CN115245502A - Drop spray type nano liposome gel three-volt patch - Google Patents
Drop spray type nano liposome gel three-volt patch Download PDFInfo
- Publication number
- CN115245502A CN115245502A CN202111114421.3A CN202111114421A CN115245502A CN 115245502 A CN115245502 A CN 115245502A CN 202111114421 A CN202111114421 A CN 202111114421A CN 115245502 A CN115245502 A CN 115245502A
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- Prior art keywords
- liposome
- gel
- drug
- solution
- patch
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Abstract
A spray-dripping type nanometer liposome gel, SANYOU Patch, is prepared by extracting active ingredients from semen Sinapis Albae, radix kansui, rhizoma corydalis and herba asari to obtain concentrated extractive solution of effective components of Chinese medicinal materials; preparing liposome by using a film evaporation-ultrasonic method; the nanometer gel is further utilized to prepare a liquid traditional Chinese medicine patch, the medicine is effectively encapsulated in the nanometer liposome gel and is accurately released to the pre-applied acupuncture point through spraying and dripping, and the stability and the transdermal permeability are good. Ensures the encapsulation performance and drug-loading rate of the product, ensures the quality and the drug effect stability of the finished product, increases the effective absorption rate of the drug and improves the application convenience and the safety. The coating is uniform, and the quality uniformity and the stability are good; the sustained release effect is stable, the liposome has no separation phase in appearance when stored for 0-180 days, and the entrapment rate is stably and gradually changed from 61.4% to 52.6%; the curative effect of external treatment of the traditional Chinese medicine is improved, and the abnormity of related biochemical indexes and the skin allergy condition are not generated. The preparation method is fine and reasonable, and is convenient for industrial production.
Description
Technical Field
The invention relates to a traditional Chinese medicine gel patch of a medicine preparation containing organic active ingredients in IPC classification A61K31/00, belongs to a liquid novel dosage form of Sanfu patch, and particularly relates to a drop spray type nano liposome gel Sanfu patch and a preparation technology thereof.
Background
The Sanfu plaster is a classic transdermal drug delivery system for external use in traditional Chinese medicine. Transdermal drug delivery systems are those which are administered to the skin, where the drug passively diffuses through the stratum corneum through the difference in drug concentration between the surface of the skin and the deep layer of the skin, reaches the capillaries in the dermis, reaches the target site through systemic or local microcirculation, and thus, has a therapeutic effect on the whole body or part of the body.
The three-volt patch is used as a traditional Chinese medicine external treatment method with the characteristics of traditional Chinese medicine, adopts the principles of 'combination of people and the day' and 'treatment before disease prevention' of the traditional Chinese medicine, combines acupuncture, meridians and Chinese pharmacology in three volt days with the most abundant yang qi in one year, directly pastes traditional Chinese medicines on specific acupuncture points, generates micro-area chemical and thermal stimulation on the acupuncture points through the traditional Chinese medicines, inspires vital qi, dispels yin and cold, and restores the balance of yin and yang, thereby achieving the effects of treating and preventing diseases.
It is thought that "three-volt patch" evolved from the concept of "Tian-moxibustion". Tian moxibustion is mainly applied to acupuncture points or affected parts by using medicines which have irritation to skin. Tang dynasty Sun Saizeng introduced the word "Dry Jin Yifang". Song Chaowang practice in acupuncture and moxibustion Zhang Shengjing, and uses herba Ecliptae for external application to treat malaria, which is regarded as the prototype of "Sanfu paste". It is also theorized that the earliest application of the three-volt patch starts in the sons generation, yu Mingqing is developed, and the famous physicians Zhang Lu in Zhang Shi Yi Tong records that in summer and three volts, mustard seed, corydalis tuber, asarum and kansui are ground into powder, musk is added, and the powder is pasted on the acupuncture points of Feishu, bailao and the like to treat cold asthma, which is regarded as a mark formed by the three-volt patch.
At present, the 'Sanfu paste' does not have a standard unified formula and proportion, and medicinal materials with foaming and yang warming effects, such as ginger, white mustard seed, euphorbia kansui, asarum and the like, can be selected by all major hospital institutions. The same medical institution and different departments may have different selected medicines and proportions. In the document ' notice of reinforcing the application and management of acupoint application technology for summer treatment of winter diseases ' of the national administration of traditional Chinese medicine ' document No. 36, published by the Chinese medicine and medical science ' 2013 ', it is pointed out that the ' Sanfu plaster ' is mainly applicable to recurrent chronic respiratory diseases and can also be used for other diseases which have clinical characteristics of recurrent episodes and winter exacerbation and are identified as cold syndromes by the traditional Chinese medicine. Although the national traditional Chinese medicine administration has a medicine selection range for the Sanfu patch, specific medicine and proportion are not clear, and ginger is replaced by garlic in some hospitals, so that the Sanfu patch has similar characteristics.
In 1979, after the concept of 'treating winter diseases in summer' was proposed in the field, the Sanfu plaster has been widely used clinically because of its better curative effect on chronic diseases such as asthma and rhinitis. According to the theory of 'summer treatment of winter diseases' in traditional Chinese medicine, the three-volt patch therapy is used for strengthening body resistance and banking up root for diseases which are easy to generate, relapse or aggravate in winter so as to inspire healthy qi and increase the disease resistance of organisms, thereby achieving the purpose of preventing and treating the diseases. Thereafter, the disease types corresponding to the therapy are developed from cold asthma to the whole lung system, so that the therapy is suitable for more yang deficiency pathologies and gradually popularized.
Published patent applications for developing new technologies of the tri-volt patch product include:
the Zhongxian-county traditional Chinese medicine hospital 201611163127.0 discloses a sanfu patch for preventing and treating asthma, which is prepared from roasted white mustard seed, rhizoma corydalis, euphorbia kansui and asarum in a mass ratio of roasted white mustard seed to rhizoma corydalis to euphorbia kansui to asarum =6: heating semen Sinapis Albae with strong fire for 2min, adding semen Sinapis Albae, heating with strong fire, and stir-frying for 5min; parching with slow fire for 12min, and stopping fire; parching with the rest heat of iron pan for 15min, and taking out when the semen Sinapis Albae turns dark yellow and has slight fragrance. The invention aims to provide a sanfu patch for preventing and treating asthma and a preparation method thereof, wherein the sanfu patch can effectively reduce the incidence rate of allergic symptoms caused by skin foaming.
The Yunnan traditional Chinese medicine university 201910771431.0 discloses a Sanfu patch with a slow release function and a preparation method thereof, wherein the Sanfu patch comprises a patch and an ointment, the ointment comprises traditional Chinese medicine active substances, an ointment matrix and a medicine slow release agent, and the traditional Chinese medicine active substances are prepared from the following raw materials in parts by weight: stir-fried mustard seed, vinegar-processed rhizoma corydalis, asarum, euphorbia kansui, herba epimedii, dried ginger, cinnamon, clove and ginger juice. The invention utilizes the compatibility and adds the drug sustained release agent, so that the active ingredients of the traditional Chinese medicine can be continuously released in a longer time to achieve the long-acting effect. Frequent administration is not needed, the times can be reduced, the blood concentration is stable, the peak valley phenomenon is avoided, and the toxic and side effects of the medicine are favorably reduced. Meanwhile, the total dosage of the medicine can be reduced, and the maximum effect can be achieved by using the minimum dosage. Vaseline is used as ointment matrix, active substances carrying traditional Chinese medicines can enter blood circulation through skin, the release speed is stable, and the ointment has a continuous and powerful treatment effect on users.
Although the triple-volt patch therapy has the advantages of simple operation, low cost, remarkable curative effect and the like, a plurality of defects are still exposed in clinical application practice, such as: the dosage can not be accurately controlled, so that the difference between different treatments of different mechanisms is large; moreover, the transdermal administration efficiency of the effective components of the medicine is low, the promotion of the penetration by using ginger juice and the like easily causes great irritation, and in addition, the traditional adhesive plaster also has the defects of weak application and the like. In addition, the traditional Sanfu patch dosage form has certain defects in use, for example, the preparation process is simple, and the difference among different batches is large; as a semisolid preparation, the penetration effect of the active ingredients of the medicine is not ideal, improper use can pollute clothes, and some can also hinder normal functions of skin and the like; these can greatly affect their use.
