CN116115682A - Pharmaceutical composition for intervening uremia skin itch, preparation method and using method - Google Patents

Abstract

The invention relates to a traditional Chinese medicine composition, and discloses a medicine composition for intervening uremic skin itch, a preparation method and a using method thereof; the medicine composition consists of the following traditional Chinese medicine raw materials: pricklyash peel, lewy peel, snake slough, cortex dictamni and poria peel; or fructus Kochiae, cortex Phellodendri, rhizoma Atractylodis, ramulus Cinnamomi, periostracum Serpentis, fructus Zanthoxyli, cortex Dictamni Radicis, and rhizoma Smilacis Glabrae; the preparation method comprises weighing the raw materials according to the mass ratio, decocting and concentrating to obtain a liquid medicine. The traditional Chinese medicine composition provided by the application can effectively relieve uremic skin itch, and the effect of the traditional Chinese medicine composition is superior to that of skin yellow itching relieving soup; and define the exact role in alleviating uremia-associated skin itch, the reason for which may be related to reducing IL-31 levels in patients and model mice.

Description

Pharmaceutical composition for intervening uremia skin itch, preparation method and using method

Technical Field

The invention relates to a traditional Chinese medicine composition, in particular to a pharmaceutical composition for intervening uremic skin itch, a preparation method and a use method.

Background

Chronic kidney disease-associated skin itch (CKD-aP), which refers to skin itch directly associated with kidney disease, is one of the common clinical complications of end stage renal disease and maintenance hemodialysis patients, wherein uremic phase complicated kidney disease-associated skin itch is also known as uremic skin itch (UP). UP prevalence is UP to 60.2%, increasing mortality in CKD patients by 15% -23% has become an urgent problem to be solved. However, there is currently no very effective intervention for uremic itch.

Disclosure of Invention

< technical problem to be solved by the invention >

At present, no effective intervention measures for uremic itching exist.

< technical scheme adopted by the invention >

Aiming at the technical problems, the invention aims to provide a pharmaceutical composition for intervening uremic skin itch, a preparation method and a use method. For uremic skin itch, the disease is mainly caused by kidney and skin, and relates to viscera such as lung, spleen, heart and liver, the basic pathogenesis is primordial qi deficiency, internal stagnation of toxin turbidity, unsmooth qi and blood circulation, and phlegm dampness stasis toxin combined with each other, and the internal and external wind invades muscular striae to cause itching, which belongs to the syndrome of the deficiency and excess.

The specific contents are as follows:

first, the invention provides a pharmaceutical composition for intervening uremic skin itch, which consists of the following traditional Chinese medicine raw materials: pricklyash peel, lewy peel, snake slough, cortex dictamni and poria peel; or fructus Kochiae, cortex Phellodendri, rhizoma Atractylodis, ramulus Cinnamomi, periostracum Serpentis, fructus Zanthoxyli, cortex Dictamni Radicis, and rhizoma Smilacis Glabrae.

The invention also provides a preparation method of the pharmaceutical composition for intervening uremic skin itch, which comprises the following steps:

weighing the raw materials according to the mass ratio, and decocting and concentrating to obtain a liquid medicine.

Third, the present invention provides a method of using the aforementioned pharmaceutical composition,

the pharmaceutical composition was diluted at 1:100 ratio the next day after dialysis and bathed for 15 minutes.

< beneficial effects achieved by the invention >

The traditional Chinese medicine composition provided by the application can effectively relieve uremic skin itch, and the effect of the traditional Chinese medicine composition is superior to that of skin yellow itching relieving soup; and define the exact role in alleviating uremia-associated skin itch, the reason for which may be related to reducing IL-31 levels in patients and model mice.

Drawings

FIG. 1 is a graph showing the results of improving degree of skin yellow antipruritic decoction and Wupi decoction on uremic skin itch;

FIG. 2 is a graph showing the results of animal tests;

fig. 3 is a schematic diagram showing an evaluation mode of skin itch.

Detailed Description

In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.

