CN103495174B - Be used for the treatment of Multi-effect external preparation of Dermal skin damage and uses thereof - Google Patents

Abstract

The invention provides a multi-effect external preparation for treating superficial skin damage and its application. The external preparation consists of 1-20% blood coagulation, 0.2-10% analgesic, 0.2-20 % of healing compound, 0.005-10% of antibacterial materials and 40-90% of pharmaceutical excipients, the topical preparation has multiple effects of hemostasis, analgesia, healing and anti-infection, and can improve superficial skin damage the therapeutic effect.

Description

Multifunctional topical formulation for treating superficial skin lesions and use thereof

technical field

The invention belongs to the technical field of medicine, in particular to the field of multi-effect external preparations for hemostasis, analgesia, healing promotion and anti-infection for superficial skin damage.

Background technique

Hemostasis is an important part of trauma treatment and treatment, and has a significant impact on the patient's recovery and daily activities. There are various hemostasis methods in the treatment of trauma, such as compression hemostasis, ligation hemostasis, electrocoagulation hemostasis, blood vessel blocking method, blood vessel repairing method and the application of hemostatic drugs. In skin injuries, blood coagulation substances are usually used for hemostasis. The currently commonly used hemostatic substances or drugs include bovine or recombinant thrombin, plasma coagulation factors FII, VII, IX, X, tranexamic acid, protamine, desamine plus Vasopressin, aminocaproic acid, etc. These coagulation substances are characterized by a clear mechanism of action, can act on all aspects of the coagulation process, have a strong coagulation effect, and can produce a strong coagulation effect at a lower concentration.

Local anesthetics such as lidocaine, tetracaine, prilocaine, bupivacaine, levobupivacaine, ropivacaine, and benzocaine have analgesic and antipruritic effects for external use. These local anesthetics The transdermal absorption is good, and it can be applied clinically to small-area mild burns and superficial II° burns.

The antibacterial effect of nanoscale metal oxides and simple metals has attracted more and more attention. These inorganic materials have broad-spectrum antibacterial capabilities and are effective against various bacteria, molds, and yeasts; inorganic materials will not dissolve quickly, Volatile, so it has a long-term antibacterial effect; in addition, many metal elements are needed by the human body, and long-term use has less toxic side effects on the human body than antibiotics. External preparations such as nano-silver have been used clinically for a long time, and their safety and effectiveness have been confirmed.

Superficial skin injuries such as abrasions, bruises, and superficial II° burns are common injuries in daily life, which usually lead to problems such as bleeding, pain, difficult healing, and infection. In superficial skin injuries, because the nerve endings are exposed to stimulation, the wound will cause severe pain. In addition, if the wound bleeding is not treated in time, it will also bring inconvenience to the patient's daily activities. Currently, topical drugs for the treatment of superficial skin lesions, such as silver sulfadiazine, povidone-iodine ointment, and Yunnan Baiyao, are all single-function (anti-infection or pain-relieving) preparations, which are difficult to meet the treatment needs. Therefore, it is very urgent to develop a class of external preparations with multiple functions of hemostasis, analgesia, healing and anti-infection to improve the treatment rate of trauma patients.

Contents of the invention

The object of the present invention is to provide a multi-effect external preparation for treating superficial skin injury and its application. The external preparation has multi-effect effects of hemostasis, pain relief, healing promotion and anti-infection.

To achieve the above object, the present invention adopts the following technical solutions:

A multi-effect external preparation for treating superficial skin injuries, the external preparation consists of 1-20% blood coagulation, 0.2-10% analgesic drugs, 0.2-20% healing substances, 0.005-10% antibacterial materials and 40-90% pharmaceutical excipients.

The coagulant is one or both of thrombin or fibrinogen, the analgesic is a local anesthetic, and the healing agent is one or both of heparin sodium or allantoin, so The antibacterial material is one or more of nanometer metals or nanometer metal oxides.