The gel is used as an external gel preparation, has simple preparation process, convenient use, easy spreading and coating, can form a transparent film on the skin, has strong adhesiveness, is easy to absorb after local administration, has good stability and has small irritation to the skin and mucous membrane.
The pharmaceutical progress, published in 2018, no. 5, no. 380-387, of the research progress of liposome natural polymer hydrogel drug delivery systems, introduces that the hydrogel is a hydrophilic three-dimensional network structure, and compared with synthetic polymers, natural polymer materials such as chitosan, hyaluronic acid, sodium alginate and the like have good biocompatibility and biodegradability and are more suitable for being used as hydrogel matrixes. The liposome is a spherical vesicle formed by lipid bilayers, the liposome hydrogel drug delivery system can not only exert the characteristics of liposome sustained and controlled release and stimulation responsiveness release of drugs, but also improve the stability of the liposome through a hydrogel barrier, and the drugs can enter the body through various drug delivery ways such as oral administration, injection, local transdermal and the like to exert drug effects, thereby being widely applied to drug delivery systems and tissue engineering. The research progress of various hydrogel systems which take natural high molecular materials as gel frameworks and contain medicine-carrying liposomes, lipoid vesicles and the like is reviewed, and the method has important reference values in the aspects of developing novel sustained and controlled release preparations, improving the transdermal absorption and bioavailability of water-soluble medicines, researching intelligent stimulation responsive drug delivery systems and the like. Liposomes are vesicles formed by encapsulating drugs in lipid bilayers and can encapsulate water-soluble and fat-soluble drugs at the same time. The liposome has the similar structure with epidermis, has good biocompatibility with skin tissue, and can play the roles of increasing the solubility of the drug, promoting the permeation of the drug and prolonging the release time of the drug, thereby lightening the adverse reaction of the drug, protecting the drug from being damaged by enzyme, and the like. However, the fluidity of the liposome solution makes it impossible to retain it on the skin surface for a long time.
In recent years, related improvement technologies have been developed more rapidly. For example:
the baicalin liposome gel prepared from Chinese herbal medicines 2021, 52 (16) (4860-4872), su Qing, etc. can obviously reduce the level of inflammatory factors of rabbit ear acne, and has a curative effect superior to that of adapalene gel in a control group.
The nux vomica total alkali liposome gel is prepared by Chinese hospital pharmacy journal, 2017, 37 (1) (36-39), wen Saijing and the like, and researches show that the accumulated permeation amount and the permeation rate of the nux vomica total alkali liposome gel are less than those of common gel, the nux vomica total alkali liposome gel can continuously release medicine in a steady state for a long time and has a slow release effect, and on the other hand, the skin retention amount of the nux vomica total alkali liposome gel is more than that of the common gel, so that the toxic and side effects caused by systemic absorption can be reduced.
The alkaloid monomer component with significant analgesic effect, lappaconitine, is prepared into liposome gel by pharmaceutical journal of China hospital, 2019, 39 (5) (466-470), xiao Wei Gong, and the like, compared with common gel, the drug accumulation and permeation amount of the liposome gel is significantly reduced, the skin retention amount is significantly increased, and the local treatment effect is favorably exerted.
When paeonol which is clinically used for treating eczema, acne and other symptoms is prepared into liposome gel in Chinese herbal medicines 2012, 35 (5) (803-807), shijun and the like, the liposome gel not only can improve the content of local skin medicines, but also can improve the transdermal quantity of the medicines.
The tea tree oil nanoliposome and the preparation and application performance of the gel thereof are disclosed in 2007 of eastern China university of science, the tea tree oil nanoliposome is prepared by adopting an ethanol injection-ultrasonic method for the first time, the prescription of the tea tree oil nanoliposome is optimized by adopting an L18 (2 x 37) orthogonal design method, the encapsulation efficiency is taken as a main evaluation index, and two factors of the particle size and the drug-loading capacity of the liposome are considered. The result shows that the concentration of lecithin is 10 mg/ml-1, the concentration of lecithin, namely cholesterol, is 5:1, the concentration of tea tree oil is 1.0 mg/ml-1, the concentration of VE is 1.0 mg/ml-1, the concentration of deoxysodium cholate is 0.5 mg/ml-1, the concentration of Tween-80 is 4.0 mg/ml-1, the optimal formula is PBS buffer solution with an aqueous phase medium of pH6.8, the prepared tea tree oil nanoliposome has the advantages of round and round appearance, 65.0nm of average particle size and narrow distribution. The storage stability of the tea tree oil nanoliposome suspension at different temperatures is inspected, and the result shows that the tea tree oil nanoliposome stored at the temperature of 4 ℃ is most stable, and the entrapment rate, the pH value, the form and the color and luster have no obvious change. Carbomer and hydroxypropyl methylcellulose (HPMC) are respectively compounded with three matrixes of 1:2 in the mass ratio of carbomer to HPMC to prepare the tea tree oil nanoliposome gel, and the in-vitro permeation rule of the tea tree oil nanoliposome gel is inspected. The result shows that the tea tree oil nanoliposome gel prepared by taking the mixed gel compounded by carbomer and HPMC as a matrix has an in vitro permeation kinetic equation of Q =20.21t +3.98 (R2 = 0.9932), conforms to the zero-order permeation rule, has good absorption performance, can slowly release the transdermal absorption of the tea tree oil, and has good skin targeting property.
The preparation of nano brucine liposome gel and the pharmacodynamic evaluation thereof are disclosed in 2009 of China eastern university of science, brucine is an effective component of traditional Chinese medicine nux vomica clinically and mainly used for treating diseases such as rheumatic arthritis, rheumatoid arthritis, osteoarthritis, traumatic pain and the like, but the clinical wide application of the nux vomica is seriously influenced by the defects of high toxicity, laggard application dosage form, slow response and the like. In the early stage of research, the research group not only reduces the toxicity of strychnine, but also improves the analgesic and anti-inflammatory curative effects of strychnine and prolongs the duration of the action of the medicament by virtue of nano lipidization. On the basis, the suspension spray preparation of the nano strychnine is developed by combining the clinical treatment of painful diseases and the characteristics of the nano particles. However, the subsequent preliminary clinical test shows that the stability of the designed liposome solution is poor and the clinical use is inconvenient. In order to solve the problems, carbomer-940 is used as a gel to construct a novel nano brucine liposome gel system, so that the formula and the preparation process of the liposome gel are optimized. The drug release, transdermal property, safety and drug effect of the nanometer brucine liposome gel are comprehensively examined through in vivo and in vitro experiments. The nanometer brucine liposome is prepared by adopting an ethanol dripping-homogeneous dispersion method process, and the liposome suspension with the average particle size of 78.6nm, the average entrapment rate of 80.1 percent and good dispersibility and stability is obtained. Optimizing and determining the gel process conditions. The optimal formula for preparing the gel is obtained by taking the stability, appearance, biological viscosity and the like of the gel as parameters: the concentration of carbomer is 1.0%, the ratio of glycerin to carbomer is 8:1, and the pH value of the gel is 6.4-7. This gives a transparent, semi-solid gel formulation with good biological viscosity on the skin. On the basis, the prepared liposome suspension is doped into blank gel to obtain liposome gel, and the in vitro release experiment result shows that the drug concentration of 0.1 percent is optimal. In vitro release experiment results show that the release rate of the strychnine liposome gel is obviously slower than that of the strychnine gel and the strychnine liposome spray preparation in the same experiment time. The release amount of the strychnine gel in 3h is 85%, the release rate of the liposome spray in 8h is 71.7%, and the liposome gel is only 42.7%, so that the action time of the medicament is greatly prolonged. In vitro transdermal experiments prove that the transdermal amount, transdermal speed and intradermal retention of the strychnine in the strychnine liposome gel have obvious advantages compared with the common free strychnine gel. The skin acute toxicity and irritation of the strychnine liposome gel are examined through in-vivo animal experiments. The results indicate that the brucine liposome gel has no significant toxicity to either damaged or intact skin. The analgesic and anti-inflammatory effects of the strychnine liposome gel are examined by utilizing an acetic acid induced mouse writhing experiment and a xylene ear swelling method, and the result shows that the liposome gel has good drug effect. Compared with strychnine liposome spray, the analgesic and anti-inflammatory effects of strychnine liposome gel are longer. The results show that compared with the spray preparation with the same dosage, the gel preparation has reduced administration times and administration amount, which has important significance for clinical application. The treatment effect of the strychnine is further improved by the compatibility of the asarum and the borneol. The asarum and borneol can improve the transdermal quantity of the strychnine gel and the analgesic and anti-inflammatory effects to a certain extent. The in vivo safety test proves that the compound preparation is safe and feasible clinically.
