A composition for preventing and improving sarcopenia, immunodeficiency caused by cancer and related treatments, and a preparation method and application thereof

Abstract

The application belongs to the technical field of biological medicine, and provides a composition for preventing and improving cancer and sarcopenia caused by related treatment and immunodeficiency, a preparation method and application thereof.The composition comprises the following components: nucleotides, beta-hydroxy beta-methyl butyrate, arginine, histidine, glutathione, fish oil, seaweed oil and vitamin E.The composition has remarkable effects on improving cancer and sarcopenia caused by related treatment and immunodeficiency in the compounding of the components.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology and provides a composition for preventing and improving sarcopenia and decreased immunity caused by cancer and related treatments, as well as its preparation method and application. Background Technology

[0002] In the early stages of cancer, patients often experience malnutrition, sarcopenia, and even cachexia. Sarcopenia not only impairs bodily function, increases the risk of falls, and leads to loss of autonomy, but also reduces respiratory function and weakens the immune system. Currently, there are no first-line drugs for treating sarcopenia. The preferred treatment strategy is nutritional intervention, such as foods and medicines for special medicinal purposes, as well as exercise intervention.

[0003] For example, Chinese invention patent application CN119866184A discloses a nutritional composition for the prevention and / or treatment of muscle degeneration-related diseases or conditions in subjects in need, comprising fish oil, L-arginine, vitamin E, vitamin C, vitamin B3, vitamin B5, vitamin B6, vitamin B1, vitamin B2, folic acid, biotin, and vitamin B12, for the prevention and / or treatment of muscle degeneration-related diseases or conditions, particularly in subjects with renal failure, renal dysfunction, or / or kidney disease, such as CKD, protein-energy depletion, ESRD, renal failure due to hospitalization in the ICU, risk of AKI, or suffering from the aforementioned conditions.

[0004] However, single nutritional interventions have limited effects on improving the body's immunity. Nucleotides are essential small organic molecules for life activities, and abnormalities in the synthesis and catabolism of purine nucleotides are fundamental to the development of certain diseases and are also targets for treatment. The occurrence and development of tumors involve numerous pathophysiological processes, including imbalances in purine nucleotide metabolism. Abnormalities in purine nucleotide metabolism can also lead to an imbalance in the antioxidant and pro-inflammatory properties of uric acid, thereby inducing tumors and promoting their progression. Abnormal purine nucleotide metabolism affects gene and protein expression by regulating signal transduction pathways, promoting malignant transformation, invasion, and metastasis of cells. Therefore, introducing nucleotide components into relevant nutritional products holds promise for achieving comprehensive interventions for sarcopenia and immune system dysfunction associated with cancer and related treatments.

[0005] Currently, there are products based on nucleotides that improve immunity and serve as adjuvant therapies for cancer. For example, Chinese invention patent application CN115067518A discloses a composition for enhancing tumor immunity, consisting of β-hydroxy-β-methylbutyrate, nucleotides, probiotics, glutamine, leucine, and arginine. This composition, through synergistic effects, can increase immunoglobulin G levels in liver cancer mice after chemotherapy, thereby enhancing the immune system of the tumor-bearing organism. It can be used in special medical purpose tumor-specific foods or pharmaceutical products for adjuvant therapy to improve immunity and fight tumors. However, its effect on sarcopenia is limited.

[0006] Studies have shown that a healthy immune system may help reduce muscle loss caused by disease. Therefore, the development of nucleotide-based biopharmaceuticals is of great significance for further improving the comprehensive prevention and treatment of sarcopenia and weakened immunity associated with tumors. Summary of the Invention

[0007] In response to the problems existing in the prior art, this invention focuses on the research of nucleotides and formulates a composition for use in biological agents by compounding β-hydroxy-β-methylbutyrate (HMB), various amino acids and peptides, as well as fish oil and vegetable oil. It has significant effects in the prevention and improvement of sarcopenia and decreased immunity caused by cancer and related treatments.

[0008] The technical solution of the present invention is as follows:

[0009] This invention provides a composition for preventing and improving sarcopenia and decreased immunity caused by cancer and related treatments. The composition comprises, by weight parts: 0.01-0.05 parts of nucleotides, 1-5 parts of β-hydroxyβ-methylbutyrate, 20-40 parts of arginine, 0.5-1 part of histidine, 0.1-0.5 parts of glutathione, 1-40 parts of fish oil, 20-50 parts of algae oil, and 0.01-0.05 parts of vitamin E.

