CN110585421A

CN110585421A - External composition for treating diabetic foot disease and preparation method and application thereof

Info

Publication number: CN110585421A
Application number: CN201910934957.6A
Authority: CN
Inventors: 邱彦龙; 巩桂丽; 孙文强
Original assignee: Individual
Current assignee: Individual
Priority date: 2019-09-29
Filing date: 2019-09-29
Publication date: 2019-12-20

Abstract

The invention provides an external composition for treating diabetic foot diseases, belonging to the technical field of treatment of diabetic complications; the external composition comprises the following raw materials: 200-300 ml of ornidazole, 12-20U of gentamicin, 3-5U of insulin, 15-25 mg of anisodamine, 100-200 IU of bovine basic fibroblast growth factor, 1-3 ml of alprostadil, 80-120 ml of 0.9% sodium chloride injection, 10-20 g of bletilla striata, 8-12 g of angelica dahurica, 10-20 g of rhizoma typhonii, 0.5-1.5 g of pseudo-ginseng powder and 8-12 g of phellodendron. The external composition can promote the healing of skin wound, has obvious inhibiting effect on staphylococcus aureus, streptococcus B and pseudomonas aeruginosa, can inhibit the synthesis of advanced glycosylation end products, relieve inflammatory reaction, improve the number of growth factors and promote the healing of diabetic foot wound.

Description

External composition for treating diabetic foot disease and preparation method and application thereof

Technical Field

The invention relates to the technical field of treatment of diabetic complications, in particular to an external composition for treating diabetic foot diseases and a preparation method and application thereof.

Background

Diabetic Foot is (DF) caused by Diabetic neuropathy, including peripheral arteriolar occlusion caused by non-tip nerve sensory disorder and vegetative nerve damage, vascular disease of lower limbs, arteriosclerosis, or Foot pain, Foot ulcer and Foot gangrene caused by skin microangiopathy and bacterial infection. Often due to a synergy of three factors, ischemia, neuropathy and infection. The main clinical manifestations include numbness of the lower limbs on one or both sides, abnormal sensation of the limbs, cold sensation, stabbing pain, ulcer, necrosis, gangrene, etc. The disease has the characteristics of acute morbidity, rapid transmission, difficult treatment and poor prognosis, and a patient with extremely serious development can finally cause amputation, so the disease has extremely high disability rate and mortality rate.

Clinical Wagner grading of diabetic feet:

diabetic foot diseases are classified into 6 grades according to the severity of the disease condition:

level 0: the skin has no open focus. It often shows insufficient blood supply to the extremities, cold skin, cyanosis or pale, numb, slow or lost sensation. Stabbing pain or burning pain at the extremities often accompanied by deformity of the toes or feet, which can be called high-risk foot.

Stage I: the limb skin has open lesions. Blisters, blebs, corns or calluses, superficial ulcers caused by frostbite or scald and other skin injuries, but the lesions have not yet spread to deep tissues.

And II, stage: the infected lesion has invaded deep muscle tissue. Mild cellulitis often occurs, with multiple pus foci and sinus tracts, or infection expands along the muscle space, resulting in penetrating ulcers or gangrene on the sole and instep, with more purulent secretions. The skin of foot or toe (finger) has dry gangrene, but tendon ligament is not damaged yet.

Grade III: tendon ligament tissue destruction. Cellulitis is fused to form large pus cavities, purulent secretion and necrotic tissues are increased, dry gangrene of feet or few toes (fingers) is caused, but bone destruction is not obvious.

IV stage: severe infections have caused bone destruction, osteomyelitis, destruction of bone joints or the formation of pseudojoints, summer joints, wet or dry severe gangrene or necrosis of parts of the toes (fingers) or parts of the extremities.

And V stage: infection or ischemia of most or all parts of the foot, resulting in severe wet or dry gangrene, dark extremities, cadaveric stems, and often involvement of the ankle and lower leg.

The diabetic feet with different degrees have different treatment effects and prognosis effects, the higher the Wager classification is, the larger the treatment difficulty is, the lower the cure rate is, and the higher the disability rate is.

The western medicine still has a plurality of disadvantages for treating the diabetic foot, and although the diabetic foot can be treated by operations such as stem cell transplantation, skin transplantation, intervention and the like, the diabetic foot still has relapse. The traditional Chinese medicine composition treats the diabetic foot through syndrome differentiation, treats both principal and secondary aspects of the diabetic foot, but often cannot achieve the effect of debridement timely and effectively. Thus, there is a need for a combination of traditional Chinese and western medicine to effectively treat diabetic foot disease.

