Active microorganism composition and application thereof to prevention and treatment of toxic and side effects of chemotherapy

Abstract

The invention belongs to the field of biological medicine, and particularly relates to a composition of active microorganisms and application of the composition to prevention and treatment of toxic and side effects of chemotherapy. The composition of the active microorganisms comprises lactobacillus rhamnosus R7970, bifidobacterium lactis Probio-M8 and lactobacillus plantarum LP-807. The invention further discloses a preparation method of the active microorganisms. The composition of the active microorganisms is used for prophylactically alleviating the chemotherapy-related skin mucosal lesions, and after the active microorganisms are prophylactically given to chemotherapy rats, the morbidity of the skin mucosal lesions of the rats is obviously reduced, and the composition has a good prevention effect on the prevention and treatment of the skin mucosal lesions generated by the chemotherapy. The invention provides a method for preventing / treating chemotherapy-related side effects, which is simple, good in compliance, high in specificity and exact in curative effect by taking a composition of active microorganisms as a pharmaceutical composition for preventing / treating chemotherapy-related hand-foot syndromes.

Description

[0001] This application is a divisional application of invention patent application No. 202310384185.X. The name of the invention is: A probiotic composition and its application. The application date is April 11, 2023, and the priority date is November 30, 2022. This application reserves the application date and priority date of invention patent application No. 202310384185.X. Technical Field

[0002] The invention belongs to the field of biomedicine, and specifically relates to a composition of active microorganisms and its use in preventing and treating the toxic and side effects of chemotherapy. Background Art

[0003] Chemotherapy is a commonly used method for treating tumors. Although it has good therapeutic effects, it causes significant damage to the skin and mucous membranes, seriously affecting the patient's quality of life and tolerance to chemotherapy.

[0004] The mechanism of chemotherapy-induced skin and mucosal damage is complex and still unclear. Possible mechanisms include: 1) Chemotherapy drugs are cleared by exocrine glands (such as sweat glands and sebaceous glands), and the accumulation of chemotherapy drugs around the exocrine glands causes damage. In addition, the hands and feet are easily rubbed, resulting in local susceptibility to damage; 2) Chemotherapy drugs damage blood vessels deep in the skin and mucosa or affect their metabolic enzymes; 3) Due to the toxic effects of chemotherapy drugs, free radicals, DNA damage and local inflammation are secondary; 4) Individual genetic susceptibility factors. This is obviously different from radiation oral mucositis. The latter is mainly due to ionizing radiation damaging cell DNA chains and chromosome breaks, leading to cell cycle interruption and cell apoptosis.

[0005] Due to the complex mechanism of chemotherapy-induced skin and mucosal damage, current prevention and treatment methods include oral vitamin B6, application of antioxidant cream, wearing gloves one size smaller, ice compresses, gargling, or food therapy. However, the above prevention and treatment methods cannot achieve the expected goals due to poor patient compliance or poor efficacy; therefore, the prevention and treatment of chemotherapy-related skin and mucosal damage is still a difficult problem in clinical practice. Summary of the invention

[0006] To solve the above technical problems, the present invention is based on a study of chemotherapy patients after taking probiotics in clinical experiments, and found that probiotics are negatively correlated with the incidence of severe oral ulcers and severe hand-foot syndrome after chemotherapy. Probiotics were used in a rat skin and mucosal protection experiment to detect the incidence of skin and mucosal damage in rats after medication, and it was found that probiotics have a good preventive and therapeutic effect on skin and mucosal damage caused by chemotherapy.

[0007] Based on this, the object of the present invention is to provide an application of a probiotic composition in the preparation of a drug for alleviating chemotherapy-related skin and mucosal damage.

[0008] In one embodiment, the present invention provides a probiotic composition, comprising Lactobacillus rhamnosus R7970, Bifidobacterium lactis Probio-M8, and Lactobacillus plantarum LP-807; preferably, the Lactobacillus rhamnosus R7970 has a preservation number of CGMCC No.22244, the Bifidobacterium lactis Probio-M8 has a preservation number of CGMCC No.18610, and the Lactobacillus plantarum LP-807 has a preservation number of CGMCC No.24952.

