阅读说明：本技术 吡罗昔康在制备治疗皮肤溃疡药物中的应用及药物制备方法 (Application of piroxicam in preparation of medicine for treating skin ulcer and preparation method of medicine ) 是由 张媛媛 孙晓东 于 2020-12-08 设计创作，主要内容包括：本发明公开了吡罗昔康在制备治疗皮肤溃疡药物中的应用及药物制备方法,所述药物由吡罗昔康和药物上可接受的辅料制备得到；吡罗昔康能促进人脐静脉内皮细胞HUVEC细胞在高糖刺激下的迁移,从而促进糖尿病足溃疡伤口愈合合；吡罗昔康对皮肤溃疡,尤其是糖尿病足溃疡有显著的疗效。(The invention discloses an application of piroxicam in preparing a medicament for treating skin ulcer and a medicament preparation method, wherein the medicament is prepared from piroxicam and pharmaceutically acceptable auxiliary materials; piroxicam can promote human umbilical vein endothelial cell HUVEC cell to migrate under high sugar stimulation, thereby promoting diabetic foot ulcer wound healing; piroxicam has remarkable therapeutic effect on skin ulcer, especially diabetic foot ulcer.)

1. The application of piroxicam in the preparation of a medicament for treating skin ulcer is characterized in that the medicament is prepared from piroxicam and pharmaceutically acceptable auxiliary materials.

2. Use of piroxicam in the preparation of a medicament for the treatment of skin ulcers according to claim 1, wherein said skin ulcers are one of vascular ulcers, traumatic ulcers, infectious ulcers, radioactive ulcers.

3. The use of piroxicam in the preparation of a medicament for the treatment of skin ulcers according to claim 1, wherein said medicament is one of tablets, capsules, patches, gels, injections, ointments.

4. Use of piroxicam in the preparation of a medicament for the treatment of skin ulcers according to claim 1, characterized in that the skin ulcers are diabetic foot ulcers.

5. The method of claim 1, comprising the steps of:

step 1: dissolving piroxicam in PEG400 to form a mixed solution A;

step 2: PEG8000 and water are fully dissolved to form a mixed solution B, and the mass ratio of the PEG8000 to the water in the mixed solution B is 2: 1;

and step 3: mixing the mixed solution A and B to obtain mixed solution C, sealing, standing at 4 deg.C overnight, and solidifying to obtain the desired medicine;

the mass ratio of PEG400 to PEG8000 to water in the mixed solution C is 2:2: 1; the concentration of the piroxicam in the mixed solution C is 0.1 mol/L-0.15 mol/L.

Technical Field

The invention relates to the technical field of biological medicines, in particular to application of piroxicam in preparation of a medicine for treating skin ulcer and a preparation method of the medicine.

Background

Skin ulcer is a common disease and a frequently encountered disease, and clinically, the skin ulcer can not be healed for a long time and the skin tissue defect is liquefied and necrotic. The wound surface is difficult to heal and the consumption is deep, so that serious psychological pressure and economic burden are brought to patients. The patients with unhealed wound surface for more than two weeks are called chronic skin ulcer, and the patients with unhealed wound surface for more than one month are called chronic intractable skin ulcer. Especially, foot ulcer caused by diabetes is a common chronic complication of diabetes, clinical manifestations comprise foot pain, foot ulcer, foot gangrene and the like, even cause amputation, and is an important factor causing disability of a diabetic patient.

The pathological mechanisms of skin ulcers include localized microcirculatory disturbance, neurological dysfunction, immune dysfunction, and the like. The skin ulcer includes vascular ulcer, traumatic ulcer, infectious ulcer, radioactive ulcer, etc. At present, no targeted treatment method for skin ulcer exists, and symptomatic and supportive treatment, such as anti-infection treatment, hyperbaric oxygen treatment and the like, is generally adopted. These treatments are not effective. Hyperbaric oxygen therapy is a method of treating diseases by allowing a patient to inhale oxygen under pressure in a closed pressure vessel (hyperbaric oxygen chamber). The hyperbaric oxygen can improve tissue hypoxia and promote ulcer healing, is used for treating diabetic foot for more than 50 years, and has better curative effect on severe ischemic ulcer wound surfaces. Hyperbaric oxygen exerts its therapeutic effect by increasing the partial pressure of arterial blood oxygen at the affected area, on the precondition of its effectiveness in blood circulation. Therefore, the utility model is not effective for patients with completely occluded artery vessels of affected limbs or severely narrowed artery vessels. Therefore, hyperbaric oxygen therapy is only one of the adjunctive treatments for diabetic foot ulcers, and strict control of indications, contraindications and methods of use is required at the time of use.

