阅读说明：本技术 一种具有治疗糖尿病足的外用制剂及其制备工艺 (External preparation for treating diabetic foot and preparation process thereof ) 是由 李秋 于 2021-10-11 设计创作，主要内容包括：本发明属中药技术领域,具体涉及一种具有治疗糖尿病足的外用制剂及其制备工艺。所述外用制剂主要由以下原料制备而成：甘油、起泡剂、纯净水、尿素、海鱼表皮粘液提取液、酯类物质。本发明的外用制剂能有效防止糖尿病足的致病菌侵染,维持湿润,不易干裂,及改善皮肤局部血液循环的综合作用。本发明的外用制剂使用方便,成本低,携带更为方便,工艺相对简单,适合进一步的工业化大生产。(The invention belongs to the technical field of traditional Chinese medicines, and particularly relates to an external preparation for treating diabetic foot and a preparation process thereof. The external preparation is mainly prepared from the following raw materials: glycerol, a foaming agent, purified water, urea, a marine fish skin mucus extracting solution and ester substances. The external preparation can effectively prevent the infection of pathogenic bacteria of diabetic feet, maintain the wetness, is not easy to crack and improves the comprehensive function of local blood circulation of skin. The external preparation of the invention has the advantages of convenient use, low cost, more convenient carrying and relatively simple process, and is suitable for further industrialized mass production.)

1. The external preparation for treating diabetic foot is characterized by being prepared from the following raw materials:

2. the external preparation according to claim 1, which is prepared mainly from the following raw materials:

3. the external preparation of claim 1, wherein the external preparation further comprises one or more of a safflower extract, a forsythia extract, a honeysuckle extract, and a lithospermum extract.

4. The external preparation according to claim 1, wherein the extract of skin mucus of sea fish is derived from one or more of cod, grouper, salmon, tuna, yellow croaker, hairtail, pomfret, Spanish mackerel, and Duobao.

5. The external preparation as claimed in claim 1, wherein the foaming agent is selected from one or more of coconut oil, amino acid, olive oil, sodium bicarbonate, sodium lauryl sulfate.

6. The external preparation as claimed in claim 1, wherein the ester is selected from one or more of phospholipids, lauric acid, myristic acid, triglyceride, lecithin, cholesterol, tween 80 and sodium deoxycholate.

7. The external preparation of claim 1, wherein the extraction process of the Chinese herbal medicine extract comprises:

1) crude extraction: adding distilled water into the materials, oscillating in water bath at 45-5 deg.C for 20-40min at oscillation frequency of 80-150 rpm, extracting under oscillation, concentrating under reduced pressure in rotary evaporator to extract at 50-60 deg.C and pH of solvent of 8.5-9.5 for 3 times, and mixing filtrates;

2) fine extraction: adsorbing the filtrate obtained in the step 1) by using macroporous adsorption resin NKA at an adsorption flow rate of 5mL/min, desorbing by using 50% ethanol water solution at a desorption flow rate of 2BV/h, concentrating the refined extract, and standing at room temperature in a dark place.

8. The external preparation as claimed in claim 1, wherein the extraction process of the marine fish epidermal mucus extract is:

1) taking several sea fish strips, placing in purified water, adding 5% sodium chloride solution at water temperature below 20 deg.C, feeding for 2-3 days, filtering with purified water, removing clear water after filtering, and collecting filtrate;

2) dissecting the marine fish, taking the skin of the marine fish, placing the skin in a high-speed tissue triturator, crushing for 35-45 min at the rotating speed of 4000-4500 r/min to obtain homogenate, mixing with the filtrate obtained in the step 1), and stirring uniformly to obtain a mixed solution;

3) and (3) adding purified water into the mixed solution obtained in the step 2), mixing, concentrating to a relative density of 1.1-1.15, adding 100% ethanol into the concentrated solution until the volume fraction reaches 70%, performing rotary evaporation to dryness, collecting precipitate, adding a proper amount of purified water into the precipitate, and preparing colloid to obtain the marine fish skin mucus extract.