The thrombin is covalently modified by polyethylene glycol, and the fibrinogen is covalently modified by polyethylene glycol.

The analgesic drug is one or more of lidocaine, tetracaine, prilocaine, bupivacaine, levobupivacaine, ropivacaine or benzocaine.

The antibacterial material is one or more of nano-silver, nano-zinc oxide, nano-magnesium oxide or nano-calcium oxide, and the particle size of the nano-silver, nano-zinc oxide, nano-magnesium oxide or nano-calcium oxide is 1-100nm .

The preparation is ointment, film, powder, emulsion, solution or gel.

The preparation method of described gel is:

① Add carbomer to ultrapure water for natural swelling to obtain a transparent colloid, add glycerin to the transparent colloid, and then stir evenly to obtain a sol; ② Add analgesic drugs to the sol, and then use triethanolamine to adjust the pH to 6 -8; ③ after step ②, add coagulant, healing compound and antibacterial material into the sol, stir and mix evenly, then add ultrapure water to obtain the mixture, stir the mixture evenly, degas, sterilize, pour Seal, pack.

The external preparation consists of 2-10% thrombin covalently modified by polyethylene glycol, 2-10% fibrinogen covalently modified by polyethylene glycol, and 0.2-2% local Anesthetics, 0.013-0.067% heparin sodium, 0.5-2% allantoin, 0.01-2% nano metal or nano metal oxide and 70-90% pharmaceutical excipients.

The local anesthetic is lidocaine, tetracaine, prilocaine or benzocaine, the nano metal is nano silver, and the nano metal oxide is nano zinc oxide, nano magnesium oxide or nano calcium oxide.

Use of the above-mentioned multi-effect external preparation for treating superficial skin damage in the preparation of a medicament for treating superficial skin damage.

The beneficial effects of the present invention are reflected in:

The external preparation of the present invention is aimed at the relevant links of the occurrence and development of superficial skin injuries such as burn wounds, can effectively prevent and eliminate wound infection, has strong and long-lasting analgesic effect, strong anti-inflammatory effect, and can effectively promote wound healing , in the prescription of the external preparation of the present invention, the clinically used medicinal ingredients are selected for combination, and compared with the traditional Chinese medicine compound preparation, the drug effect is clearer and the safety is better, and the drug combination of the external preparation of the present invention promotes Synergistic in healing and fighting infection.

Detailed ways

The present invention will be further described below in conjunction with embodiment.

A multi-effect external preparation for hemostasis, analgesia, healing promotion, and anti-infection for superficial skin injuries, including medically acceptable coagulants, analgesics, healing-promoting compounds, anti-infection materials, and pharmaceutical excipients . The above-mentioned pharmaceutical excipients include conventional carriers in the pharmaceutical field, and the preparation may contain carbomer, glycerin, triethanolamine, polyethylene glycol 400 and the like.

Example 1 Multi-effect external preparation (gel) prescription and preparation (in 100g)

Prescription: lidocaine 0.5g; nano silver 35mg; polyethylene glycol-modified bovine thrombin 5g; polyethylene glycol-modified fibrinogen 5g; heparin sodium 5000U (calculated as 150U per 1mg); allantois Su 1g; Carbomer-9401g; Glycerin 20mL; Triethanolamine 1.5mL; Ultrapure water balance.

Preparation Process:

1) Add the prescribed amount of Carbomer-940 to ultrapure water and swell naturally (>12h) at 4±2°C to make a transparent colloid. Add the prescribed amount of glycerin to the transparent colloid, stir evenly to obtain a sol, and set aside .

2) Dissolve the prescribed amount of lidocaine in ultrapure water, then slowly add it to the above sol, and add triethanolamine dropwise to adjust the pH to 6-8.

3) After step 2), the prescribed amount of coagulant (polyethylene glycol-modified fibrinogen and polyethylene glycol-modified bovine thrombin), healing-promoting substances (heparin sodium and allantoin) and nano silver Dissolve separately, then slowly add to the sol, stir to mix evenly, add ultrapure water to 100g, stir evenly, degas, cobalt-60 irradiated for sterilization, then potting and packaging to obtain the product.