Piroxicam (Piroxicam), also called Piroxicam, has the chemical name: 2-methyl-4-hydroxy-N- (2-pyridyl) -2H-1, 2-benzothiazine-3-carboxamide 1, 1-dioxide having the formula: c₁₅H₁₃N₃O₄And S. Is a non-selective non-steroidal anti-inflammatory drug, has analgesic, anti-inflammatory and antipyretic effects, and can be used for treating osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, etc. There are no studies and reports related to the use of the compound for treating skin ulcer.

Disclosure of Invention

Aiming at the problems in the prior art, the invention provides an application of piroxicam in preparing a medicament for treating skin ulcer and a medicament preparation method, wherein the piroxicam can promote the human umbilical vein endothelial cell HUVEC cell to migrate under the stimulation of high sugar, so as to promote the healing of skin ulcer.

The technical scheme adopted by the invention is as follows: use of piroxicam in the preparation of a medicament for the treatment of skin ulcers, said medicament being prepared from piroxicam and a pharmaceutically acceptable adjuvant.

Further, the skin ulcer is one of vascular ulcer, traumatic ulcer, infectious ulcer and radioactive ulcer.

Further, the medicine is one of tablets, capsules, sticking tablets, gels, injections and ointments.

Further, the skin ulcer is a diabetic foot ulcer.

The preparation method of the medicine comprises the following steps:

step 1: dissolving piroxicam in PEG400 to form a mixed solution A;

step 2: PEG8000 and water are fully dissolved to form a mixed solution B, and the mass ratio of the PEG8000 to the water in the mixed solution B is 2: 1;

and step 3: mixing the mixed solution A and B to obtain mixed solution C, sealing, standing at 4 deg.C overnight, and solidifying to obtain the desired medicine;

the mass ratio of PEG400 to PEG8000 to water in the mixed solution C is 2:2: 1; the concentration of the piroxicam in the mixed solution C is 0.1 mol/L-0.15 mol/L.

The invention has the beneficial effects that:

(1) the present invention provides an effective treatment for skin ulcers, particularly diabetic foot ulcers;

(2) the piroxicam can promote the migration of HUVEC cells of human umbilical vein endothelial cells under the stimulation of high sugar, thereby promoting the wound healing of diabetic foot ulcer.

Drawings

FIG. 1 is a graph showing the degree of healing of scratches in piroxicam group and control group in example 1 of the present invention.

Fig. 2 is a schematic diagram of the degree of wound healing on the back of mice in the piroxicam group and the control group in example 2 of the present invention.

FIG. 3 is a graph showing the degree of wound healing on the back of rats in the piroxicam group and the control group in example 3 of the present invention.

Detailed Description

The invention is further described with reference to the following figures and specific embodiments.

An application of piroxicam in preparing the medicine for treating skin ulcer is disclosed, wherein the medicine is prepared from piroxicam and the pharmacologically acceptable auxiliary. In particular to a tablet, a capsule, a patch, a gel, an injection or an ointment which is prepared from an effective component piroxicam and pharmaceutically acceptable auxiliary materials. The skin ulcer is one of vascular ulcer, traumatic ulcer, infectious ulcer, and radioactive ulcer. Especially diabetic foot ulcers.

The preparation method is illustrated by taking ointment as an example and comprises the following steps:

step 1: dissolving piroxicam in PEG400 to form a mixed solution A;

step 2: PEG8000 and water are fully dissolved to form a mixed solution B, and the mass ratio of the PEG8000 to the water in the mixed solution B is 2: 1;

and step 3: mixing the mixed solution A and B to obtain mixed solution C, sealing, standing at 4 deg.C overnight, and solidifying to obtain the desired medicine;

the mass ratio of PEG400 to PEG8000 to water in the mixed solution C is 2:2: 1; the concentration of the piroxicam in the mixed solution C is 0.1 mol/L-0.15 mol/L.

Example 1

Since one of the pathological mechanisms of diabetic foot ulcers is local hypoxia, Human Umbilical Vein Endothelial Cells (HUVEC) were selected for this example. The vascular ischemia state caused by diabetes is simulated by culturing human umbilical vein endothelial cells for 24h under the condition of high sugar and low serum, and the cell migration negligence of human umbilical vein endothelial primary amine cultured for 24h under the condition of high sugar and low serum and cultured for 24h under the normal condition is respectively detected by a CCK-8 cell proliferation activity detection experiment, a scratching experiment and a tube formation experiment.

The method comprises the following steps:

HUVEC human umbilical vein endothelial cells were cultured in high-glucose DMEM medium containing 10% Fetal Bovine Serum (FBS) at 37 deg.C and 5% CO₂Subculturing in an incubator. When the cells reached 90% confluence, they were passaged on cell culture plates and randomly divided into three groups for relevant experiments.

