Preparation method for promoting transdermal absorption of externally-applied medicine, externally-applied medicine composition and application of externally-applied medicine composition

Abstract

The invention provides a preparation method for promoting transdermal absorption of an externally-applied medicine, an externally-applied medicine composition and application of the externally-applied medicine composition, and the composition comprises multiple traditional Chinese medicine raw materials such as cortex lycii radicis, radix cyathulae and radix astragali and further comprises oat beta-glucan, laurocapram and the like. The radix astragali is processed by a specific honey roasting process, and the Chinese fevervine herb extract is extracted by supercritical CO2. The preparation method comprises the following steps: extracting and concentrating part of medicinal materials to obtain extract, grinding the rest of medicinal materials into powder, adding the powder into the extract, mixing, preparing oat beta-glucan and lecithin into a nano-emulsion, dropwise adding the nano-emulsion into the mixture, adding laurocapram through gradient heating, stirring, and finally adding pearl powder to prepare an external application dosage form. According to the pharmaceutical composition, aiming at complex pathogenesis such as neuropathy, vasculopathy and infection of the diabetic foot, multiple medicinal materials synergistically play a role, drug absorption and utilization are effectively promoted, and the pharmaceutical composition has the effects of clearing heat and cooling blood, tonifying kidney and reducing blood sugar, activating blood and stimulating menstrual flow, dispersing blood stasis and stopping bleeding, promoting ulcer healing, controlling infection, relieving pain, improving neurological functions and the like, and has a wide application prospect. The medicine is suitable for treating diabetic foot through external application.

Description

Technical Field

[0001] The invention relates to the technical field of drug preparation, and in particular to a preparation method capable of promoting the transdermal absorption of externally applied drugs, and an externally applied drug composition and application thereof. Background Art

[0002] Diabetic foot is one of the common and serious chronic complications of diabetes. It is mainly caused by the interaction of multiple factors such as neuropathy, vascular disease and local infection caused by the long-term high blood sugar level in diabetic patients. Diabetic neuropathy can lead to decreased or loss of sensation in the feet, making it difficult for patients to detect foot injuries; vascular disease causes poor blood circulation in the feet, tissue ischemia and hypoxia, and insufficient supply of nutrients, which in turn affects the ability to heal wounds; once local infection occurs, it is very easy to spread rapidly and difficult to control on the basis of the above pathology. In severe cases, it can lead to gangrene and even the risk of amputation, which brings great pain to the patient's physical and mental health, and also imposes a heavy economic burden on the family and society.

[0003] At present, there are many different treatments for diabetic foot. In terms of drug treatment, Western medicine mostly uses antibiotics to control infection, microcirculation-improving drugs to promote blood circulation, and neurotrophic drugs to repair nerve damage. However, long-term use of antibiotics can easily lead to the production of drug-resistant bacteria, and these drugs can often only intervene in a single pathological link, making it difficult to comprehensively improve the complex condition of diabetic foot. For example, although some antibiotics can inhibit bacterial growth to a certain extent, they have limited effect on the repair of damaged nerve and vascular tissues.

[0004] Traditional Chinese medicine also has many applications in the treatment of diabetic foot, such as taking Chinese medicine orally to regulate the body's qi, blood, yin and yang, but the direct effect on local lesions is relatively weak; although Chinese medicine washing or fumigation can improve local symptoms to a certain extent, the penetration and absorption efficiency of the active ingredients of the medicine is low, and it is difficult to penetrate into the diseased tissue to exert a lasting and comprehensive therapeutic effect. In addition, some existing topical medicines for diabetic foot are not comprehensive in their formula composition, and may only focus on promoting blood circulation and removing blood stasis or clearing away heat and detoxifying. There is a lack of comprehensive consideration of the multiple causes and pathological mechanisms of diabetic foot, resulting in unsatisfactory treatment effects, which is difficult to meet the urgent needs of clinical treatment of diabetic foot. Therefore, it is of great practical significance to develop a more efficient, comprehensive and safe drug composition for the treatment of diabetic foot. Summary of the invention

[0005] In view of this, the present invention proposes a preparation method and an external application drug composition and application thereof for promoting the transdermal absorption of external application drugs to solve the above problems.

[0006] The technical solution of the present invention is achieved as follows: a preparation method for promoting the transdermal absorption of externally applied drugs, comprising the following steps:

[0007] S1. Wash the root bark of Lycium bark, Cyathula officinalis, Salvia miltiorrhiza, Lonicera japonica and Gallwood separately, grind them into coarse powder after drying, pass through a 40-60 mesh sieve, add 6-8 times the volume of 60-80% ethanol solution, soak for 1-2 hours, use ultrasonic assisted extraction 1-3 times, each time with an ultrasonic power of 300-500W and an ultrasonic time of 30-40 minutes, combine the extracts, and concentrate under reduced pressure to an extract with a relative density of 1.05-1.15.

