Application of skin disease and blood poison composition in preparation of products for preventing and treating or reducing side effects of tumor targeted drugs

Abstract

The invention belongs to the technical field of medicines, and particularly relates to application of a skin disease blood poison composition in preparation of products for preventing or reducing side effects of tumor targeted drugs. The skin disease blood poison composition can significantly improve skin scale and / or pruritus and / or skin lesion caused by a targeted drug, and significantly improve red and swollen mouth, nose and eyelids caused by the targeted drug. The composition for treating the blood poison of the skin diseases has the characteristics of convenience in drug intake, quick effect taking and strong relieving effect, and can improve weight loss caused by targeted drugs and enhance the body quality, which may be related to the components of angelica sinensis, prepared rehmannia root and the like for enhancing immunity and tonifying deficiency and qi in the pills for treating the blood poison of the skin diseases. Good application prospects are realized.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and particularly relates to the application of a skin disease hemotoxin composition in the preparation of a product for preventing, treating or reducing the side effects of a tumor-targeting drug. Background Art

[0002] Targeted cancer drugs (such as epidermal growth factor receptor inhibitors (EGFRi) and ALK inhibitors) may cause adverse skin reactions during treatment, with rash being a common side effect. Targeted drugs (such as EGFR inhibitors) may interfere with the proliferation, differentiation, and repair of skin cells, leading to hair follicle inflammation and epidermal barrier damage. Furthermore, these drugs may trigger the release of local inflammatory factors (such as IL-1 and TNF-α), exacerbating skin inflammation.

[0003] Common drugs include EGFR inhibitors (gefitinib, erlotinib), ALK inhibitors (crizotinib), and anti-HER2 drugs (lapatinib). Erlotinib and gefitinib were the first molecularly targeted anti-tumor drugs to be marketed in China and are the main representatives of EGFR-TKIs. More than half of patients taking these drugs experience skin toxicity, often accompanied by symptoms such as itching and pain, primarily manifesting as a rash on the face, trunk, and limbs. This can easily cause anxiety in patients and seriously affect their quality of life. Severe rashes may lead patients to discontinue the drug, compromising treatment effectiveness.

[0004] The conventional treatment options for rashes caused by tumor-targeted drugs are:

[0005] (1) Mild rash (grade 1-2):

[0006] Topical hormones: hydrocortisone cream (weak effect) or mometasone (medium effect);

[0007] Antibiotics: topical clindamycin gel or oral doxycycline (anti-inflammatory effect).

[0008] (2) Moderate to severe rash (≥Grade 2):

[0009] Short-term oral corticosteroids (prednisone);

[0010] Add antibiotics (such as cephalosporins) when there is concurrent infection;

[0011] Adjust the dose of targeted drugs if necessary (requires evaluation by an oncologist).

[0012] Existing conventional treatment drugs are mostly hormones or antibiotics, which have the problems of short duration of efficacy and easy recurrence after discontinuation of medication; and hormones or antibiotics themselves have side effects, which aggravate the impact on the patient's body and increase the psychological burden on the patient.

[0013] Traditional Chinese medicine has attracted a certain amount of attention due to its advantages of multiple targets, few side effects, and overall regulation.

[0014] Chinese invention patent application CN201710572715.8 discloses a traditional Chinese medicine composition for treating skin diseases caused by damp-heat, blood dryness and disharmony of blood vessels. The purpose is to provide a traditional Chinese medicine composition for treating skin diseases caused by damp-heat, blood dryness and disharmony of blood vessels based on the understanding mechanism of skin diseases caused by damp-heat, blood dryness and disharmony of blood vessels in traditional Chinese medicine. The components of the traditional Chinese medicine composition and their mass proportions are as follows: Acuta acutus, Indigo naturalis, Clam shell, Sagittaria sagittifolia, Rubia cordifolia, Peach kernel, Snake skin (fried with wine), American ginseng, Red peony root, Angelica sinensis, Kochia scoparia, Citrus aurantium (fried), Xanthium sibiricum (fried), Raw Rehmannia root, Prepared Rehmannia root, Panax notoginseng, Forsythia suspensa, Honeysuckle, Coptis chinensis, Small red ginseng, Polygonum cuspidatum, Smilax glabra, Phellodendron amurense, Sophora flavescens thorn, Platycodon grandiflorum, Motherwort, Bitter almond (peeled and fried), Saposhnikovia divaricata, Red Poria cocos, White peony root, Cicada shell, Arctium lappa (fried), Paeonia suffruticosa bark, Dictamni bark, Rhubarb fried with wine, Honeysuckle vine, etc.