According to the problem that the anti-cancer drugs are difficult to be accurately controlled and released at tumor sites, a double-response liposome nano gel carrier is designed by publishing 2019 (052) 003 of Tianjin university, and a pH and reduction double-sensitive liposome nano gel (pH/R-lipogels) is constructed by a template in-situ polymerization method, wherein the pH and reduction double-sensitive liposome nano gel comprises a pH sensitive liposome membrane and a disulfide bond cross-linked redox sensitive nano gel inner core, the particle size distribution and the morphology of the pH/R-lipogels are researched by a laser particle sizer and a transmission electron microscope, and the result proves that the pH/R-lipogels have narrow particle size distribution and present a regular spherical structure. The in vitro drug release experiment result shows that the drug-loaded double-sensitive liposome nanogel (DOX @ pH/R-lipogels) can rapidly respond to the change of the pH value and the GSH concentration, and the release rate of the adriamycin hydrochloride (DOX) is improved. In vitro cell experiments show that DOX can be effectively released to promote apoptosis of 4T1 cells under the stimulation of DOX @ pH/R-lipogels in a tumor cell microenvironment.
Paclitaxel nanoliposome gel is prepared by carrying out preparation and in-vitro transdermal research on paclitaxel nanoliposome gel in 2015 (032) 002 of China modern applied medicine, particle size distribution, entrapment rate, in-vitro release degree and transdermal characteristic methods of the paclitaxel nanoliposome gel are examined, paclitaxel nanoliposome is prepared by adopting a thin film evaporation high-pressure microfluidics method, carbomer is used as a gel matrix, paclitaxel nanoliposome gel is developed, and an optimal process is explored by adopting an orthogonal test. Measuring the particle size and the particle size distribution of the liposome by using a particle size measuring instrument, measuring the encapsulation efficiency by using a low-speed-ultra-speed phase combination method, carrying out an in vitro release test by using a dialysis membrane diffusion method, and investigating the in vitro transdermal property by using an in vitro mouse skin combination improved Franz diffusion device; the result shows that the optimum process of the paclitaxel nano liposome comprises the following steps that the content of lecithin is 2 percent, the mass ratio of the medicine to the phospholipid is 1: 30, and the mass ratio of the phospholipid to the cholesterol is 10: 1; the measured particle size was 81.8nm; the particle size distribution coefficient is 0.180; the average encapsulation efficiency is 73.2%; the cumulative release percentage of the nanoliposome gel for 72h is 79.04 percent; the cumulative permeation amount per unit area of 48h is 429.68 mug cm < -2 >; the conclusion is that the preparation has simple preparation process, easy coating, higher encapsulation efficiency, smaller particle size, uniform distribution and slow in-vitro release; the nano-liposome can promote paclitaxel which is fat-soluble medicine to permeate skin.
The nanoliposome developed in recent years has attracted much attention as a drug carrier, for example, zhang Xiujuan and the like prepare about 200nm hydroxycamptothecin nanoliposome with uniform size, and the nanoliposome has high encapsulation efficiency, stable drug release and liver targeting. Although nanotechnology has shown significant advantages in the extraction and administration of effective ingredients of traditional Chinese medicines; however, the research on the traditional Chinese medicine nanotechnology is still less at present, a complete theory and application system are not formed, and particularly, few reports are made on the research on the aspects of improving the administration efficiency of the effective ingredients of the medicine, enhancing the use convenience and the like by replacing the traditional adhesive plaster used in the patch with a new preparation form. On the other hand, modern gel dressings are concerned about because of the advantages of quick and effective covering, excellent biocompatibility, good mechanical property and the like; researches show that the gel dressing has obvious effects on improving the slow release effect of the medicament, reducing the cytotoxicity of the medicament and the like. The related documents in this respect are less published, for example:
chinese patent application 202011482486.9 provided by Hubei Kangyuan pharmaceutical industry Co., ltd discloses a Shangtongning liposome gel plaster and a preparation method thereof. The plaster comprises the following raw materials: radix Angelicae Dahuricae, rhizoma corydalis, cortex Phellodendri, carthami flos, catechu, soybean phospholipid, cholesterol, mentholum, borneolum Syntheticum, camphora, methyl salicylate, sodium polyacrylate, aluminum hydroxide, glycerol, azone, carbomer 940, citric acid and water. The preparation method comprises the following steps: sequentially extracting radix Angelicae Dahuricae, rhizoma corydalis, cortex Phellodendri, carthami flos and Catechu by supercritical CO2 extraction to obtain volatile oil and extract powder; preparing soybean phospholipid, cholesterol, menthol, borneol and camphor into liposome containing borneol, menthol and camphor, and mixing the volatile oil, the extract powder, the liposome and the matrix to obtain the gel plaster.
Chinese patent application 201810812548.4, which is provided by Wuhan university of Engineers, discloses liposome-loaded gel with electrical stimulation and nerve scar inhibition effects and a preparation method thereof, and raw materials for preparing the gel comprise: hydroxyethyl cellulose, asiaticoside, chitosan, graphene oxide, vitamin E, phospholipid and cholesterol; the method comprises the following steps: oxidizing hydroxyethyl cellulose by using sodium periodate to obtain aldehyde hydroxyethyl cellulose, preparing asiaticoside liposome by adopting a film dispersion method, and preparing cross-linked gel from the aldehyde hydroxyethyl cellulose, the asiaticoside liposome and chitosan. The gel adopts liposome technology to encapsulate asiaticoside which is a traditional Chinese medicine extract and has the effect of inhibiting scars, so as to improve the absorption rate of the medicine, reduce the irritation and increase the stability of the medicine; the conductive substance graphene oxide, hydroxyethyl cellulose and chitosan are mixed and crosslinked, so that the mechanical property of the gel is improved to a certain extent.
Chinese patent application 201710325262.9 proposed by Wuhan Aimin pharmaceutical Co., ltd discloses an anti-swelling pharmaceutical composition, which is composed of aescin A or its salt, aescin B or its salt, and diethylamine salicylate at a ratio of 0.3-1.5: 0.5-1: 2-5. Also discloses compound aescin A, B liposome hydrogel patch containing the composition and a preparation method thereof.
Chinese patent application 200610098476.9 by sfield technologies limited discloses a patch-type gel for nano skin containing liposome nano water, which can stably and effectively deliver cosmetic active substances, such as those having the effect of moisturizing the skin, into and through the skin. The patch-type cosmetic composition for transdermal delivery based on the gel for nano skin comprises 0.01-80.0 WT% of nano water based on the total weight of the gel for nano skin; 0.01 to 10.0WT% of a skin compatible polymer; and 5.0 to 20.0WT% of a polyol.
The Chinese patent application 202110571886.5 proposed by the second subsidiary hospital of the university of Nanchang relates to a drug delivery system of a gel drug-loaded patch, wherein the gel drug-loaded patch is lipid gel, takes lyotropic liquid crystal formed by combining soybean lecithin and glycerol dioleate as a matrix, and also comprises a drug, a photo-thermal agent, absolute ethyl alcohol and deionized water; the gel drug-carrying patch drug delivery system is characterized in that a gel drug-carrying patch encapsulated with drugs is pasted at a skin defect part, the surface of the gel drug-carrying patch is irradiated by near infrared spectrum, a photo-thermal agent generates heat after receiving near infrared radiation and induces lipid gel to be transformed into liquid, the drugs are released, irradiation is stopped, the temperature is reduced, the liquid phase is transformed into gel, and the drugs are stopped being released.