[0009] In one embodiment, the content ratio of Lactobacillus rhamnosus R7970, Bifidobacterium lactis Probio-M8, and Lactobacillus plantarum LP-807 in the composition is 1-100:1-100:1-100.

[0010] In one embodiment, the content ratio of Lactobacillus rhamnosus R7970, Bifidobacterium lactis Probio-M8, and Lactobacillus plantarum LP-807 in the composition is 1-10:1-10:1-10.

[0011] In one embodiment, the content ratio of Lactobacillus rhamnosus R7970, Bifidobacterium lactis Probio-M8, and Lactobacillus plantarum LP-807 in the composition is 1-5:1-5:1-5.

[0012] In one embodiment, the content ratio of Lactobacillus rhamnosus R7970, Bifidobacterium lactis Probio-M8, and Lactobacillus plantarum LP-807 in the composition is 3:4:3.

[0013] In one embodiment, the composition further comprises at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant and vehicle.

[0014] In one embodiment, the present invention provides a pharmaceutical preparation comprising the probiotic composition.

[0015] In one embodiment, the pharmaceutical formulation comprises a solid dosage form, a semisolid dosage form, a liquid dosage form, or a gaseous dosage form.

[0016] In one embodiment, the pharmaceutical preparation includes powders, tablets, pills, films, granules, capsules, ointments, suppositories, pastes, solutions, emulsions, suspensions, injections, sprays, and aerosols.

[0017] In one embodiment, the present invention provides a food comprising the probiotic composition.

[0018] In one embodiment, the food includes beverages, dairy products, chewing gum and any other food in solid or liquid form that is convenient for people to eat; preferably, the dairy product includes yogurt.

[0019] In one embodiment, the present invention provides a skin care product, comprising the probiotic composition.

[0020] In one embodiment, the present invention provides the use of the probiotic composition, the pharmaceutical preparation, the food or the skin care product in the preparation of a medicament for treating and / or preventing chemotherapy-related skin and mucosal damage; the treatment and / or prevention of chemotherapy-related skin and mucosal damage includes reducing chemotherapy-related skin and mucosal damage.

[0021] In one embodiment, the chemotherapy-related skin and mucosal injuries include oral mucositis and hand-foot syndrome caused by chemotherapy.

[0022] Beneficial Effects

[0023] The present invention uses a probiotic composition to preventively reduce chemotherapy-related skin and mucosal damage. After probiotics are given to chemotherapy rats preventively, the incidence of skin and mucosal damage in rats is significantly reduced, and the present invention has a good preventive effect on the prevention and treatment of skin and mucosal damage caused by chemotherapy. The present invention uses a probiotic composition as a pharmaceutical composition for preventing / treating chemotherapy-related hand-foot syndrome, providing a simple, compliance-friendly, highly specific and effective method for preventing / treating chemotherapy-related side effects.

[0024] Biological Deposit

[0025] The Lactobacillus plantarum provided by the present invention was deposited in the General Microbiology Center of the China Culture Collection Administration (No. 3, Yard No. 1, Beichen West Road, Chaoyang District, Beijing, Institute of Microbiology, Chinese Academy of Sciences) on May 23, 2022. The abbreviation of the depository unit is CGMCC, and the strain deposit number is CGMCC No. 24952. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0027] Figure 1The following are the skin and mucosal injuries of rats after they were given probiotics and placebo in the animal experiment of the present invention. A) The incidence of skin and mucosal injuries of rats, B) The representative diagram of skin and mucosal injuries;

[0028] Figure 2 Representative images of oral ulcers in chemotherapy patients after being given probiotics and placebo in the clinical trial of the present invention;

[0029] Figure 3 The figures are representative of hand-foot syndrome in chemotherapy patients after being given probiotics and placebo in the clinical trial of the present invention. DETAILED DESCRIPTION

[0030] In order to make the technical problems, technical solutions and advantages to be solved by the present invention more clear, they will be described in detail below with reference to the accompanying drawings and specific embodiments, but the protection scope of the present invention is not limited to the following specific embodiments.