[0008] S2, astragalus, frankincense, myrrh, dragon's blood, dracaena resin, ficus pumila, alpinia oxyphylla, Dalbergia odorifera, scutellaria baicalensis extract and borneol are respectively ground into fine powder, passed through 80-100 mesh sieve, and the obtained fine powder is added to the above extract, heated to 40-50°C, and dispersed by high shear to make it fully and evenly mixed.

[0009] S3. Dissolve oat β-glucan and lecithin in 1-3 times the volume of deionized water, stir to form a uniform dispersion, emulsify through high-pressure microfluidization to obtain emulsion droplets, and then add them to the above mixture. After stirring evenly, add laurocapram at a gradient temperature, continue stirring for 10-15 minutes, and finally add pearl powder and stir for 5-10 minutes.

[0010] The gradient heating of S3 is divided into three steps to add laurocapram. The first stage: first, the temperature of the drug mixture is 30-35°C, 1 / 3 of laurocapram is added, and stirred evenly. At this time, the lower temperature can allow laurocapram to slowly interact with other ingredients, and preliminarily improve the transdermal performance of the drug mixture. In this temperature range, laurocapram can better penetrate between drug molecules, further enhancing its role in promoting transdermal absorption of drugs. The second stage: the temperature is raised to 40-45°C, half of the remaining laurocapram is added, and stirring is continued; in this temperature range, laurocapram can better penetrate between drug molecules, further enhancing its role in promoting transdermal absorption of drugs; the third stage: the temperature is raised to 50-55°C, the last laurocapram is added, and stirred thoroughly; through this gradient heating addition method, laurocapram can be more evenly distributed in the drug composition, and its function as a transdermal enhancer is fully exerted, thereby improving the drug's ability to penetrate the site of diabetic foot lesions.

[0011] S4. Prepare the final drug mixture into an external application dosage form.

[0012] Furthermore, the rotation speed of the high shear disperser S2 is 2000-3000 rpm, and the processing time is 5-10 min.

[0013] Furthermore, the pressure of the high-pressure microfluidic emulsification of S3 is 100-200 MPa, the temperature is 20-40° C., the flow rate is controlled at 10-30 L / h, the microchannel diameter is 50-200 μm, and the number of cycles is 3-6 times.

[0014] Furthermore, the pharmaceutical composition of the external application dosage form comprises the following raw materials in parts by weight: 12-18 parts of Lycium bark, 10-13 parts of Cyathula officinalis, 20-30 parts of Astragalus, 15-20 parts of Salvia miltiorrhiza, 10-15 parts of Honeysuckle, 5-10 parts of frankincense, 5-10 parts of Myrrh, 13-18 parts of Dragon's Blood, 8-12 parts of Dracaena resin, 5-10 parts of Ficus pumila, 3-8 parts of Gallwood, 3-8 parts of Alpinia oxyphylla, 2-5 parts of Dalbergia odorifera, 1-3 parts of Cistanche deserticola extract, 1-3 parts of borneol, 5-12 parts of oat β-glucan, 3-6 parts of laurocapram, 2-5 parts of lecithin and 1-4 parts of pearl powder, and the particle size of the pearl powder is 20-50 nm.

[0015] Furthermore, the pharmaceutical composition in the form of an external application comprises the following raw materials in parts by weight: 15 parts of Lycium bark, 12 parts of Cyathula capitata, 25 parts of Astragalus, 18 parts of Salvia miltiorrhiza, 12 parts of Honeysuckle, 8 parts of frankincense, 8 parts of Myrrh, 15 parts of Dragon's Blood, 10 parts of Dracaena resin, 8 parts of Ficus pumila, 5 parts of Gallbladderwood, 5 parts of Alpinia oxyphylla, 3 parts of Dalbergia odorifera, 2 parts of Cistanche deserticola extract, 2 parts of borneol, 8 parts of oat β-glucan, 5 parts of laurocapram, 4 parts of lecithin and 3 parts of pearl powder.

[0016] Furthermore, the astragalus is honey-roasted astragalus, which is prepared by uniformly mixing the astragalus with refined honey at 100-118° C. in a weight ratio of 10:1-2, and then stewing for 1-3 hours, frying until dark yellow, and then crushing into coarse powder after cooling, and passing through a 40-60 mesh sieve.

[0017] Furthermore, the extract of Croton rotundus is obtained by supercritical CO2 extraction, with an extraction pressure of 20-30MPa, an extraction temperature of 40-50°C, a CO2 flow rate of 15-25kg / h, an extraction time of 2-4 hours, and separation and filtration to obtain the Croton rotundus extract.

