Traditional Chinese medicine external application film for preventing and treating postoperative adhesion and preparation method thereof

Abstract

The invention provides a traditional Chinese medicine external application film for preventing and treating postoperative adhesion and a preparation method thereof, the external application film comprises a plurality of traditional Chinese medicine components, such as angelica sinensis, ligusticum wallichii, red peony root and the like, as well as auxiliary materials such as sodium hyaluronate, polyvinyl alcohol and the like, and a preservative and a ventilation enhancer which are mixed in proportion are also added. The preparation method comprises the following steps: preparation of active extract concentrated gel, preparation of a basic solution of a film-forming solution, compound dispersion of active components, addition of an air permeability enhancer and a preservative, drug fusion, film preparation, molding and the like. Wherein a substrate subjected to special hydrophilic treatment is uniformly coated with the film forming liquid, and the film is formed through low-temperature drying and pulsed electric field treatment. The traditional Chinese medicine external application film has the effect of preventing and treating postoperative adhesion, and has good application value in the aspect of preparing the medicine for preventing and treating postoperative adhesion.

Description

Technical Field

[0001] The invention relates to the field of traditional Chinese medicine preparations, and in particular to a traditional Chinese medicine external application film for preventing and treating postoperative adhesion and a preparation method thereof. Background Art

[0002] Postoperative adhesion is one of the common and difficult complications after surgical operations. Its essence is pathological scar hyperplasia caused by abnormal deposition of fibrin during tissue repair. It can occur after a variety of surgeries, such as abdominal surgery, pelvic surgery, cardiovascular surgery, etc., seriously affecting the patient's postoperative recovery and quality of life. At present, although there are various clinical prevention and treatment methods for postoperative adhesion, they all have certain limitations.

[0003] In terms of drug treatment, although traditional anti-inflammatory drugs and anticoagulants can reduce inflammatory responses and blood coagulation to a certain extent and reduce the risk of adhesion, their mechanism of action is relatively simple and cannot fully take into account the multiple pathophysiological links in the process of postoperative adhesion formation. For example, anti-inflammatory drugs mainly inhibit inflammatory responses and lack effective dissolution and absorption of already formed adhesion tissues; anticoagulants focus on preventing blood coagulation and have limited effects on promoting tissue repair and regeneration. Moreover, long-term or large-scale use of these drugs may also bring a series of adverse reactions, such as gastrointestinal discomfort, bleeding tendency, etc., which increase the patient's pain and medical risks.

[0004] Physical barrier methods are another commonly used means of preventing postoperative adhesions, such as using materials such as biofilms and gels to form a physical barrier between the surgical wound and surrounding tissues to reduce contact and adhesion between tissues. However, existing physical barrier materials often have poor biocompatibility problems and are prone to induce immune responses, leading to new inflammation and adhesions around the materials. In addition, the degradation rate of these materials is difficult to accurately control. They either degrade too quickly and cannot provide an effective barrier effect during the critical period; or they degrade too slowly and remain in the body for a long time, increasing the chance of infection and other complications.

[0005] Traditional Chinese medicine has certain potential in preventing and treating postoperative adhesions. Some Chinese herbal prescriptions can play a certain role in improving local blood circulation and reducing inflammatory reactions after surgery by virtue of their effects of promoting blood circulation, removing blood stasis, reducing swelling and relieving pain. However, traditional Chinese medicine preparations have many disadvantages. In terms of preparation technology, traditional extraction methods such as decoction and immersion methods are difficult to fully extract the effective ingredients in Chinese medicine, resulting in unstable efficacy and significant differences in quality between different batches of products, which seriously affects the consistency of treatment effects. Moreover, during the preparation molding process, there is a lack of precise control technology for drug release, and drugs are often released too quickly. Taking traditional Chinese medicine ointments as an example, the drug components will be released rapidly after application, and it is impossible to maintain effective drug concentrations for a long time, making it difficult to continuously play a role in preventing and treating postoperative adhesions.

[0006] In addition, external dosage forms such as Chinese medicine ointments also have the problem of poor air permeability. When such dosage forms are applied to the skin surface, they will hinder the normal gas exchange and sweat discharge of the skin, leaving the local skin in a hot and humid environment. This will not only reduce the patient's comfort, but also easily cause adverse reactions such as skin allergies, itching, redness and swelling, further affecting the therapeutic effect of the drug and patient compliance. Summary of the invention

[0007] In view of this, the present invention provides a traditional Chinese medicine external application film for preventing and treating postoperative adhesion and a preparation method thereof to solve the above problems.

[0008] The technical scheme of the present invention is implemented as follows: a Chinese medicine external compress for preventing and treating postoperative adhesion, comprising the following raw materials in parts by weight: 10-20 parts of angelica, 8-15 parts of chuanxiong, 8-12 parts of red peony root, 5-10 parts of safflower, 5-8 parts of frankincense, 5-8 parts of myrrh, 3-6 parts of dragon's blood, 2-5 parts of borneol, 15-25 parts of astragalus, 10-18 parts of salvia miltiorrhiza, 10-15 parts of tuckahoe, 8-12 parts of atractylodes macrocephala, 10-20 parts of radix scutellariae, 10-20 parts of ... 0-15 parts, Panax notoginseng 5-10 parts, turmeric 3-8 parts, Bletilla striata 5-10 parts, Ganoderma lucidum 3-8 parts, Artemisia argyi 3-5 parts, Aloe vera 5-10 parts, Houttuynia cordata 3-5 parts, Sodium hyaluronate 3-8 parts, Polyvinyl alcohol 10-20 parts, Glycerin 5-10 parts, Water 100-200 parts, Bioactive glass particles 2-6 parts, Chitosan quaternary ammonium salt 1-4 parts, the molecular weight of the sodium hyaluronate is (5-10)×10 5 Dalton, the thickness of the traditional Chinese medicine external application film is 0.2-0.5mm.