Wherein, the synthetic method of bovine thrombin and fibrinogen modified by polyethylene glycol is as follows:

Bovine thrombin and fibrinogen were covalently modified using activated monomethoxypolyethylene glycol (mPEG), and the specific reaction conditions were as follows: in 0.05mM Tris-HCl buffer (PH=7.8) For incubation, the molecular ratio of mPEG to bovine thrombin is 6:1; the molecular ratio of mPEG to fibrinogen is 7:1. Reference [Zhou Jiangang, Tan Yuanyou. Chemical modification of porcine thrombin by polyethylene glycol and its effect analysis. Hubei Agricultural Science [J], 2009,48(6):1432-1435]. The reason for the modification is that the protein is unstable and easy to degrade when used directly, and its stability is increased after modification.

Example 2 Multi-effect external preparation (gel) prescription and preparation (in 100g)

Prescription: tetracaine 0.6g; nano-silver 35mg; polyethylene glycol-modified bovine thrombin 5g; polyethylene glycol-modified fibrinogen 5g; heparin sodium 5000U (150U per 1mg); allantois Su 1g; Carbomer-9401g; Glycerin 20mL; Triethanolamine 1.5mL; Ultrapure water balance.

The preparation process is the same as in Example 1.

Example 3 Multi-effect external preparation (gel) prescription and preparation (in 100g)

Prescription: prilocaine 0.5g; nano-zinc oxide 100mg; polyethylene glycol-modified porcine thrombin 5g; polyethylene glycol-modified fibrinogen 5g; heparin sodium 5000U (calculated as 150U per 1mg); Bursulin 1g; Carbomer-9341g; Glycerin 20mL; Triethanolamine 1.5mL; Ultrapure water balance.

The preparation process is the same as in Example 1.

Example 4 Multi-effect external preparation (gel) prescription and preparation (in 100g)

Prescription: benzocaine 0.8g; nano-magnesium oxide 100mg; polyethylene glycol-modified porcine thrombin 5g; polyethylene glycol-modified fibrinogen 5g; heparin sodium 5000U (calculated as 150U per 1mg); Allantoin 1g; Carbomer-9411g; Glycerin 20mL; Triethanolamine 1.5mL; Ultrapure water balance.

The preparation process is the same as in Example 1.

Example 5 Multi-effect external preparation (gel) prescription and preparation (in 100g)

Prescription: lidocaine 0.8g; nano-calcium oxide 100mg; polyethylene glycol-modified porcine thrombin 5g; polyethylene glycol-modified fibrinogen 5g; heparin sodium 5000U (calculated as 150U per 1mg); urine Bursulin 1g; Carbomer-9711g; Glycerin 20mL; Triethanolamine 1.5mL; Ultrapure water balance.

The preparation process is the same as in Example 1.

Pharmacodynamic experiment

1) Analgesic experiment

Experimental materials: 40 SD rats, 180-220g, provided by the Experimental Animal Center of the Fourth Military Medical University; Lincomycin Lidocaine Gel (Shandong Fangming Pharmaceutical); Automatic Heat Pain Stimulator; Example 1 The multi-effect external preparation prepared in -5.

Experimental method: Before the burn (0h) and 1, 4, and 24 (h) after the burn, respectively, use the BME-403Von Frey Pain Meter to stimulate the area around the scalded part of the plantar of the rat, and touch it for 2 to 3 seconds, and the feet will withdraw or lick The reading at the time of response was the mechanical withdrawal threshold (MWT). After the operation, the rats were raised in the laboratory, and the rats were placed in a plexiglass box for 15 minutes before the test. The upper and lower thresholds were stimulated 3 times, with an interval of 5 minutes, repeated three times, and the average value was taken. The interval between each stimulus should be at least 15 seconds, and the response caused by the stimulus (such as foot licking, leg swinging, etc.) should disappear completely.