The Chinese patent application 201610055874.6 proposed by Shenzhen aeolian regenerative medicine science and technology Limited company relates to a preparation method of a skin patch for repairing skin burn, and comprises the following steps: respectively obtaining adipose-derived stem cells and allogenic Pi Jizhi; mixing the adipose-derived stem cells with hydrogel and then inoculating the mixture to the allogenic dermal matrix; wherein the adipose-derived stem cells are autologous to the patient with the skin burn; the hydrogel is prepared by mixing alginate solution and gelatin solution. The autologous adipose-derived stem cells are loaded in the alginate-gelatin hydrogel, so that bacteria can be blocked, the adipose-derived stem cells and skin wounds can keep a humid environment, a good repairing environment is provided, immune rejection is reduced, the phenomenon that the skin tissues are newly regenerated due to adhesion between the patch and the wounds when the patch is replaced can be avoided, the purpose of rapidly repairing the skin is achieved, the pain of a patient can be relieved, and scars and the like formed by accumulation of pigments at the wound parts are not easily caused.
Chinese patent application 200710060470.7 proposed by Zhongbao pharmaceutical Co., ltd, tianjin relates to a gel patch for treating migraine and a preparation method thereof. The invention discloses a traditional Chinese medicine patch for treating migraine, which is a medicinal preparation consisting of 2-100% of traditional Chinese medicine extract and 98-0% of pharmaceutic adjuvant, wherein the ligusticum wallichii, the ligusticum sinense and the rhizoma cyperi are all fat-soluble extracts extracted by a supercritical fluid extraction method.
Chinese patent application 201710168358.9 provided by Jingchu theory academy of technology discloses a tamoxifen flexible nano liposome gel and a preparation method thereof, wherein the gel is prepared from tamoxifen, cholesterol, a phospholipid material, a water-soluble gel matrix, a transdermal penetration enhancer, a surfactant, a preservative, a humectant, a pbs buffer solution, ammonia water, distilled water and ethanol which are used as raw materials according to a certain proportion. The preparation method comprises the following steps: 1) Preparing tamoxifen flexible nanoliposome suspension; 2) Preparing a blank gel matrix; 3) And uniformly mixing the blank gel matrix and the tamoxifen flexible nano liposome suspension to obtain the tamoxifen flexible nano liposome gel.
Therefore, modern gel dressings are concerned about the advantages of quick and effective covering, excellent biocompatibility, good mechanical property and the like; researches show that the gel dressing has obvious effects on improving the slow release effect of the medicament, reducing the cytotoxicity of the medicament and the like. However, no inspired and studied advances in gel dressing technology combined with traditional Chinese medicinal plasters have been found in the prior art.
The existing Sanfu paste products and technologies are all in the form of traditional medicine pastes, obviously, the activity of effective medicines is easily influenced in complicated production and preparation procedures, and the application effect is restricted; the difference between different treatments of different mechanisms is large due to the fact that the dosage cannot be accurately controlled, the transdermal administration efficiency of active ingredients of the medicine is low, the ginger juice and the like are used for promoting penetration, the irritation is high, and the traditional adhesive plaster is not firm in pasting and the like. Moreover, the general cloth-based carrier cannot give consideration to both the packing and the air permeability. When applied to large blood vessels or subcutaneous fat-poor sites, such as Baliao, the patch is difficult to heal once ulcerated and may cause a series of problems such as inflammation. Including itching, causalgia, blister and other adverse reaction symptoms to cause external heat counseling. Although the regular medical institutions are also continuously searching and adjusting the application position, time, application interval and total application times, accidents still do not occur, and the foaming time is slightly wrong, so that burns and festers are easily caused. In addition, for example, among the acupuncture points for immunity, the acupuncture points at the joint are not suitable for application, and the acupuncture points "Jiexi" are located at the ankle joint, which may affect the joint movement if it is ulcerated.
Disclosure of Invention
The invention aims to provide a spray-dropping type nano liposome gel tri-volt patch, researches and develops a new tri-volt patch transdermal drug delivery dosage form, ensures the encapsulation performance of a product, accurately controls the drug-loading rate, increases the effective absorption rate of a drug, and improves the application convenience and safety.
The aim of the invention is achieved by the following technical measures:
the preparation method comprises the following steps: 1) Weighing the raw materials of the medicinal materials according to the same amount, wherein the raw materials comprise semen brassicae, euphorbia kansui, rhizoma corydalis and asarum, and obtaining the concentrated extract of the active ingredients of the raw materials of the medicinal materials in a Soxhlet extractor by adopting an ethanol evaporation method or a thin film evaporation method plus a supercritical carbon dioxide method; 2) Preparing a nano-scale refined and uniformly distributed traditional Chinese medicine active ingredient drug-loaded liposome solution by adopting a film evaporation-ultrasonic method or a film evaporation method plus a supercritical carbon dioxide method; ultrasonically dissolving egg yolk lecithin and cholesterol with a small amount of absolute ethyl alcohol, and evaporating under reduced pressure until a uniform and transparent film is formed on the wall of the bottle; drying in a vacuum drying oven to ensure removal of all ethanol; cooling to room temperature, uniformly mixing the concentrated extract of the active ingredients of the medicinal raw materials with distilled water, adding the mixture into a round-bottom flask to enable a film to fall off, stirring in a water bath for hatching, and finally performing ultrasonic treatment to obtain a drug-loaded liposome solution; active ingredients of the medicine are finely and uniformly distributed in the medicine-carrying liposome solution in a nanometer scale. 3) Weighing polyvinyl alcohol in a beaker, adding distilled water, naturally expanding in a refrigerator overnight, and uniformly stirring at 50-95 ℃ until the polyvinyl alcohol is completely dissolved into a polyvinyl alcohol solution; respectively weighing citric acid and chitosan auxiliary raw materials, adding distilled water, and stirring at 45 ℃ until the citric acid and the chitosan auxiliary raw materials are completely dissolved to obtain a chitosan solution; respectively weighing polyvinyl alcohol solution, chitosan solution and glycerol, uniformly stirring at 55 ℃, cooling to room temperature, adding the drug-loaded liposome solution, and uniformly stirring to obtain liposome gel; the film forming time of the liposome gel is about 30-35min. 4) The liposome gel is prepared into a liquid drop spray type nano liposome gel three-volt patch traditional Chinese medicine patch, and active ingredients of medicinal raw materials are encapsulated in the nano liposome gel, so that the separation of the medicine and a matrix is avoided.
Especially, the medicinal materials also comprise at least one of earthworm, cicada shell, stiff silkworm, scorpion, centipede and leech.
In particular, the raw materials of the medicinal materials by weight are 1-1.25.
In particular, the sinapine thiocyanate content in the concentrated extract of the active ingredients of the medicinal materials is 0.6672mg/ml.
In particular, the particle size of the drug-loaded liposome solution is about 120-150nm.
In particular, the concentration (A) of the egg yolk lecithin is 20-30 mg/ml; the mass ratio of the egg yolk lecithin to the cholesterol (B) is 10:1 to 5:1; the volume ratio (C) of the concentrated extract to the distilled water during mixing is 1:1 to 4:1.
in particular, the liposome gel is prepared by 1) weighing 8g of semen Sinapis Albae, radix kansui, lumbricus, rhizoma corydalis and herba asari respectively according to prescription amount, extracting with 70% ethanol 8 times of the amount of the medicinal materials under reflux in a Soxhlet extractor for 3h, and removing ethanol from the extractive solution with rotary evaporator. About 45mL of the concentrated extract of the effective components of the traditional Chinese medicine is obtained and is stored for standby at 4 ℃ in a refrigerator. 2) Preparing liposome by thin film evaporation-ultrasonic method, weighing 0.25g egg yolk lecithin and 0.03g cholesterol, ultrasonic dissolving with small amount of anhydrous ethanol, transferring into 250mL round bottom flask, and evaporating at 45 deg.C under reduced pressure in rotary evaporator until a uniform transparent film is formed on the wall of the flask. Drying was carried out in a vacuum oven at 45 ℃ for 1h to ensure removal of all ethanol. Cooling to room temperature, mixing 2mL of the concentrated extract of the effective components of the traditional Chinese medicine with 8mL of distilled water, adding into a round-bottom flask, shaking gently to make the film fall off, incubating for 1h in a water bath under stirring at 55 ℃, finally performing ultrasound for 10min to obtain a liposome solution, and storing in a refrigerator at 4 ℃.