[0009] Furthermore, a Chinese medicine external compress for preventing and treating postoperative adhesion comprises the following raw materials in parts by weight: 15 parts of angelica, 12 parts of chuanxiong, 10 parts of red peony root, 7 parts of safflower, 6 parts of frankincense, 6 parts of myrrh, 5 parts of dragon's blood, 4 parts of borneol, 20 parts of astragalus, 15 parts of salvia miltiorrhiza, 13 parts of poria, 10 parts of atractylodes, 12 parts of centella asiatica, 8 parts of panax notoginseng, 5 parts of turmeric, 80 parts of bletilla striata, 5 parts of ganoderma lucidum, 4 parts of wormwood, 8 parts of aloe, 4 parts of houttuynia cordata, 5 parts of sodium hyaluronate, 15 parts of polyvinyl alcohol, 7 parts of glycerin, 150 parts of water, 4 parts of bioactive glass particles, and 3 parts of chitosan quaternary ammonium salt.

[0010] Furthermore, the average particle size of the bioactive glass particles is 10-50 μm, and the atomic ratio of calcium, phosphorus and silicon in the bioactive glass particles is (3-5):(1-2):(1-3).

[0011] Furthermore, the traditional Chinese medicine external application film also includes 2-5 parts of preservatives and 4-8 parts of air permeability enhancers.

[0012] Furthermore, the air permeability enhancer is a mixture of sodium carboxymethyl cellulose, nano-silicon dioxide and menthol in a mass ratio of (1-3):(4-9):(2.5-5.5), and the average particle size of the nano-silicon dioxide is 20-50 nm.

[0013] Furthermore, the preservative is a mixture of methylparaben and propylparaben in a mass ratio of 2:1 to 3:1.

[0014] Furthermore, a method for preparing a traditional Chinese medicine external application film for preventing and treating postoperative adhesion comprises the following steps:

[0015] S1, Active Extract Concentrated Gel:

[0016] (1) Wash angelica sinensis, chuanxiong, red peony root, safflower, frankincense, myrrh, dragon's blood, astragalus, salvia miltiorrhiza, poria, atractylodes macrocephala, centella asiatica, panax notoginseng, turmeric, bletilla striata, ganoderma lucidum, wormwood leaf, aloe vera, and houttuynia cordata, and dry them at 60-70°C for 4-6 hours until the water content is less than 5%;

[0017] (2) subjecting the dried Chinese medicine raw material to ultrafine grinding, passing through a 300-400 mesh sieve to obtain ultrafine Chinese medicine powder, adding water to soak for 30-50 minutes, wherein the mass volume ratio of Chinese medicine powder to water is 12-50:100 g / mL,

[0018] (3) subjecting the soaked Chinese medicine powder solution to microwave extraction, with a microwave power of 200-1200 W, a pressure of 10-22 MPa, a temperature of 100-200° C., and an extraction time of 30-60 min. The obtained extract is sheared and homogenized in a high-speed shearing machine at a speed of 10,000 rpm to form a uniform mixed solution, which is then injected into a field flow separation device, and the electric field strength is adjusted to 5-50 V / cm and the flow rate is 20-60 mL / min to enrich the nanoscale active particles in the mixed solution to obtain a concentrated gel rich in nanoscale active particles, which is then vacuum dried to obtain a concentrated gel powder;

[0019] S2. Preparation of the basic solution of the membrane-forming liquid: Weigh polyvinyl alcohol according to the formula amount, add it to water, and stir it in a constant temperature water bath at 80-90°C for 60-90 minutes to completely dissolve the polyvinyl alcohol and form a uniform solution. When the solution is cooled to 40-50°C, add glycerol and continue stirring for 20-30 minutes to fully disperse the glycerol in the solution to obtain the basic solution of the membrane-forming liquid;

[0020] S3, composite dispersion of active ingredients: sodium hyaluronate is added to the base solution of the film-forming liquid, and stirred at 30-35°C and a stirring speed of 300-400 rpm for 40-60 min to fully dissolve and evenly disperse the sodium hyaluronate, and bioactive glass particles and chitosan quaternary ammonium salt are added, and the ultrasonic equipment is turned on, and ultrasonic dispersion is performed at an ultrasonic power of 400-500 W for 20-30 min to evenly disperse the bioactive glass particles and chitosan quaternary ammonium salt in the solution;

[0021] S4, adding air permeability enhancer and preservative: mix sodium carboxymethyl cellulose, nano silicon dioxide and menthol in a mass ratio to prepare an air permeability enhancer, add the air permeability enhancer to the above solution, stir for 30-45 minutes at 35-40° C. and a stirring speed of 250-350 rpm, then add the preservative, and continue stirring for 15-20 minutes to ensure that all ingredients are evenly mixed;