Experimental results: As shown in Table 1, the multi-effect external preparation can significantly increase the mechanical withdrawal threshold (MWT), and its efficacy is the same as that of the active drug lincomycin lidocaine gel.

Table 1 MWT determination of mechanical hyperalgesia in superficial II° burn rats with multi-effect external preparations (n=5)

Note: ^** P<0.01, ^* P<0.05 compared with negative control group; negative control is excipient.

2) Rat scald anti-infection experiment

Experimental materials: 80 SD rats, weighing 180-220g, half male and half male, provided by the Experimental Animal Center of Fourth Military Medical University, silver sulfadiazine ointment (Guangdong Hengjian Pharmaceutical Co., Ltd.), green ointment (Shanghai Xinya Pharmaceutical Co., Ltd. ); the standard strain of Pseudomonas aeruginosa ATCC27853 (provided by the clinical laboratory of Xijing Hospital); the multi-effect external preparation prepared in Examples 1-5.

Experimental method: back burn rat model: 24 hours before the test, the hair on both sides of the pre-injured back of the rat was cut off, and then depilated with 8% sodium sulfide. General anesthesia with sodium pentobarbital was performed before injury. Use constant temperature water at 75°C for 8s, with a diameter of about 20mm, to establish a superficial II° rat scald model.

80 SD rats were randomly divided into: control group (inoculated with bacteria without treatment), silver sulfadiazine group, green ointment group and multi-effect external preparation groups. After successful modeling, the wounds of rats in each group were inoculated with Pseudomonas aeruginosa standard strain ATCC27853 (1×10 ⁹ cfu). After 30 minutes, the medicines of each group were applied to the scalded parts of the rats in the corresponding treatment group; the control group did not use medicine, and the dressing was changed once a day, and the bacterial content under the scab was investigated: the scab was taken aseptically at 24, 48, and 72 hours after the wound was inoculated with bacteria Put the lower tissue into a sterile glass homogenizer, add 2mL of sterile saline, connect the glass homogenizer to an electric stirrer, and make a homogenate from the tissue. The homogenate is diluted in multiples, and 0.1mL of the dilution is taken for Viable bacteria count, calculation formula: bacterial content per gram of tissue (cfu/g) = number of colonies (cfu) × dilution factor/tissue weight (g), and the colonies on the plate were taken for Gram staining and biochemical reactions to identify the bacterial species.

Experimental results: Compared with the control group, the multi-effect external preparation can significantly inhibit Pseudomonas aeruginosa on the burn wound, and the effect is stronger than the commercially available anti-infective drugs sulfadiazine silver cream and green ointment.

The results are shown in Table 2:

Table 2 Effects of multi-effect topical preparations on subescar tissue at various time points (n=10)

Note: ^a Compared with the control group, P<0.05; ^b Compared with the silver sulfadiazine group, P<0.05; ^c Compared with the green ointment group, P<0.05.

3) Hemostasis experiment

Experimental materials: 180-220 g of SD rats, provided by the Experimental Animal Center of Fourth Military Medical University, Yunnan Baiyao Powder (Yunnan Baiyao Group), the multi-effect external preparation prepared in Examples 1-5.

Experimental method: 36 rats with a body weight of 180-220 g were randomly divided into groups, 6 rats in each group, which were respectively the positive control group and the multi-effect external preparation groups. A rat model of hepatic hemorrhage after mid-lobectomy was prepared. Rats were anesthetized by intraperitoneal injection of 1 mL of 10% chloral hydrate, the abdominal muscles were cut along the midline of the abdomen under the costal arch, the abdomen was squeezed to squeeze out the middle lobe of the liver from the incision, and the peritoneal fluid around the liver was sucked dry, and the weighed sterile The gauze was placed under the middle lobe of the liver, and the middle lobe of the liver was quickly resected 2 cm above the lower edge of the middle lobe of the liver, and the same amount of positive drugs and experimental drugs were evenly applied to the incision, and the timing was started until the bleeding stopped. Observe the hemostasis and coagulation process in each group, and record the bleeding time and bleeding volume. Bleeding time was from the beginning of resection of the middle lobe of liver to the cessation of bleeding, and the amount of bleeding was the difference in weight of sterile gauze before and after resection.