Disclosure of Invention

The invention aims to provide an external composition for treating diabetic foot diseases, a preparation method and application thereof.

In order to achieve the above object, the present invention provides the following technical solutions:

the invention provides an external composition for treating diabetic foot diseases, which comprises the following raw materials: 200-300 ml of ornidazole, 12-20U of gentamicin, 3-5U of insulin, 15-25 mg of anisodamine, 100-200 IU of bovine basic fibroblast growth factor, 1-3 ml of alprostadil, 80-120 ml of 0.9% sodium chloride injection, 10-20 g of bletilla striata, 8-12 g of angelica dahurica, 10-20 g of rhizoma typhonii, 0.5-1.5 g of pseudo-ginseng powder and 8-12 g of phellodendron.

Preferably, the composition for external use comprises the following raw materials: 250mL of ornidazole, 16U of gentamicin, 4U of insulin, 20mg of anisodamine, 150IU of bovine basic fibroblast growth factor, 2mL of alprostadil, 100mL of 0.9% sodium chloride injection, 15g of bletilla striata, 10g of angelica dahurica, 15g of rhizoma typhonii, 1g of pseudo-ginseng powder and 10g of phellodendron.

The invention also provides a preparation method of the external composition in the scheme, which comprises the following steps:

1) mixing the bletilla striata, the angelica dahurica, the rhizoma typhonii, the pseudo-ginseng powder and the phellodendron, and then crushing to obtain traditional Chinese medicine fine powder;

2) mixing the traditional Chinese medicine fine powder, ornidazole, gentamicin, insulin, anisodamine, bovine basic fibroblast growth factor 150IU, alprostadil and 0.9% sodium chloride injection to obtain the external composition.

Preferably, the pulverization in step 1) comprises grinding.

Preferably, the Chinese medicine powder in the step 1) is ground into fine powder.

The invention also provides application of the external composition in the scheme in preparation of a medicine for treating diabetic foot diseases.

The invention has the beneficial effects that: the invention provides an external composition for treating diabetic foot diseases, which comprises the following raw materials: 200-300 ml of ornidazole, 12-20U of gentamicin, 3-5U of insulin, 15-25 mg of anisodamine, 150IU of bovine basic fibroblast growth factor, 1-3 ml of alprostadil, 80-120 ml of 0.9% sodium chloride injection, 10-20 g of bletilla striata, 8-12 g of angelica dahurica, 10-20 g of rhizoma typhonii, 0.5-1.5 g of pseudo-ginseng powder and 8-12 g of phellodendron bark. The external composition can obviously promote the healing of skin wound surfaces, has obvious inhibiting effect on staphylococcus aureus, streptococcus B and pseudomonas aeruginosa, can inhibit the synthesis of advanced glycosylation end products, relieves inflammatory reaction, improves the number of growth factors and promotes the healing of diabetic foot wound surfaces. On the basis of thorough and effective debridement, the wound healing promoting agent can obviously improve local symptoms of the wound of a patient, promote the wound to heal quickly, effectively relieve the symptoms of the patient, reduce inflammatory indexes and delay the expiration time and risk of the patient. And the local symptoms and the wound area are obviously reduced along with the prolonging of the treatment time, and when the treatment is carried out for 6 weeks, the local symptom integral of a test group is obviously reduced compared with that of a control group, and the wound area is obviously reduced.

Detailed Description

In the invention, the ornidazole is preferably ornidazole sodium chloride injection; the gentamicin is preferably gentamicin sulfate injection; the insulin is preferably a rapid-acting insulin; the anisodamine is preferably racanisodamine injection; the bovine basic fibroblast growth factor is preferably a recombinant bovine basic fibroblast growth factor external solution; the alprostadil is preferably an alprostadil injection.