[0018] Furthermore, the topical application dosage form prepared by the preparation method is used in the preparation of drugs for treating diabetic foot.

[0019] Compared with the prior art, the present invention has the following beneficial effects:

[0020] The compatibility of the prescription of the present invention follows the principle of monarch, minister, assistant and envoy, so as to achieve synergistic enhancement, balance the medicinal properties and accurately target the treatment of diabetic foot; the monarch medicine uses Astragalus to greatly replenish the vital energy, support the poison and promote the growth of granulation, and the blood clotting and dragon blood tree resin promote blood circulation and remove blood stasis, stop bleeding and promote granulation, improve the blood circulation of the foot, eliminate blood stasis and blockage, and its hemostasis and granulation can effectively control wound bleeding and promote the growth of new meat, and match Astragalus, the three are coordinated as the monarch medicine, and focus on the two aspects of qi and blood double replenishment and blood circulation and blood stasis, and treat both the symptoms and the root causes. The ministerial medicine Salvia miltiorrhiza promotes blood circulation and removes blood stasis, cools blood and eliminates carbuncle and leads medicine to the diseased area, which can lead all medicines directly to the diseased area, which is the key in the ministerial medicine, and frankincense and myrrh promote blood circulation, qi and pain, reduce swelling and promote granulation, and assist the monarch medicine to strengthen the effect of removing blood stasis, reducing swelling and relieving pain. The adjuvant Radix Rehmanniae can clear away heat and cool blood, and the two drugs of honeysuckle can remove local heat and toxicity, prevent and control the spread of infection, and at the same time can restrain the warm and dry nature of the main drug, so that the whole prescription is warm but not dry, without the disadvantage of hurting yin, and they are adjuvants to clear away heat and toxicity. Fructus Ficus and Radix Gallbladderwood can clear away heat, promote dampness and detoxify to improve the local environment, borneol can open the mind, clear away heat and relieve pain, preserve and promote muscle growth and promote transdermal absorption, and the extract of Glechoma longituba can help improve symptoms, and together help the main and ministerial drugs to play their role. The adjuvant oat β-glucan, laurocapram, and lecithin can promote drug transdermal penetration, pearl powder can astringe and promote muscle growth and harmonize the drugs, and Alpinia oxyphylla and Dalbergia odorifera can help the main and ministerial drugs and harmonize the drug properties. The drugs in the whole prescription are used together to replenish qi and activate blood circulation, clear away heat and dampness, detoxify and reduce swelling, promote muscle growth and relieve pain. Multiple targets are targeted at the etiology and pathogenesis of diabetic foot, promoting healing and symptom relief. DETAILED DESCRIPTION

[0021] In order to better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.

[0022] Unless otherwise specified, the experimental methods used in the embodiments of the present invention are all conventional methods.

[0023] Unless otherwise specified, the materials, reagents, etc. used in the embodiments of the present invention can be obtained from commercial sources.

[0024] The following is based on the "Chinese Pharmacopoeia", "Chinese Materia Medica Dictionary", "Li Medicine and Li Medicine" and "Li Nationality Pharmacopoeia".

[0025] Introduce the basic information of main APIs:

[0026] Radix Lycii: Nature and flavor Meridians: Sweet, cold; enters the lung, liver, and kidney meridians. Functions and indications: Cools blood and removes steam, clears lungs and reduces fire.

[0027] Sichuan Cyathula: Nature and flavor: neutral; sweet, slightly bitter; liver and kidney meridians. Functions: promote blood circulation and menstruation, dispel wind and dampness, promote urination and relieve stranguria.

[0028] Danshen: Nature and flavor: bitter, slightly cold; enters the heart meridian, liver meridian, spleen meridian, and lung meridian. Functions and indications: promote blood circulation and remove blood stasis, soothe the liver and relieve depression, regulate the spleen and stomach, moisten the lungs and relieve cough.

[0029] Honeysuckle: Nature and flavor: sweet, cold. Enters the lung, heart and stomach meridians. Functions and indications: clears away heat and detoxifies, dispels wind-heat.

[0030] Gallbladderwood: Nature and flavor: bitter, cold; enters the liver and gallbladder meridians. Functions and indications: clearing away heat and detoxifying, removing phlegm and relieving cough, relieving pain, reducing swelling, and promoting diuresis.

[0031] Astragalus: Nature and flavor: sweet, warm; enters the spleen and lung meridians. Functions and indications: replenishing qi and strengthening the exterior, promoting diuresis and expelling toxins, draining pus, healing sores and promoting tissue regeneration. Used for symptoms such as qi deficiency and fatigue, poor appetite and loose stools, sinking of middle qi, chronic diarrhea and prolapse of the anus, bloody stool and metrorrhagia, spontaneous sweating due to exterior deficiency, and edema due to qi deficiency.