First, the invention provides a pharmaceutical composition for intervening uremic skin itch, which consists of the following traditional Chinese medicine raw materials: pricklyash peel, leonurus skin, snake slough, cortex dictamni, poria cocos skin, or fructus kochiae, phellodendron bark, rhizoma atractylodis, cassia twig, snake slough, pricklyash peel, cortex dictamni and rhizoma smilacis glabrae.

Further, the components of the pharmaceutical composition are, by weight, 7-15 g of pepper, 7-15 g of corium Erinacei Seu Hemiechianus, 12-20 g of snake slough, 12-20 g of cortex dictamni, and 12-20 g of poria cocos peel.

Further, the components of the pharmaceutical composition are, by weight, 10g of pepper, 10g of corium Erinacei, 15g of snake slough, 15g of cortex dictamni and 15g of poria cocos peel.

Further, 25-40 g of fructus kochiae, 15-28 g of amur corktree bark, 10-20 g of swordlike atractylodes rhizome, 10-20 g of cassia twig, 10-25 g of snake slough, 8-15 g of Chinese prickly ash, 12-25 g of dittany bark and 25-40 g of glabrous greenbrier rhizome.

Further, 30g of fructus kochiae, 20g of amur corktree bark, 15g of rhizoma atractylodis, 15g of cassia twig, 15g of snake slough, 10g of Chinese prickly ash, 20g of cortex dictamni and 30g of rhizoma smilacis glabrae.

Further, the pharmaceutical composition is formulated into concentrates, ointments, films and pastes by adding or omitting pharmaceutically acceptable excipients.

The invention also provides a preparation method of the pharmaceutical composition for intervening uremic skin itch, which comprises the following steps:

weighing the raw materials according to the mass ratio, and decocting and concentrating to obtain a liquid medicine.

Third, the present invention provides a pharmaceutical composition as mentioned above, which is used by diluting the pharmaceutical composition at 1:100 ratio the next day and later in dialysis, and bathing for 15 minutes.

< example >

Example 1

A pharmaceutical composition for intervening uremia skin itch comprises, by weight, 10g of Chinese prickly ash, 10g of corium stomachium, 15g of snake slough, 15g of cortex dictamni and 15g of poria cocos peel.

Decocting the above raw materials, concentrating into medicinal liquid, and packaging with 500 ml/bottle transparent glass bottle. The night of the next day of dialysis, the temperature is suitable for soaking bath after dilution according to the proportion of 1:100, and 15 minutes are needed each time.

Example 2

The difference between the present example and example 1 is that the components of the pharmaceutical composition are 8g of pricklyash peel, 8g of corium stomachium, 18g of snake slough, 18g of cortex dictamni and 18g of poria cocos peel.

Example 3

The difference between the present example and example 1 is that the components of the pharmaceutical composition are 10g of pricklyash peel, 14g of corium stomachium, 15g of snake slough, 12g of cortex dictamni and 15g of poria cocos peel.

Example 4

30g of fructus kochiae, 20g of amur corktree bark, 15g of swordlike atractylodes rhizome, 15g of cassia twig, 15g of snake slough, 10g of Chinese prickly ash, 20g of dittany bark and 30g of glabrous greenbrier rhizome.

Decocting the above raw materials, concentrating into medicinal liquid, and packaging with 500 ml/bottle transparent glass bottle. The night of the next day of dialysis, the temperature is suitable for soaking bath after dilution according to the proportion of 1:100, and 15 minutes are needed each time.

Example 5

The difference between the present example and example 4 is that the components of the pharmaceutical composition are 27g of fructus kochiae, 25g of cortex phellodendri, 12g of rhizoma atractylodis, 18g of cassia twig, 20g of snake slough, 10g of pepper, 18g of cortex dictamni and 22g of rhizoma smilacis glabrae.

Example 6

The difference between the present example and example 4 is that the components of the pharmaceutical composition are 32g of fructus kochiae, 18g of cortex phellodendri, 18g of rhizoma atractylodis, 15g of cassia twig, 18g of snake slough, 10g of pepper, 20g of cortex dictamni and 25g of rhizoma smilacis glabrae.