[0015] However, there are no reports on the efficacy of oral or topical Chinese medicine for the treatment of rash-like symptoms caused by tumor-targeted drugs. Summary of the Invention

[0016] In view of the deficiencies in the prior art, the present invention provides an application of a skin disease hemotoxicity composition in the preparation of a product for preventing and treating the skin side effects of tumor-targeted drugs.

[0017] The technical solution adopted in the present invention is as follows:

[0018] Application of a skin disease hemotoxin composition in preparing a product for preventing, treating or reducing the side effects of tumor-targeted drugs.

[0019] The purpose of this patent is to provide a drug that can not only relieve the clinical symptoms of rash caused by tumor-targeted drugs but also regulate the body's functions. The advantages of traditional Chinese medicine are overall conditioning, small side effects, and suitability for chronic disease management. In order to address the shortcomings of conventional treatment drugs for rashes caused by tumor-targeted drugs, the skin disease blood poisoning drug formula (skin disease blood poisoning pills) prepared by Beijing Tong Ren Tang Pharmaceutical Co., Ltd. was analyzed. The skin disease blood poisoning pills are composed of 39 herbs with a unique formula. According to the pathogenesis of skin diseases, it adopts the concept of treating the disease from the perspective of blood and treating external diseases from the inside. It has both ingredients that can quickly relieve symptoms and ingredients that regulate the body in all aspects, achieving the effect of alleviating the disease and enhancing its own functions to resist the disease.

[0020] Furthermore, the skin disease hemotoxicity composition is used in the preparation of a product that can significantly improve weight loss caused by the targeted drug gefitinib.

[0021] Furthermore, the skin disease hemotoxicity composition is used in the preparation of products for preventing, treating or reducing the skin side effects of tumor-targeted drugs.

[0022] Preferably, the skin disease hemotoxicity composition is used in the preparation of a product that can significantly improve the rash-like side effects caused by targeted drugs.

[0023] Preferably, the skin disease hemotoxic composition is used in the preparation of a product that can significantly improve skin scaling and / or itching and / or skin lesions caused by targeted drugs.

[0024] Preferably, the skin disease hemotoxicity composition is used in the preparation of a product that can significantly improve redness and swelling of the mouth, nose and eyelids caused by targeted drugs.

[0025] Preferably, the tumor targeting drug is an epidermal growth factor receptor inhibitor EGFRi or an ALK inhibitor.

[0026] Preferably, the tumor targeting drug is gefitinib, erlotinib, crizotinib or lapatinib.

[0027] Furthermore, the raw materials of the skin disease blood poisoning composition include madder, peach kernel, schizonepeta spicate, snake skin, red peony root, angelica, cogongrass root, kochia fruit, xanthium sibiricum fruit, rehmannia root, forsythia suspensa, honeysuckle, bitter herb, smilax glabra, phellodendron amurense, soapberry thorn,

[0028] Platycodon grandiflorum, motherwort, bitter almond, siler, red tuckahoe, white peony root, cicada shell, burdock fruit, peony bark, Dictamni root bark, Rehmannia root, rhubarb, honeysuckle vine, lithospermum officinale, Fritillaria thunbergii, Chuanxiong, licorice, angelica dahurica, tiankui fruit, bauhinia bark, millettia reticulata, duckweed and safflower.

[0029] Preferably, the skin disease blood toxin composition is skin disease blood toxin pills or a combination of skin disease blood toxin pills and glucocorticoids. Preferably, the skin disease blood toxin composition is skin disease blood toxin pills.

[0030] Preferably, according to the human dosage, the dosage of each administration of the Skin Disease Blood Toxin Pill is 0.04-0.16 g / kg, preferably 0.1 g / kg.