Experimental results: The results are shown in Table 3. In the rat middle lobe resection bleeding model, the bleeding time and bleeding volume of each group of multi-effect topical preparations were not significantly different from those of the positive control group, and the hemostatic effect was the same as that of the positive control drug. (P>0.05)

The hemostatic effect of table 3 multi-effect topical preparation

4) Healing-promoting experiment

Experimental materials: 80 SD rats, weighing 180-220g, half male and half male, provided by the Experimental Animal Center of the Fourth Military Medical University; silver sulfadiazine ointment (Guangdong Hengjian Pharmaceutical Co., Ltd.), Kang Ruibao (Germany MERZ); Example 1 The multi-effect external preparation prepared in -5.

Experimental method: 80 rats were randomly divided into 8 groups, 10 rats in each group, half male and half male. 24 hours before the test, the hair on both sides of the back of the rat was cut off, and then depilated with 8% sodium sulfide, with an area of 3cm×3cm. General anesthesia with sodium pentobarbital was performed before injury. Use constant temperature water at 90°C for 8s to establish a superficial II° rat burn model. After successful modeling, the blank control group did not use medication, the positive control group evenly applied silver sulfadiazine ointment to the wound surface, and the remaining groups evenly applied the multi-effect external preparations described in Examples 1-5 to the wound surface. Change dressing 1 time/day. Continuous observation for 14 days. Inspection items: ①General observation: The standard for superficial II° burn wounds is that scabs fall off and new hairs grow. When necessary, vital signs such as rectal temperature, respiration and heart rate were measured throughout the experiment. ②Wound healing time: comparison of wound healing time in each group. ③Wound healing rate:

Wound healing rate = [(original wound area - unhealed wound area)/original wound area] × 100%

Experimental results: ①General observation: 1-2 days after injury, the swelling, exudation and redness of the wounds in the control group and the Kangruibao group were the most obvious, while the rest of the groups were lighter; after 3 days, the wounds in each group were dry and formed dry scabs, while the control group formed The scab drying speed was the slowest, and the Kangruibao group was also very slow, the silver sulfadiazine group was slightly faster, and the multi-effect topical preparation groups were the fastest. ②Wound healing time: the control group was 17.2±0.81d, the Kangruibao group was 16.4±1.25d, the silver sulfadiazine group was 14.03±0.72d, and the multi-effect external preparation groups were 12.58±0.85d, 13.18±0.75d, 12.28d respectively ±0.45d, 11.64±0.65d, 12.03±0.72d. The wound healing time of each group of multi-effect topical preparations was significantly shorter than that of the control group and the Kangruibao combined with silver sulfadiazine group. ③ Wound healing rate: see Table 4.

Table 4 Wound healing rate of each group (x±SD,%, n=6)

Note: ^a Compared with the control group, P<0.05; ^b Compared with the Kang Ruibao group, P<0.05; ^c Compared with the silver sulfadiazine group, P<0.05.

The above experimental results show that the multi-effect external preparations prepared in Examples 1-5 have significant anti-infection, analgesic, hemostatic and healing-promoting effects, wherein the analgesic effect is not inferior to the commercially available green ointment. It has a synergistic effect on promoting healing: its anti-infection effect is better than that of commercially available drugs Green Ointment and Silver Sulfadiazine Cream, and its healing effect is better than that of commercially available drugs Kang Ruibao and Silver Sulfadiazine Cream.