< test example >

Test subjects

30 UP patients, 16 men and 14 women, with the age range of 28-81 years, which are continuously subjected to maintenance hemodialysis in a hemodialysis center of a traditional Chinese medicine hospital affiliated to the university of medical science of southwest and accord with inclusion standards are selected from 3 months 2019 to 6 months 2019.

The test was approved by the test subjects, informed consent was signed, and the clinical test was registered by the chinese clinical test center (registration number ChiCTR 1900020635) and was approved by the ethical management committee of the clinical test of the affiliated chinese medical science university of southwest medical science (ethical number YJ-KY 2019007/FS-07). The whole test process is implemented by referring to ethical, ethical and scientific principles required by medical ethical guidelines of the world medical society of Hull octyl statement and national medical clinical test quality management standards related laws and regulations.

Evaluation method of skin itch

VAS visual simulation scoring method: the VAS scoring scale adopts a scale (shown below) with a scale of 10cm, the non-scaled side faces the patient, the patient points out the position corresponding to the most itching moment on the scale according to subjective feeling, the 0cm position is free of itching, and the 10cm position is the most intense itching which is difficult to tolerate, and the most intense itching is marked as 0-10 minutes respectively. And layering the severity of itch according to the score value of itch: none (0), mild (1-3), moderate (4-6), severe (7-8), very severe (9-10), see in particular FIG. 3.

Diagnostic criteria for UP (uremic itch of skin)

(1) Uremia diagnostic criteria: uremia is a syndrome consisting of a series of clinical manifestations that occur when CKD patients enter the end stage and is not an independent disease, and reference is made to the definition of CKD phase 5 in kidney disease, wang Haiyan: GFR <15 ml/(min 1.73m 2) or dialysis has started, with corresponding symptoms of other systems such as electrolyte disorders, renal anaemia, etc.

(2) Diagnostic criteria for cutaneous pruritus: itching is a symptom of self-sensation, which starts to appear after suffering from kidney disease or dialysis, and after itching is eliminated from other non-kidney disease factors, only skin itching without primary skin lesions is shown, skin is mainly shown as dryness and scales, secondary skin lesions can appear along with the later period of scratching of patients, at least 3 or more itching attacks can appear within nearly 2 weeks, each time lasting for seconds or minutes, and discomfort sensation of regular itching appears within nearly 1 month.

And (3) according to the two items (1) and (2), the uremia-related skin itch can be diagnosed.

Inclusion, exclusion, rejection and shedding criteria for assays

1. Inclusion criteria

(1) The hemodialysis treatment is carried out at the hemodialysis center law of the traditional Chinese medicine hospital attached to the university of southwest medical science, and the same dialysis mode is adopted for 3 times per week for 3-4 hours per time; (2) meets the diagnostic criteria for UP; (3) Other medicines for treating itch are not used or are not used for more than 1 week; (4) no other diseases that can cause itch of skin; (5) The age is more than or equal to 18 years old, the sex is unlimited, and female patients have no fertility potential or are using acceptable contraceptive methods; (6) VAS score is more than or equal to 4; (7) The basic disease and the complicating disease are relatively stable, and the factors influencing the life safety are effectively controlled; (8) Voluntarily taking part in the experimental study, and signing an informed consent; all of the above inclusion criteria must be met at the same time to be able to enter a group.

2. Exclusion criteria for test

(1) Those known to be allergic to the test drug composition; (2) Severe hypertension (systolic >180 and/or diastolic >110 mmHg) is pooled; (3) cardiac functional classification class III, class IV of NYHA; (4) combining severe anaemia (Hb <60 g/L); (5) Severely anxious, with communication disturbances, the experimenter cannot complete; (6) Patients with other primary dermatoses and skin imperfections, such as urticaria, psoriasis, etc.; (7) At the discretion of the researcher, there are other lesions or conditions that reduce the likelihood of inclusion or complicate inclusion, such as those of mental illness, frequent changes in living and working environments, and other volatile visits. (8) Other interventional clinical testers are participating or are enrolled within 12 weeks prior to the trial; if any of the above exclusion criteria are met, no group can be entered.

