peak number | S compound | No. | Peak 8 | Peak 9 | Peak 13 | Peak 14 | |
Peak 16 | Peak 26 |
| Peak 8 | Chlorogenic acid | fsi | 1.00 | 1.05 | 1.11 | 0.50 | 0.41 | 0.48 | 0.16 |
| Peak 9 | Hydroxy safflower yellow A | fsi | 0.95 | 1.00 | 1.06 | 0.48 | 0.39 | 0.46 | 0.15 |
| Peak 13 | Rutin | fsi | 0.90 | 0.95 | 1.00 | 0.45 | 0.37 | 0.43 | 0.14 |
| Peak 14 | Isochlorogenic acid B | fsi | 1.99 | 2.10 | 2.21 | 1.00 | 0.81 | 0.96 | 0.32 |
| |
Isochlorogenic acid A | fsi | 2.46 | 2.59 | 2.73 | 1.24 | 1.00 | 1.18 | 0.39 |
| Peak 16 | Isochlorogenic acid C | fsi | 2.08 | 2.19 | 2.32 | 1.05 | 0.85 | 1.00 | 0.33 |
| Peak 26 | Eupatilin | fsi | 6.28 | 6.62 | 6.98 | 3.15 | 2.55 | 3.02 | 1.00 |
Example 5: preparation of self-heating ladle
The heat production principle of the self-heating ladle is that the reduced iron powder and oxygen in the air generate oxidation-reduction reaction to release heat. Single-factor tests show that the dosage of the reduced iron powder is in direct proportion to the heating temperature and the duration of the self-heating bag; the using amount of the active carbon is in direct proportion to the heating temperature of the self-heating bag and in inverse proportion to the heating duration; the vermiculite powder has the function of heat preservation, the dosage in a certain range is in direct proportion to the continuous heating time, but if the dosage is excessive, the heating temperature can be reduced; the amounts of sodium chloride and water used are directly proportional to the rate of heat generation initiation. In addition, the charging sequence is important to avoid contact of the iron powder with water prior to sealing.
Weighing 4-6 parts of reduced iron powder, 1-2 parts of vermiculite powder (200-300 meshes), 1-2 parts of activated carbon (200-300 meshes), 1-2 parts of sodium chloride, 1-2 parts of resin and 1-2 parts of water. Firstly, mixing water and resin to expand the resin into slurry; then uniformly mixing the reduced iron powder, the vermiculite powder, the activated carbon and the sodium chloride; and (3) rapidly mixing the prepared slurry with the mixture, and then sealing and bagging to prepare the self-heating bag. Five parts are prepared in parallel, timing is started from opening the sealed package, the temperature of the self-heating package is measured by an infrared thermometer, the continuous heating time is recorded, and the following table shows the highest temperature of the natural package and the continuation of the highest temperature.
Example 6: safety test
1. Skin irritation test
24 adult healthy rabbits were selected and tested in four groups, namely, a complete skin gel plaster group, a complete skin combination group (gel plaster combined self-heating pack), a damaged skin gel plaster group and a damaged skin combination group (gel plaster combined self-heating pack), and 6 rabbits were selected and tested. Both sides of the back of each rabbit were dehaired 24 hours before the test, and the left and right sides of the back of the same rabbit were used as self-control. The depilating area on the left side of the back is used as a control area, and non-woven fabrics with the same area are applied; the depilatory area on the right side of the back is the gel plaster area for external application, and is applied and fixed according to the dosage. Continuously applying for 2 weeks, applying for 6 hr every day, cleaning corresponding parts after removing the plaster and before applying the plaster, observing the status, behavior, physical sign of rabbit and local skin reaction such as erythema, edema, desquamation, scab, etc., observing whether pigmentation, pachylosis or thin skin, etc., stopping applying, and continuing to observe for 3 days.
No mortality occurred in any of the groups of rabbits during the test period. In both groups, no erythema, edema, desquamation, incrustation and pigmentation, rough skin or thin skin were observed at the administration site at each observation time point. The gel plaster prepared by the invention is proved to be externally applied to intact and damaged skin of rabbits for one time or multiple times, and no irritation reaction appears.