9. The external preparation according to any one of claims 1 to 8, wherein the external preparation is in a clinically acceptable dosage form; further, the external preparation is an external ointment; further, the external ointment is one or more of ointment, cataplasm, a film coating agent, a liniment and foamed milk; further, the external ointment is foam milk.

10. The preparation method of the external preparation of claim 9, wherein the foamed milk is prepared by the following steps:

1) mixing the skin mucus of the marine fish with glycerol, water and urea, adding an ester substance, finally adding a mixed solution of a foaming agent, and stirring for 10-30min in a sterile environment at the temperature of 45-50 ℃;

2) placing the mixed solution into a mousse bottle for later use.

Technical Field

The invention relates to the field of clinical disease prevention, in particular to foam milk for treating foot skin of a diabetic patient and a preparation method thereof.

Background

The diabetic foot is a general term for the pathological changes of foot pain, deep skin ulcer, acromelic gangrene and the like caused by diabetes comprehensive factors and is one of chronic complications of diabetes.

Foot ulcers are a manifestation of diabetes, mainly due to narrowing or obstruction of blood vessels in the lower limbs of patients, resulting in a significant reduction in blood supply to the foot, susceptibility to severe infections, and poor healing of wounds that eventually form ulcers, even requiring amputation in the critically ill. Since diabetic patients are also easy to suffer from peripheral nerve lesions, the protective sensation of feet is reduced or lost, and once inflammation, trauma and the like occur, the patients often cannot timely perceive the lesions, so that the lesions are enlarged and serious consequences are caused.

Therefore, foot protection for diabetics is very important. At present, no protective articles specially used for protecting the feet of the diabetic patients exist in the market.

Disclosure of Invention

In view of the defects of the prior art, the invention provides an external preparation for treating diabetic foot and a preparation process thereof. The external preparation is mainly prepared from the following raw materials: glycerol, a foaming agent, purified water, urea, a traditional Chinese medicine extracting solution, a marine fish skin mucus extracting solution and ester substances.

Specifically, the external preparation of the invention comprises the following components in percentage by volume and weight:

more preferably:

furthermore, the external preparation can also be added with traditional Chinese medicine extracting solution, and the traditional Chinese medicine extracting solution can be one or a combination of a safflower extracting solution, a forsythia extracting solution, a honeysuckle extracting solution and a lithospermum extracting solution.

Further, the marine fish skin mucus extractive solution is derived from marine fish, such as one of cod, grouper, salmon, tuna, Carnis Pseudosciaenae, hairtail, butterfish, Scomberomorus niphonius, and Duobao fish.

Further, the foaming agent is selected from one or more of coconut oil, amino acid, olive oil, sodium bicarbonate and sodium lauryl sulfate. Further, the foaming agent is selected from amino acids and coconut oil in volume ratio, and the amino acids: olive oil 2: 3.

Further, the ester is selected from one or more of phospholipid, lauric acid, myristic acid, triglyceride, lecithin, cholesterol, tween 80 and sodium deoxycholate. Further, the ester is selected from the group consisting of triglycerides and cholesterol, in weight ratios, triglyceride: cholesterol 1: 1.

Further, in order to improve the treatment effect of the diabetic foot, the extraction process of the traditional Chinese medicine extract disclosed by the invention comprises the following steps:

1) crude extraction: adding distilled water into the materials, oscillating in water bath at 45-5 deg.C for 20-40min at oscillation frequency of 80-150 rpm, extracting under oscillation, concentrating under reduced pressure in rotary evaporator to extract at 50-60 deg.C and pH of solvent of 8.5-9.5 for 3 times, and mixing filtrates;

2) fine extraction: adsorbing the filtrate obtained in the step 1) by using macroporous adsorption resin NKA at an adsorption flow rate of 5mL/min, desorbing by using 50% ethanol water solution at a desorption flow rate of 2BV/h, concentrating the refined extract, and standing at room temperature in a dark place.

Further, the extraction process of the traditional Chinese medicine extract comprises the following steps:

1) crude extraction: adding distilled water (liquid-material ratio of 20mL/g) into the Chinese medicinal materials, oscillating in water bath at 55 deg.C for 30min, maintaining oscillation frequency at 120 rpm, extracting under oscillation, concentrating under reduced pressure in rotary evaporator to obtain extract with temperature of 55 deg.C and pH of solvent of 9.0, extracting for 3 times, and mixing filtrates.