[0022] S5, drug fusion: add the concentrated gel powder obtained in step S1 to the solution, stir at 30-35°C and 350-450rpm for 60-90min to fully integrate the Chinese medicine components into the film-forming solution;

[0023] S6. Film making and molding: evenly apply the degassed film-forming liquid on a specially hydrophilically treated polyethylene terephthalate (PET) substrate, place the substrate coated with the film-forming liquid in a low-temperature drying oven, dry at 25-30°C for 3-4 hours, then heat to 35-40°C and continue drying for 6-8 hours, so that the film-forming liquid forms a thin film with a thickness of 0.2-0.5 mm, apply a pulsed electric field to the film three times under nitrogen protection to promote the formation of a polysaccharide-protein three-dimensional network, dry, peel off, cut and package, and obtain a traditional Chinese medicine external application film for preventing and treating postoperative adhesion.

[0024] Furthermore, the hydrophilic treatment in step S6 is to immerse the substrate in a dopamine solution with a mass fraction of 3-5% for 12-24 hours, then rinse it with deionized water and dry it.

[0025] Furthermore, the pulse electric field in step S6 has a field strength of 12-20 kV / m and a duration of 0.1-0.3 ms.

[0026] Furthermore, the Chinese medicine external application film for preventing and treating postoperative adhesion is used in preparing a medicine for preventing and treating postoperative adhesion.

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] (1) The prescription of the present invention follows the compatibility principle of promoting blood circulation and removing blood stasis + antibacterial and anti-inflammatory + repair and healing, and Angelica and Astragalus are the main drugs. Angelica is sweet and warm, and can both nourish blood and promote blood circulation, and can improve the state of qi and blood stasis after surgery; Astragalus is slightly warm in nature, greatly replenishes vital energy, and enhances the body's repair ability. The two are both qi and blood replenishing and regulating, and play a leading therapeutic role in the core cause of postoperative adhesion. Chuanxiong, Salvia miltiorrhiza, and Paeonia lactiflora are the assistant drugs. Chuanxiong promotes blood circulation and qi, and is a blood qi drug, which enhances the main drug's function of promoting blood circulation and removing blood stasis; Salvia miltiorrhiza promotes blood circulation and removes blood stasis, improves circulation, and cools blood and prevents heat; Paeonia lactiflora clears heat and cools blood, disperses blood stasis and relieves pain, and assists the main drug in improving blood circulation and reducing inflammation. The adjuvants include many categories, such as safflower, frankincense, myrrh, dragon's blood, notoginseng, and turmeric, which can promote blood stasis and relieve pain, promote blood stasis and wound healing; Poria and Atractylodes macrocephala, which can strengthen the spleen and remove dampness, promote the formation of qi and blood; Houttuynia cordata, which can clear away heat and toxins, can remove heat and relieve inflammation; Centella asiatica, Bletilla striata, Ganoderma lucidum, and Aloe vera, which can repair and promote healing, can accelerate tissue repair and reduce scars; Borneol is an adjuvant drug, which can guide the drugs, clear heat and relieve pain, and prevent other drugs from being warm, hot, and dry. The adjuvant drug is Artemisia argyi, which can harmonize the drugs and coordinate the properties of the whole prescription. Its warming and unblocking nature can also assist the blood-activating drugs to play their role, guide the drugs to the diseased area, and play a role in preventing and treating postoperative adhesions.

[0029] (2) The synergistic design of the biomaterials of the present invention has obvious advantages. The high air permeability of the air permeability enhancer maintains the balance of the wound microenvironment. Sodium carboxymethyl cellulose controls the pore connectivity through the hydrogen bond network and optimizes the drug release kinetics. The bioactive glass particles have good biological activity and osteoinductivity, can activate tissue regeneration in situ, and the collagen ordered scaffold reduces the fiber interlacing degree, thereby preventing more fibrous tissue from connecting.

[0030] (3) Advantages of preparation technology: ultrafine grinding, microwave extraction, field flow separation and other technologies can extract and retain the active ingredients in traditional Chinese medicine to the greatest extent under mild conditions. Field flow separation can accurately obtain nano-scale active particles, improve the purity and activity of drugs, make drugs work better, and slowly release drugs to avoid side effects caused by high concentrations in the early stage. Through ultrasonic dispersion, stirring and other processes, ensure that the bioactive glass particles, chitosan quaternary ammonium salts, air permeability enhancers, preservatives and other ingredients are evenly distributed in the film-forming liquid, ensure the consistency of the performance of each part of the film, and improve the stability of product quality. Applying a pulsed electric field during the preparation process can improve the internal structure of the film, promote the formation of a three-dimensional polysaccharide-protein network, enhance the mechanical strength and stability of the film, prolong the retention time of the film in the body, achieve slow and continuous release of drugs, and improve drug utilization.

[0031] The Chinese medicine external application film of the present invention can effectively prevent and treat postoperative adhesion, promote wound healing, and enable the prevention and treatment of postoperative adhesion to move from a "passive barrier" to an "active regulation" stage, with significant clinical transformation value. DETAILED DESCRIPTION

[0032] In order to better understand the technical content of the present invention, specific embodiments are provided below to further illustrate the present invention.

[0033] Unless otherwise specified, the experimental methods used in the embodiments of the present invention are all conventional methods.