[0031] Unless otherwise defined, all professional terms used below have the same meanings as those generally understood by those skilled in the art. The professional terms used herein are only for the purpose of describing specific embodiments and are not intended to limit the scope of protection of the present invention.

[0032] Unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or prepared by existing methods.

[0033] Example 1

[0034] SD rats (8-9 weeks old, 200-250g) were randomly divided into chemotherapy + probiotics 1 group (Chemo + Probiotics 1), chemotherapy + probiotics 2 group (Chemo + Probiotics 2), chemotherapy + placebo group (Chemo + placebo), and normal control group (Control). Rats in the chemotherapy + probiotics group (referring to probiotics group 1 and group 2) were injected with the chemotherapy drug doxorubicin (2 mg / kg, once a week, for four consecutive weeks) through the tail vein, and the probiotic strips in the probiotics group 1 group (twice a day, 1 active microbial group strip / rat, a total of 10 billion bacteria / rat each time) and the probiotic strips in the probiotics group 2 group (twice a day, 1 active microbial group strip / rat, a total of 10 billion bacteria / rat each time) were orally fed to the rats. Rats in the chemotherapy + placebo group were injected with the chemotherapy drug doxorubicin (2 mg / kg, once a week, for four consecutive weeks) through the tail vein, and the placebo strips were fed to the rats twice a day, 1 placebo strip / rat. The normal control group was injected with normal saline.

[0035] Among them, the strains of probiotic group 1 are Lactobacillus rhamnosus R7970, Bifidobacterium lactis Probio-M8 and Lactobacillus plantarum LP-807. The usage of Lactobacillus rhamnosus R7970 is 3 billion CFU, the usage of Bifidobacterium lactis Probio-M8 is 4 billion CFU, and the usage of Lactobacillus plantarum LP-807 is 3 billion CFU per mouse per day; the preservation number of the Lactobacillus rhamnosus R7970 is CGMCC No.22244, the preservation number of the Bifidobacterium lactis Probio-M8 is CGMCC No.18610, and the preservation number of the Lactobacillus plantarum LP-807 is CGMCC No.24952.

[0036] The probiotic group 2 strains include Bifidobacterium infantis BI-G201, Lactobacillus acidophilus LA-G80, Bifidobacterium bifidum BB-G90, and Bifidobacterium lactis BL-G101 (the above strains are from Runying Bioengineering (Shanghai) Co., Ltd.). The daily usage of Bifidobacterium infantis BI-G201, Lactobacillus acidophilus LA-G80, Bifidobacterium bifidum BB-G90, and Bifidobacterium lactis BL-G101 in each mouse is 2.5 billion CFU.

[0037] Result analysis:

[0038] like Figure 1 As shown,

[0039] The incidence of skin and mucosal damage in the chemotherapy + probiotics group was significantly lower than that in the chemotherapy + placebo group, which shows that probiotics have a positive effect on skin and mucosal damage caused by chemotherapy. At the same time, the incidence of skin and mucosal damage in the probiotics 1 group was significantly lower than that in the probiotics 2 group.

[0040] Example 2

[0041] A total of 6 female breast cancer patients who needed to receive chemotherapy containing doxorubicin liposome injection after surgery were included and received at least 4 cycles of treatment. They were randomly divided into two groups (3 people in each group), one group took oral active microorganisms A (square group active microorganism strips), and the other group took oral active microorganisms B (rectangular group active microorganism strips) once a day in the morning and evening, and the incidence and severity of oral mucositis and hand-foot syndrome were recorded.

[0042] Among them, the strain composition of microbial group A (square group) is Bifidobacterium infantis BI-G201, Lactobacillus acidophilus LA-G80, Bifidobacterium bifidum BB-G90, and Bifidobacterium lactis BL-G101 (the above strains are from Runying Bioengineering (Shanghai) Co., Ltd.), and the amount of Bifidobacterium infantis BI-G201, Lactobacillus acidophilus LA-G80, Bifidobacterium bifidum BB-G90 and Bifidobacterium lactis BL-G101 used by each person each time is 2.5 billion CFU.