[0010] Preferably, the composition comprises, by weight parts: 0.02-0.04 parts of nucleotides, 3-5 parts of β-hydroxy-β-methylbutyrate, 30-40 parts of arginine, 0.6-0.8 parts of histidine, 0.1-0.3 parts of glutathione, 20-30 parts of fish oil, 30-40 parts of algae oil, and 0.01-0.03 parts of vitamin E.

[0011] More preferably, the composition comprises, by weight parts: 0.03 parts nucleotides, 4 parts β-hydroxyβ-methylbutyrate, 35 parts arginine, 0.75 parts histidine, 0.2 parts glutathione, 25 parts fish oil, 35 parts algae oil and 0.02 parts vitamin E.

[0012] In some specific embodiments of the present invention, the composition comprises the following components:

[0013] The daily dose is about 0.167 mg to about 0.833 mg of nucleotides per kg of the subject's body weight; preferably, the daily dose is about 0.333 mg to about 0.667 mg of nucleotides per kg of the subject's body weight; more preferably, the daily dose is about 0.5 mg of nucleotides per kg of the subject's body weight.

[0014] The daily dose is about 16.7 mg to about 83.3 mg of β-hydroxy-β-methylbutyrate per kg of the subject's body weight; preferably, the daily dose is about 50 mg to about 83.3 mg of β-hydroxy-β-methylbutyrate per kg of the subject's body weight; more preferably, the daily dose is about 66.7 mg of β-hydroxy-β-methylbutyrate per kg of the subject's body weight.

[0015] The daily dose is about 333 mg to about 667 mg of arginine per kg of the subject's body weight; preferably, the daily dose is about 500 mg to about 667 mg of arginine per kg of the subject's body weight; more preferably, the daily dose is about 583 mg of arginine per kg of the subject's body weight.

[0016] The daily dose is about 8.33 mg to about 16.7 mg of histidine per kg of the subject's body weight; preferably, the daily dose is about 10 mg to about 13.3 mg of histidine per kg of the subject's body weight; more preferably, the daily dose is about 12.5 mg of histidine per kg of the subject's body weight.

[0017] The daily dose is about 1.67 mg to about 8.33 mg of glutathione per kg of the subject's body weight; preferably, the daily dose is about 1.67 mg to about 5 mg of glutathione per kg of the subject's body weight; more preferably, the daily dose is about 3.33 mg of glutathione per kg of the subject's body weight.

[0018] The daily dose is about 16.7 mg to about 667 mg of fish oil per kg of the subject's body weight; preferably, the daily dose is about 333 mg to about 500 mg of fish oil per kg of the subject's body weight; more preferably, the daily dose is about 417 mg of fish oil per kg of the subject's body weight.

[0019] The daily dose is about 333 mg to about 833 mg of algae oil per kg of the subject's body weight; preferably, the daily dose is about 500 mg to about 667 mg of algae oil per kg of the subject's body weight; more preferably, the daily dose is about 583 mg of algae oil per kg of the subject's body weight.

[0020] The daily dose is about 0.167 mg to about 0.833 mg of vitamin E per kg of the subject's body weight; preferably, the daily dose is about 0.167 mg to about 0.5 mg of vitamin E per kg of the subject's body weight; more preferably, the daily dose is about 0.333 mg of vitamin E per kg of the subject's body weight.

[0021] Furthermore, the nucleotide includes nicotinamide mononucleotide.

[0022] Furthermore, the nucleotides also include one or more of the following: 5'-inosine monophosphate, 5'-cytidine monophosphate, 5'-uridine monophosphate, 5'-adenosine monophosphate, disodium 5'-inosinate, disodium 5'-guanylate, disodium 5'-uridine, and disodium 5'-cytidine.

[0023] In some specific embodiments of the present invention, the nucleotide is any one of the following combinations: nicotinamide mononucleotide + disodium 5'-inosinate, nicotinamide mononucleotide + disodium 5'-guanylate, nicotinamide mononucleotide + disodium 5'-uridine, or nicotinamide mononucleotide + disodium 5'-cytidine. Preferably, the mass ratio of the two nucleotides in the aforementioned composition is 1:0.01-0.5.