2) Fine extraction: fine extraction: adsorbing the filtrate obtained in the step 1) by using macroporous adsorption resin NKA at an adsorption flow rate of 5mL/min, desorbing by using 50% ethanol water solution at a desorption flow rate of 2BV/h, concentrating the refined extract, and standing at room temperature in a dark place for later use.

Further, the preparation process of the marine fish skin mucus extract comprises the following steps:

1) taking several sea fish strips, placing in purified water, adding 5% sodium chloride solution at water temperature below 20 deg.C, feeding for 2-3 days, filtering with purified water, removing clear water after filtering, and collecting filtrate;

2) dissecting the marine fish, taking the skin of the marine fish, placing the skin in a high-speed tissue triturator, crushing for 35-45 min at the rotating speed of 4000-4500 r/min to obtain homogenate, mixing with the filtrate obtained in the step 1), and stirring uniformly to obtain a mixed solution;

3) mixing the mixed solution obtained in the step 2) with purified water, concentrating to relative density of 1.1-1.15, adding 100% ethanol into the concentrated solution to make volume fraction reach 70%, rotary evaporating to dryness, collecting precipitate,

adding appropriate amount of purified water into the precipitate to obtain colloid, and obtaining extractive solution of mucus on skin of marine fish.

The preparation is an external preparation, and is preferably an external ointment, wherein the external ointment is one or more of ointment, cataplasm, a film coating agent, a liniment and foamed milk. The external ointment is foam milk.

The second purpose of the invention is to provide the components and the preparation process of the foam milk:

1) mixing the skin mucus of the marine fish with glycerol, water and urea, adding the traditional Chinese medicine extract and the ester substances, finally adding the mixed solution of the foaming agent, and stirring for 10-30min in a sterile environment at the temperature of 45-50 ℃;

2) placing the mixed solution into a mousse bottle for later use.

Compared with the prior art, pharmacological experiments and clinical experiments respectively prove that the external preparation has a treatment effect, and the treatment effect of the external preparation is shown in the treatment effects of the external preparation at 7 th, 10 th and 14 th days after treatment by taking a mouse as an example.

The external preparation of the invention has the advantages of convenient use, low cost, more convenient carrying and relatively simple process, and is suitable for further industrialized mass production.

Drawings

FIG. 1: changes before and after the diabetic foot after 1 day of treatment using the milk foam of example 5 of the present invention.

DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Example 1: the extraction process of the traditional Chinese medicine extract comprises the following specific steps:

1) crude extraction: adding distilled water (liquid-material ratio of 20mL/g) into the Chinese medicinal materials, oscillating in water bath at 55 deg.C for 30min, maintaining oscillation frequency at 120 rpm, extracting under oscillation, concentrating under reduced pressure in rotary evaporator to obtain extract with temperature of 55 deg.C and pH of solvent of 9.0, extracting for 3 times, and mixing filtrates.

2) Fine extraction: fine extraction: adsorbing the filtrate obtained in the step 1) by using macroporous adsorption resin NKA at an adsorption flow rate of 5mL/min, desorbing by using 50% ethanol water solution at a desorption flow rate of 2BV/h, concentrating the refined extract, and standing at room temperature in a dark place for later use.

The traditional Chinese medicine raw material can be any one of safflower, forsythia, honeysuckle and lithospermum or more than two of the safflower, the forsythia, the honeysuckle and the lithospermum can be mixed and extracted.