[0034] Unless otherwise specified, the materials, reagents, etc. used in the embodiments of the present invention can be obtained from commercial sources.

[0035] Example 1

[0036] A Chinese medicine external compress for preventing and treating postoperative adhesion comprises the following raw materials by weight: 10 grams of angelica, 8 grams of chuanxiong, 8 grams of red peony root, 5 grams of safflower, 5 grams of frankincense, 5 grams of myrrh, 3 grams of blood clotting, 2 grams of borneol, 15 grams of astragalus, 10 grams of salvia miltiorrhiza, 10 grams of tuckahoe, 8 grams of atractylodes, 10 grams of centella asiatica, 5-10 grams of panax notoginseng, 3 grams of turmeric, 5 grams of bletilla striata, 3 grams of ganoderma lucidum, 3 grams of wormwood, 5 grams of aloe, 3 grams of houttuynia cordata, 3 grams of sodium hyaluronate, 10 grams of polyvinyl alcohol, 5 grams of glycerol, 100 grams of water, 2 grams of bioactive glass particles, 1 gram of chitosan quaternary ammonium salt, 2 grams of preservatives and 4 grams of air permeability enhancer; the molecular weight of the sodium hyaluronate is 5×10 5 Dalton, the average particle size of the bioactive glass particles is 10 μm, and the atomic ratio of calcium, phosphorus and silicon in the bioactive glass particles is 3:1:1, the permeability enhancer is a mixture of sodium carboxymethyl cellulose, nano-silicon dioxide and menthol in a mass ratio of 1:4:2.5, the average particle size of the nano-silicon dioxide is 20 nm, and the preservative is a mixture of methyl parahydroxybenzoate and propyl parahydroxybenzoate in a mass ratio of 2:1 to 3:1.

[0037] Example 2

[0038] A Chinese medicine external compress for preventing and treating postoperative adhesion comprises the following raw materials by weight: 20 grams of angelica, 15 grams of chuanxiong, 12 grams of red peony root, 10 grams of safflower, 8 grams of frankincense, 8 grams of myrrh, 6 grams of dragon's blood, 5 grams of borneol, 25 grams of astragalus, 18 grams of salvia, 15 grams of tuckahoe, 12 grams of atractylodes, 15 grams of centella asiatica, 10 grams of notoginseng, 8 grams of turmeric, 10 grams of bletilla striata, 8 grams of ganoderma lucidum, 5 grams of wormwood, 10 grams of aloe, 5 grams of houttuynia, 8 grams of sodium hyaluronate, 20 grams of polyvinyl alcohol, 10 grams of glycerol, 200 grams of water, 6 grams of bioactive glass particles, 4 grams of chitosan quaternary ammonium salt, 5 grams of preservatives and 8 grams of air permeability enhancer; the molecular weight of the sodium hyaluronate is 10×10 5Dalton, the average particle size of the bioactive glass particles is 50 μm, and the atomic ratio of calcium, phosphorus and silicon in the bioactive glass particles is 5:2:3, the permeability enhancer is a mixture of sodium carboxymethyl cellulose, nano-silicon dioxide and menthol in a mass ratio of 3:9:5.5, the average particle size of the nano-silicon dioxide is 50 nm, and the preservative is a mixture of methyl parahydroxybenzoate and propyl parahydroxybenzoate in a mass ratio of 3:1.

[0039] Example 3

[0040] A Chinese medicine external compress for preventing and treating postoperative adhesion comprises the following raw materials by weight: 15 grams of angelica, 12 grams of chuanxiong, 10 grams of red peony root, 7 grams of safflower, 6 grams of frankincense, 6 grams of myrrh, 5 grams of dragon's blood, 4 grams of borneol, 20 grams of astragalus, 15 grams of salvia, 13 grams of tuckahoe, 10 grams of atractylodes, 12 grams of centella asiatica, 8 grams of notoginseng, 5 grams of turmeric, 80 grams of bletilla striata, 5 grams of ganoderma lucidum, 4 grams of wormwood, 8 grams of aloe, 4 grams of houttuynia, 5 grams of sodium hyaluronate, 15 grams of polyvinyl alcohol, 7 grams of glycerol, 150 grams of water, 4 grams of bioactive glass particles, 3 grams of chitosan quaternary ammonium salt, 3 grams of preservatives and 6 grams of air permeability enhancer; the molecular weight of the sodium hyaluronate is (5-10)×10 5 Dalton, the average particle size of the bioactive glass particles is 10-50 μm, and the atomic ratio of calcium, phosphorus and silicon in the bioactive glass particles is 4:2:2, the permeability enhancer is a mixture of sodium carboxymethyl cellulose, nano-silicon dioxide and menthol in a mass ratio of 2:7:4, the average particle size of the nano-silicon dioxide is 30 nm, and the preservative is a mixture of methyl parahydroxybenzoate and propyl parahydroxybenzoate in a mass ratio of 3:1;

[0041] The above examples 1-3 adopt the following preparation method:

[0042] S1, Active Extract Concentrated Gel:

[0043] (1) Wash angelica sinensis, Chuanxiong, red peony root, safflower, frankincense, myrrh, dragon's blood, astragalus, salvia miltiorrhiza, Poria, Atractylodes macrocephala, Centella asiatica, Panax notoginseng, turmeric, Bletilla striata, Ganoderma lucidum, Artemisia argyi, aloe vera, and Houttuynia cordata, and dry them at 65°C for 5 h until the water content is less than 5%;

[0044] (2) The dried Chinese medicine raw material is subjected to ultrafine grinding, passed through a 400-mesh sieve to obtain ultrafine Chinese medicine powder, and water is added to soak for 40 minutes, wherein the mass volume ratio of Chinese medicine powder to water is 30:100 g / mL.