[0032] Frankincense: Nature and flavor: pungent, bitter, warm in nature; enters the heart, liver, and spleen meridians. Functions and indications: promotes blood circulation, promotes qi, relieves pain, reduces swelling and promotes tissue regeneration. Used for symptoms such as heart and abdomen pain, tendon spasm, traumatic injury, sores, swelling and pain.

[0033] Myrrh: Nature and flavor Meridian: Pungent, bitter, neutral; enters the heart meridian, liver meridian, spleen meridian. Functions and indications: dissipates blood stasis, relieves pain, reduces swelling and promotes tissue regeneration.

[0034] Xuejie: ​​Nature and flavor: sweet, salty, neutral; enters the heart and liver meridians. Functions and indications: activate blood circulation and relieve pain, dissipate blood stasis and stop bleeding, promote tissue regeneration and heal sores.

[0035] Dragon Blood Tree: Sweet and cool. Enters the lung, spleen and kidney meridians. Functions and indications: It has the effects of promoting blood circulation and dispersing blood stasis, relieving pain and stopping bleeding, and healing sores and promoting tissue regeneration.

[0036] Ficus pumila: Nature and flavor: sweet, sour, neutral; enters the kidney, stomach, and large intestine meridians. Functions and indications: dispel wind and dampness, promote blood circulation and dredge collaterals, detoxify and reduce swelling.

[0037] Alpinia oxyphylla: Nature and flavor Meridians: Spicy, warm; enters the spleen and kidney meridians. Functions and indications: warms the spleen, stops diarrhea, controls saliva, warms the kidney, consolidates essence, and reduces urination.

[0038] Dalbergia odorifera: Nature and flavor: Spicy, warm in nature; enters the liver and spleen meridians. Functions and indications: dissipates blood stasis and stops bleeding, regulates qi and relieves pain.

[0039] Cistanche deserticola: sweet, sour, neutral in nature. Enters the spleen, stomach, liver, and lung meridians. Functions and indications: dispel wind and dampness, detoxify and reduce swelling, promote blood circulation and relieve pain.

[0040] Borneol: Nature and flavor: pungent, bitter, slightly cold; enters the heart, spleen, and lung meridians. Functions and indications: invigorates the mind, clears away heat and relieves pain. Example 1

[0041] A topical medicinal composition comprises the following raw materials in parts by weight: 12 parts of cortex lycii, 10 parts of cyathula, 20 parts of astragalus, 15 parts of salvia miltiorrhiza, 10 parts of honeysuckle, 5 parts of frankincense, 5 parts of myrrh, 13 parts of dragon's blood, 8 parts of dracaena resin, 5 parts of ficus pumila, 3 parts of gallwood, 3 parts of alpinia oxyphylla, 2 parts of dalbergia odorifera, 1 part of scutellaria baicalensis extract, 1 part of borneol, 5 parts of oat beta-glucan, 3 parts of laurocapram, 2 parts of lecithin and 1 part of pearl powder.

[0042] The astragalus is honey-roasted astragalus, which is prepared by uniformly mixing the astragalus with 100° C. refined honey in a weight ratio of 10:1, and then steaming for 1 hour, frying until dark yellow, and then crushing into coarse powder after cooling, and passing through a 40-mesh sieve.

[0043] The extract of Croton rotundus is obtained by supercritical CO2 extraction, with an extraction pressure of 20MPa, an extraction temperature of 40°C, a CO2 flow rate of 15kg / h, an extraction time of 2 hours, and separation and filtration to obtain the extract of Croton rotundus. Example 2

[0044] A topical medicinal composition comprises the following raw materials in parts by weight: 18 parts of cortex lycii, 13 parts of rhizoma cyrtonemae, 30 parts of astragalus, 20 parts of salvia miltiorrhiza, 15 parts of honeysuckle, 10 parts of frankincense, 10 parts of myrrh, 18 parts of dragon's blood, 12 parts of dracaena resin, 10 parts of ficus pumila, 8 parts of radix scutellariae, 8 parts of alpinia oxyphyllae, 5 parts of dalbergia odorifera, 3 parts of scutellaria baicalensis extract, 3 parts of borneol, 12 parts of oat beta-glucan, 6 parts of laurocapram, 5 parts of lecithin and 4 parts of pearl powder.

[0045] The astragalus is honey-roasted astragalus, which is prepared by uniformly mixing the astragalus with 118° C. refined honey in a weight ratio of 10:2, and then steaming for 3 hours, frying until dark yellow, and then crushing into coarse powder after cooling, and passing through a 60-mesh sieve.