3. Reject and drop criteria

(1) Scheme violation: the subject is treated with an antipruritic agent or is treated with an antipruritic agent prior to the end of the trial; (2) Researchers have taken it off (including researchers who have poor compliance, severe complications or complications, severe adverse events, etc. consider it quite dangerous to continue the study, etc.); (3) Although the test was completed, the dosage was less than 80% of the application; (4) The side effects of the test medicine cannot be tolerated, serious complications or disease deterioration and the like cannot meet the inclusion standard or the test cannot be completed continuously; (5) subject was asked to withdraw from the study.

Grouping and intervention

The enrolled UP patients were randomized into 3 groups: placebo group, skin yellow antipruritic soup group, five skin soup group, 10 cases of each group.

A first group: placebo group

Placebo consists of edible pigments: lemon yellow, scarlet, blue and chocolate brown are prepared into concentrated stock solution according to the proportion of 5:2:1:6, and then the concentrated stock solution is diluted 10000 times by distilled water, and is sterilized and assembled, and is packaged by adopting a transparent glass bottle of 500 ml/bottle. The next night of dialysis, diluted in a ratio of 1:100, is bathed with a suitable temperature for 15 minutes each time.

Second group: skin-whitening itching-relieving soup set

30g of fructus kochiae, 20g of amur corktree bark, 15g of swordlike atractylodes rhizome, 15g of cassia twig, 15g of snake slough, 10g of Chinese prickly ash, 20g of dittany bark and 30g of glabrous greenbrier rhizome. Decocting the raw materials of the self-skin-simulating yellow antipruritic soup, concentrating into a liquid medicine, and subpackaging with 500 ml/bottle transparent glass bottle. The night of the next day of dialysis, the temperature is suitable for soaking bath after dilution according to the proportion of 1:100, and 15 minutes are needed each time.

Third group: five-skin soup set

The five-skin soup comprises the following raw materials of 10g of pepper, 10g of corium leonuri, 15g of snake slough, 15g of cortex dictamni and 15g of poria cocos peel. Decocting the raw materials of the five-skin decoction, concentrating into liquid medicine, and subpackaging with 500 ml/bottle transparent glass bottle. The night of the next day of dialysis, the temperature is suitable for soaking bath after dilution according to the proportion of 1:100, and 15 minutes are needed each time.

Patients after group entry adopt conventional diet and life work and rest, the same dialysis mode (Fei Senyou S4008S and Jinbao AK200S dialysis machines, ultrapure dialysis liquid, bicarbonate buffer, dialysis frequency of 3 times/week, 3-4 hours/time) and conventional Western medicine basic treatment (namely etiology and symptomatic treatment of basic diseases and complications except UP for each patient); placebo was medicated for 15 minutes on the next dialysis day, and Fuhuang Zhi Ling Tang and Wupi Tang groups were medicated for 15 minutes on the next dialysis day, each group was continuously intervened for 12 weeks.

Test results

The test results show that:

the results are shown in Table 1.

Table 1 results of the various tests

Neither the wupi decoction, the fuhuang antipruritic decoction nor the placebo significantly improved renal function (serum creatinine SCR and urea nitrogen BUN) in uremic patients.

Compared with placebo, the five-skin decoction and the skin-yellow itching-relieving decoction can obviously improve the pruritus score (VAS) of uremic patients, and simultaneously obviously reduce the content of pruritus related factor IL31 in the blood of the patients, so that the five-skin decoction and the skin-yellow itching-relieving decoction have obvious curative effects of treating uremic skin pruritus. Meanwhile, liver function (AST, ALT) detection shows that the five-skin soup and the skin yellow itching relieving soup can not cause liver function damage of patients, and good safety is prompted.