[0024] Further, the β-hydroxy-β-methylbutyrate is selected from one or more of calcium β-hydroxy-β-methylbutyrate, sodium β-hydroxy-β-methylbutyrate, and potassium β-hydroxy-β-methylbutyrate; preferably, the β-hydroxy-β-methylbutyrate is calcium β-hydroxy-β-methylbutyrate.

[0025] The present invention also provides a method for preparing any of the compositions described above, comprising the following steps:

[0026] (1) Dissolve nucleotides, arginine, histidine and glutathione in water to obtain an aqueous phase, and sterilize it for later use;

[0027] (2) Mix fish oil and seaweed oil, and add vitamin E to obtain a mixed oil phase;

[0028] (3) Add the oil phase to the aqueous phase and homogenize to obtain an emulsion;

[0029] (4) Add β-hydroxy-β-methylbutyrate and glutathione to the emulsion and stir until they are evenly mixed.

[0030] Furthermore, the total concentration of the nucleotides, arginine, histidine, and glutathione in water is 50-80 wt.%.

[0031] Furthermore, the homogenization is carried out under high pressure, specifically by cyclic homogenization at a pressure of 40-80 MPa for 3-10 times.

[0032] The present invention also provides the use of any of the above-described compositions in the preparation of medicaments for the prevention and / or improvement of sarcopenia and immunodeficiency caused by cancer and related treatments.

[0033] In some specific embodiments of the present invention, the cancer-related treatment can be cancer chemotherapy drugs such as cisplatin, paclitaxel, etc.

[0034] Compared with the prior art, the present invention has the following beneficial effects:

[0035] This invention focuses on the combination of nucleotides (especially nicotinamide mononucleotide) with β-hydroxy-β-methylbutyrate (HMB), various amino acids and peptides, as well as fish oil and algal oil, which have significant effects on improving tumor-induced immunosuppression and sarcopenia. In particular, fish oil and algal oil have a significant synergistic effect in improving sarcopenia under specific ratios.

[0036] In addition, for nucleotides, nicotinamide mononucleotide is combined with one or more of the following nucleotides: 5'-inosine monophosphate, 5'-cytidine monophosphate, 5'-uridine monophosphate, 5'-adenosine monophosphate, disodium 5'-inosinate, disodium 5'-guanylate, disodium 5'-uridine, and disodium 5'-cytidine, which further enhances the effect on improving tumor-induced immunosuppression.

[0037] The composition of this invention has a simple preparation process. The addition of vitamin E and its combination with glutathione improves the stability of the composition. Under the action of specific components, the composition obtained by multi-stage mixing and addition of raw materials has good stability and long shelf life. Detailed Implementation

[0038] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0039] The fish oil (60% specification, active ingredients DHA 24% + EPA 36%) and algae oil (50% specification, extracted from deep-sea diatoms) used in the embodiments of this invention were purchased from Xi'an Weisbo Biotechnology Co., Ltd.

[0040] Examples 1-7

[0041] Take each component according to the dosage in Table 1, and prepare the composition as follows:

[0042] (1) Dissolve nucleotides, arginine, histidine and glutathione in 10 mL of water to obtain an aqueous phase, and sterilize it for later use;

[0043] (2) Mix fish oil and seaweed oil, and add vitamin E to obtain a mixed oil phase;

[0044] (3) Add the oil phase to the aqueous phase and homogenize at 80 MPa, 60 MPa and 40 MPa in sequence, each time for 3 min, to obtain an emulsion;

[0045] (4) Add β-hydroxy-β-methylbutyrate and glutathione to the emulsion and stir until they are mixed evenly to obtain composition 1-7.

[0046] Table 1

[0047]

[0048] Comparative Example 1

[0049] Take each component according to the dosage in Table 2, and prepare the composition as follows:

[0050] (1) Dissolve nucleotides, arginine and glutathione in 10 mL of water to obtain an aqueous phase, and sterilize it for later use;

[0051] (2) Mix fish oil and seaweed oil, and add vitamin E to obtain a mixed oil phase;

[0052] (3) Add the oil phase to the aqueous phase and homogenize at 80 MPa, 60 MPa and 40 MPa in sequence, each time for 3 min, to obtain an emulsion;

[0053] (4) Add calcium β-hydroxy-β-methylbutyrate and glutathione to the emulsion and stir until they are evenly mixed to obtain composition 8.