In particular, 10 to 20 weight percent of polyvinyl alcohol aqueous solution and 3 to 5 weight percent of chitosan solution are prepared, and the same amount of citric acid is contained; swelling polyvinyl alcohol at 0-8 ℃ overnight, and mixing the components in a ratio of 5: weighing polyvinyl alcohol solution and chitosan solution according to the mass ratio of 1, uniformly stirring at 55 ℃, cooling to room temperature, and mixing the mixed solution and the drug-loaded liposome solution 2:1, adding the drug-loaded liposome solution, and uniformly stirring to obtain the liposome gel.
In particular, the liposome is a hydrophilic three-dimensional network structure hydrogel, and is a spherical vesicle formed by lipid bilayers; in addition, the liposome can also be polysaccharide natural polymer containing chitosan, hyaluronic acid, alginate, dextran pullulan, and xanthan gum; or natural protein polymers including collagen and gelatin, and mixed material gels.
Particularly, the dosage of polyvinyl alcohol, chitosan and glycerol is determined by taking account of the film forming time of the liposome gel and the adhesion factor of the film to the skin of a patient; further determining the preferred process as follows: weighing 10g of polyvinyl alcohol in a beaker, adding 50g of distilled water, naturally expanding in a refrigerator overnight, and uniformly stirring at 80 ℃ until the polyvinyl alcohol is completely dissolved; respectively weighing 2g of citric acid and chitosan, adding 46g of distilled water, and stirring at 35 ℃ until the citric acid and the chitosan are completely dissolved to prepare a 4% chitosan solution; weighing two solutions of the concentrated extract and the liposome solution of the traditional Chinese medicine active ingredients and glycerol of 20g respectively according to the mass ratio of 5:1, uniformly stirring at 55 ℃, cooling to room temperature, adding 10mL of the liposome solution, and uniformly stirring to obtain the liposome gel, wherein the film forming time is about 30-35min.
The invention has the advantages and effects that: the liquid traditional Chinese medicine patch is prepared by utilizing the nanoscale gel, so that the fat-soluble medicine enters the skin through a fat-soluble channel, and the slow release effect is obvious. The preparation process avoids the problem of separation of the medicine and the matrix, and the preparation method is fine and reasonable and is convenient for industrial production. The medicine is effectively encapsulated in the nano liposome gel, is accurately and slowly released to preset acupuncture points through spraying and dripping, and has good stability and transdermal permeability. The coating has higher drug loading and encapsulation effects, is uniform in coating and convenient to use, retains volatile components to a greater extent, and has better quality uniformity and stability; meanwhile, the liposome also has the sustained and controlled release effect, the liposome has no phase separation in appearance when stored for 0 to 180 days, and the entrapment rate is stably and gradually changed from 61.4 percent to 52.6 percent; is favorable for the stable release of the medicine and prolongs the treatment time.
Particularly, the invention adopts a new spray-drop gel preparation form to replace the traditional adhesive base material such as adhesive plaster used in the patch, reliably improves the administration efficiency of the effective components of the medicine, enhances the convenience of use, innovatively promotes and enriches related researches. Compared with the prior art, the invention can more effectively ensure the quality and the stable drug effect of the finished product, has no irritation to skin no matter in blank or drug-loaded liposome gel, obviously improves the transdermal drug absorption efficiency, and has no abnormity of related biochemical indexes and skin allergy in clinical tests; the anti-swelling effect and the anti-swelling safety are better, the application powder dosage is convenient to control, the comfort is improved, the side effect is reduced, and the medicine utilization value is improved.
Drawings
FIG. 1 is an HPLC chart of a sinapine thiocyanate control solution in the examples.
FIG. 2 is a transmission electron micrograph of the liposome solution in the example.
FIG. 3 is a graph of the cumulative amount of sinapine thiocyanate active ingredient in the permeate over time as a function of time for the examples.
Fig. 4 and 5 are a graph of the evaluation criteria and a graph of the evaluation criteria of the study group in example 1, respectively.
FIG. 6 is a graph of the correlation between paired samples before and after treatment in the study groups of the examples.
FIG. 7 is a graph showing the correlation between the paired samples before and after the treatment of the control group in the examples.
FIG. 8 is a statistical chart of the study group and the control group after treatment in the examples.
FIG. 9 is a graph of the test results of the independent samples in the examples.
FIG. 10 is a statistical chart of two pre-and post-treatment groups of the ACT table in the examples.
FIG. 11 is a graph of the test results of two groups of independent samples before and after treatment in the ACT table of the example.
Fig. 12 is a block diagram of the process steps of preparing the drop spray type nanoliposome gel tri-volt patch in the example.
Detailed Description
The principle of the invention lies in that on the basis of a prescription for treating cold asthma carried by Zhang's Yi Tong', a new formulation Sanfu paste preparation is obtained by preparing a drug-loaded liposome by a thin film evaporation-ultrasonic method and combining the drug-loaded liposome with a gel dressing, and the research also carries out quantitative analysis on the biotoxicity, the drug-loaded efficiency, the administration effect and the like of the preparation, thereby providing a research basis for further clinical use.
The liposome gel is prepared by combining the liposome and the gel, so that the problem of fluidity can be effectively solved, the retention, stability and slow release of the medicament can be improved, and the toxic and side effects, irritation and the like of the medicament can be reduced. On the other hand, the nano technology is introduced into the extraction and preparation of the traditional Chinese medicine and the development of a new preparation form, so that a better effect is achieved.
In the principle of the invention, the nano liposome is used as a drug carrier, and has the following advantages: the transdermal drug delivery system can simultaneously entrap hydrophilic and lipophilic drugs, is nontoxic and biodegradable, has no stimulation to skin, can realize transdermal drug delivery of the entrapped drugs through a hydration mechanism, a fusion mechanism, a penetration mechanism and the like, and is easy to functionalize to realize targeted drug delivery. The nano liposome has better effects on improving the utilization rate of the medicament, reducing the toxic and side effects of the medicament and the like.
In the research of the invention, the detection research of drug absorption, cytotoxicity and skin sensitivity of animals and the clinical research are also carried out; the development of a new transdermal drug delivery preparation and a new application mode increases the effective absorption rate of the drug, reduces toxic and side effects, is beneficial to developing traditions, digging the self efficacy of the three-volt patch, promoting the formation of the general standard of the three-volt patch therapy accepted by the public and promoting the further development of the three-volt patch therapy.
The invention is suitable for respiratory system diseases such as bronchial asthma, chronic bronchitis, bronchiectasis, chronic pharyngitis, rhinitis, chronic obstructive pulmonary disease, repeated upper respiratory tract infection, emphysema, pulmonary heart disease and the like. Can dredge channels and collaterals, regulate qi and blood, relieve chest stuffiness and descending qi, strengthen the spleen and stomach, invigorate yang qi, regulate the lung and spleen functions of a human body, and continuously enhance the immune function of the organism, thereby achieving the effects of exciting yang qi, promoting blood circulation, dispelling cold evil and improving the defense and external functions.
The invention is further illustrated by the following figures and examples.