[0045] (3) subjecting the soaked Chinese medicine powder solution to microwave extraction at a microwave power of 700 W, a pressure of 15 MPa, a temperature of 150° C., and an extraction time of 50 min; the obtained extract was sheared and homogenized in a high-speed shearing machine at a speed of 10,000 rpm to form a uniform mixed solution, which was then injected into a field flow separation device, and the electric field strength was adjusted to 30 V / cm and the flow rate was 40 mL / min to obtain a concentrated gel rich in nano-scale active particles, which was vacuum dried to obtain a concentrated gel powder;

[0046] S2. Preparation of the basic solution of the membrane-forming liquid: Weigh polyvinyl alcohol according to the formula amount, add it to water, and stir it in a constant temperature water bath at 85°C for 70 minutes to completely dissolve the polyvinyl alcohol and form a uniform solution. When the solution is cooled to 45°C, add glycerol and continue stirring for 25 minutes to fully disperse the glycerol in the solution to obtain the basic solution of the membrane-forming liquid;

[0047] S3. Composite dispersion of active ingredients: sodium hyaluronate was added to the base solution of the film-forming liquid, and stirred at 33°C and 350 rpm for 50 min to fully dissolve and evenly disperse the sodium hyaluronate, and bioactive glass particles and chitosan quaternary ammonium salt were added, and the ultrasonic equipment was turned on, and ultrasonic dispersion was performed at an ultrasonic power of 450 W for 25 min to evenly disperse the bioactive glass particles and chitosan quaternary ammonium salt in the solution;

[0048] S4, adding air permeability enhancer and preservative: sodium carboxymethyl cellulose, nano silicon dioxide and menthol are mixed uniformly according to the mass ratio to prepare an air permeability enhancer, and the air permeability enhancer is added to the above solution, stirred at 38° C. and 300 rpm for 40 minutes, and then the preservative is added, and stirring is continued for 18 minutes to ensure that all ingredients are evenly mixed;

[0049] S5, drug fusion: add the concentrated gel powder obtained in step S1 into the solution, stir at 32°C and 400 rpm for 80 min, so that the Chinese medicine components are fully integrated into the film-forming solution;

[0050] S6. Film making and molding: the degassed film-forming liquid is evenly coated on the polyethylene terephthalate substrate which has been specially hydrophilically treated. The hydrophilic treatment is to immerse the substrate in a 4% dopamine solution by mass for 20 hours, then rinse it with deionized water and dry it. The substrate coated with the film-forming liquid is placed in a low-temperature drying oven, first dried at 28°C for 3 hours, then heated to 38°C and continued to dry for 7 hours, so that the film-forming liquid forms a thin film with a thickness of 0.3 mm. The film is subjected to a pulsed electric field three times under nitrogen protection to promote the formation of a polysaccharide-protein three-dimensional network. The pulsed electric field has a field strength of 15 kV / m and a duration of 0.2 ms. Drying, peeling, cutting and packaging are performed to obtain a traditional Chinese medicine external application film for preventing and treating postoperative adhesions.

[0051] Comparative Example 1

[0052] The difference between this comparative example and Example 3 is that the raw materials of the Chinese medicine external application film do not contain Salvia miltiorrhiza, Red Peony Root, and Centella asiatica, and specifically include the following raw materials by weight: 20 grams of Angelica sinensis, 15 grams of Chuanxiong, 10 grams of Carthamus tinctorius, 8 grams of frankincense, 8 grams of Myrrh, 6 grams of Sanguisorba officinalis, 5 grams of Borneol, 25 grams of Astragalus, 15 grams of Poria, 12 grams of Atractylodes macrocephala, 10 grams of Panax notoginseng, 8 grams of Curcuma longa, 10 grams of Bletilla striata, 8 grams of Ganoderma lucidum, 5 grams of Artemisia argyi, 10 grams of Aloe vera, 5 grams of Houttuynia cordata, 8 grams of sodium hyaluronate, 20 grams of polyvinyl alcohol, 10 grams of glycerin, 200 grams of water, 6 grams of bioactive glass particles, 4 grams of chitosan quaternary ammonium salt, 5 grams of preservatives and 8 grams of air permeability enhancer.

[0053] Comparative Example 2

[0054] The difference between this comparative example and Example 3 is that the bioactive glass particles in the raw materials of the traditional Chinese medicine external application film are replaced by an equal amount of calcium carbonate particles.

[0055] Comparative Example 3

[0056] The difference between this comparative example and Example 3 is that the air permeability enhancer in the raw materials of the traditional Chinese medicine external application film is replaced by an equal amount of microcrystalline cellulose.

[0057] Comparative Example 4

[0058] The difference between this comparative example and Example 3 is that the air permeability enhancer in the raw materials of the traditional Chinese medicine external application film does not contain menthol, and is sodium carboxymethyl cellulose and nano silicon dioxide in a mass ratio of 2:7.