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] (1) The application of the patented Chinese medicine composition for treating skin diseases and blood poisoning in the treatment of skin rashes caused by tumor-targeted drugs is the first discovery, providing a new treatment method for skin rashes caused by tumor-targeted drugs.

[0033] (2) In order to verify the use of the traditional Chinese medicine composition for treating rashes caused by tumor-targeted drugs, a mouse rash model was induced by gefitinib, and 1.6g / kg, 0.8g / kg, and 0.4g / kg of the Dermatology Blood Poison Pills were administered for preventive treatment, respectively, to investigate the drug's effect on alleviating skin inflammation. The results showed that the redness and swelling of the skin, mouth, nose, and eyelids in the Dermatology Blood Poison Pills medium-dose group (0.8g / kg) and the combination group were significantly better than those in the model group from the onset of the disease on the 10th day of administration to the end of the experiment.

[0034] (3) The combination of medium-dose Dermatology Blood Poison Pills and hydrocortisone cream can significantly relieve the scales on the skin and redness and swelling around the mouth and eyelids of mice, and the therapeutic effect and onset time are better than those of the group treated with hydrocortisone cream alone. However, there is no significant difference in the skin damage of mice compared with the group treated with Dermatology Blood Poison Pills alone, indicating that the positive drug did not play the role of preventing drug-induced rash when the combination was given in advance. Oral administration of medium-dose Dermatology Blood Poison Pills can prevent and treat the side effects of rash caused by the targeted drug gefitinib to a large extent.

[0035] (4) A medium dose of Dermatopathy Blood Toxin Pills can significantly improve the weight loss caused by the targeted drug gefitinib and enhance the physical fitness of mice. The weight of mice in the combined drug group also showed a significant improvement trend compared with the model group, but the effect was weaker than that of the Dermatopathy Blood Toxin Pills alone group. There may be two reasons for this. First, hydrocortisone cream, as a hormone drug, has certain side effects, which can cause skin atrophy and allergies in mice, and will affect the weight of mice. On the other hand, hydrocortisone cream is applied to the rash area, which affects the penetration and absorption of the drug, slows down the onset of the drug, and affects the survival status of the mice.

[0036] (5) A certain dose of Dermatology Blood Poison Pills can prevent and relieve the rash-like side effects caused by gefitinib. It has the characteristics of convenient drug intake, fast onset time, and strong relief effect. At the same time, it can improve the weight loss caused by targeted drugs and enhance the body's fitness. This may be related to the ingredients in Dermatology Blood Poison Pills, such as Angelica sinensis and Rehmannia glutinosa, which enhance immunity and replenish deficiency and qi. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 Figure 3. Body weight changes in mice with targeted drug-induced rash. Data are expressed as x ± SD. Compared with the control group, #p < 0.05, ##p < 0.01, ###p < 0.001. Compared with the model group, *p < 0.05, **p < 0.01, ***p < 0.001.

[0038] Figure 2 The effect of the test drug on the clinical scores of mice with targeted drug-induced rash. Data are expressed as x ± SD. Compared with the model group, *p < 0.05, **p < 0.01, ***p < 0.001. DETAILED DESCRIPTION

[0039] The present invention will be further described below in conjunction with specific embodiments. The following raw materials are all commercially available conventional raw materials.

[0040] Example 1

[0041] The skin disease and blood toxin composition of the present invention: Skin Disease and Blood Toxin Pills, provided by Beijing Tong Ren Tang Pharmaceutical Co., Ltd., with national medicine standard Z11020834 and product batch number 24082224.

[0042] The present invention's skin disease blood poisoning composition is used in the efficacy experiment of the skin side effects of tumor targeting drugs

[0043] 1. Experimental Materials

[0044] 1.1 Animals:

[0045] Female BALB / C mice, 6-8 weeks old, weighing 18-20 g, were purchased from Beijing Yaokang Biotechnology Co., Ltd. under the Animal Experimental License No. SCXK(Beijing)2023-0008. Animals were housed in an SPF-grade animal room at the Laboratory Animal Center, Institute of Materia Medica, Chinese Academy of Medical Sciences, with free access to food and water. The room temperature was 22-25°C, the relative humidity was 55-65%, and the photoperiod was 12 h. All animal experiments were conducted in accordance with the guidelines of the Laboratory Animal Ethics Committee of the Chinese Academy of Medical Sciences and Peking Union Medical College. The Animal Experimental Ethics Review Form number is 00009550.