The present invention has following characteristics:

① It has multiple functions of hemostasis, analgesia, healing promotion and anti-infection, and can be used as a first-time treatment for superficial skin abrasions, lacerations, wounds, and burns; ② Good transdermal absorption reduces the number of clinical medications , which reduces the treatment cost and facilitates medication; ③ overcomes the shortcomings of traditional Chinese medicine compound analgesics, such as complex ingredients, large dosage, unclear material basis, insignificant analgesic effect, and slow onset; ④ has the characteristics of broad-spectrum antibacterial, drug-resistant The rate is extremely low, and it has a synergistic effect in promoting healing and anti-infection, and is more effective than similar drugs.

Claims (8)

1. be used for the treatment of a Multi-effect external preparation for Dermal skin damage, it is characterized in that: this external preparation is made up of the promoting healing thing of the analgesic of the coagulation matters of 1-20%, 0.2-10%, 0.2-20%, the anti-biotic material of 0.005-10% and the pharmaceutic adjuvant of 40-90% by mass fraction; Described coagulation matters is one or both in thrombin or Fibrinogen, and described promoting healing thing is one or both in heparin sodium or allantoin, and described anti-biotic material is one or more in nano metal or nano-metal-oxide; Described analgesic is one or more in lignocaine, tetracaine, prilocaine, bupivacaine, levobupivacaine, ropivacaine or benzocaine.

2. according to claim 1 a kind of be used for the treatment of Dermal skin damage Multi-effect external preparation, it is characterized in that: described thrombin is through Polyethylene Glycol covalent modification, and Fibrinogen is through Polyethylene Glycol covalent modification.

3. according to claim 1 a kind of be used for the treatment of Dermal skin damage Multi-effect external preparation, it is characterized in that: described anti-biotic material is nanometer silver, nano zine oxide, one or more in nano magnesia or nano calcium oxide, described nanometer silver, nano zine oxide, the particle diameter of nano magnesia or nano calcium oxide is 1-100nm.

4. according to claim 1 a kind of be used for the treatment of Dermal skin damage Multi-effect external preparation, it is characterized in that: described preparation is ointment, membrane, powder, Emulsion, solution or gel.

5. according to claim 4 a kind of be used for the treatment of Dermal skin damage Multi-effect external preparation, it is characterized in that: the preparation method of described gel is:

1. carbomer is added in ultra-pure water carry out nature swelling transparent colloid, in transparent colloid, add glycerol, then stir to obtain colloidal sol; 2. analgesic is joined in described colloidal sol, then regulate pH to 6-8 with triethanolamine; 3. through step 2. after, coagulation matters, promoting healing thing and anti-biotic material are joined in described colloidal sol, add ultra-pure water after being uniformly mixed again and obtain mixture, degassed after mixture is stirred, sterilizing, embedding, packaging.

6. according to claim 1 a kind of be used for the treatment of Dermal skin damage Multi-effect external preparation, it is characterized in that: described external preparation is by the thrombin through Polyethylene Glycol covalent modification of mass fraction by 2-10%, the Fibrinogen through Polyethylene Glycol covalent modification of 2-10%, the local anesthetic of 0.2-2%, 0.013-0.067% heparin sodium, the allantoin of 0.5-2%, the pharmaceutic adjuvant composition of the nano metal of 0.01-2% or nano-metal-oxide and 70-90%, described thrombin, Fibrinogen, local anesthetic, heparin sodium, allantoin, the mass fraction sum of nano metal or nano-metal-oxide and pharmaceutic adjuvant is 100%.

7. according to claim 6 a kind of be used for the treatment of Dermal skin damage Multi-effect external preparation, it is characterized in that: described local anesthetic is lignocaine, tetracaine, prilocaine or benzocaine, described nano metal is nanometer silver, and described nano-metal-oxide is nano zine oxide, nano magnesia or nano calcium oxide.

8. one kind is used for the treatment of the purposes of Multi-effect external preparation in preparation treatment Dermal skin damage medicine of Dermal skin damage as claimed in claim 1.