Example 2: the preparation process of the marine fish skin mucus extract comprises the following steps:

1) 10kg of sea fish is taken and put in 1.5L of purified water, and 5% sodium chloride solution (water: feeding at 15-20 deg.C for 2-3 days with sodium hydroxide volume ratio of 1:0.15), filtering with purified water, removing the clear water, and collecting the filtrate;

2) dissecting the marine fish, taking the skin of the marine fish, placing the skin in a high-speed tissue triturator, crushing for 35-45 min at the rotating speed of 4000-4500 r/min to obtain homogenate, mixing with the filtrate obtained in the step 1), and stirring uniformly to obtain a mixed solution;

3) and (3) adding purified water into the mixed solution obtained in the step 2), mixing, concentrating to a relative density of 1.1-1.15, adding 100% ethanol into the concentrated solution to make the volume fraction reach 70%, performing rotary evaporation to dryness, collecting a precipitate, adding purified water (calculated by g/mL, the precipitate: water is 1:0.5), and colloid is prepared to obtain the marine fish skin mucus extract.

The sea fish skin mucus extractive solution is prepared from one or more of sea fish such as cod, grouper, salmon, tuna, Carnis Pseudosciaenae, hairtail, pomfret, Spanish mackerel, and Duobao fish by mixing and extracting. See the examples for details.

Example 3: a foam milk composition for foot skin of diabetic patients comprises the following components in percentage by volume:

the preparation method comprises the following steps:

1) mixing the cod skin mucus extract with glycerol, water and urea, adding glycerol and cholesterol, finally adding the mixed solution of amino acid and olive oil, and stirring for 10-30min in a sterile environment at the temperature of 45-50 ℃;

2) placing the mixed solution into a mousse bottle for later use.

Example 4: a foam milk composition for foot skin of diabetic patients comprises the following components in percentage by volume:

the preparation method comprises the following steps:

1) mixing the cod skin mucus extract with glycerol, water and urea, adding the safflower extract, the glycerol and the cholesterol, finally adding the mixed solution of amino acid and olive oil, and stirring for 10-30min in a sterile environment at the temperature of 45-50 ℃;

2) placing the mixed solution into a mousse bottle for later use.

Example 5: a foam milk composition for foot skin of diabetic patients comprises the following components in percentage by volume:

the preparation method comprises the following steps:

1) mixing the cod skin mucus extract with glycerol, water and urea, adding the safflower extract, the glycerol and the cholesterol, finally adding the mixed solution of amino acid and olive oil, and stirring for 10-30min in a sterile environment at the temperature of 45-50 ℃;

2) placing the mixed solution into a mousse bottle for later use.

Example 6: a foam milk composition for foot skin of diabetic patients comprises the following components in percentage by volume:

the preparation method is the same as example 3.

Example 7: a cream composition for foot skin of diabetic patients comprises the following components by volume ratio:

the preparation method of the cream comprises the following steps:

1) mixing the cod skin mucus extract with glycerol, water and urea, adding the safflower extract, the glycerol and the cholesterol, finally adding the mixed solution of amino acid and olive oil, and stirring for 10-30min in a sterile environment at the temperature of 45-50 ℃;

2) placing the mixed solution into a packaging bottle for later use.

Example 8: a foam milk composition for foot skin of diabetic patients comprises the following components in percentage by volume:

the preparation method is the same as example 3.

Comparative example 1: a foam milk composition for foot skin of diabetic patients comprises the following components in percentage by volume:

the preparation method is the same as example 3.

Comparative example 2: a foam milk composition for foot skin of diabetic patients comprises the following components in percentage by volume:

the preparation method is the same as example 3.

Comparative example 3: a foam milk composition for foot skin of diabetic patients comprises the following components in percentage by volume:

the preparation method is the same as example 3.

Comparative example 4: a foam milk composition for foot skin of diabetic patients comprises the following components in percentage by volume:

the preparation method is the same as example 3.

Verification examples

1) Antibacterial test of the pharmaceutical composition of the present invention

1.1 materials and methods

1) Strains and culture medium: sabouraud medium, Staphylococcus aureus, Candida albicans, Escherichia coli and Pseudomonas aeruginosa

The strains (all the strains are purchased from Beijing Beinanna Chuanglian union Biotechnology research institute).

2) Medicine preparation: the raw materials and the method of the invention in the embodiment 3-8 and the comparative example 1-4 are used to prepare the raw liquid of the medicine composition.