Example 1: as shown in fig. 12, the development process includes the following steps:
firstly, carrying out supercritical extraction on the raw materials of white mustard seed, corydalis tuber, asarum, euphorbia kansui and earthworm to obtain the effective components of the raw materials;
secondly, treating the traditional Chinese medicine active ingredients obtained in the first step by a thin film evaporation method and a supercritical carbon dioxide method to obtain nano-scale refined and uniformly distributed traditional Chinese medicine active ingredient drug-loaded liposome;
thirdly, comparing the medicinal materials of the white mustard seed, the corydalis tuber, the asarum, the euphorbia kansui and the earthworm in the first step with the drug-loaded liposome obtained in the second step in terms of biological activity and toxicity;
fourthly, matching the drug-loaded liposome obtained in the second step with chitosan, gelatin and glacial acetic acid auxiliary raw materials to prepare liposome gel;
fifthly, performing a biotoxicity experiment on the liposome gel prepared in the fourth step;
sixthly, performing animal experiments on the administration effect of the liposome gel prepared in the fourth step;
seventhly, preparing a novel spray dripping type nano liposome gel Sanfu paste spray;
eighthly, the novel nano liposome gel Sanfu paste spray for the drop spray is clinically applied.
In this embodiment, the preparation technique of the drop spray type nanoliposome gel vodka specifically includes:
A. extracting effective components of the traditional Chinese medicine, and preparing a concentrated extracting solution of the effective components of the traditional Chinese medicine.
The effective components of the Sanfu patch prescription are extracted by ethanol reflux extraction, and the Sanfu patch prescription comprises semen Sinapis Albae, radix kansui, lumbricus, rhizoma corydalis and herba asari. The quality standard of the preparation is evaluated by measuring sinapine thiocyanate content of main effective component of semen Sinapis Albae by high performance liquid chromatography.
a1, the extraction process comprises:
weighing 8g of semen Sinapis Albae, radix kansui, lumbricus, rhizoma corydalis and herba asari according to the prescription amount, extracting with 70% ethanol 8 times of the amount of the raw materials under reflux in a Soxhlet extractor for 3 hr, and removing ethanol from the extractive solution with rotary evaporator. About 45mL of the concentrated extract of the effective components of the traditional Chinese medicine is obtained and is stored for standby at 4 ℃ in a refrigerator.
a2, content determination:
the chromatographic condition for measuring the content of sinapine thiocyanate;
a chromatographic column: zorbaxExtend C 18 Columns (250 mm. Times.4.6 mm,5 μm); mobile phase: acetonitrile-0.05 mol. L -1 Potassium dihydrogen phosphate (20: 80); flow rate 1.0 mL/min -1 (ii) a Detection wavelength: 326nm; sample introduction amount: 10 mu L of the solution; column temperature: at 30 ℃. Standard curve: y =56.27X +0.00089r =0.9998 (0.0005-0.005 mg/mL); as shown in figure 1, HPLC of sinapine cyanate control solution is shown, and the sinapine thiocyanate content in the concentrated extractive solution of the effective components of the obtained traditional Chinese medicine is 0.6672mg/ml.
a3, preparing a liposome solution;
according to different proportions of the traditional Chinese medicines used in the Sanfu patch, the recommended application ranges of the yolk lecithin concentration (A), the lecithin-cholesterol mass ratio (B) and the volume ratio (C) of the extracted liquid medicine to water are as follows: 20-30 mg/ml, 10. The proportion of the five raw material medicines in the embodiment is 1.
Determining yolk lecithin concentration (A), lecithin-cholesterol mass ratio (B), volume ratio of extracted liquid medicine to water (C) and the like as main investigation factors by taking liposome encapsulation efficiency as an index, designing an orthogonal experiment, and optimizing the liposome preparation process as follows:
preparing liposome by thin film evaporation-ultrasonic method, weighing 0.25g egg yolk lecithin and 0.03g cholesterol, ultrasonic dissolving with small amount of anhydrous ethanol, transferring into 250mL round bottom flask, and evaporating at 45 deg.C under reduced pressure in rotary evaporator until a uniform transparent film is formed on the wall of the flask. Drying was carried out in a vacuum oven at 45 ℃ for 1h to ensure removal of all ethanol. Cooling to room temperature, mixing 2mL of the concentrated extract of the effective components of the traditional Chinese medicine with 8mL of distilled water, adding into a round-bottom flask, shaking gently to make the film fall off, incubating for 1h in a water bath with stirring at 55 ℃, finally performing ultrasonic treatment for 10min to obtain a liposome solution, and storing in a refrigerator at 4 ℃.
Orthogonal experimental design table and results:
the obtained liposome solution has a particle size of about 120-150nm as shown in figure 2.
The stability of the liposomes at 4 ℃ over a longer period of time was investigated:
a4, preparing liposome gel;
preparing 10-20 wt% polyvinyl alcohol water solution and 3-5 wt% chitosan solution (containing the same amount of citric acid). Swelling polyvinyl alcohol at 0-8 ℃ overnight, and mixing the components in a ratio of 5: weighing polyvinyl alcohol solution and chitosan solution according to the mass ratio of 1, uniformly stirring at 55 ℃, cooling to room temperature, adding liposome solution according to the mass ratio of the mixed solution to the liposome solution 2:1, and uniformly stirring to obtain the gel.
The dosage of polyvinyl alcohol, chitosan and glycerin is considered by the factors of film forming time, adhesive force of the film to the skin and the like, and the optimal process is determined as follows:
10g of polyvinyl alcohol is weighed into a beaker, 50g of distilled water is added, the mixture is naturally expanded in a refrigerator overnight, and the mixture is stirred uniformly at 80 ℃ until the polyvinyl alcohol is completely dissolved. 2g of citric acid and chitosan are weighed respectively, 46g of distilled water is added, and the mixture is stirred at the temperature of 35 ℃ until the mixture is completely dissolved, so that a 4% chitosan solution is prepared. Weighing the two solutions and glycerol at a mass ratio of 5:1 of 20g respectively, stirring uniformly at 55 ℃, cooling to room temperature, adding 10mL of liposome solution, and stirring uniformly to obtain liposome gel, wherein the film forming time is about 30-35min.
a5, in-vitro permeation experiment;
in vitro permeation experiments were performed using Franz diffusion Chi Duichuan Tongzhutie and liposome gel of the same drug dosage, and the content of effective component, sinapine thiocyanate, in the permeate at different times was measured, and the relationship between the cumulative permeation amount and time was shown in FIG. 3. Wherein, for the convenience of comparison, the traditional Sanfu patch comprises the following components in a mass ratio of 1.
As can be seen from the cumulative permeation curve, the Sanfu patch liposome gel shows a remarkable slow release effect.
a6, skin irritation test;
6 mice were harvested and depilated on both sides of the spine with 8% sodium sulfide, each side having an area of about 3cm 2 After 24 hours, a blank gel matrix is coated on the left depilating area of the rat, a drug-loaded gel is coated on the right depilating area of the rat, a preservative film is covered after the drug is coated, the rat is bound by gauze, after 6 hours of drug administration, the residual drug is cleaned by warm water, and the conditions of erythema, edema and the like of the drug administration part are observed at 1h,24h,48h and 72 h. The scoring criteria are shown in FIG. 4 and the evaluation criteria are shown in FIG. 5.
a7, evaluation results;
the average score = (erythema reaction total score + edema reaction total score)/animal, blank gel value is 0, drug-loaded liposome gel value is 0.33; the results show that neither the blank nor the loaded liposome gel is irritating to the skin.
B. Summary of clinical studies;
b1, a study object; the study subjects were selected from 7/2020 to 9/2020 patients.
b2, estimating and grouping sample amount;
according to a clinical sample amount estimation method, the sample amount is determined to be 50 cases by combining the small sample clinical observation test of the project. The clinical random control test method is adopted, and the method is divided into two groups according to a random number table: based on the treatment based on syndrome differentiation of traditional Chinese medicine, 50 cases of traditional treatment groups are treated by adopting a traditional plaster method, and 50 cases of novel preparation groups are treated by adopting a novel plaster method. The study group and the conventional treatment group did not complete 2 cases of each study.
b3, diagnosis standard;
1) The traditional Chinese medicine diagnosis standard is as follows: the diagnosis and treatment guideline for common diseases in the internal medicine of traditional Chinese medicine (ZYXH/T5-2008) is published according to the Chinese medical society.
