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CN111714616A - Composition for resisting tumor - Google Patents

Composition for resisting tumor Download PDF

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Publication number
CN111714616A
CN111714616A CN201910644468.7A CN201910644468A CN111714616A CN 111714616 A CN111714616 A CN 111714616A CN 201910644468 A CN201910644468 A CN 201910644468A CN 111714616 A CN111714616 A CN 111714616A
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beta
vitamin
lna
omega
oxy
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王志强
徐增松
张新明
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Jiangsu Xihong Biomedical Co ltd
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Jiangsu Xihong Biomedical Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
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    • A61K33/00—Medicinal preparations containing inorganic active ingredients
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    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
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    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/01—Hydrolysed proteins; Derivatives thereof
    • A61K38/012—Hydrolysed proteins; Derivatives thereof from animals
    • A61K38/014—Hydrolysed proteins; Derivatives thereof from animals from connective tissue peptides, e.g. gelatin, collagen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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Abstract

The invention relates to a high-safety anti-tumor pharmaceutical composition, which comprises L-arginine, L-glutamine, collagen, carbohydrate, vitamin C, vitamin E, ionic calcium, ionic zinc, beta methyl-beta-hydroxy butyric acid (calcium) salt, Omega-3 fatty acid and nucleotide.

Description

Composition for resisting tumor
[ technical field ] A method for producing a semiconductor device
The invention relates to a composition for resisting tumors. More particularly, the present invention relates to an anti-tumor composition comprising a nutrient and a nucleotide.
[ technical background ] A method for producing a semiconductor device
Tumors are one of the major diseases seriously harming human life and health, and are manifested by abnormal cell hyperproliferation and differentiation. The WHO experts forecast that the tumor incidence of the global population will reach 2000 million people and the death number will reach 1200 million people in 2020, and the tumor will become the first killer of the human in the century and form the most serious threat to the human survival. The morbidity and mortality of lung cancer, colorectal cancer, gastric cancer, liver cancer and the like are in the prostate of various malignant tumors. According to statistics of (2012 annual report of Chinese tumor registration) issued by national tumor registration center, about 312 million new tumor cases occur every year, 8550 people are in average every day, and 6 people are diagnosed as cancer every minute in the whole country.
Chemotherapy is one of the effective methods for treating tumors. The action mechanism of traditional chemotherapeutic drugs is mainly to prevent the synthesis of deoxyribonucleic acid (DNA), ribonucleic acid (RNA) or protein, or directly act on these macromolecules, thereby inhibiting the division and proliferation of tumor cells and leading the tumor cells to die. Some drugs may also inhibit tumor growth by altering hormonal balance in the body. Anti-tumor drugs have been developed into 6 major classes: anti-metabolism medicine; (ii) an alkylating agent; ③ cytotoxin antibiotics; plant alkaloid and other natural medicines; anti-tumor hormones; sixthly, platinum and other antineoplastic drugs. However, chemotherapeutic agents have major toxic side effects.
With the change of clinical treatment modes and the discovery of some new antitumor drug targets, the research and development of the field of antitumor drugs have changed greatly: in terms of the action mechanism of the drug, the traditional nonspecific cytotoxic drug is shifted to the non-cytotoxic targeted drug development. Among FDA-approved antitumor drugs in 2012, small molecule Tyrosine Kinase Inhibitors (TKIs) became the most popular class of antitumor drugs to be developed, especially TKIs acting on multiple targets (about 3/4), and the number of us FDA-approved TKIs reached to 6 months in 2013. In addition, other hot-spot mechanism-of-action drugs include immunostimulants, angiogenesis inhibitors, cell cycle inhibitors, immunosuppressants and stimulants, protein kinase inhibitors, and the like. However, these therapeutic agents still have some toxic side effects.
Therefore, there is still a great need to develop a tumor therapeutic agent with no or low toxic side effects and high safety.
[ summary of the invention ]
The present inventors have surprisingly found that administration of a composition comprising a nutrient and a nucleotide provides an anti-tumor, better therapeutic and prophylactic effect, with no or low toxic side effects and high safety.