In the specific implementation process of the invention, the ornidazole sodium chloride injection is purchased from Sichuan Kelun pharmaceutical industry Co., Ltd, and the specification is 250 ml: 0.5 g; the gentamicin sulfate injection is purchased from Shandong Ruiyang pharmaceutical Co., Ltd, and the specification is 2 ml: 8 ten thousand units; the quick-acting insulin is purchased from Wanbang Biochemical medicine GmbH of Jiangsu, and has the specification of 10 ml: 400 units; the racanisodamine injection is purchased from Wuzhou Tong pharmaceutical Co., Ltd in Hunan, and the specification is 1 ml: 10 mg; the external solution of the recombinant bovine basic fibroblast growth factor is purchased from Zhuhaisheng biopharmaceutical Limited company, and has the specification of 63000IU/15 ml; the alprostadil injection is purchased from Siranofu pharmaceutical Limited and has the specification of 10ug/2 ml; the 0.9% sodium chloride injection is from conventional commercial sources.

In the invention, the bletilla striata is preferably bletilla striata of Sichuan; the angelica dahurica is preferably Sichuan angelica dahurica; the rhizoma typhonii is preferably rhizoma typhonii; the pseudo-ginseng powder is preferably Yunnan pseudo-ginseng powder; the phellodendron is preferably Jilin phellodendron.

In the invention, the bletilla striata, the angelica dahurica, the rhizoma typhonii, the pseudo-ginseng powder and the golden cypress are from conventional markets, and in the specific implementation process of the invention, the traditional Chinese medicine decoction pieces are purchased from Kangyu limited company in Linyi city.

In the invention, the bletilla striata, the angelica dahurica, the rhizoma typhonii, the pseudo-ginseng powder and the phellodendron are ground into fine powder and then dissolved in the western medicine solution to form the suspension, and the suspension has the advantages of easy coating, difficult bleeding and quick drying, can form a protective film which is difficult to wipe off after drying, can delay the medicine to generate a slow release effect and the like.

In the present invention, insulin controls blood glucose; ornidazole and gentamicin have bactericidal effect on anaerobe and pseudomonas aeruginosa, and can control infection; the alprostadil expands blood vessels, enhances tissue regeneration, improves microcirculation and has repairing effect on diabetic neuropathy; the racanisodamine has analgesic and spasmolytic effects; the recombinant bovine basic fibroblast growth factor has the effects of promoting wound healing, repairing and regenerating and improving local blood circulation.

The diabetic foot diseases are mainly caused by the syndrome of dampness-heat toxin, and the traditional Chinese medicine powder takes phellodendron as a monarch drug, has the effects of clearing heat, drying dampness, purging fire and detoxifying, and can quickly improve the infection condition of the wound surface; the pseudo-ginseng powder and the rhizoma typhonii are ministerial drugs, the pseudo-ginseng stops bleeding, removes stasis, reduces swelling and relieves pain, and the rhizoma typhonii detoxifies, dissipates stasis and relieves pain; the angelica dahurica and the bletilla striata are adjuvant drugs, the angelica dahurica dehumidifies, disinfects, expels pus, promotes tissue regeneration, removes necrotic tissues and promotes tissue regeneration, and the bletilla striata stops bleeding, reduces swelling, removes necrotic tissues and promotes tissue regeneration.

1) mixing the bletilla striata, the angelica dahurica, the rhizoma typhonii, the pseudo-ginseng powder and the phellodendron, and then crushing to obtain traditional Chinese medicine powder;

2) mixing the traditional Chinese medicine powder, ornidazole, gentamicin, insulin, anisodamine, bovine basic fibroblast growth factor, alprostadil and 0.9% sodium chloride injection to obtain the external composition.

Firstly, mixing bletilla striata, angelica dahurica, rhizoma typhonii, pseudo-ginseng powder and phellodendron, and then crushing to obtain traditional Chinese medicine powder; the invention has no special limit on the crushing mode and time, and the crushing is carried out on the basis of crushing into fine powder; in the specific implementation process of the invention, the crushing mode is grinding.

After the traditional Chinese medicine powder is obtained, the traditional Chinese medicine powder, ornidazole, gentamicin, insulin, anisodamine, bovine basic fibroblast growth factor, alprostadil and 0.9% sodium chloride injection are mixed to obtain a suspension which can be stored for 30 days in a refrigerator without a stability test; the invention has no special limitation on the mixing mode and time, and the uniform mixing is taken as the standard.

In the invention, the external composition is used for treating the diabetic foot disease, and the application mode is that the external composition is uniformly shaken when used and then is smeared on an affected part three times a day.

The technical solutions provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.