3) The method comprises the following steps: preparing Sabouraud medium, filling into conical flask, and sterilizing with damp heat. 1ml of each of the inventive examples 3 to 6, comparative examples 1 to 4 and 1: 20 of the sterilized physiological saline solution was aseptically dispensed into a sterilized dish, 10 dishes (10 cm in diameter) were prepared per dose, and the resulting mixture was poured into a flask of Sabouraud's culture to inoculate the above four kinds of bacteria (colonies having a diameter of about 0.5 mm). Incubate (37 ℃) for 6 days. The growth state of colonies and the presence or absence of growth of foreign bacteria were observed, and the diameter (mm) of the colonies was measured and compared with a blank group.

TABLE 1 antibacterial Effect of the respective example groups: (n＝10)

Note: in contrast to comparative example 1,^*P＜0.05，^&P＜0.01；

in contrast to comparative example 4,^#P＜0.05，^@P＜0.01；

as can be seen from table 1 above, examples 3 to 6 of the present invention have significant antibacterial effects, and have significant inhibitory or killing effects on pathogenic bacteria such as staphylococcus aureus, candida albicans, escherichia coli, pseudomonas aeruginosa, and the like, and it can be seen that the antibacterial effects of examples 5 to 8 are superior to those of examples 3 to 4, while the antibacterial effects of examples 3 to 4 are superior to those of comparative examples 1 to 4.

2) Clinical trial and typical cases

(I) clinical efficacy observation of the traditional Chinese medicine composition for treating diabetic foot

1 data and method

1.1 general data

Patients with Diabetic Foot Ulcer (DFU) who were admitted to Shandong provincial Hospital from 1 month to 2021 month in 2019 were selected, 30 of them that met the clinical trial standards were selected as study subjects, and were randomly divided into an observation group and a control group by a random number table.

The observation group consisted of 10 cases, 5 men and 5 women; the age is 50-65 years, and the average age (55.44 +/-4.50) years; the course of diabetes is 5-10 years, and the average (7.11 +/-1.22) years; the disease course of DFU is 10-25 d, and the average (15.66 +/-7.14) d; ulcer area (5.77 +/-3.39) cm²(ii) a Wagner classification: stage I1, stage II 8, stage III 1 and stage IV 0.

Control 1 group consisted of 10 cases, 5 men and 5 women; age 51-66 years, mean (56.58 ± 5.60) years; the course of diabetes is 5-12 years, and the average (7.38 +/-3.55) year; the disease course of DFU is 10-24 d, and the average (16.03 +/-4.91) d; ulcer area (5.88 +/-3.20) cm²(ii) a Wagner classification: stage I2, stage II 7, stage III 0 and stage IV 1.

Control 2 groups consisted of 10 cases, 5 men and 5 women; age 52-65 years, PingAll (55.58 + -3.21) years old; the course of diabetes is 5-11 years, and the average (7.22 +/-2.57) years; the disease course of DFU is 11-25 d, and the average (15.03 +/-3.91) d; ulcer area (6.28 +/-2.20) cm²(ii) a Wagner classification: stage I1, stage II 6, stage III 2 and stage IV 1.

By comparing the general data of the observation group and the treatment group, the difference between the two groups in terms of age, disease course, ulcer area and the like is not statistically significant (P > 0.05) and is not comparable.

1.2 diagnostic criteria and enrollment criteria

1.2.1 diagnostic criteria

The method comprises the following steps: and (3) Western diagnosis: refer to the Chinese guidelines for diagnosis and treatment of diabetic foot, which has a definite history of diabetes, and the feet have dry cracks, infection, ulcer or gangrene, and are confirmed to be DFU by auxiliary examination.

Secondly, the step of: the age is 50-65 years old, and the blood sugar is well controlled.

③: wagner grades I-IV, the area of the wound surface is less than or equal to 10cm²。

Fourthly, the method comprises the following steps: signing the informed consent.

1.2.2 exclusion criteria

Compliance with the "diagnostic criteria of 1.2.1" was included in the clinical trial. But the following (1) to (6) are to be excluded

(1) Combined genetic, infectious disease or malignancy; (2) obviously liver and kidney insufficiency or serious malnutrition; (3) severe infection is combined to cause systemic symptoms, the body temperature is more than 38 ℃, and the white blood cell count is more than 11 multiplied by 10⁹Per liter; (4) pregnant or lactating women, (5) history of psychiatric illness; (6) the history of drug allergy.