The experiment was divided into two groups, group 1 (high glucose model group, i.e. control group) and group 2 (piroxicam group).

Group 1 treatments were as follows: a2% FBS-containing high-sugar DMEM culture solution was added, and glucose was added to make the glucose concentration 50 mmol/L.

Group 2 treatments were as follows: adding DMEM culture solution containing 2% FBS high-glucose, adding glucose to make the concentration of common sugar reach 50mmol/L, and simultaneously adding piroxicam, wherein the addition amount of piroxicam is 3.31 ug/ml.

After the cells reached fusion, the cells were vertically scratched with a 100ul pipette tip, with a width of about 500um, grouped, and the degree of scratch healing was photographed with an inverted phase contrast microscope after culturing for 4h and 8h, as shown in fig. 1.

As can be seen from the figure, piroxicam can significantly promote the healing of the scratches of HUVEC cells and improve the migration capability of HUVEC cells.

Example 2

Piroxicam ointment was first prepared according to the following steps:

step 1: dissolving 30mg of piroxicam in 3.4ml of PEG400 to form a mixed solution A;

step 2: fully mixing PEG8000 and water according to the mass ratio of 2:1 to form 5.1ml of mixed solution B;

and step 3: and (3) fully and uniformly mixing the mixed solution A and the mixed solution B, pouring the mixture into a flat-bottom open container, sealing, standing overnight at the temperature of 4 ℃, and solidifying into paste for use.

The blank ointment was prepared as follows:

step 1: dissolving 20g of PEG8000 in 10ml of water to form a mixed solution A;

step 2: fully and uniformly mixing 20ml of PEG400 with the mixed solution A in the step 1, pouring the mixture into a flat-bottom open container, and sealing; standing overnight at 4 deg.C, and solidifying to obtain paste.

Establishing a rat skin ulcer model

8-week-old C57BL/6 male rats were selected and weighed and randomly divided into the following two groups according to body weight: control and piroxicam groups, 7 per group, were fed ad-hoc for 3 days. Two groups of rats are anesthetized by intraperitoneal injection of pentobarbital sodium, and then a hole is punched on the back by a skin biopsy device with the diameter of 10mm, so that a rat skin ulcer model is obtained.

The rats in the control group are coated with the blank control ointment 1 time per day on the back wound surface, and the rats in the piroxicam group are coated with the piroxicam ointment 1 time per day on the back wound surface. Photographs of the back wound were then taken periodically to observe the extent of wound healing, as shown in fig. 2.

As can be seen from the figure, the healing speed of the wound on the back of the piroxicam rats is obviously faster than that of the control group, and after 14 days, the wound on the back of the piroxicam rats is basically healed. The piroxicam can obviously promote the wound healing of the skin ulcer of the rat.

Example 3

Establishing diabetic rat skin ulcer model

SD male rats of 8 weeks old are selected and weighed, and are randomly divided into the following two groups according to body weight: control and piroxicam groups, 7 per group, were fed ad-hoc for 3 days.

Rats were intraperitoneally injected with streptozotocin STZ 65mg/kg and fed with high-fat diet for 2 weeks. Then measuring 4 hours of fasting blood sugar, and screening the patients with fasting blood sugar more than or equal to 13.4g/dL to judge that the diabetes molding is successful.

Control group: the rats successfully molded were anesthetized with pentobarbital by intraperitoneal injection, and then a hole was made in the back using a skin biopsy instrument with a diameter of 10mm, and the control group wound was coated with the blank control ointment prepared in example 2 1 time per day.

Piroxicam group: the rats successfully molded were anesthetized with pentobarbital by intraperitoneal injection, and then a hole was made in the back using a skin biopsy instrument with a diameter of 10mm, and the wound was coated with the piroxicam ointment prepared in example 2 1 time per day.

Photographs of the wounds on the backs of rats were taken periodically to observe the degree of wound healing, as shown in fig. 3. The healing speed of the back wound of the piroxicam rats is obviously faster than that of the control group, and after 10 days, the back wound of the piroxicam rats is basically healed. The piroxicam can obviously promote the wound healing of the skin ulcer of the diabetic rat.

Diabetic foot ulcers, which are mainly caused by severe hypoperfusion of blood, are associated with ischemic injury of blood vessels, and thus promoting angiogenesis to increase blood perfusion is a therapeutic strategy for treating diabetic foot ulcers. Piroxicam promotes the migration of HUVEC cells of human umbilical vein endothelial cells under high sugar stimulation, and the examples demonstrate that the piroxicam can promote the healing of ulcer wounds of diabetic rats. Therefore, piroxicam has remarkable curative effect on skin ulcer, especially diabetic foot ulcer.