[0059] Comparative Example 5

[0060] The difference between this comparative example and Example 3 is that in the method for preparing the traditional Chinese medicine external application film, the field flow separation step is omitted in step S1, and only ordinary centrifugal separation (3000 rpm×20 min) is used.

[0061] Comparative Example 6

[0062] The difference between this comparative example and Example 3 is that in the method for preparing the traditional Chinese medicine external application film, step S6 does not perform pulse electric field treatment, but directly performs thermal drying and molding.

[0063] Effect verification

[0064] 1. The incidence of postoperative adhesion

[0065] 1. Test method: Establish an abdominal wall defect model in SD rats.

[0066] 2. Establishment of experimental animal model: Healthy adult SD rats were selected, and after adaptive feeding for 1 week, they were randomly divided into an experimental group (using the Chinese medicine external application film of Examples 1-3), 6 comparative groups and a blank control group, with 20 rats in each group.

[0067] 3. Surgical operation: Full-thickness incision of 2×2 cm abdominal wall tissue was performed to expose the retroperitoneum and suture the stent mesh.

[0068] 4. External film treatment:

[0069] The experimental group immediately covered the surgical incision with a normal Chinese medicine external compress and fixed it with medical tape;

[0070] The control group used the external application film of the corresponding proportion formula, and the treatment method was the same as the experimental group;

[0071] The blank control group did not receive any external application treatment.

[0072] Evaluation criteria: 14 days after surgery, the rats were killed, the abdominal cavity was opened, the adhesion of the cecum to the surrounding tissues was observed, and the adhesion area was tested by image acquisition. The adhesion area measurement of each animal was repeated 3 times, and the average value was taken as the final result. The following adhesion grading criteria were used for evaluation:

[0073] Grade 0: no adhesion;

[0074] Grade 1: Mild adhesion, with only a small amount of fiber connection, easy to separate;

[0075] Grade 2: Moderate adhesion, with more fibrous tissue connections, requiring a little force when separating;

[0076] Grade 3: Severe adhesion, tissues are tightly adhered and difficult to separate.

[0077] The incidence of adhesion in each group was calculated (number of rats with adhesion / total number of rats in each group×100%).

[0078] Statistical analysis: Fisher's exact test was used to compare the differences among the groups.

[0079] 2. Collagen precipitation

[0080] 1. Test method: Sirius red polarized light microscopy analysis

[0081] 2. Sample processing: Take tissue from the center of the wound, fix it with 10% formaldehyde, embed it in paraffin, and slice it at 4 μm

[0082] 3. Staining steps: Sirius red staining method (pH 2.5 acidic environment, staining for 12 hours), dehydration and sealing;

[0083] 4. Quantitative analysis: Use Image-ProPlus6.0 software to calculate the percentage of collagen fiber area;

[0084] 5. Verification method: Hydroxyproline spectrophotometric calibration (detection wavelength 558nm).

[0085] Test results:

[0086]

[0087]

[0088] According to the above results, it can be seen that the adhesion area of ​​the experimental group is generally smaller than that of the comparative group and the blank control group, and the results of the adhesion incidence are consistent with the adhesion area trend; this shows that the Chinese medicine external application film of Example 3 has the best effect in reducing postoperative adhesion. The amount of collagen precipitation reflects the degree of fibrosis in the tissue repair process. The amount of collagen precipitation in the example group is lower than that in the comparative group, indicating that it can better inhibit the excessive deposition of collagen fibers and reduce the occurrence of fibrosis.

[0089] 3. Air permeability (WVT) test (Comparative Example 3)

[0090] 1. Test standard: ASTM E96 / E96M-22 water vapor transmission method;

[0091] 2. Experimental setup:

[0092] Test cup diameter: 7.5cm

[0093] Environmental conditions: 38℃±1℃, 90%±2%RH (controlled constant temperature and humidity chamber)

[0094] Weighing interval: Record weight changes every hour using a 1 / 10,000 balance.

[0095] 3. Calculation formula:

[0096] WVT=(Δm×24) / (S×t); Δm is the weight increase of the moisture permeable cup in time t (g), S is the effective moisture permeability area of ​​the external coating film (m 2 ), t is the measurement time (h);

[0097] 4. Test Results

[0098]

[0099]

[0100] It is explained that the present invention effectively optimizes the air permeability of the traditional Chinese medicine external application film by using a specific ratio of sodium carboxymethyl cellulose, nano silicon dioxide and menthol, wherein the nano silicon dioxide forms a microporous structure to improve the water vapor permeability, and the menthol forms pore channels after volatilization to reduce the accumulation of moisture and heat in the film; sodium carboxymethyl cellulose regulates the pore connectivity through hydrogen bonds.

[0101] 4. Membrane stability test

[0102] 1. In vitro degradation experiment: The external application films of the experimental group and the comparative example 6 group were respectively placed in conical flasks containing 100 ml of phosphate buffer (pH 7.4), placed in a constant temperature shaker at 37° C., and shaken at a speed of 100 r / min.

[0103] 2. Determination of film residual rate: Take out the external application film at different time points (such as 1 day, 3 days, 5 days, 7 days), rinse it with deionized water, and weigh the film after drying. Calculate the film residual rate according to the following formula:

[0104] Film residual rate (%) = (W t / W0)×100%;

[0105] Among them, W t is the weight of the film at time point t (g), and W0 is the initial weight of the film (g).