[0046] The extract of Croton rotundus is obtained by supercritical CO2 extraction, with an extraction pressure of 30MPa, an extraction temperature of 50°C, a CO2 flow rate of 25kg / h, an extraction time of 4 hours, and separation and filtration to obtain the Croton rotundus extract. Example 3

[0047] A topical medicinal composition comprises the following raw materials in parts by weight: 15 parts of cortex lycii, 12 parts of rhizoma cyrtonemae, 25 parts of astragalus, 18 parts of salvia miltiorrhiza, 12 parts of honeysuckle, 8 parts of frankincense, 8 parts of myrrh, 15 parts of dragon's blood, 10 parts of dracaena resin, 8 parts of ficus pumila, 5 parts of radix strychnifoliae, 5 parts of alpinia oxyphylla, 3 parts of dalbergia odorifera, 2 parts of scutellaria baicalensis extract, 2 parts of borneol, 8 parts of oat beta-glucan, 5 parts of laurocapram, 4 parts of lecithin and 3 parts of pearl powder.

[0048] The astragalus is honey-roasted astragalus, which is prepared by uniformly mixing the astragalus with 115° C. refined honey in a weight ratio of 10:2, and then steaming for 2 hours, frying until dark yellow, and then crushing into coarse powder after cooling, and passing through a 560-mesh sieve.

[0049] The extract of Croton rotundus is obtained by supercritical CO2 extraction, with an extraction pressure of 25MPa, an extraction temperature of 45°C, a CO2 flow rate of 20kg / h, an extraction time of 3 hours, and separation and filtration to obtain the extract of Croton rotundus.

[0050] The above examples 1-3 adopt the following preparation method:

[0051] S1. Wash the root bark of Lycium bark, Cyathula officinalis, Salvia miltiorrhiza, honeysuckle and Gallwood separately, dry them and grind them into coarse powder, pass them through a 50-mesh sieve, add 7 times the amount of 70% ethanol solution, soak them for 2 hours, and use ultrasonic assisted extraction twice, each time with an ultrasonic power of 400 W and an ultrasonic time of 35 minutes. Combine the extracts and concentrate them under reduced pressure to an extract with a relative density of 1.1;

[0052] S2, astragalus, frankincense, myrrh, dragon's blood, dracaena resin, ficus pumila, oxyphylla, Dalbergia odorifera, scutellaria baicalensis extract and borneol were ground into fine powder respectively, passed through a 90-mesh sieve, and the obtained fine powder was added to the above extract, heated to 45°C, and dispersed by high shear, the speed of the high shear disperser was 2500rpm, and the processing time was 8min, so that it was fully mixed;

[0053] S3, dissolving oat β-glucan and lecithin in deionized water, stirring to form a uniform dispersion, and emulsifying by high-pressure microfluidization, the pressure of high-pressure microfluidization emulsification is 150MPa, the temperature is 30°C, the flow rate is controlled at 20L / h, the microchannel diameter is 100μm, the number of cycles is 5 times, so that the solution forms nano-scale emulsion droplets, and adding them to the above mixture, stirring evenly, and then adding laurocapram by gradient heating. The first stage: first, the temperature of the drug mixture is 35°C, 1 / 3 of laurocapram is added, and stirring evenly, the second stage: the temperature is raised to 42°C, half of the remaining laurocapram is added, and stirring is continued; the third stage: the temperature is raised to 55°C, the remaining laurocapram is added, and stirring is continued for 15 minutes, and finally, pearl powder is added, and stirring is continued for 10 minutes;

[0054] S4. Prepare the final mixture into an external application dosage form.

[0055] Comparative Example 1

[0056] The difference between this comparative example and Example 3 is that an external application pharmaceutical composition comprises the following raw materials in parts by weight: 15 parts of Lycium bark, 12 parts of Cyathula officinalis, 25 parts of Astragalus, 18 parts of Salvia miltiorrhiza, 12 parts of Honeysuckle, 8 parts of frankincense, 8 parts of Myrrh, 15 parts of Dragon's Blood, 2 parts of Dracaena resin, 1 part of Ficus pumila, 1 part of Gallwood, 5 parts of Alpinia oxyphylla, 1 part of Dalbergia odorifera, 1 part of Cistanche deserticola extract, 2 parts of borneol, 8 parts of oat β-glucan, 5 parts of laurocapram, 4 parts of lecithin and 3 parts of pearl powder.

[0057] Comparative Example 2

[0058] The difference between this comparative example and Example 3 is that high-pressure microfluidization is not performed in step S3 of the preparation method; specifically, oat β-glucan and lecithin are dissolved in 2 volumes of deionized water and stirred to form a uniform dispersion.