EXAMPLE 1A topical composition for the treatment of diabetic foot

1) Mixing 15g of bletilla striata, 10g of angelica dahurica, 15g of rhizoma typhonii, 1g of pseudo-ginseng powder and 10g of phellodendron, and grinding to obtain traditional Chinese medicine powder;

2) mixing the traditional Chinese medicine powder, 250ml of ornidazole, 16U of gentamicin, 4U of insulin, 20mg of anisodamine, 2ml of bovine basic fibroblast growth factor, 2ml of alprostadil and 100ml of 0.9% sodium chloride injection to obtain the external composition.

Example 1

1. Comparison conditions

Control group: aiming at type II diabetes mellitus, diabetic foot disease and Wagner classification II-grade injection conventional western medicines: 100ml of 0.9 percent sodium chloride injection and 480 million u of penicillin are injected into the mixture by intravenous drip twice a day; 100ml of 0.9% sodium chloride injection and 5u of alprostadil are added into a kettle once a day for intravenous drip; insulin aspart 30 (pen core) 16u, protamine biosynthetic human insulin (premixed) 30R pen core 16u, and the two medicines are injected subcutaneously 30min before breakfast and supper;

experimental groups: injecting conventional western medicines: 100ml of 0.9 percent sodium chloride injection and 480 million u of penicillin are injected into the mixture by intravenous drip twice a day; 100ml of 0.9% sodium chloride injection and 5u of alprostadil, and the bottle is instilled once a day; insulin aspart 30 (pen core) 16u, protamine biosynthetic human insulin (premixed) 30R pen core 16u, and the two medicines are injected subcutaneously 30min before breakfast and supper); the external composition prepared in example 1 was applied externally (150 ml of ornidazole, 8 million U of gentamicin, 5U of insulin, 10mg of anisodamine, 150IU of bovine basic fibroblast growth factor, 3ml of alprostadil, 120ml of 0.9% sodium chloride injection, 10g of bletilla striata, 8g of angelica dahurica, 10g of rhizoma typhonii, 0.5g of pseudo-ginseng powder and 8g of phellodendron bark). For a total of 42d observation period.

2. Patient data:

1) gender comparisons between the two groups of patients are shown in Table 1.

TABLE 1 comparison of control group to Experimental group gender

Note: TABLE 1 control and experimental groups, two groups tested for gender by chi-square test, X²＝0.601，P＝0.438(P>0.05), no significant difference, two groups were comparable.

2) The age comparisons of the two groups of patients are shown in Table 2.

TABLE 2 comparison of age (year) of control group with that of experimental group

Note: table 2 is a comparison of the age of patients in the control group and the experimental group, wherein the control group is 75 years old at the maximum age and 45 years old at the minimum age, and the average age is 61.13 ± 7.30; the maximum age in the experimental group was 75 years, the minimum age was 35 years, and the mean age was 60.20 ± 9.70. The ages of the two groups are in accordance with normal distribution, and the t is 0.421 and P is 0.065(P is more than 0.05) through t test analysis of independent samples, so that the two groups have no significant difference and are comparable.

3) The disease course of the two groups of patients is compared in table 3.

TABLE 3 comparison of the course of diabetes between the control and the experimental groups (year)

Table 3 shows the comparison of the diabetes courses of the control group and the experimental group, wherein the longest diabetes course in the control group is 23 years, the shortest diabetes course is 3 years, and the average diabetes course is 9.66 ± 4.75; the longest course of the experimental group is 21 years, and the average course of the shortest course is 9.33 +/-4.48 in 2 years. The two sets of data fit to a normal distribution,

when analyzed by t-test on independent samples, P ═ 0.756(P >0.05), there was no statistical difference, and the two groups were comparable.

4) The efficacy of the two groups of ulcers is compared in table 4.

TABLE 4 comparison of curative effects on ulcer surface of control group and experimental group

Group of	Total number of cases	Recovery method	Show effect	Is effective	Invalidation	High efficiency	Treatment period (Tian)
								Control group	30	4	12	11	3	90％	36
Experimental group	30	7	16	5	2	94.3％	36

As can be seen from table 4, the differences between the curative effects of the ulcer wounds of the control group and the experimental group are statistically significant through the rank sum test of z-2.082, P-0.037 and P < 0.05.

5) The ulcer wounds before and after treatment in two groups are compared in table 5.