1-1 attack wheezing in the throat, dyspnea, even opening mouth and raising shoulder, inability to lie flat, or cyanosis of lips and nails.
1-2 is recurrent and is often induced by sudden change of climate, improper diet, emotional disorder, and fatigue. Before the onset, symptoms such as nasal itching, sneezing, cough, chest distress and the like often occur.
1-3 has a history of allergy or family history.
1-4 two lungs can hear wheezing or accompanied by damp crackle.
1-5 blood eosinophils can be increased.
Eosinophils were visible on sputum smears 1-6.
No special change is observed in chest X-ray examination (1-7), and emphysema is observed after long-term treatment.
2) Western diagnostic criteria: refer to the guidelines for bronchial asthma control (the respiratory disease division of the Chinese medical society, the asthma group, 2016 edition).
Clinical symptoms and signs of typical asthma:
2-1 recurrent wheezing, shortness of breath, with or without chest distress or cough, frequent nights and interties, often associated with exposure to allergens, cold air, physical and chemical irritations, upper respiratory infections, exercise, etc.;
2-2 during attack, the two lungs can hear the wheeze sound scattered or diffused, and the expiratory phase is prolonged;
2-3 the above symptoms and signs can be therapeutically or spontaneously alleviated.
3) Objective examination of variable airflow restriction:
3-1 bronchodilator test positive (FEV 1 increased >12% and FEV1 absolute value increased >200m1 after bronchodilator inhalation);
3-2 bronchial excitation test is positive;
3-3 Peak Expiratory Flow (PEF) mean diurnal variability (7 d of Per day Total variability/7) at least >10%, or PEF Zhou Bianyi Rate [ (maximum PEF value-minimum PEF value within 2 weeks) ]/[ (maximum PEF value + minimum PEF) within 2 weeks x 1/2] × 100% ] >20%.
The compound preparation meets the symptoms and signs, has any one of objective examination of airflow limitation, and can be used for diagnosing asthma except wheezing, short breath, chest distress and cough caused by other diseases.
4) Inclusion criteria;
4-1 meets the traditional Chinese medicine diagnosis standard;
4-2 meets the Western diagnosis standard;
4-3 years of age 18-65 years;
4-4 signing an informed consent form;
5) Exclusion criteria;
5-1 those that do not meet inclusion criteria;
5-2 serious primary diseases such as heart, brain, liver and hematopoietic system;
5-3 patients being treated with hormones and or immunosuppressive agents;
5-4 the traditional Chinese medicine syndrome diagnosis belongs to the patients with heat asthma.
6) Exiting the standard;
6-1, finding out the patients who do not accord with the case inclusion standard;
6-2, the medicine has no adverse reaction in the medication process, but the treatment is interrupted due to other unpredictable reasons;
6-3 patients give up the trial by themselves;
6-4 patients who have to stop taking the medicine due to serious adverse reactions;
those who meet the above requirements are all withdrawal cases, and the reason for the withdrawal should be recorded faithfully.
7) Researching observation indexes;
the method of clinical random control test is divided into two groups: the observation indexes of 50 traditional treatment groups and 50 novel preparation groups are mainly three aspects:
firstly, safety indexes (observed before treatment and after 2 months of treatment +/-5 days) comprise blood, urine, feces routine and liver functions (ALT, AST), kidney functions (BUN, cr) and electrocardiogram; the indexes are not found to be abnormal indexes in the traditional treatment group and the novel preparation group during the treatment period.
The second is the clinical efficacy index (observed before treatment and after 2 months +/-5 days), which mainly comprises the rate of improving the clinical efficacy or the equivalence, and is evaluated according to the improvement of symptoms and physical signs and an asthma control test (ACT table).
Thirdly, the traditional Chinese medicine syndrome curative effect index is evaluated by adopting a traditional Chinese medicine symptom integral quantity table.
8) Evaluating the curative effect;
evaluating a standard;
8-1 asthma control test (ACT Table);
and (3) complete control: 25 minutes; and part of control: 20 to 24 minutes; not controlled < 20 min.
8-2, the traditional Chinese medicine syndrome curative effect judgment standard;
clinical symptoms and physical signs disappear or basically disappear, and the traditional Chinese medicine syndrome integral is reduced by more than or equal to 95 percent;
the clinical symptoms and physical signs are obviously improved, and the traditional Chinese medicine syndrome integral is reduced by more than or equal to 70 percent;
the effective clinical symptoms and physical signs are improved, and the syndrome integral of the traditional Chinese medicine is reduced by more than or equal to 30 percent;
ineffective clinical symptoms and physical signs are not obviously improved or even aggravated, and the traditional Chinese medicine syndrome integral is reduced by less than 30%;
9) Statistical analysis of clinical studies;
9-1, estimating the content of the sample;
the method of clinical random control test and small sample clinical observation test are adopted to determine the sample amount to be 50 cases.
9-2, statistics and analysis of research data;
comparison before and after treatment for each group: checking by using pairing t; independent T-tests were used for post-treatment comparisons between study and treatment groups. Statistical analysis was done using SPSS statistical software.
10 SPSS output clinical study results:
10-1 study group statistical analysis results before and after treatment;
the correlation between paired samples before and after treatment in the study group is shown in the following table:
the paired sample is tested as shown in FIG. 6;
the results show that the P before and after treatment of the study group is less than 0.05, and the significant difference exists.
Comparison before and after treatment of 10-2 control group: the correlation between the paired samples before and after treatment in the control group is shown in the following table;
the results show that the P before and after treatment of the study group is less than 0.05, and the significant difference exists.
Study group versus control group post-treatment comparison: the statistical results of the study group and the control group after treatment are shown in figure 8, the test results of the independent samples are shown in figure 9, and the results show that the P before and after treatment of the study group is less than 0.01 and has significant difference.
10-3 ACT table two pre-and post-treatment comparisons: ACT table two pre-and post-treatment group statistical plots are shown in FIG. 10; ACT table the results of two independent sample tests before and after treatment are shown in figure 11.
The results show that there is a significant difference between the study groups with pre-and post-treatment ACT values P < 0.01.
11 Study results analysis summary:
the basic research of the novel three-volt-patch preparation based on the liposome gel is that the active ingredients in the traditional Chinese medicinal materials are effectively extracted to obtain the drug-loaded liposome gel with proper physical properties on the basis, the drug absorption, cytotoxicity and skin sensitivity detection research of animals is completed simultaneously, and the result shows that the drug-loaded liposome gel obviously improves the transdermal drug absorption efficiency and is safe and reliable. And the preparation of the product for the test of the novel drug-loaded liposome gel tri-volt patch is completed.
On the basis, the clinical research carried out by the novel three-volt patch of the drug-loaded liposome gel obtains expected effects, is obviously higher than the traditional three-volt patch in the aspects of convenience, practicability and curative effect, has great popularization and achievement conversion values, greatly improves the absorption rate of the drug, promotes the curative effect of external treatment of the traditional Chinese medicine, and prompts that the drug-loaded liposome gel has great potential value in external treatment of the traditional Chinese medicine. The safety of the method is also reflected in clinical research, and no case exists because the drug-carrying drop spray type nano liposome gel three-volt patch has the abnormal conditions of related biochemical indexes and skin allergy.
In the above embodiment, the liposome is a hydrophilic hydrogel with a three-dimensional network structure, and compared with synthetic polymers, chitosan, hyaluronic acid and sodium alginate natural polymer materials have good biocompatibility and biodegradability, and are also suitable for being used as a liposome hydrogel matrix.
In the above example, the liposome is a spherical vesicle formed by lipid bilayer. In addition, the liposome can also be polysaccharide natural polymer containing chitosan, hyaluronic acid, alginate, dextran pullulan, and xanthan gum; or natural protein polymers including collagen and gelatin, and mixed material gels. The liposome takes natural high molecular materials as a gel skeleton, the liposome hydrogel drug delivery system can not only exert the characteristics of liposome sustained and controlled release and stimulation responsiveness release of drugs, but also improve the stability of the liposome through a hydrogel barrier, and the drugs can enter the body through a local transdermal drug delivery way to exert drug effects, thereby being widely applied to drug delivery systems and tissue engineering.