Accordingly, the present invention relates to a pharmaceutical composition comprising L-arginine, L-glutamine, collagen, carbohydrate, vitamin C, vitamin E, ionic calcium, ionic zinc, beta methyl-beta-hydroxybutyric acid (calcium) salt, Omega-3 fatty acid and nucleotide, which is highly safe for anti-tumor.
The invention further relates to a package comprising a pharmaceutical composition of the invention and a label and/or package insert instructing administration of the composition to a subject to provide the composition.
Furthermore, the present invention relates to the use of L-arginine, L-glutamine, collagen, carbohydrate, vitamin C, vitamin E, ionic calcium, ionic zinc, beta methyl-beta-hydroxybutyrate (calcium) salt, Omega-3 fatty acid and nucleotide in the manufacture of a medicament for anti-tumor, wherein the medicament comprises L-arginine, L-glutamine, collagen, carbohydrate, vitamin C, vitamin E, ionic calcium, ionic zinc, beta methyl-beta-hydroxybutyrate (calcium) salt, Omega-3 fatty acid and nucleotide.
In a first aspect, the present invention provides a pharmaceutical composition for anti-tumor comprising L-arginine, L-glutamine, collagen, carbohydrate, vitamin C, vitamin E, ionic calcium, ionic zinc, beta methyl-beta-hydroxybutyrate (calcium) salt, Omega-3 fatty acid and nucleotide.
In a second aspect, the invention provides a package comprising a pharmaceutical composition of the invention and a label and/or package insert instructing administration of the composition to a subject to provide L-arginine, L-glutamine, collagen, carbohydrates, vitamin C, vitamin E, ionic calcium, ionic zinc, beta methyl-beta-hydroxybutyrate (calcium) salt, Omega-3 fatty acids, and nucleotides. The packages of the present invention are suitable for use in anti-tumor applications.
In a third aspect, the present invention provides a use of L-arginine, L-glutamine, collagen, carbohydrate, vitamin C, vitamin E, ionic calcium, ionic zinc, a beta methyl-beta-hydroxybutyrate (calcium) salt, Omega-3 fatty acid and nucleotide in the manufacture of a medicament for use in the treatment of cancer, wherein the medicament comprises L-arginine, L-glutamine, collagen, carbohydrate, vitamin C, vitamin E, ionic calcium, ionic zinc, a beta methyl-beta-hydroxybutyrate (calcium) salt, Omega-3 fatty acid and nucleotide. The medicine is used for resisting tumor.
The ratio of L-arginine, L-glutamine, collagen, carbohydrate, beta methyl-beta-hydroxybutyrate (calcium) salt and Omega-3 fatty acid used in the invention is 1: 0.5-1.5: 0.1-0.8: 0.5-2: 0.1-0.8: 0.5-1.5: 0.5-5 (weight ratio). The total weight of L-arginine, L-glutamine, collagen, carbohydrate, beta methyl-beta-hydroxybutyrate (calcium) salt, Omega-3 fatty acid is 10-95% (weight ratio), preferably 25-85% (weight ratio), more preferably 40-75% (weight ratio) of the total weight of the whole composition. The single administration individual amounts of L-arginine, L-glutamine, collagen, carbohydrate, beta methyl-beta-hydroxybutyrate (calcium) salt and Omega-3 fatty acid used in the invention are 3-15g of L-arginine, 3-15g of L-glutamine, 1-5g of collagen, 3-20g of carbohydrate, 0.5-5 g of beta methyl-beta-hydroxybutyrate (calcium) salt and 0.1-5g of Omega-3 fatty acid, and the most preferable administration amount is 7g of L-arginine, 7g of L-glutamine, 2.5g of collagen, 8.2g of carbohydrate, 1.5 g of beta methyl-beta-hydroxybutyrate (calcium) salt and 1g of Omega-3 fatty acid.