TABLE 5 comparison (cm. + -.s) of ulcer area before and after treatment (X. + -.s) of control group with that of experimental group²)

Group of	Total number of cases	Before treatment	After treatment
				Control group	30	9.15±2.71	4.31±2.73*
Experimental group	30	9.10±2.21	2.87±3.05*△

Comparison within group,. P <0.05, comparison between groups,. DELTA.P > 0.05.

As suggested by table 5: after treatment, the ulcer areas of the control group and the experimental group are tested by matching sample rank sum, wherein z is-1.925, P is 0.054, P is more than 0.05, and no statistical difference exists between the two groups; the control group and the experimental group before and after treatment have statistical difference in comparison in two groups through independent sample t test t is 20.131, P is 0.000, P is 0.05.

6) Safety observations in the experimental groups

The results of comparing erythrocytes, hemoglobin, platelets, glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, creatinine, and urea nitrogen in the pre-treatment and post-treatment experimental groups of patients are shown in table 6.

TABLE 6 comparison of safety before and after treatment between control group and experimental group

Index (I)

Group of

Total number of cases

Before treatment

After treatment

T

P

RBC(10^12/L)

Experimental group

30

4.43±0.43

4.54±0.42

-1.297

0.205

HGB(g/l)

Experimental group

30

137.00±12.68

135.10±12.00

0.960

0.345

PLT(10^9/L)

Experimental group

30

208.70±59.13

213.36±41.9

-0.469

0.642

AST(U/L)

Experimental group

30

23.06±8.90

20.10±8.04

0.727

0.473

ALT(U/L)

Experimental group

30

22.20±12.93

22.26±6.20

1.220

0.232

CRE(mmol/L)

Experimental group

30

65.28±15.27

62.67±11.58

1.042

0.306

BUN(mmol/L)

Experimental group

30

5.34±1.59

5.50±1.37

-0.170

0.866

As can be seen from Table 6, when comparing the test of matched samples t, the p of the test group before treatment and the test group after treatment for red blood cells, hemoglobin, platelets, glutamic-oxalacetic transaminase, glutamic-pyruvic transaminase, creatinine and urea nitrogen is greater than 0.05, and no statistical difference exists.

7) The control group and experimental group were compared for wound symptom scores and levels of associated inflammatory factors, see table 7.

TABLE 7 comparison of wound surface symptom scores and related inflammatory factor levels between control and experimental groups

Note: PCT: procalcitonin; CRP: c-reactive protein; IL-6: interleukin-6; normal value range: PCT < 0.1. mu.g/L, CRP <10mg/L, IL-6<1.5ng/L

As can be seen from Table 7, PCT, CRP and IL-6 in the pre-treatment group and the post-treatment group were significantly different at 3 weeks of treatment (P < 0.05); the score of the wound symptoms is obviously different in 6 weeks of treatment (P is less than 0.05)

As can be seen from the above examples, the external composition of the present invention can effectively alleviate the symptoms of patients, reduce the inflammatory index in laboratories, and delay the time and risk of the patient expiration, on the basis of thorough and effective debridement, for different types of wounds, according to Wagner classification.

The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Claims

1. A composition for external use for treating diabetic foot disease comprises the following raw materials: 200-300 ml of ornidazole, 12-20U of gentamicin, 3-5U of insulin, 15-25 mg of anisodamine, 100-200 IU of recombinant bovine basic fibroblast growth factor, 1-3 ml of alprostadil, 80-120 ml of 0.9% sodium chloride injection, 10-20 g of bletilla striata, 8-12 g of angelica dahurica, 10-20 g of rhizoma typhonii, 0.5-1.5 g of pseudo-ginseng powder and 8-12 g of phellodendron.

2. The composition for external use according to claim 1, which comprises the following raw materials: 250mL of ornidazole, 16U of gentamicin, 4U of insulin, 20mg of anisodamine, 150IU of bovine basic fibroblast growth factor, 2mL of alprostadil, 100mL of 0.9% sodium chloride injection, 15g of bletilla striata, 10g of angelica dahurica, 15g of rhizoma typhonii, 1g of pseudo-ginseng powder and 10g of phellodendron.

3. A process for preparing the composition for external use of claim 1 or 2, comprising the steps of:

4. The method according to claim 3, wherein the pulverization in step 1) comprises grinding.

5. The method as claimed in claim 3 or 4, wherein the Chinese medicinal materials in step 1) are ground into fine powder.

6. Use of the composition for external use according to claim 1 or 2 for the manufacture of a medicament for the treatment of diabetic foot disease.