[0054] Comparative Example 2

[0055] Take each component according to the dosage in Table 2, and prepare the composition as follows:

[0056] (1) Dissolve nucleotides, arginine, leucine and glutathione in 10 mL of water to obtain an aqueous phase, and sterilize it for later use;

[0057] (2) Mix fish oil and seaweed oil, and add vitamin E to obtain a mixed oil phase;

[0058] (3) Add the oil phase to the aqueous phase and homogenize at 80 MPa, 60 MPa and 40 MPa in sequence, each time for 3 min, to obtain an emulsion;

[0059] (4) Add calcium β-hydroxy-β-methylbutyrate and glutathione to the emulsion and stir until they are evenly mixed to obtain composition 9.

[0060] Comparative Example 3

[0061] Take each component according to the dosage in Table 2, and prepare the composition as follows:

[0062] (1) Dissolve nucleotides, arginine, histidine and glutathione in 10 mL of water to obtain an aqueous phase, and sterilize it for later use;

[0063] (2) Mix fish oil and seaweed oil to obtain a mixed oil phase;

[0064] (3) Add the oil phase to the aqueous phase and homogenize at 80 MPa, 60 MPa and 40 MPa in sequence, each time for 3 min, to obtain an emulsion;

[0065] (4) Add calcium β-hydroxy-β-methylbutyrate and glutathione to the emulsion and stir until they are evenly mixed to obtain composition 10.

[0066] Comparative Example 4-5

[0067] Take each component according to the dosage in Table 2, and prepare compositions 11 and 12 according to the preparation method in Example 1.

[0068] Table 2

[0069]

[0070] Test Example 1: Effects of the composition of the present invention on sarcopenia and immunity caused by tumors

[0071] I. Experimental grouping and drug administration:

[0072] Four-week-old female Balb / c mice weighing 20±2g were selected and administered 1×10 6After subcutaneous injection of C26 colon cancer cells into mice, tumors were clearly formed 14 days later, indicating successful modeling. The successfully modeled mice were randomly divided into 16 groups of 10 mice each: model control group, positive control group, low-dose group of Example 1, medium-dose group of Example 1, high-dose group of Example 1, groups of Example 2-7, and comparative groups of Example 1-5. An additional normal control group (n=10) was also set up. In this study, the positive control group was orally administered 160 mg / kg of megestrol acetate (MA). The low-dose group, medium-dose group, and high-dose group of Example 1 were each administered Composition 1. Compositions 1-12 were each dissolved in 100 mL of distilled water to prepare a solution for administration. The daily recommended human dose was (low dose: 0.833 g; medium dose: 1.67 g; high dose: 3.33 g; standard human body weight: 60 kg; human / mouse dose equivalent factor: 12; taking the medium dose as an example, the mouse dose calculation was: 0.34 g / kg = 1.67 g / 60 kg × 12). The groups in Examples 2-7 and Comparative Examples 1-5 were orally administered Compositions 2-12 (at the medium dose). The normal control group and the model control group were given an equal volume of distilled water. The treatment was administered once daily for 7 days.

[0073] II. Detection Indicators:

[0074] 2.1 After the experiment was terminated, the mice were euthanized, blood was collected from the heart, and serum was separated by centrifugation. The levels of IgG, IgA, IgM, complement C3, and complement C4 in the serum were quantified by ELISA, and the results are shown in Table 3.

[0075] 2.2 Proteins were extracted from the quadriceps femoris muscle of each mouse and the levels of myosin heavy chain (MyHC) and myoblast determinant 1 (MyoD) relative to β-actin were measured and calculated by Western blotting. The results are shown in Table 4.

[0076] All indicators were processed using statistical software and expressed as follows: The expression indicates that if the variances are homogeneous, a one-way ANOVA is used; if the variances are not homogeneous, the Dunnett's test is used, and P < 0.05 is considered statistically significant.

[0077] III. Experimental Results

[0078] Table 3

[0079]

[0080] Note: Compared with the normal control group, # p < 0.05 ## p < 0.01; compared with the model control group, & p < 0.05 && p < 0.01.

[0081] Immunoglobulins (such as IgA, IgG, and IgM) and complement (C3, C4) in animal blood play important roles in humoral immunity. As shown in the table above, the composition of this invention can significantly reduce the levels of IgA, IgG, IgM, and complement C3 and C4 in tumor-bearing mice in a dose-dependent manner.