[0106]

[0107] Comparison between the embodiment and comparative example 6 shows that applying a pulsed electric field three times to the film under nitrogen protection promotes the formation of a polysaccharide-protein three-dimensional network, while comparative example 6 does not use a pulsed electric field treatment, resulting in insufficient crosslinking, which affects the mechanical strength of the film.

[0108] 5. In vitro drug release test

[0109] (1) Experimental setup: dynamic dialysis system

[0110] Dialysis membrane: cellulose membrane with a molecular weight cutoff of 12-14 kDa

[0111] Release medium: pH 7.4 phosphate buffer + 0.1% Tween 80 (maintain sink conditions)

[0112] Temperature control: 37℃±0.5℃ (water bath circulation system)

[0113] Sampling time: 0.5h, 1h, 2h, 4h, 8h, 12h, 24h

[0114] (2) Testing instruments:

[0115] High Performance Liquid Chromatography (HPLC):

[0116] Chromatographic column: C18 column (250mm×4.6mm, 5μm)

[0117] Mobile phase: acetonitrile-0.1% phosphoric acid (gradient elution, see Table 1)

[0118] Flow rate: 1.0mL / min

[0119] Detection wavelength: Tanshinone ⅡA (280nm), paeoniflorin (230nm), asiaticaside (205nm)

[0120] (3) Data processing

[0121] Calculate the cumulative drug release rate: According to the concentration of the target drug in the release medium at each time point, the cumulative drug release rate is calculated according to the following formula:

[0122]

[0123] Where: Q t is the cumulative release rate of the drug at time t (%); C i is the concentration of the drug in the release medium at the i-th sampling (mg / mL); Vi is the volume of the i-th sampling (mL); C n is the concentration of the drug in the release medium at the last sampling (mg / mL); V is the total volume of the release medium (mL); V0 is the volume of each sampling (mL); m is the initial content of the target drug in the sample (mg).

[0124] (4) Data results

[0125]

[0126] From the above results, it can be seen that the release amount of Tanshinone ⅡA in Example 3 is 22.4% at 2h, and the release amount of Comparative Example 5 is 47.2%, and the burst release rate is increased by 111%. Ordinary centrifugation causes the effective ingredients to be unable to be effectively retained in the nanocarrier, thereby quickly releasing freely. The release curve of Example 3 shows a gentle upward trend, while the release rate of Comparative Example 5 drops significantly after 8h, resulting in weak release in the later stage, such as the difference in the total release of paeoniflorin in 24h. Ordinary centrifugation is difficult to purify active particles of a specific particle size; it shows that the present invention performs field flow separation on the extracted mixed solution to better retain nanoscale particles, which can slowly release drugs and avoid side effects caused by high concentrations in the early stage. Centrifugation may not be able to effectively retain these small particles, resulting in rapid release of most drugs in the initial stage.

[0127] 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 Chinese medicine external application film for preventing and treating postoperative adhesion, characterized in that: The invention comprises the following raw materials in parts by weight: 10-20 parts of angelica sinensis, 8-15 parts of chuanxiong rhizome, 8-12 parts of red peony root, 5-10 parts of safflower, 5-8 parts of frankincense, 5-8 parts of myrrh, 3-6 parts of dragon's blood, 2-5 parts of borneol, 15-25 parts of astragalus, 10-18 parts of salvia miltiorrhiza, 10-15 parts of tuckahoe, 8-12 parts of atractylodes macrocephala, 10-15 parts of centella asiatica, 5-10 parts of panax notoginseng, 3-8 parts of turmeric, 5-10 parts of bletilla striata, 3-8 parts of ganoderma lucidum, 3-5 parts of wormwood leaf, 5-10 parts of aloe vera, 3-5 parts of houttuynia cordata, 3-8 parts of sodium hyaluronate, 10-20 parts of polyvinyl alcohol, 5-10 parts of glycerol, 100-200 parts of water, 2-6 parts of bioactive glass particles, and 1-4 parts of chitosan quaternary ammonium salt. The molecular weight of the sodium hyaluronate is (5-10)×10 5 Dalton, the thickness of the traditional Chinese medicine external application film is 0.2-0.5mm.

2. The Chinese medicine external application film for preventing and treating postoperative adhesion according to claim 1, characterized in that: The invention comprises the following raw materials in parts by weight: 15 parts of angelica sinensis, 12 parts of chuanxiong rhizome, 10 parts of red peony root, 7 parts of safflower, 6 parts of frankincense, 6 parts of myrrh, 5 parts of dragon's blood, 4 parts of borneol, 20 parts of astragalus, 15 parts of salvia miltiorrhiza, 13 parts of tuckahoe, 10 parts of atractylodes macrocephala, 12 parts of centella asiatica, 8 parts of panax notoginseng, 5 parts of turmeric, 80 parts of bletilla striata, 5 parts of ganoderma lucidum, 4 parts of wormwood leaf, 8 parts of aloe vera, 4 parts of houttuynia cordata, 5 parts of sodium hyaluronate, 15 parts of polyvinyl alcohol, 7 parts of glycerin, 150 parts of water, 4 parts of bioactive glass particles and 3 parts of chitosan quaternary ammonium salt.

3. The Chinese medicine external application film for preventing and treating postoperative adhesion according to claim 1, characterized in that: The average particle size of the bioactive glass particles is 10-50 μm, and the atomic ratio of calcium, phosphorus and silicon in the bioactive glass particles is (3-5):(1-2):(1-3).