2. Skin allergy test
Taking 32 healthy guinea pigs, wherein the male and female parts are respectively divided into a blank group, a positive control group, a gel plaster group and a combined group at random, and each group comprises 8 animals and the female and male parts are respectively half. The guinea pigs were depilated 24h prior to the test, with an area of approximately 6cm x 6cm on both sides of the back. The left epilation zone was used for sensitization and the right epilation zone was used for stimulation of sensitization. The site should be cleaned after each removal of the administration substance and before administration of the substance.
Sensitization contact test was performed in the first two weeks, once on each of day 1, day 7 and day 14, for 6h each time. Applying non-woven fabrics to the blank group; the positive control group was coated with 1% 2, 4-dinitrochlorobenzene and covered with oiled paper and medical gauze; the gel plaster group is given with Aitong gel plaster; after the combined group was given the moxa-pine gel patch, a self-heating pack was added.
Sensitization contact test is carried out 14d after the last application, an excitation allergy test is carried out in a right depilating area, and a non-woven fabric is applied to a blank group; the positive control group was coated with 1% 2, 4-dinitrochlorobenzene and covered with oiled paper and medical gauze; the gel plaster group is given with Aitong gel plaster; after the combined group was given the moxa-pine gel patch, a self-heating pack was added. After 6h, the patch was removed, washed with warm water, and the skin was immediately observed for local and systemic allergic reactions at 24, 48, and 72h, respectively.
The gel plaster group, the combined group and the blank group have no skin anaphylactic reaction such as erythema, edema and the like and other reactions, the positive control group has obvious erythema, edema reaction occurs, and the sensitization rate is 100%. Compared with a positive control group, the gel plaster group and the combined group have obvious difference. The gel plaster prepared by the invention has no allergic reaction to guinea pigs when being externally used.
Example 7: percutaneous absorption in vitro
1. Preparation of animal skin in vitro
The skin of the abdomen of the mouse is thin, the subcutaneous fat layer is easy to separate and is close to the skin of a human body, so the skin of the mouse is selected to carry out an in vitro transdermal absorption experiment. Taking SPF-level Kunming mice, removing neck, killing, removing hair from abdomen, peeling skin from abdomen, cleaning with 0.9% NaCl solution, sealing with preservative film, and storing in refrigerator for use. The skin was thawed from the freezer before the skin penetration test and then soaked in a beaker containing 0.9% NaCl solution.
2. Transdermal diffusion test
The Franz diffusion cell is adopted, and specifically comprises a diffusion cell and a receiving cell (the receiving cell volume is 6.5ml, and the effective area of the receiving cell is 2.8 cm)2). Spreading the skin of the mouse soaked to room temperature on a diffusion pool and fixing, wherein one side of the horny layer faces the diffusion pool, and one side of the dermis is connected with a receiving poolThe receiving pool is filled with 0.9% NaCl solution, and the water bath temperature is (37 +/-1) DEG C. The prepared gel plaster is evenly pasted on the in vitro skin cuticle of the diffusion cell, a magnetic stirring rod is started to stir at the speed of 200 r/min, 0.5mL of receiving liquid is sucked from the receiving cell when 2,4, 6, 8, 10 and 12 hours are respectively carried out, and simultaneously 0.9% NaCl solution with the same volume and temperature is supplemented. Centrifuging the obtained receiving solution at high speed for 15min, collecting supernatant, determining contents of hydroxysafflor yellow A and isochlorogenic acid A according to chromatographic conditions in the quality evaluation research, and calculating the accumulated permeation amount according to a formula:
in the formula QnThe cumulative permeation amount per unit area of isochlorogenic acid A and hydroxysafflor yellow A at the nth sampling point, CnThe concentrations of isochlorogenic acid A and hydroxysafflor yellow A, C in the receiving solution at the nth sampling pointiThe concentrations of isochlorogenic acid A and hydroxysafflor yellow A in the receiving liquid of the ith (i is less than or equal to n-1) sampling point, V is the volume of the receiving pool, V is the concentration of isochlorogenic acid A and hydroxysafflor yellow A in the receiving liquid of the ith sampling point0Is the sample volume and S is the effective contact area for the drug to diffuse.
The lipid-soluble components and the micromolecule components easily penetrate through the stratum corneum by the principle of similar intermiscibility and the synergistic effect of the penetration enhancer, and the data show that the medicament in the developed gel plaster penetrates through the skin barrier of the mouse to be a passive diffusion behavior, and the penetration amount is increased along with the increase of time.