The ratio of the vitamin C, the vitamin E, the ionic calcium and the ionic zinc used in the invention is 1: 0.01-0.2: 0.5-2: 0.01-0.2 (weight ratio). The total weight of the vitamin C, vitamin E, ionic calcium and ionic zinc used in the present invention is 0.05-10% (by weight), preferably 0.1-5% (by weight), more preferably 0.5-2% (by weight) of the total weight of the whole composition. The single administration amounts of the vitamin C, the vitamin E and the ionized calcium are respectively 50-1000mg, 5-60mg and 50-500mg of ionized zinc 3-30mg, and the most preferable administration amounts are vitamin C300 mg, vitamin E15 mg and 200mg of ionized calcium and 9.5mg of ionized zinc.
The nucleotide used in the present invention is selected from the group consisting of LNA oligonucleotide and cGAMP (cyclic-GMP-AMP).
The LNA oligonucleotide is selected from one of the following sequences:
a)AGTCTAACAGGCATTAGACAGATAAGCTGAGCTCC；
b)AGTCTAACAGGCATTAGACAGAGAAGCTGAGCTCC；
c)AGTATCACAGGCATTAGACAGATAAGCTGAGCTAC；
d)AGTATCACAGGCATTAGACAGAGAAGCTGAGCTAC，
wherein G is a G-beta-D-oxy-LNA nucleotide analogue, C is a C-beta-D-oxy-LNA nucleotide analogue, A is an A-beta-D-oxy-LNA nucleotide analogue, and T is a T-beta-D-oxy-LNA nucleotide analogue. The above sequences are all synthesized by Exiqon, and reference can be made specifically to: http:// www.biomart.cn/infosupl y/11085229. htm; http:// www.biomart.cn/infosuply/19919667. htm.
The LNA oligonucleotide can be applied to preparation of medicaments, and the medicaments are used for treating diseases with miR-21 expression obviously up-regulated. The diseases with the miR-21 expression being remarkably up-regulated can be tumors and angiogenesis with the miR-21 expression being remarkably up-regulated.
The tumors with the miR-21 expression being remarkably up-regulated can be prostatic cancer, lung cancer, breast cancer, testicular cancer, cervical cancer and colon cancer.
The LNA oligonucleotides described above can be used in a variety of pharmaceutically acceptable salts. The above "pharmaceutically acceptable salts" refer to salts that retain the desired biological activity of the LNA oligonucleotide and exhibit minimal undesirable toxicological effects. Non-limiting examples of such salts may be formed with organic amino acids, with base addition salts and metal cations such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, sodium, potassium and the like, with cations formed from ammonia, N-dibenzylethylenediamine, D-glucamine, tetraethylammonium or ethylenediamine; or combinations thereof, such as zinc tannate salts and the like.
The cGAMP (cyclic-GMP-AMP) described above is synthesized catalytically by cyclic cGAMP-AMP dinucleotide synthetase (cGAS) under the activation conditions after binding DNA according to the literature method. The purity is more than 98%. (PingweiLi, et al., Immunity, 2013, 39(6), 1019-
The cGAMP can inhibit the growth of various tumor cells, has obvious antitumor effect and can be used for preparing antitumor drugs.
The ratio of LNA oligonucleotide and cGAMP used in the present invention is 1: 0.01-10 (weight ratio), preferably 1: 0.05-5, more preferably 1: 0.1-2. The total weight of the LNA oligonucleotide and cGAMP used in the present invention is 0.1-30% (by weight), preferably 0.5-20% (by weight), more preferably 1-10% (by weight) based on the total weight of the whole composition. The individual amounts of LNA oligonucleotide and cGAMP administered in a single administration are 5-1000mg, preferably 5-600mg, more preferably 50-500mg, most preferably 150-300mg, respectively.
Omega-3 polyunsaturated fatty acids are a class of fatty acids that are beneficial to human health. The main active ingredients of Omega-3 fatty acids for human health are eicosapentaenoic acid (EPA, chemical structure shown below) and docosahexaenoic acid (DHA, chemical structure shown below). EPA and DHA are essential for normal healthy human survival, but are not synthesized by themselves and are therefore called essential fatty acids for humans.