[0046] 1.2 Test reagents:

[0047] Targeted drug for inducing rash: Xinjiwei gefitinib tablets, national medicine standard H20203359, product batch number 2031240108, Shanghai Chuangnuo Pharmaceutical Co., Ltd.

[0048] Test sample: Skin Disease Xuedu Pills of Example 1;

[0049] Positive drugs: Hydrocortisone butyrate cream, national medicine standard number H10940095, product batch number 22051003, Tianjin Jinyao Pharmaceutical Co., Ltd.

[0050] 2. Test methods

[0051] 2.1 Grouping and disposal:

[0052] BALB / C mice were housed at the Laboratory Animal Center of the Institute of Materia Medica, Chinese Academy of Medical Sciences, with free access to food and water. The room temperature was 22–25°C, the relative humidity was 55–65%, and the light cycle was 12 h. All animal experiments were conducted in accordance with the guidelines of the Laboratory Animal Ethics Committee of the Chinese Academy of Medical Sciences and Peking Union Medical College and were approved by the Ethics Committee.

[0053] BALB / C mice were randomly divided into 7 groups according to body weight: control group, model group, positive drug group (hydrocortisone butyrate cream 40 μL / 20 g body weight), high (1.6 g / kg), medium (0.8 g / kg), low (0.4 g / kg) dose groups of Dermatology Xuedu Pills and combination drug group, with 10 mice in each group.

[0054] 2.2 Model establishment and drug administration

[0055] Hair was removed from the chest area (approximately 2 cm x 2 cm) and the area below the neck. The model group, positive drug group, combination drug group, and Dermatology Xuedu Pill high, medium, and low dose groups received a targeted drug infusion at a dose of 150 mg / kg once daily, with a volume of 100 μL per 10 g body weight, for 21 consecutive days. The normal control group received an equal volume of sterile deionized water.

[0056] From the first day, the combined medication group and the high, medium and low dose groups of Dermatology Xuedu Pills were given the corresponding drug solution by gavage every day.

[0057] Combined medication group: medium dose of Dermatology Xuedu Pills (0.8 g / kg) + hydrocortisone butyrate cream (40 μL / 20 g body weight);

[0058] High-dose group of Dermatosis Blood Du Pills: Dermatosis Blood Du Pills 1.6 g / kg;

[0059] Dermatosis and Blood Du Pills medium dose group: Dermatosis and Blood Du Pills 0.8g / kg;

[0060] The low-dose group of Dermatosis Blood Du Pills: Dermatosis Blood Du Pills 0.4 g / kg;

[0061] Positive drug group: hydrocortisone butyrate cream 40 μL / 20 g body weight;

[0062] The hydrocortisone cream was applied after removal from the mold.

[0063] The blank control and model groups were gavaged with a blank vehicle solution at a volume of 100 μL / 10 g body weight. Modeling was performed between 9:00 AM and 11:00 AM, and drug administration was performed between 3:00 PM and 5:00 PM, with a 6-hour interval. Mice were sacrificed 24 hours after the last administration for sample collection.

[0064] 3. Evaluation indicators

[0065] 3.1 Weight

[0066] From the first day of the experiment to the end of the experiment, the body weight of mice in each group was measured every 2 days.

[0067] 3.2 rating

[0068] From day 0 until the end of the experiment, mice were scored every two days. The pruritus behavior scoring table is shown in Table 1. Each group of mice was scored and the changes in skin lesions were observed. Lesion sites were photographed and recorded.

[0069] Table 1

[0070]

[0071] 4. Data Processing and Analysis

[0072] Experimental data are expressed as mean ± SD. Continuous data were compared using analysis of variance (ANOVA) followed by Duncan's test; discrete data were analyzed using the nonparametric Kruscal-Wallis ANOVA and Median Test. Results were analyzed and presented graphically using GraphPad Prism version 8.0 software.