[0059] Comparative Example 3

[0060] The difference between this comparative example and Example 3 is that in step S3 of the preparation method, laurocapram is directly added to the mixture, specifically, oat β-glucan and lecithin are dissolved in deionized water, stirred to form a uniform dispersion, and emulsified by high-pressure microjet, the pressure of the high-pressure microjet emulsification is 150 MPa, the temperature is 30°C, the flow rate is controlled at 20 L / h, the microchannel diameter is 100 μm, the number of cycles is 5 times, so that the solution forms nano-scale emulsion droplets, which are added to the above mixture, stirred evenly, and then laurocapram is added, stirring is continued for 15 minutes, and finally pearl powder is added and stirred for 10 minutes.

[0061] Test Example 1-Drug Absorption Experiment

[0062] 1. Experimental Materials

[0063] 1. Pharmaceutical composition: a pharmaceutical composition prepared according to Examples 1-3 and Comparative Examples 1-3.

[0064] 2. Experimental animals: Select male Wistar rats weighing 200-250 g.

[0065] 2. Experimental Methods

[0066] 1. Animal preparation: The experimental animals were adaptively fed for 1 week before the experiment, and were allowed to drink water and eat freely. During the experiment, the animals were anesthetized with a suitable anesthetic (sodium pentobarbital), and then the hair on the back of the animals was shaved to expose a skin area of ​​about 3 cm × 3 cm.

[0067] 2. Drug application: 3mg / cm 2 The drug composition is evenly applied to the exposed area of ​​the animal's back skin, and then covered with a dressing with good air permeability to prevent the drug from falling off and being contaminated.

[0068] 3. Setting of sampling time points: At 1 hour, 4 hours, 8 hours, 12 hours, 24 hours and other time points after application of the medicine, sample the skin tissue from the application site and a certain range around it (within a radius of 1 cm from the center of the application).

[0069] 4. Skin tissue processing and drug extraction: Rinse the removed skin tissue with saline to remove residual drugs on the surface, and then homogenize the skin tissue with a tissue homogenizer. Add 5mL of methanol-water (7:3, v / v) mixed solution, shake on an oscillator for 30 minutes, then centrifuge at 10000rpm for 10 minutes, and take the supernatant as the sample to be tested.

[0070] 5. Determination of drug content: The HPLC method was used to determine the content of the main active ingredients of the drug composition in the skin tissue extract.

[0071] 6. Experimental Results

[0072] Table 1: Drug absorption test results

[0073]

[0074] In the above table, it can be seen that the Example group performs better than the Comparative Example in terms of drug absorption indicators, indicating that the formulation or preparation process of the pharmaceutical composition of the present invention and other factors make the drug have better release and absorption characteristics, which is more conducive to playing a role in the treatment of diabetic foot. The pharmaceutical composition of Example 3 has the best drug absorption effect in skin tissue.

[0075] Comparison between Example 3 and Comparative Example 1 shows that the drug can achieve better absorption effect under a specific ratio. Compared with Comparative Example 2, the contact area between oat β-glucan and lecithin and other drug ingredients is increased by high-pressure microfluidization, thereby improving their dispersibility and stability. At the same time, nano-scale particles can more easily penetrate the skin barrier, thereby enhancing the transdermal absorption effect of the drug, and better exerting a comprehensive therapeutic effect together with other ingredients such as Radix Rehmanniae Root and Salvia Miltiorrhiza Root that have antibacterial, anti-inflammatory, and wound healing properties, thereby improving the overall therapeutic effect on diabetic foot.

[0076] Compared with Comparative Example 3, the addition of laurocapram in a gradient temperature increase can effectively improve the transdermal absorption efficiency of the drug composition, allowing the drug ingredients to penetrate the skin stratum corneum more and faster to reach the site of diabetic foot lesions and exert a therapeutic effect.

[0077] Test Example 2-Validity Verification

[0078] 1. Experimental Subjects

[0079] 1. Inclusion criteria

[0080] Patients aged between 30 and 75 years old, diagnosed with type 2 diabetes and with diabetic foot that meets Wagner classification 1-3. Patients with clear ulcers, infections or neuropathy symptoms on the feet, and the ulcer area is between 1-10 cm². Patients who have not received other local or systemic treatments related to diabetic foot in the past 2 weeks (except for conventional hypoglycemic treatment) have voluntarily signed informed consent and are able to cooperate in the entire experimental process and follow-up.

[0081] 2. Exclusion criteria

[0082] Patients with severe heart, liver, kidney dysfunction or other serious systemic diseases that may affect the experimental results or cannot tolerate the experimental drugs.

[0083] Patients with foot ulcers with malignant lesions or severe osteomyelitis.

[0084] Allergic to experimental drugs or their excipients.

[0085] Pregnant or breastfeeding women.

[0086] People with mental illness or those who are unable to communicate normally.

[0087] Through volunteer recruitment, a total of 108 eligible patients were included, and the patients were divided into an observation group and a control group using a random number table method, with 54 cases in each group. The two groups of patients were tested for balance in terms of baseline data such as age, gender, duration of diabetes, blood sugar control level (HbA1c), severity of foot lesions (Wagner grade, ulcer area, depth, etc.), ensuring that there was no statistical difference (P>0.05).