EPA（all-cis-5,8,11,14,17-eicosapentaenoic acid）
Figure DEST_PATH_IMAGE002
DHA（all-cis-4,7,10,13,16,19-docosahexaenoic acid）
Figure DEST_PATH_IMAGE004
An increasing number of epidemiological and clinical investigations have shown that EPA and DHA have preventive and palliative effects on a number of diseases, including atherosclerosis, cardiovascular disease, stroke, neurological disease, obesity, type 2 diabetes and autoimmune diseases. However, higher animals, including humans, lack omega-3 and delta-12 desaturases and therefore lose the ability to synthesize such fatty acids de novo (Nakamura,2004), necessitating their acquisition from food.
Omega-3 fatty acids (EPA and DHA) also have anti-cancer effects, particularly in breast, colon, and prostate cancers. There is evidence that oral Omega-3 nutraceuticals may be beneficial to cancer patients, including improving appetite, increasing weight, and improving quality of life.
The Omega-3 fatty acid and the nucleotide have synergistic effect, and the antitumor activity is enhanced.
Omega-3 fatty acids and the above-mentioned nucleotides, although having the above-mentioned benefits, may also show some side effects in some cases. These side effects are particularly pronounced when high doses (e.g., 6-12 grams per day) are used in the treatment of some diseases. The main side effects include bad breath, "heartburn" (heartburn), dyspepsia, constipation, bloating and diarrhea.
L-arginine, L-glutamine, collagen, carbohydrate, vitamin C, vitamin E, ionic calcium, ionic zinc and beta methyl-beta-hydroxy butyric acid (calcium) salt can better relieve the side effects and synergistically enhance the antitumor activity of Omega-3 fatty acid and the nucleotide.
The composition of the invention can be used for resisting tumors, including but not limited to gastric cancer, lung cancer, colon cancer, liver cancer, prostate cancer, pancreatic cancer, lung cancer, breast cancer, testicular cancer, cervical cancer and the like.
Experimental research shows that the composition disclosed by the invention is used for resisting tumors, and has the advantages of strong antitumor activity, low toxicity, small side effect and good effect.
The pharmaceutical compositions and medicaments of the present invention may be prepared by any conventional method known in the art. In addition to the active ingredients described above, the pharmaceutical compositions and medicaments of the present invention may also comprise pharmaceutically or physiologically acceptable excipients. Suitable pharmaceutically acceptable excipients include, but are not limited to, dextrin-maltose, lactose, sucrose, mannitol, starch, microcrystalline cellulose, carboxymethylcellulose, talc, and magnesium stearate.
The pharmaceutical compositions and medicaments of the present invention may be formulated into suitable dosage forms, such as tablets, powders, granules, capsules, liquids and suspensions, for use in various routes of administration. The pharmaceutical compositions and medicaments of the invention may be administered via any suitable route, preferably via the oral or parenteral route. Any known packaging and printing method can be used to make the packages of the present invention.
[ examples ] A method for producing a compound
Examples 1 to 1
Composition 1-1 formulation (1 single dose):
7G of L-arginine, 7G of L-glutamine, 2.5G of collagen, 8.2G of carbohydrate, 1.5G of beta methyl-beta-hydroxybutyrate (calcium) salt, 300mg of vitamin C, 15mg of vitamin E, 200mg of ionized calcium, 9.5mg of ionized zinc, 1G of Omega-3 fatty acid, LNA oligonucleotide (sequence: AGTCTAACAGGCATTAGACAGATAAGCTGAGCTCC, wherein G is a G-beta-D-O-LNA nucleotide analogue, C is a C-beta-D-O-LNA nucleotide analogue, A is an A-beta-D-O-LNA nucleotide analogue, and T is a T-beta-D-O-LNA nucleotide analogue) 300mg and cGAMP 200 mg.