[0073] 5. Test results

[0074] 5.1 Effect of the test drug on the body weight of mice with rash

[0075] The weight of mice is the most intuitive indicator of their health status. In order to observe the status of mice in each treatment group, the weight of mice in each group was recorded every two days from the beginning to the end of the experiment. Figure 1 The weight of mice in the control group continued to increase steadily, while the weight of mice in the modeling group gradually decreased. Starting from the 10th day, the weight dropped rapidly and was significantly lower than that in the control group. The weight of mice in the medium-dose Dermatopathy Blood Toxin Pills group continued to increase slowly, which was significantly improved compared with the model group. The weight of mice in the group treated with the medium-dose Dermatopathy Blood Toxin Pills and hydrocortisone emulsion combined medication group showed an improving trend, but there was no statistical difference. There was no statistical difference or obvious trend in the weight changes of mice in the other medication groups.

[0076] In addition, the number of samples during the experiment is shown in Table 2 below.

[0077] Table 2

[0078]

[0079] 5.2. Effects of the test drugs on skin lesions and clinical scores in mice

[0080] Giving mice 150 mg / kg of gefitinib daily will cause rash-like side effects in mice, mainly manifested as erythema, dryness, desquamation and other lesions on the face, nose, neck, chest and upper limbs. In order to evaluate the effect of each drug on the rash side effect caused by gefitinib, the skin lesions of each group of mice were observed every day from the beginning to the end of the experiment, clinical scores were performed every two days, and photographic records were taken every week.

[0081] See the results Figure 2 As shown in Table 3, mice began to develop skin lesions starting on day 7 of modeling, primarily characterized by dry, mild desquamation. By day 10, noticeable lumpy scales and subcutaneous hemorrhages developed. With continued gefitinib administration, thickening of the skin, accompanied by dry scales, appeared on the neck, face, and upper limbs. Symptoms included redness, swelling, ulceration of the mouth and nose, and eyelid swelling. Compared with the model group, the skin of mice treated with the medium-dose Dermatology Xuedu Pills (0.8 g / kg) and the combination therapy group was smoother and more delicate, with improved redness, swelling, and edema of the mouth, nose, and eyelids. The high-dose Dermatology Xuedu Pills (1.6 g / kg) group showed improvement in skin scales and decreased clinical scores two weeks after administration, on days 14, 17, and 20, but these improvements were not statistically significant compared to the model group. The low-dose Dermatology Xuedu Pills (0.4 g / kg) group did not significantly improve the skin lesions. The active drug group began applying the drug after the onset of skin lesions on day 10, and after one week, the lesions were effectively treated. The experimental results show that Dermatology Xuedu Pills can significantly prevent and improve the rash side effects caused by the anti-tumor targeted drug gefitinib at the set dose.

[0082] Table 3 Effects of the test drugs on the clinical scores of mice

[0083]

[0084] Note: Data are expressed as X±SD. Compared with the model group, *p<0.05, **p<0.01, ***p<0.001.