1.3 methods

The patients of the observation group and the experimental group take the hypoglycemic drug to control the blood sugar level, improve the microcirculation, control the blood pressure, the blood fat level and other conditions. The control group and the observation group are treated by a conventional method, and the blood sugar of the patients is controlled and the wound infection is prevented.

The diabetic feet of the observation group are externally smeared with the foam milk of the invention example 5 for 3 times a day with the interval time of 8 hours, the dosage is evenly smeared, and the foam thickness is 1-2 cm.

The diabetic feet of the control group 1 were topically applied with the foam cream of comparative example 2 3 times a day at intervals of 8 hours, at a uniform application rate, and the foam thickness was 1-2 cm.

The control group 2 had diabetes mellitus sufficient the foam cream of this comparative example 4 was applied externally 3 times a day with an interval of 8 hours, and the amount was applied evenly with a foam thickness of 1-2 cm.

Both groups were evaluated for clinical treatment efficacy after 4 weeks of continuous treatment.

1.4 Observation index

All test items were performed before, 2 weeks and 4 weeks after treatment:

(1) the SK-III skin moisture detector measures the moisture content of the inner side of the forearm, 5 points are taken for measurement, the arithmetic mean value is taken, the testee uses the foam cream to evenly paint the foam cream on all feet until the foam cream is completely absorbed, the skin moisture tester is used for measuring the moisture content of the inner side of the forearm after 2 hours, 5 points are taken for measurement, and the arithmetic mean value is taken.

(2) Adverse reactions occurring during the course of treatment were recorded and observed.

1.5 therapeutic index

1.5.1 skin moisture content

The skin moisture content increase rate after 2 hours of using the milk foam was the average skin moisture after 2 hours of using the milk foam-the average skin moisture before using the milk foam.

1.5.2 treatment criteria for diabetic foot

And (3) curing: the degree of the dry skin crack of the foot is completely relieved, the moisture degree is more than 90%, and the increase of the average moisture of the skin is more than 5%.

The effect is shown: the degree of the dry skin of the foot is obviously relieved, the moisture degree is more than 80%, and the increase of the average moisture of the skin is 3-5%.

The method has the following advantages: the degree of the dry skin of the foot is effectively relieved, the moisture degree is more than 70%, and the increase of the average moisture of the skin is 0-3%.

And (4) invalidation: the dry cracking degree of the foot skin is not relieved, the wetness is below 70 percent, and the average moisture of the skin is not increased or even increased.

The total effective rate is the cure rate + the significant efficiency + the effective rate.

1.6 statistical methods

Statistical analysis using SPSS26.0 software for data measurementThe comparison among groups is shown by using independent sample t test, counting data is shown by percent, chi-square test is adopted, and P is less than 0.05, so that the difference has statistical significance.

2 results

2.1 Effect of the foam cream of the present invention on diabetic foot

Table 2 skin moisture test results table (n＝10)

Note: in comparison with the control 1 group,^*P＜0.05，^#P＜0.01；

in comparison with the control 2 group,^￥P＜0.05，^△P＜0.01。

as can be seen from the above table 2, the foam cream in the embodiment 5 of the invention has a good moisturizing effect, can obviously improve the moisture content of skin after being used, and has the effects of moisturizing and moistening diabetes. Wherein the moisturizing effect of the observation group of example 5 was superior to that of the control groups 1-2.

TABLE 3 comparison of clinical efficacy of two groups of patients (example,%)

Group of	Cure of disease	Show effect	Is effective	Invalidation	Total effective rate
						Observation group	2(20)	7(70)	1(10)	0(0)	100
Control 1 group	1(10)	5(50)	3(30)	1(10)	90
						Control 2 group	0(0)	6(60)	2(20)	2(20)	80

As can be seen from Table 3 above, the milk foam of example 5 of the present invention has a very good therapeutic effect, and the therapeutic effect of the observation group of example 5 is superior to that of the control groups 1-2.