Comparative example 1-1
Compositions 1-2 formulation (1 single dose):
7G of L-arginine, 7G of L-glutamine, 2.5G of collagen, 8.2G of carbohydrate, 1.5G of beta methyl-beta-hydroxybutyrate (calcium) salt, 300mg of vitamin C, 15mg of vitamin E, 200mg of ionized calcium, 9.5mg of ionized zinc, 1G of Omega-3 fatty acid and 300mg of LNA oligonucleotide (sequence: AGTCTAACAGGCATTAGACAGATAAGCTGAGCTCC, wherein G is a G-beta-D-O-LNA nucleotide analogue, C is a C-beta-D-O-LNA nucleotide analogue, A is an A-beta-D-O-LNA nucleotide analogue, and T is a T-beta-D-O-LNA nucleotide analogue).
Comparative examples 1 to 2
Compositions 1-3 formulations (1 single dose):
7g of L-arginine, 7g of L-glutamine, 2.5g of collagen, 8.2g of carbohydrate, 1.5 g of beta methyl-beta-hydroxy butyric acid (calcium) salt, 300mg of vitamin C, 15mg of vitamin E, 200mg of ionized calcium, 9.5mg of ionized zinc, 1g of Omega-3 fatty acid and 200mg of cGAMP.
Comparative examples 1 to 3
Compositions 1-4 formulations (1 single dose):
7G of L-arginine, 7G of L-glutamine, 2.5G of collagen, 8.2G of carbohydrate, 1.5G of beta methyl-beta-hydroxybutyrate (calcium) salt, 300mg of vitamin C, 15mg of vitamin E, 200mg of ionized calcium, 9.5mg of ionized zinc, 300mg of LNA oligonucleotide (sequence: AGTCTAACAGGCATTAGACAGATAAGCTGAGCTCC, wherein G is G-beta-D-O-LNA nucleotide analogue, C is C-beta-D-O-LNA nucleotide analogue, A is A-beta-D-O-LNA nucleotide analogue, and T is T-beta-D-O-LNA nucleotide analogue) and 200mg of cGAMP.
Comparative examples 1 to 4
Compositions 1-5 formulations (1 single dose):
omega-3 fatty acid 1G, LNA oligonucleotide (SEQ ID: AGTCTAACAGGCATTAGACAGATAAGCTGAGCTCC, wherein G is a G- β -D-O-LNA nucleotide analogue, C is a C- β -D-O-LNA nucleotide analogue, A is an A- β -D-O-LNA nucleotide analogue, and T is a T- β -D-O-LNA nucleotide analogue) 300mg, and cGAMP 200 mg.
Example 2-1
Composition 2-1 formulation (1 single dose):
20G of L-arginine, 2G of L-glutamine, 5G of collagen, 0.2G of carbohydrate, 5G of beta methyl-beta-hydroxybutyrate (calcium) salt, 500mg of vitamin C, 100mg of vitamin E, 500mg of ionized calcium, 90mg of ionized zinc, 10G of Omega-3 fatty acid, 1G of LNA oligonucleotide (sequence: AGTCTAACAGGCATTAGACAGAGAAGCTGAGCTCC, wherein G is G-beta-D-O-LNA nucleotide analogue, C is C-beta-D-O-LNA nucleotide analogue, A is A-beta-D-O-LNA nucleotide analogue, and T is T-beta-D-O-LNA nucleotide analogue) and 1G of cGA.
Comparative example 2-1
Composition 2-2 formulation (1 single dose):
20G of L-arginine, 2G of L-glutamine, 5G of collagen, 0.2G of carbohydrate, 5G of beta methyl-beta-hydroxybutyrate (calcium) salt, 500mg of vitamin C, 100mg of vitamin E, 500mg of ionized calcium, 90mg of ionized zinc, 10G of Omega-3 fatty acid and 1G of LNA oligonucleotide (sequence: AGTCTAACAGGCATTAGACAGAGAAGCTGAGCTCC, wherein G is G-beta-D-O-LNA nucleotide analogue, C is C-beta-D-O-LNA nucleotide analogue, A is A-beta-D-O-LNA nucleotide analogue, and T is T-beta-D-O-LNA nucleotide analogue).