[0082] Compared with the dosage group in Example 1, Comparative Example 1 omitted histidine and increased the amount of arginine accordingly, while Comparative Example 2 replaced histidine with arginine. The levels of IgA, IgG, IgM and complement C3 and C4 in tumor mice decreased less. It can be seen that histidine and arginine play a synergistic role in improving the immunity of tumor mice in the composition of this application.

[0083] Compared with the dosage group in Example 1, the dosage of nucleotides or glutathione in Comparative Examples 4 and 5 was unreasonable, resulting in a decrease in the effect of the composition on improving the immunity of tumor mice. It can be seen that the components of the present invention can only play a better role in improving the immunity of tumor mice when they are within a specific ratio range.

[0084] Furthermore, compared with the dosage group in Example 1, the levels of IgA, IgG, IgM, and complement C3 and C4 in tumor mice were further reduced after nicotinamide mononucleotide was combined with 5'-uridine mononucleotide or 5'-guanylate disodium in Examples 2-4. However, the reduction was less pronounced when 5'-uridine mononucleotide or 5'-guanylate disodium was used in Example 5. This indicates that the nucleotides of the present invention, especially nicotinamide mononucleotide or nicotinamide mononucleotide combined with other nucleotides, have a more significant effect on improving the immunity of tumor mice.

[0085] Table 4

[0086]

[0087] Note: Compared with the normal control group, # p < 0.05 ## p < 0.01; compared with the model control group, & p < 0.05 && p < 0.01.

[0088] MyHC plays a crucial role in muscle contraction, while MyoD plays a crucial role in improving muscle mass. As shown in Table 4, the compositions of this invention have a direct effect on increasing muscle endurance, strength, and muscle mass. Furthermore, in inhibiting tumor-induced sarcopenia, the compositions of this invention exhibit comparable or even better therapeutic effects compared to megestrol acetate (MA), a commonly used drug for treating weight loss in cancer patients.

[0089] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A composition for preventing and improving sarcopenia and decreased immunity caused by cancer-related treatments, characterized in that, The composition comprises, by weight, the following components: 0.01-0.05 parts nucleotides, 1-5 parts β-hydroxy-β-methylbutyrate, 20-40 parts arginine, 0.5-1 part histidine, 0.1-0.5 parts glutathione, 1-40 parts fish oil, 20-50 parts algae oil, and 0.01-0.05 parts vitamin E; The nucleotide is one or more of nicotinamide mononucleotide, disodium 5'-guanylate, and disodium 5'-uridineate. The β-hydroxy-β-methylbutyrate is one or more of calcium β-hydroxy-β-methylbutyrate, sodium β-hydroxy-β-methylbutyrate, and potassium β-hydroxy-β-methylbutyrate.

2. The composition according to claim 1, characterized in that, The composition comprises, by weight, the following components: 0.02-0.04 parts nucleotides, 3-5 parts β-hydroxy-β-methylbutyrate, 30-40 parts arginine, 0.6-0.8 parts histidine, 0.1-0.3 parts glutathione, 20-30 parts fish oil, 30-40 parts algae oil, and 0.01-0.03 parts vitamin E.

3. The composition according to claim 2, characterized in that, The composition comprises, by weight, the following components: 0.03 parts nucleotides, 4 parts β-hydroxy-β-methylbutyrate, 35 parts arginine, 0.75 parts histidine, 0.2 parts glutathione, 25 parts fish oil, 35 parts algae oil, and 0.02 parts vitamin E.

4. The method for preparing the composition according to any one of claims 1-3, characterized in that, Includes the following steps: (1) Dissolve nucleotides, arginine, histidine and glutathione in water to obtain an aqueous phase, and sterilize it for later use; (2) Mix fish oil and seaweed oil, and add vitamin E to obtain a mixed oil phase; (3) Add the oil phase to the aqueous phase and homogenize to obtain an emulsion; (4) Add β-hydroxy-β-methylbutyrate and glutathione to the emulsion and stir until they are evenly mixed.

5. The preparation method according to claim 4, characterized in that, The total concentration of the nucleotides, arginine, histidine, and glutathione in water is 50-80 wt.%.

6. The preparation method according to claim 4, characterized in that, The homogenization process employs high-pressure homogenization, specifically: cyclic homogenization at a pressure of 40-80 MPa for 3-10 cycles.

7. The use of the composition according to any one of claims 1-3 or the composition prepared by any one of claims 4-6 in the preparation of a drug for preventing and / or improving sarcopenia and immunodeficiency caused by cancer-related treatments.

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