Example 8: determination of drug efficacy
1. Examination of analgesic Effect by acetate writhing method
The method comprises the steps of taking 48 SPF-grade healthy Kunming mice, dividing male and female halves of the mice into 4 groups randomly according to body weight, namely a blank group (blank matrix), a positive control group (Gutong plaster), a test article 1 group (gel plaster) and a test article 2 group (gel plaster combined self-heating bag). All mice were depilated 24h before administration, raised 24h after depilation, and examined for the presence of skin on the depilated areaThe injury, if not damaged, is applied to the skin of the mouse in the depilated area for 6 hours in a dosage mode, and is continuously applied for 7 days. 30min after the last administration, 0.6% glacial acetic acid solution is injected into the abdominal cavity, the incubation period of pain (namely the time of the first writhing response) of the mice and the writhing frequency in 15min are observed, and the analgesic rate is calculated according to the formula: the analgesic rate of acetic acid writhing is (average writhing times of blank group-average writhing times of administration group)/average writhing times of blank group. The results are shown in the following table, in which the values of the pain latency and the number of writhing are
| Group of | Number of mice/mouse | Latency to pain | Number of wriggling within 15min | Rate of analgesia |
| Blank group | 12 | 171.2±7.4 | 39.5±3.5 | — |
| Positive control group | 12 | 216.2±7.0* | 26.3±4.0* | 33.5 |
| Test article 1 group | 12 | 220.7±7.8* | 26.1±4.5* | 34.0 |
| Test article 2 groups | 12 | 222.1±7.3* | 24.2±3.9* | 38.8 |
From the above results, the pain latency of the mice in 15min in the test article 1 group and the test article 2 group is significantly prolonged compared with the blank group, the difference has statistical significance (P <0.05), the writhing frequency is significantly reduced compared with the blank group, and the difference has statistical significance (P <0.05), which indicates that the developed gel plaster alone or in combination with the self-heating bag can relieve the pain of the mice caused by acetic acid. Compared with the test article 2, the test article 1 group has no significant difference, but the pain latent period of the mice of the test article 2 group is prolonged compared with that of the test article 1 group, which shows that the combined self-heating temperature-wrapped moxibustion has the tendency of improving the effect of the gel plaster on relieving the pain of the mice caused by acetic acid.
2. Examination of anti-inflammatory action by influencing the swelling of rat feet caused by egg white
32 rats, male and female, were randomly divided into 4 groups, namely a blank group, a positive control group (gutong plaster), a test sample 1 group (gel plaster) and a test sample 2 group (gel plaster combined self-heating bag). 24h before administration, all rats are subjected to unhairing treatment on the abdomen, raised for 24h after unhairing, and checked whether the skin of the unhairing area has damage, if no damage, the skin of the unhairing area of the mouse is applied for 6h according to the dose, and the administration is continued for 7 d. Measuring foot volume of part below left ankle joint of rat 30min after last administration with toe volume measuring instrument, and injecting fresh egg white 0.1ml under tendon membrane of left ankle joint of each ratThe volume of the left foot of each mouse is repeatedly measured every 1h for 4h continuously after the mice are inflamed, the difference between the volume of the left foot of each mouse at different time after the mice are inflamed and the volume before the inflammation is taken as the swelling degree, the result is shown in the following table, and the numerical value in the table is
| Group of | 1h | 2h | 3h | 4h |
| Blank group | 0.52±0.07 | 0.55±0.08 | 0.54±0.07 | 0.54±0.08 |
| Positive control group | 0.47±0.05 | 0.44±0.15** | 0.40±0.05** | 0.39±0.05** |
| Test article 1 group | 0.46±0.03* | 0.43±0.05** | 0.39±0.06** | 0.37±0.09** |
| Test article 2 groups | 0.45±0.08* | 0.42±0.05** | 0.41±0.10** | 0.36±0.05** |
It can be seen from the table that statistical analysis showed that the test article 1 group and the test article 2 group inhibited the swelling of rat feet caused by egg white (P <0.05, P <0.01) for more than 4 h.
The above description is only for the purpose of illustrating the present invention and the appended claims are not to be construed as limiting the scope of the invention, which is intended to cover all modifications, equivalents and improvements that are within the spirit and scope of the invention as defined by the appended claims.
Claims (12)
1. A warm moxibustion type gel plaster for relieving pain of bone diseases is characterized in that the warm moxibustion type gel plaster for relieving pain of bone diseases comprises an external traditional Chinese medicine composition for relieving pain of bone diseases, a matrix, a far infrared material and a self-heating material.