[0088] 2. Experimental Methods

[0089] 1. Observation Group

[0090] The external application drug of Example 3 of the present invention was given for treatment, and the drug was evenly applied to the diabetic foot lesion site, and the dressing was changed twice a day. During the treatment period, the patient's local symptom changes were closely observed, and relevant examinations were performed regularly. At the same time, the patient's medication compliance and possible adverse reactions were recorded.

[0091] 2. Control Group

[0092] Mupirocin ointment was given for treatment, and the standard dosage was also followed, with the dressing changed twice a day. The observation indicators were consistent with those of the observation group, and the patients' medication and adverse reactions were also paid attention to.

[0093] III. Criteria for determining efficacy

[0094] 1. Criteria for determining ulcer healing

[0095] Complete healing: The ulcer surface is completely covered by epithelial tissue, the skin color is close to normal, the texture is soft, there is no exudate, and the patient has no pain or other discomfort symptoms.

[0096] Markedly effective: The ulcer area is reduced by ≥70%, the wound surface becomes shallower, fresh granulation tissue grows, the exudate is significantly reduced, and the pain is significantly relieved.

[0097] Effective: The ulcer area was reduced by 30%-69%, the wound surface was improved to a certain extent, granulation tissue partially grew, exudate was reduced, and pain was relieved.

[0098] Ineffective: The ulcer area is reduced by less than 30%, or the ulcer surface has no obvious change or even expands, there is still a lot of exudation on the wound surface, and the pain has no obvious improvement or worsens.

[0099] 2. Infection control criteria

[0100] Cure: The bacterial culture results of the ulcer surface secretions are negative for two consecutive times, the local inflammatory symptoms (redness, swelling, heat and pain) completely disappear, and the inflammation score drops to 0.

[0101] Markedly effective: The positive rate of bacterial culture decreased by ≥70% compared with that before treatment, the inflammatory symptoms were significantly alleviated, and the inflammation score decreased by ≥2 points.

[0102] Effective: The positive rate of bacterial culture decreased by 30%-69% compared with before treatment, the inflammatory symptoms were alleviated, and the inflammation score decreased by 1 point.

[0103] Ineffective: The positive rate of bacterial culture decreased by <30%, the inflammatory symptoms did not improve significantly or even worsened, and the inflammatory score did not change or increased.

[0104] 3. Pain relief criteria

[0105] Complete remission: The patient's foot pain completely disappeared, the VAS score dropped to 0, and there was no recurrence of pain during the follow-up observation period.

[0106] Markedly effective: VAS score decreased by ≥5 points compared with before treatment, and the frequency and severity of pain attacks were significantly reduced.

[0107] Effective: VAS score decreased by 2-4 points compared with before treatment, and pain was alleviated.

[0108] Ineffective: VAS score decreased by <2 points compared with before treatment, or pain did not improve significantly or even worsened.

[0109] 4. Criteria for determining improvement in neurological function

[0110] Significant improvement: sensory nerve conduction velocity (SNCV) and motor nerve conduction velocity (MNCV) increased by ≥10m / s compared with before treatment, and the sensory function of the foot skin (touch, pain, temperature) basically returned to normal.

[0111] Improvement: SNCV and MNCV increased by 3-9 m / s compared to before treatment, the sensory function of the foot skin was partially restored, and the area of ​​decreased or abnormal sensation was reduced.

[0112] No change: SNCV and MNCV changed by less than 3 m / s compared with before treatment, and there was no significant improvement in the sensory function of the foot skin.

[0113] Worsening: SNCV and MNCV are lower than before treatment, and the sensory function of the foot skin is reduced or the abnormal area is enlarged.

[0114] IV. Efficacy Evaluation Results

[0115] Table 2: Ulcer healing results

[0116]

[0117] Table 3: Infection control results

[0118]

[0119] Table 4: Pain relief results

[0120]

[0121] Table 5: Neurological function improvement results

[0122]

[0123] Based on the results of the above four aspects, the observation group was superior to the control group in the treatment of diabetic foot. Whether it was promoting ulcer healing, controlling infection, relieving pain or improving nerve function, the observation group showed higher effectiveness.