[0043] The strain composition of microorganism group B (rectangular group) is Lactobacillus rhamnosus R7970, Bifidobacterium lactis Probio-M8 and Lactobacillus plantarum LP-807; the usage amount of Lactobacillus rhamnosus R7970 per person each time is 3 billion CFU, the usage amount of Bifidobacterium lactis Probio-M8 is 4 billion CFU, and the usage amount of Lactobacillus plantarum LP-807 is 3 billion CFU. The Lactobacillus rhamnosus R7970 is deposited as CGMCC No.22244, the Bifidobacterium lactis Probio-M8 is deposited as CGMCC No.18610, and the Lactobacillus plantarum LP-807 is deposited as CGMCC No.24952.

[0044] Result analysis:

[0045] As shown in Table 1, the incidence of oral mucositis (OM) and hand-foot syndrome (HFS) in the oral active microbial group B (rectangle group) was significantly lower than that in the oral microbial group A (square group). This result is consistent with the animal experiment results of Example 1, proving that different microbial formulations and different microbial strains have very different effects on oral mucosal damage and hand-foot syndrome caused by chemotherapy.

[0046] Table 1

[0047]

[0048] Example 3

[0049] Clinical chemotherapy patients were randomly divided into a placebo group or a probiotic group, and the probiotic group patients were supplemented with a probiotic formula throughout the chemotherapy process (from the beginning of the first chemotherapy to the end of the last chemotherapy); the placebo group patients were supplemented with a placebo (the placebo strips used contained all the excipients except the probiotics in the probiotic strips package, and were identical to the probiotic strips in shape, size and smell) throughout the chemotherapy process (from the beginning of the first chemotherapy to the end of the last chemotherapy). Each cycle was graded and recorded according to the standards formulated by the World Health Organization (WHO) for the occurrence and severity of its skin and mucosal damage. Wherein, the strain composition of the probiotic group formula is Lactobacillus rhamnosus R7970, Bifidobacterium lactis Probio-M8 and Lactobacillus plantarum LP-807; the Lactobacillus rhamnosus R7970 is deposited as CGMCC No.22244, the Bifidobacterium lactis Probio-M8 is deposited as CGMCC No.18610, and the Lactobacillus plantarum LP-807 is deposited as CGMCC No.24952.

[0050] The specific steps of the test are as follows:

[0051] A total of 115 female patients with stage I-III breast cancer were systematically screened and communicated with. After obtaining consent from the patients and their families, they were included in the experiment and randomly divided into a placebo group or a probiotic group.

[0052] Probiotic group: Probiotics are supplemented to patients in the probiotic group throughout the chemotherapy process (from the beginning of the first chemotherapy to the end of the last chemotherapy). The specific method is to take the active microbial group strips orally twice a day with warm water half an hour after a meal. Each time, the amount of Lactobacillus rhamnosus R7970 used is 3 billion CFU, the amount of Bifidobacterium lactis Probio-M8 used is 4 billion CFU, and the amount of Lactobacillus plantarum LP-807 used is 3 billion CFU. The Lactobacillus rhamnosus R7970 is deposited as CGMCC No. 22244, the Bifidobacterium lactis Probio-M8 is deposited as CGMCC No. 18610, and the Lactobacillus plantarum LP-807 is deposited as CGMCC No. 24952.

[0053] Placebo group: The patients in the placebo group were supplemented with placebo strips during the entire chemotherapy process (from the beginning of the first chemotherapy to the end of the last chemotherapy). The placebo strips used contained all the excipients in the probiotics strips except the probiotics, and were the same in shape, size and smell as the probiotics strips. The specific method was also to take the placebo strips orally twice a day, twice a day, with warm water half an hour after a meal. The incidence and severity of oral ulcers and hand-foot complications in the above-mentioned placebo and probiotics groups after chemotherapy were evaluated.

[0054] Oral mucositis caused by chemotherapy is divided into four grades from I to IV according to the WHO standard: Grade I: erythema and pain of the oral mucosa; Grade II: erythema and ulcers of the oral mucosa, but solid food can be eaten; Grade III: oral mucosal ulcers, need for liquid food; Grade IV: severe ulcers make it impossible to eat, and parenteral or enteral nutritional support is required.