In the invention, researches show that the existence of the liposome can provide the effects of the sustained and controlled release and the responsive release of the hydrogel system to the drugs, thereby avoiding burst effect, increasing local drug concentration, reducing side effect and improving drug effect; the hydrogel matrix can protect the integrity of the liposome, improve the stability of the liposome, is suitable for local administration and expands the application range of the liposome. Although liposomes have significant advantages as ideal drug carriers, they also have some drawbacks, such as: due to blood circulation, the liposome is easily phagocytized by reticuloendothelial system macrophages in vivo and is easily and rapidly eliminated and metabolized; secondly, the liposome also has the problems of physical and chemical stability, and when the conditions such as pH, temperature and the like of the external environment change, the phenomena of aggregation, drug leakage, phospholipid oxidation hydrolysis and the like can be generated, so that the quality guarantee period of the medicine is shortened, and researches show that the pH and the temperature can influence the fluidity of a lipid bilayer and the hydrolysis rate of phospholipid.
Claims (10)
1. The drop spray type nano liposome gel three-volt patch is characterized in that the preparation method comprises the following steps:
1) Weighing the raw materials of the medicinal materials according to the same amount, wherein the raw materials comprise semen Sinapis Albae, radix kansui, rhizoma corydalis and herba asari, and concentrating the extract of the effective components of the raw materials in a Soxhlet extractor by adopting an ethanol evaporation method or a thin film evaporation method plus a supercritical carbon dioxide method;
2) Preparing a drug-loaded liposome solution by adopting a film evaporation-ultrasonic method or a film evaporation method plus a supercritical carbon dioxide method; ultrasonically dissolving egg yolk lecithin and cholesterol with a small amount of absolute ethyl alcohol, and evaporating under reduced pressure until a uniform and transparent film is formed on the wall of the bottle; drying in a vacuum drying oven to ensure removal of all ethanol; cooling to room temperature, uniformly mixing the concentrated extract of the active ingredients of the medicinal raw materials with distilled water, adding the mixture into a round-bottom flask to enable a film to fall off, stirring in a water bath for hatching, and finally performing ultrasonic treatment to obtain a drug-loaded liposome solution; active ingredients of the medicine are finely and uniformly distributed in a nanometer level in the medicine-carrying liposome solution;
3) Weighing polyvinyl alcohol in a beaker, adding distilled water, naturally expanding in a refrigerator overnight, and uniformly stirring at 50-95 ℃ until the polyvinyl alcohol is completely dissolved into a polyvinyl alcohol solution; respectively weighing citric acid and chitosan auxiliary raw materials, adding distilled water, and stirring at 45 ℃ until the citric acid and the chitosan auxiliary raw materials are completely dissolved to obtain a chitosan solution; respectively weighing polyvinyl alcohol solution, chitosan solution and glycerol, uniformly stirring at 55 ℃, cooling to room temperature, adding the drug-loaded liposome solution, and uniformly stirring to obtain liposome gel; the film forming time of the liposome gel is 30-35 min;
4) The liposome gel is prepared into a liquid drop spray type nano liposome gel three-volt patch traditional Chinese medicine patch, and active ingredients of medicinal raw materials are encapsulated in the nano liposome gel, so that the separation of the medicine and a matrix is avoided.
2. The drip spray type nanoliposome gel trioxane patch according to claim 1, wherein the medicinal material further comprises at least one of earthworm, cicada shell, stiff silkworm, scorpion, centipede and leech.
3. The spray-dropping type nano liposome gel-containing couch paste according to claim 1, wherein the raw materials of the medicinal materials by weight are 1-1.25.
4. The spray-dripping type nanoliposome gel trioxane patch according to claim 1, wherein the content of sinapine thiocyanate in the concentrated extract of the active ingredients of the medicinal materials is 0.6672mg/ml.
5. The drop spray type nanoliposome gel trioxypane patch according to claim 1, wherein the particle size of the drug-loaded liposome solution is 120-150nm.
6. The spray-dripping type nanoliposome gel vodka according to claim 1, wherein the concentration of egg yolk lecithin (A) is 20-30 mg/ml; the mass ratio (B) of the egg yolk lecithin to the cholesterol is 10 to 5:1; the volume ratio (C) of the concentrated extract to the distilled water during mixing is 1:1-4:1.
7. The nano liposome gel three-volt patch as claimed in claim 1, wherein the liposome gel is prepared by 1) weighing 8g of semen Sinapis Albae, radix kansui, lumbricus, rhizoma corydalis and herba asari respectively according to the prescription amount, extracting with 70% ethanol 8 times of the amount of the medicinal materials under reflux in a Soxhlet extractor for 3h, and removing ethanol from the extractive solution with a rotary evaporator. Obtaining about 45mL of concentrated extract of the active ingredients of the medicinal raw materials, and storing the concentrated extract in a refrigerator at 4 ℃ for later use;
2) Preparing liposome by thin film evaporation-ultrasonic method, weighing 0.25g egg yolk lecithin and 0.03g cholesterol, ultrasonic dissolving with small amount of anhydrous ethanol, transferring into 250mL round bottom flask, and evaporating at 45 deg.C under reduced pressure in rotary evaporator until a uniform transparent film is formed on the wall of the flask. Drying was carried out in a vacuum oven at 45 ℃ for 1h to ensure removal of all ethanol. Cooling to room temperature, uniformly mixing 2mL of concentrated extract of active ingredients of the raw materials of the medicinal materials with 8mL of distilled water, adding the mixture into a round-bottom flask, slightly shaking to enable a film to fall off, carrying out water bath stirring incubation for 1h at 55 ℃, finally carrying out ultrasound for 10min to obtain a drug-loaded liposome solution, and storing the drug-loaded liposome solution in a refrigerator at 4 ℃;
3) Weighing 10g of polyvinyl alcohol in a beaker, adding 50g of distilled water, naturally expanding in a refrigerator overnight, and uniformly stirring at 80 ℃ until the polyvinyl alcohol is completely dissolved; respectively weighing 2g of citric acid and chitosan, adding 46g of distilled water, and stirring at 35 ℃ until the citric acid and the chitosan are completely dissolved to obtain a 4% chitosan solution; weighing two solutions of the concentrated extract of the active ingredients of the medicinal raw materials and the drug-loaded liposome solution and glycerol at the mass ratio of 5:1, respectively, stirring uniformly at 55 ℃, cooling to room temperature, adding 10mL of liposome solution, and stirring uniformly to obtain the liposome gel.
8. The drop spray type nanoliposome gel trioxypane patch according to claim 1, wherein in the preparation method 3), 10-20 wt% of polyvinyl alcohol aqueous solution and 3-5 wt% of chitosan solution are prepared, containing the same amount of citric acid; swelling the polyvinyl alcohol at 0-8 ℃ overnight; weighing the polyvinyl alcohol solution and the chitosan solution according to the mass ratio of 5:1, uniformly stirring at 55 ℃, cooling to room temperature, adding the drug-loaded liposome solution according to the mass ratio of the mixed solution to the drug-loaded liposome solution 2:1, and uniformly stirring to obtain the liposome gel.
9. The drop spray type nanoliposome gel three-dimensional patch according to claim 1, wherein the liposome is a hydrophilic three-dimensional space network structure hydrogel, spherical vesicle formed by lipid bilayers; in addition, the liposome can also be polysaccharide natural polymer containing chitosan, hyaluronic acid, alginate, dextran pullulan, and xanthan gum; or natural protein polymers including collagen and gelatin, and mixed material gels.
10. The drop spray type nanoliposome gel three-voltage patch according to claim 1, wherein the dosage of the auxiliary material is determined according to the principle of considering both the film forming time of the liposome gel and the adhesive force of the formed film to the skin of the patient.
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