[0124] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for promoting the transdermal absorption of topical drugs, characterized in that: The following steps are involved: S1. Wash the root bark of Lycium bark, Cyathula officinalis, Salvia miltiorrhiza, honeysuckle and Gallwood separately, dry them and grind them into coarse powder, pass them through a 40-60 mesh sieve, add 6-8 times the volume of 60-80% ethanol solution, soak for 1-2 hours, perform ultrasonic assisted extraction 1-3 times, each time with an ultrasonic power of 300-500W and an ultrasonic time of 30-40 minutes, combine the extracts, and concentrate under reduced pressure to an extract with a relative density of 1.05-1.15; S2, astragalus, frankincense, myrrh, dragon's blood, dracaena resin, ficus pumila, alpinia oxyphylla, Dalbergia odorifera, scutellaria baicalensis extract and borneol are ground into fine powder respectively, passed through 80-100 mesh sieve, and the obtained fine powder is added to the above extract, heated to 40-50°C, and dispersed by high shear to make it fully mixed; S3, dissolving oat β-glucan and lecithin in 1-3 times the volume of deionized water, stirring to form a uniform dispersion, emulsifying by high-pressure microfluidization, obtaining emulsion droplets and then adding them to the above mixture, stirring evenly, adding laurocapram by gradient heating, continuing to stir for 10-15 minutes, and finally adding pearl powder and stirring for 5-10 minutes; The gradient temperature increase is divided into three steps to add laurocapram. In the first stage, the temperature of the drug mixture is first raised to 30-35°C, 1 / 3 of the laurocapram is added, and stirred evenly. In the second stage, the temperature is raised to 40-45°C, half of the remaining laurocapram is added, and stirring is continued. In the third stage, the temperature is raised to 50-55°C, the remaining laurocapram is added, and stirring is thorough. S4. Prepare the final drug mixture into an external application dosage form.

2. A method for preparing a drug for external application that promotes transdermal absorption as claimed in claim 1, characterized in that: The rotation speed of the high shear disperser S2 is 2000-3000 rpm, and the processing time is 5-10 min.

3. A method for preparing a drug for external application that promotes transdermal absorption as claimed in claim 1, characterized in that: The pressure of the high-pressure microfluidic emulsification of S3 is 100-200 MPa, the temperature is 20-40° C., the flow rate is controlled at 10-30 L / h, the microchannel diameter is 50-200 μm, and the number of cycles is 3-6 times.

4. A method for preparing a drug for external application that promotes transdermal absorption as claimed in claim 1, characterized in that: The pharmaceutical composition of the external application dosage form comprises the following raw materials in parts by weight: 12-18 parts of cortex lycii, 10-13 parts of rhizoma cyrtonemae, 20-30 parts of astragalus, 15-20 parts of salvia miltiorrhiza, 10-15 parts of honeysuckle, 5-10 parts of frankincense, 5-10 parts of myrrh, 13-18 parts of dragon blood tree resin, 8-12 parts of dracaena resin, 5-10 parts of ficus pumila, 3-8 parts of galactopsis pilosula, 3-8 parts of alpinia oxyphylla, 2-5 parts of dalbergia odorifera, 1-3 parts of scutellaria baicalensis extract, 1-3 parts of borneol, 5-12 parts of oat beta-glucan, 3-6 parts of laurocapram, 2-5 parts of lecithin and 1-4 parts of pearl powder, and the particle size of the pearl powder is 20-50 nm.

5. A method for preparing a drug for external application that promotes transdermal absorption as claimed in claim 4, characterized in that: The pharmaceutical composition of the external application dosage form comprises the following raw materials in parts by weight: 15 parts of Lycium bark, 12 parts of Cyathula officinalis, 25 parts of Astragalus, 18 parts of Salvia miltiorrhiza, 12 parts of Honeysuckle, 8 parts of Frankincense, 8 parts of Myrrh, 15 parts of Dragon's Blood, 10 parts of Dracaena resin, 8 parts of Ficus pumila, 5 parts of Gallwood, 5 parts of Alpinia oxyphylla, 3 parts of Dalbergia odorifera, 2 parts of Cistanche deserticola extract, 2 parts of Borneolum, 8 parts of oat β-glucan, 5 parts of Laurocapram, 4 parts of lecithin and 3 parts of pearl powder.

6. A method for preparing a drug for external application that promotes transdermal absorption as claimed in claim 4, characterized in that: The astragalus is honey-roasted astragalus, which is prepared by uniformly mixing the astragalus with refined honey at 100-118° C. in a weight ratio of 10:1-2, and then stewing for 1-3 hours, frying until dark yellow, and then crushing into coarse powder after cooling, and passing through a 40-60 mesh sieve.

7. A method for preparing a drug for external application that promotes transdermal absorption as claimed in claim 4, characterized in that: The extract of Croton rotundus is obtained by supercritical CO2 extraction, with an extraction pressure of 20-30MPa, an extraction temperature of 40-50°C, a CO2 flow rate of 15-25kg / h, an extraction time of 2-4 hours, and separation and filtration to obtain the extract of Croton rotundus.

8. Use of the topical application formulation prepared by the preparation method according to any one of claims 1 to 7 in preparing a drug for treating diabetic foot.

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