The improvement degree of the skin yellow itching relieving decoction and the five-skin decoction on uremic skin itch is further compared and analyzed, and the result is shown in figure 1.

Subtracting the VAS score of the patient after the patient is dosed from the VAS score of the patient before the patient is dosed to obtain a VAS score change value before and after the patient is dosed; IL-31 values of patients after and before administration were subtracted from IL-31 values of patients before and after administration to obtain IL-31 change values.

The results show that the VAS score change value and the IL-31 change value of the five-skin decoction group are obviously higher than those of the skin yellow itching relieving decoction group, and the five-skin decoction has better effect of improving uremic skin itch compared with the skin yellow itching relieving decoction.

<Animal test>

40 male ICR mice of 6-8 weeks of age were selected and randomly divided into 4 groups: a false operation group, a model group, a skin yellow itching relieving soup group and a five-skin soup group.

After 1 week of adaptive feeding, 5/6 nephrectomy (first resecting left kidney, 1 week later ligating upper and lower 1/3 of contralateral kidney) was performed on the last 3 groups (model group, yellow skin antipruritic soup group, five skin soup group); skin and muscle incision suture treatment is performed on the same part of the sham operation group at the same time. The mice of each group consisted of: false operation n=10, model group n=9, skin yellow antipruritic decoction group n=8, five skin decoction group n=9 (note: skin yellow antipruritic decoction group, death after nephrectomy 2, five skin decoction group, death after nephrectomy 1). The 4 groups of mice were kept for 12 weeks after the operation under the same and appropriate conditions.

The tail tip blood was collected at week 12, and serum creatinine and urea nitrogen were measured, wherein the model group, the skin yellow antipruritic soup group and the five-skin soup group were all of the 5/6 kidney-cut group.

The results show that: there were statistical differences in blood creatinine and urea nitrogen levels in sham and 5/6 kidney cut groups (see FIG. 2-A below), suggesting that 5/6 kidney cut mice developed a renal failure phenotype.

After a defined 5/6 kidney cut model was successful, the model and drug administration groups were subjected to the next modeling treatment: beta 2 microglobulin (20 ug/100 ug/ml beta 2 microglobulin liquid medicine is injected into the skin at the back of the neck, 0.2ml each) is injected 1 time a day for 7 days. Wherein, for the administration group, skin yellow antipruritic soup (drug concentration 0.33 g/ml) is smeared on the skin of the neck and back of the administration group 60min, 40min and 20min before beta 2 microglobulin is injected. After daily intradermal injections of β2 microglobulin, the scratching behavior of each mouse was recorded with a camera for 30min, 7 consecutive days, without external intervention, and finally each group of scratching behavior was counted as the following fig. 2-B.

After the mice are obtained, paraffin embedding treatment is carried out on partial skin of the injection area at the back of the neck, and HE staining and IL31 immunohistochemistry are carried out after slicing, fishing, baking, dewaxing and rehydration. HE staining: hematoxylin staining for 1 min-washing with running water for 10 min-eosin staining for 30s, air drying, sealing with neutral resin, observing and photographing. IL31 immunohistochemistry: microwave method antigen repair-natural cooling-endogenous peroxidase blocking-primary antibody overnight-secondary antibody-DAB color development, airing and sealing, observing and photographing. The rest skin of the materials is preserved at-80 degrees and is used for extracting protein and performing Western Blot (WB) of Western blot experiments. The protein extraction steps are as follows: grinding fresh frozen skin, cracking lysate, centrifuging, collecting supernatant, measuring concentration, boiling for denaturation to obtain WB-like protein sample, and preserving at-20deg.C. The WB procedure is as follows: SDS-PAGE gels were prepared according to instructions and then run sequentially through electrophoresis-transfer-blocking-primary overnight-secondary-development.

In fig. 2:

A. statistical graphs of urea nitrogen and creatinine in blood of sham-operated and 5/6 kidney-resected mice. From A, it is clear that the 2 groups of mice have poor kidney function ratios and have statistical significance, which indicates that 5/6 kidney-resected mice have kidney failure phenotype.