2. The warming moxibustion type gel plaster for relieving pain of bone disease as claimed in claim 1, wherein the external traditional Chinese medicine composition for relieving pain of bone disease comprises 30-50 parts of folium artemisiae argyi, 5-10 parts of safflower, 10-30 parts of lycopodium clavatum, 10-30 parts of garden balsam stem, 5-10 parts of cassia twig, 5-10 parts of angelica sinensis, 5-10 parts of radix angelicae pubescentis and 1-5 parts of rhizoma zingiberis.
3. The warming moxibustion type gel plaster for alleviating pain as defined in claim 1, wherein said base is composed of 10-40 parts of sodium polyacrylate, 1-10 parts of dihydroxyaluminum glycoxide, 1-5 parts of povidone, 1-5 parts of tartaric acid, glycerin60-100 parts of kaolin and 3-10 parts of penetration enhancer consisting of lauryl nitrogen
The ketone and the propylene glycol are 1:1, and the dosage of the total penetration enhancer is 2-5%.
4. The warming moxibustion type gel plaster for alleviating pain as claimed in claim 1, wherein the far infrared material is ultra micro powder level far infrared ceramic powder.
5. The warming moxibustion type gel patch for alleviating pain as claimed in claim 1, wherein the self-heating material is: 4-6 parts of reduced iron powder, 1-2 parts of vermiculite powder, 1-2 parts of activated carbon, 1-2 parts of sodium chloride, 1-2 parts of resin and 1-2 parts of water.
6. A method for preparing warming moxibustion type gel patch for alleviating pain as bone disease according to any one of claims 1 to 5, which comprises the steps of:
taking prescription decoction pieces with the mass fraction of four fifths to prepare prescription extract; taking one fifth of prescription decoction pieces by mass, and crushing into 300-mesh ultrafine powder;
step two, taking a proper amount of folium artemisiae argyi to prepare folium artemisiae argyi essential oil;
and step three, preparing the Aitong gel plaster.
And step four, preparing the self-heating bag.
7. The method for preparing warming moxibustion type gel patch for alleviating pain as in claim 6, wherein the preparing of the prescription extract in the first step comprises:
crushing the decoction pieces of the medicinal materials in the prescription into coarse powder, soaking the coarse powder in 50% ethanol for 30 minutes, extracting the coarse powder twice in a reflux extraction mode by using 8 times of 50% ethanol as an extraction solvent for 2 hours for the first extraction and 1.5 hours for the second extraction, filtering, combining the extracting solutions, and concentrating the extracting solutions under reduced pressure to obtain an extract with the relative density of 1.20-1.25.
8. The method for preparing warming moxibustion type gel patch for alleviating pain as in claim 6, wherein the step two, the preparing of essential oil of artemisia argyi includes:
cutting folium Artemisiae Argyi with scissors, weighing appropriate amount, placing in round bottom flask, adding 3% (g/mL) NaCl solution, soaking for 20min, ultrasonically strengthening under 150W for 20min, and steam distilling. The experimental conditions of steam distillation are that the liquid-material ratio is 15:1 and the distillation time is 2 h. Separating the oil-water mixture after distillation, and adding a dehydrating agent into the oil phase to dehydrate to obtain the folium artemisiae argyi essential oil.
9. The method for preparing warming moxibustion type gel patch for alleviating pain as bone disease according to claim 6, wherein the preparing of the moxa roll gel patch in the third step comprises:
extracting folium Artemisiae Argyi essential oil and laurel nitrogen
Mixing ketone, propylene glycol and polysorbate 80, and making into phase I; dissolving tartaric acid in appropriate amount of water, and mixing to obtain phase II; adding sodium polyacrylate, dihydroxyaluminum glycolate and polyvidone into glycerol according to the proportion of the prescription, uniformly mixing, adding the prescription extract, the medicinal material ultrafine powder, the ultrafine powder far infrared ceramic powder, kaolin and the I-phase mixed solution, and uniformly mixing to obtain a III phase; slowly dripping the phase II into the phase III, and uniformly stirring to obtain a viscous and elastic paste. And (3) after the paste is prepared, immediately coating, covering a film, standing for 24h until the paste is solidified and formed, cutting, sealing and storing. Can be cut into common type, knee joint type, cervical vertebra type, shoulder type and back protecting type according to the using position.