4. The Chinese medicine external application film for preventing and treating postoperative adhesion according to claim 1, characterized in that: The traditional Chinese medicine external application film also includes 2-5 parts of preservatives and 4-8 parts of air permeability enhancers.

5. The Chinese medicine external application film for preventing and treating postoperative adhesion according to claim 4, characterized in that: The air permeability enhancer is a mixture of sodium carboxymethyl cellulose, nano silicon dioxide and menthol in a mass ratio of (1-3):(4-9):(2.5-5.5), and the average particle size of the nano silicon dioxide is 20-50 nm.

6. The Chinese medicine external application film for preventing and treating postoperative adhesion according to claim 1, characterized in that: The preservative is a mixture of methyl parahydroxybenzoate and propyl parahydroxybenzoate in a mass ratio of 2:1 to 3:

1.

7. A method for preparing a Chinese medicine external application film for preventing and treating postoperative adhesion as claimed in claim 5, characterized in that: The following steps are involved: S1, Active Extract Concentrated Gel: (1) Wash angelica sinensis, chuanxiong, red peony root, safflower, frankincense, myrrh, dragon's blood, astragalus, salvia miltiorrhiza, poria, atractylodes macrocephala, centella asiatica, panax notoginseng, turmeric, bletilla striata, ganoderma lucidum, wormwood leaf, aloe vera, and houttuynia cordata, and dry them at 60-70°C for 4-6 hours until the water content is less than 5%; (2) subjecting the dried Chinese medicine raw material to ultrafine grinding, passing through a 300-400 mesh sieve to obtain ultrafine Chinese medicine powder, adding water to soak for 30-50 minutes, wherein the mass volume ratio of Chinese medicine powder to water is 12-50:100 g / mL, (3) subjecting the soaked Chinese medicine powder solution to microwave extraction, with a microwave power of 200-1200 W, a pressure of 10-22 MPa, a temperature of 100-200° C., and an extraction time of 30-60 min. The obtained extract is sheared and homogenized in a high-speed shearing machine at a speed of 10,000 rpm to form a uniform mixed solution, which is then injected into a field flow separation device, with the electric field strength adjusted to 5-50 V / cm and the flow rate adjusted to 20-60 mL / min to obtain a concentrated gel rich in nano-scale active particles, which is then vacuum dried to obtain a concentrated gel powder; S2. Preparation of the basic solution of the membrane-forming liquid: Weigh polyvinyl alcohol according to the formula amount, add it to water, and stir it in a constant temperature water bath at 80-90°C for 60-90 minutes to completely dissolve the polyvinyl alcohol and form a uniform solution. When the solution is cooled to 40-50°C, add glycerol and continue stirring for 20-30 minutes to fully disperse the glycerol in the solution to obtain the basic solution of the membrane-forming liquid; S3, composite dispersion of active ingredients: sodium hyaluronate is added to the base solution of the film-forming liquid, and stirred at 30-35°C and a stirring speed of 300-400 rpm for 40-60 min to fully dissolve and evenly disperse the sodium hyaluronate, and bioactive glass particles and chitosan quaternary ammonium salt are added, and the ultrasonic equipment is turned on, and ultrasonic dispersion is performed at an ultrasonic power of 400-500 W for 20-30 min to evenly disperse the bioactive glass particles and chitosan quaternary ammonium salt in the solution; S4, adding air permeability enhancer and preservative: mix sodium carboxymethyl cellulose, nano silicon dioxide and menthol in a mass ratio to prepare an air permeability enhancer, add the air permeability enhancer to the above solution, stir for 30-45 minutes at 35-40° C. and a stirring speed of 250-350 rpm, then add the preservative, and continue stirring for 15-20 minutes to ensure that all ingredients are evenly mixed; S5, drug fusion: add the concentrated gel powder obtained in step S1 to the solution, stir at 30-35°C and 350-450rpm for 60-90min to fully integrate the Chinese medicine components into the film-forming solution; S6. Film making and molding: evenly apply the degassed film-forming liquid on a specially hydrophilically treated polyethylene terephthalate substrate, place the substrate coated with the film-forming liquid in a low-temperature drying oven, dry at 25-30°C for 3-4 hours, then heat to 35-40°C and continue drying for 6-8 hours, so that the film-forming liquid forms a thin film with a thickness of 0.2-0.5 mm, apply a pulsed electric field to the film three times under nitrogen protection, dry, peel off, cut and package, and you can get a traditional Chinese medicine external application film for preventing and treating postoperative adhesion.

8. A method for preparing a Chinese medicine external application film for preventing and treating postoperative adhesion as claimed in claim 7, characterized in that: The hydrophilic treatment in step S6 is to immerse the substrate in a dopamine solution with a mass fraction of 3-5% for 12-24 hours, then rinse it with deionized water and dry it.

9. A method for preparing a Chinese medicine external application film for preventing and treating postoperative adhesion as claimed in claim 7, characterized in that: The pulse electric field in step S6 has a field strength of 12-20 kV / m and a duration of 0.1-0.3 ms.

10. Use of the traditional Chinese medicine external application film for preventing and treating postoperative adhesion according to any one of claims 1 to 5 in preparing a medicine for preventing and treating postoperative adhesion.

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