[0085] 6. Summary

[0086] A gefitinib-induced mouse rash model was used, and 1.6g / kg, 0.8g / kg, and 0.4g / kg of Dermatology Blood Poison Pills were administered for preventive treatment to investigate the drug's alleviating effect on skin inflammation. The results showed that the mid-dose Dermatology Blood Poison Pills group (0.8g / kg) and the combination group showed significantly better skin, nose, and eyelid redness and swelling than the model group from the onset of the disease on the 10th day of administration to the end of the experiment. The high-dose Dermatology Blood Poison Pills group (1.6g / kg) showed some improvement in skin scaling and decreased clinical scores two weeks after administration, but there was no statistical difference compared to the model group. Hydrocortisone cream, a positive drug, was administered starting after the onset of a clear rash (day 10). After one week of application (day 17), there was a trend toward improvement in the dermatitis symptoms in the mice, but there was no statistical difference. The combination of a medium-dose Fubingxuedu Pill and hydrocortisone cream significantly alleviated skin scaling and redness around the mouth and eyelids in mice. The therapeutic effect and onset of action were superior to those in the group receiving hydrocortisone cream alone. However, there was no significant difference in skin lesions compared to the group receiving Fubingxuedu Pill alone. This suggests that the preemptive combination therapy did not prevent the drug-induced rash. However, oral administration of a medium-dose Fubingxuedu Pill significantly prevented and alleviated the rash side effect caused by the targeted drug gefitinib. Furthermore, a medium-dose Fubingxuedu Pill significantly ameliorated weight loss induced by the targeted drug gefitinib and enhanced the mice's stamina. The weight of mice in the combination group also showed a significant improvement compared to the model group, but the effect was weaker than that of Fubingxuedu Pill alone. This may be due to two factors: first, hydrocortisone cream, as a hormonal drug, has certain side effects, causing skin atrophy and allergies in mice, which in turn affects their weight. Second, hydrocortisone cream is applied to the rash site, which affects drug penetration and absorption, slowing the onset of the drug and affecting the mice's survival.

[0087] In summary, a certain dose of Dermatology Blood Poison Pills can prevent and relieve the rash-like side effects caused by gefitinib. It has the characteristics of convenient drug intake, fast onset of action, and strong relief effect. At the same time, it can improve the weight loss caused by targeted drugs and enhance the body's fitness. This may be related to the ingredients in Dermatology Blood Poison Pills, such as Angelica sinensis and Rehmannia glutinosa, which enhance immunity and replenish deficiency and qi.

[0088] The above detailed description is a specific description of one feasible embodiment of the present invention. This embodiment is not intended to limit the patent scope of the present invention. Any equivalent implementation or modification that does not depart from the present invention should be included in the scope of the technical solution of the present invention.

Claims

1. Application of the skin disease hemotoxic composition in the preparation of products for preventing, treating or reducing the side effects of tumor-targeted drugs.

2. The use according to claim 1, characterized in that The skin disease hemotoxicity composition is used in preparing a product that can significantly improve weight loss caused by the targeted drug gefitinib.

3. The use according to claim 1, characterized in that The skin disease hemotoxicity composition is used in preparing products for preventing, treating or reducing skin side effects of tumor-targeted drugs.

4. The use according to claim 3, characterized in that The skin disease hemotoxicity composition is used in the preparation of a product that can significantly improve the rash-like side effects caused by targeted drugs.

5. The use according to claim 3, characterized in that The skin disease hemotoxic composition is used in the preparation of a product that can significantly improve skin scales and / or itching and / or skin lesions caused by targeted drugs.

6. The use according to claim 1, characterized in that The skin disease hematotoxin composition is used in preparing a product that can significantly improve redness and swelling of the mouth, nose and eyelids caused by targeted drugs.

7. The use according to claim 1, characterized in that The tumor targeting drug is an epidermal growth factor receptor inhibitor EGFRi or an ALK inhibitor.

8. The use according to claim 1, characterized in that The tumor targeting drug is gefitinib, erlotinib, crizotinib or lapatinib.

9. The use according to claim 1, characterized in that The raw materials of the skin disease blood toxin composition include madder, peach kernel, schizonepeta spicate, snake skin, red peony root, angelica, white cyperus root, kochia fruit, Xanthium sibiricum fruit, rehmannia root, forsythia, honeysuckle, bitter gentian, smilax glabra, phellodendron, honeysuckle thorn, platycodon, motherwort, bitter almond, siler, red tuckahoe, white peony root, cicada skin, burdock fruit, peony bark, white peony root, prepared rehmannia root, rhubarb, honeysuckle vine, lithospermum officinale, fritillaria thunbergii, ligusticum chuanxiong, licorice, angelica dahurica, scutellaria baicalensis, bauhinia bark, millettia reticulata, duckweed and safflower.

10. The use according to any one of claims 1 to 9, characterized in that The skin disease blood poison composition is a skin disease blood poison pill or a combination of a skin disease blood poison pill and a glucocorticoid. According to the human dosage, the daily dosage of the skin disease blood poison pill is 0.04-0.16 g / kg.

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