10. The method for preparing warming moxibustion type gel patch for alleviating pain as bone disease according to claim 6, wherein the preparing of the self-heating pack in the fourth step comprises:
weighing 4-6 parts of reduced iron powder, 1-2 parts of vermiculite powder, 1-2 parts of activated carbon, 1-2 parts of sodium chloride, 1-2 parts of resin and 1-2 parts of water. Firstly, mixing water and resin to expand the resin into slurry; then uniformly mixing the reduced iron powder, the vermiculite powder, the activated carbon and the sodium chloride; and (3) rapidly mixing the prepared slurry with the mixture, and then sealing and bagging. The self-heating bag is classified into a general type, a knee joint type, a cervical vertebra type, a shoulder type and a back protection type according to the use position.
11. Use of the warming moxibustion type gel patch for alleviating pain of bone diseases and the preparation method thereof according to any one of claims 1 to 10 in products such as medicines or medical instruments for preventing, treating and alleviating pain of bone diseases.
12. The moxibustion-type gel patch for relieving pain caused by bone diseases as claimed in claim 6, which is prepared by the method for preparing moxibustion-type gel patch, wherein the standard fingerprint pattern and the quality consistency evaluation method of the standard formulation pattern of the gel patch are characterized by comprising the steps of:
step one, preparing a test solution
Taking 1 piece of gel plaster, equally dividing into 12 parts according to the size, placing one of the gel plaster into a conical flask with a plug, precisely adding 50 percent (V/V) ethanol 50mL, weighing, carrying out ultrasonic treatment for 30min, cooling, weighing again, complementing the loss weight by 50 percent (V/V) ethanol, shaking up, centrifuging at 3000rpm for 15min, precisely absorbing 5mL of supernate, placing into a 50mL measuring flask, adding 50 percent (V/V) ethanol to dilute to a scale, shaking up, and obtaining the gel plaster, wherein a 0.45 mu m filter membrane is used for filtering before sample injection;
step two, preparing a mixed reference substance solution
Preparing a mixed reference solution, wherein the mixed reference solution comprises the following components in concentration: 0.22mg/ml of chlorogenic acid, 0.40mg/ml of isochlorogenic acid A, 0.24mg/ml of isochlorogenic acid B, 0.40mg/ml of isochlorogenic acid C, 0.22mg/ml of rutin, 0.07mg/ml of eupatilin and 0.08mg/ml of hydroxysafflor yellow A;
step three, chromatographic conditions
The chromatographic column takes octadecylsilane chemically bonded silica as a bonding phase, the length of the chromatographic column is 15-25cm, the inner diameter is 4.6mm, and the particle size is 5 mu m; the flow rate is 0.8-1.2 mL/min; setting ultraviolet detection wavelengths to be 237nm, 250nm, 280nm, 300nm and 326nm, and simultaneously collecting a 190-400 nm three-dimensional chromatogram by using DAD; the column temperature is 25-40 ℃; the sample amount is 1-50 mul; mobile phase composition and gradient elution procedure were as follows:
step four, fingerprint spectrum checking method
The number of common fingerprint peaks of a test sample under the fusion of detection wavelengths of 237nm and five wavelengths of 237nm, 250nm, 280nm, 300nm and 326nm is 26, wherein isochlorogenic acid A is used as a reference peak for identification and recognition of the common fingerprint peaks, and the macro qualitative similarity of the fingerprint of the test sample is not less than 0.90 and is between 80 and 120 percent respectively calculated according to the peak area and the retention time of the common fingerprint peaks;
step five, index component quantitative method
The standard curve method can be used for quantitative determination of 7 compound components in the test sample, and the linearity, range, detection limit and quantitative limit of the 7 compound components in the test sample are as follows:
the method comprises the following steps of quantitatively measuring 7 compound components in a test sample by using a first-line multiple evaluation method, wherein the S compound is any one of chlorogenic acid, isochlorogenic acid A, isochlorogenic acid B and isochlorogenic acid C, and the concentrations of other 6 compounds can be obtained by measuring the peak area of the S compound with a known concentration during analysis, and the calculation formula is as follows:
wherein A issIs measured as the peak area of the compound, CsTo determine the concentration of the compound, AiPeak area of compound to be evaluated, CiThe concentration of the multi-evaluation compound to be tested; relative correction factor values f for seven of the compoundssiThe following were used:
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