B. For the statistical result of the pruritus of 4 groups of mice, the result shows that the scratching times of the mice in the skin yellow itching relieving decoction group and the five skin decoction group are obviously lower than those of the mice in the model group, and the skin yellow itching relieving decoction and the five skin decoction can obviously relieve uremia skin pruritus; notably, the number of scratches of the five-skin decoction group mice was significantly lower than the skin yellow antipruritic decoction group. The result shows that the five-skin decoction has better curative effect of relieving uremic skin itch than the skin yellow itching relieving decoction, which is consistent with the clinical observation of the patients.

C. HE staining and IL-31 immunohistochemistry for skin pathology pictures of mice. The results suggest that, compared with the sham operation group, the model group shows that the epidermis layer of the skin is thickened, the dermis layer has a large amount of inflammatory cell infiltration, and the skin yellow itching relieving soup group and five-skin Shang Zuyan sex cell infiltration are reduced after administration; IL-31 immunohistochemistry suggests that the dermis layer of the model group has a large amount of IL-31 expression compared with the sham operation group, and the IL-31 of the skin yellow antipruritic decoction group and the five-skin decoction group is obviously reduced compared with the model group.

D. IL-31WB was also suggested to be elevated in the 4 groups of mice compared to the sham operated group and reduced in IL-31 following dosing.

The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (8)

1. The pharmaceutical composition for intervening uremia skin itch is characterized by comprising the following traditional Chinese medicine raw materials: pricklyash peel, lewy peel, snake slough, cortex dictamni and poria peel; or (b)

Fructus Kochiae, cortex Phellodendri, rhizoma Atractylodis, ramulus Cinnamomi, periostracum Serpentis, fructus Zanthoxyli, cortex Dictamni Radicis, and rhizoma Smilacis Glabrae.

2. The pharmaceutical composition for intervening uremic skin itch according to claim 1, wherein each component of the pharmaceutical composition comprises 7-15 g of pepper, 7-15 g of corium Erinacei Seu Hemiechianus, 12-20 g of snake slough, 12-20 g of cortex dictamni and 12-20 g of poria cocos peel by weight.

3. The pharmaceutical composition for intervention of uremic skin itch according to claim 1 or 2, wherein each component of the pharmaceutical composition is 10g of pepper, 10g of corium galli, 15g of snake slough, 15g of cortex dictamni and 15g of poria cocos peel by weight.

4. The pharmaceutical composition for intervening uremic skin itch according to claim 1, wherein each component of the pharmaceutical composition comprises 25-40 g of fructus kochiae, 15-28 g of amur corktree bark, 10-20 g of swordlike atractylodes rhizome, 10-20 g of cassia twig, 10-25 g of snake slough, 8-15 g of Chinese prickly ash, 12-25 g of cortex dictamni and 25-40 g of glabrous greenbrier rhizome by weight.

5. The pharmaceutical composition for intervention of uremic skin itch according to claim 1 or 4, wherein the composition comprises 30g of belvedere fruit, 20g of amur corktree bark, 15g of swordlike atractylodes rhizome, 15g of cassia twig, 15g of snake slough, 10g of Chinese prickly ash, 20g of dittany bark and 30g of glabrous greenbrier rhizome.

6. The pharmaceutical composition for the intervention of uremic skin itch according to claim 1, wherein the pharmaceutical composition is prepared into concentrates, ointments, films and pastes by adding or omitting pharmaceutically acceptable auxiliary materials.

7. The method for preparing a pharmaceutical composition for intervention in uremic skin itch according to any one of claims 1 to 6, comprising the steps of:

weighing the raw materials according to the mass ratio, and decocting and concentrating to obtain a liquid medicine.

8. A pharmaceutical composition according to any one of claim 1 to 6, or 7, a method of use thereof,

the pharmaceutical composition was diluted at 1:100 ratio the next day after dialysis and bathed for 15 minutes.

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