[0055] The WHO grading system for hand-foot syndrome is divided into four levels: I to IV. Level I: numbness or paresthesia of the hands and feet, tingling; erythema can be seen, and histology shows dilation of blood vessels in the epidermal reticular tissue. Level II: discomfort when holding objects or walking, painless swelling or erythema, and redness and swelling may also occur; Level III: painful erythema and swelling of the palms and soles, erythema and swelling around the nails, skin cracking can be seen, and histology shows isolated necrotic keratinocytes in the epidermis. Level IV: desquamation, ulcers, blisters, severe pain, and histology shows complete necrosis of the epidermis.

[0056] As shown in Table 2 and Table 3, Figure 2 , Figure 3 As shown, according to the incidence and severity evaluation of oral ulcers and hand-foot complications in each group of breast cancer patients after chemotherapy, it can be seen that the probiotic group can reduce the incidence and severity of chemotherapy-induced hand-foot complications (HFS) and oral ulcers (OM).

[0057] Table 2

[0058]

[0059]

[0060] Table 3

[0061]

[0062]

[0063] According to the above research, the probiotics of the present invention are used as medicines, foods or skin care products to reduce chemotherapy-related hand-foot syndrome and oral ulcers. By using the probiotic composition as a medicine composition, health food or skin care product for preventing / treating chemotherapy-related hand-foot syndrome, a simple method for preventing / treating chemotherapy-related side effects with good compliance, high specificity, definite efficacy and synergistic effects is provided.

[0064] The above is a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A composition of active microorganisms, characterized in that: The composition comprises Lactobacillus rhamnosus R7970, Bifidobacterium lactis Probio-M8, and Lactobacillus plantarum LP-807; Preferably, the Lactobacillus rhamnosus R7970 is deposited under CGMCC No. 22244, the Bifidobacterium lactis Probio-M8 is deposited under CGMCC No. 18610, and the Lactobacillus plantarum LP-807 is deposited under CGMCC No. 24952.

2. The composition of active microorganisms according to claim 1, characterized in that: The content ratio of Lactobacillus rhamnosus R7970, Bifidobacterium lactis Probio-M8 and Lactobacillus plantarum LP-807 in the composition is 1-100:1-100:1-100; preferably, the content ratio of Lactobacillus rhamnosus R7970, Bifidobacterium lactis Probio-M8 and Lactobacillus plantarum LP-807 is 1-10:1-10:1-10; preferably, the content ratio of Lactobacillus rhamnosus R7970, Bifidobacterium lactis Probio-M8 and Lactobacillus plantarum LP-807 is 1-5:1-5:1-5; preferably, the content ratio of Lactobacillus rhamnosus R7970, Bifidobacterium lactis Probio-M8 and Lactobacillus plantarum LP-807 is 3:4:

3.

3. The composition of active microorganisms according to claim 1, characterized in that: The composition further comprises at least one of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant and vehicle.

4. A pharmaceutical preparation, characterized in that The pharmaceutical preparation comprises the composition of active microorganisms according to any one of claims 1 to 3.

5. The pharmaceutical preparation according to claim 4, characterized in that The pharmaceutical preparation includes solid dosage forms, semisolid dosage forms, liquid dosage forms or gaseous dosage forms; preferably, the pharmaceutical preparation includes powders, tablets, pills, films, granules, capsules, ointments, suppositories, pastes, solutions, emulsions, suspensions, injections, sprays, and aerosols.

6. A food, characterized in that The food comprises the composition of active microorganisms according to any one of claims 1 to 3.

7. The food according to claim 6, characterized in that The food includes beverages, dairy products and chewing gum.

8. A skin care product, characterized in that: The skin care product comprises the composition of active microorganisms according to any one of claims 1 to 3.

9. Use of the composition according to any one of claims 1 to 3 or the pharmaceutical preparation according to any one of claims 4 to 5 in the preparation of a medicament for treating and / or preventing chemotherapy-related skin and mucosal injuries.

10. The use according to claim 9, characterized in that: The chemotherapy-related skin and mucosal damage includes oral mucositis and / or hand-foot syndrome caused by chemotherapy.

Images