Comparative example 2-2
Compositions 2-3 formulation (1 single dose):
20g of L-arginine, 2g of L-glutamine, 5g of collagen, 0.2g of carbohydrate, 5g of beta methyl-beta-hydroxy butyric acid (calcium) salt, 500mg of vitamin C, 100mg of vitamin E, 500mg of ionic calcium, 90mg of ionic zinc, 10g of Omega-3 fatty acid and 1g of cGAMP.
Comparative examples 2 to 3
Compositions 2-4 formulation (1 single dose):
20G of L-arginine, 2G of L-glutamine, 5G of collagen, 0.2G of carbohydrate, 5G of beta methyl-beta-hydroxybutyrate (calcium) salt, 500mg of vitamin C, 100mg of vitamin E, 500mg of ionized calcium, 90mg of ionized zinc, 1G of LNA oligonucleotide (sequence: AGTCTAACAGGCATTAGACAGAGAAGCTGAGCTCC, wherein G is G-beta-D-O-LNA nucleotide analogue, C is C-beta-D-O-LNA nucleotide analogue, A is A-beta-D-O-LNA nucleotide analogue, and T is T-beta-D-O-LNA nucleotide analogue) and 1G of cGAMP.
Example 3-1
Composition 3-1 formulation (total of 20 single doses):
1G of L-arginine, 20G of L-glutamine, 0.5G of collagen, 22G of carbohydrate, 0.5G of beta methyl-beta-hydroxybutyrate (calcium) salt, 50mg of vitamin C, 10mg of vitamin E, 50mg of ionized calcium, 8mg of ionized zinc, 30G of Omega-3 fatty acid, 50mg of LNA oligonucleotide (sequence: AGTATCACAGGCATTAGACAGATAAGCTGAGCTAC, wherein G is G-beta-D-O-LNA nucleotide analogue, C is C-beta-D-O-LNA nucleotide analogue, A is A-beta-D-O-LNA nucleotide analogue, T is T-beta-D-O-LNA nucleotide analogue) and 50mg of cGAMP.
Comparative example 3-1
Composition 3-2 formulation (1 single dose):
1G of L-arginine, 20G of L-glutamine, 0.5G of collagen, 22G of carbohydrate, 0.5G of beta methyl-beta-hydroxybutyrate (calcium) salt, 50mg of vitamin C, 10mg of vitamin E, 50mg of ionized calcium, 8mg of ionized zinc, 30G of Omega-3 fatty acid and 50mg of LNA oligonucleotide (SEQ ID NO: AGTATCACAGGCATTAGACAGATAAGCTGAGCTAC, wherein G is a G-beta-D-O-LNA nucleotide analogue, C is a C-beta-D-O-LNA nucleotide analogue, A is an A-beta-D-O-LNA nucleotide analogue, and T is a T-beta-D-O-LNA nucleotide analogue).
Comparative example 3-2
1g of L-arginine, 20g of L-glutamine, 0.5g of collagen, 22g of carbohydrate, 0.5g of beta methyl-beta-hydroxybutyrate (calcium) salt, 50mg of vitamin C, 10mg of vitamin E, 50mg of ionic calcium, 8mg of ionic zinc, 30g of Omega-3 fatty acid and 50mg of cGAMP.
Compositions 3-3 formulation (1 single dose):
comparative examples 3 to 3
Compositions 3-4 formulation (1 single dose):
1G of L-arginine, 20G of L-glutamine, 0.5G of collagen, 22G of carbohydrate, 0.5G of beta methyl-beta-hydroxybutyrate (calcium) salt, 50mg of vitamin C, 10mg of vitamin E, 50mg of ionized calcium, 8mg of ionized zinc, 50mg of LNA oligonucleotide (sequence: AGTATCACAGGCATTAGACAGATAAGCTGAGCTAC, wherein G is G-beta-D-O-LNA nucleotide analogue, C is C-beta-D-O-LNA nucleotide analogue, A is A-beta-D-O-LNA nucleotide analogue, and T is T-beta-D-O-LNA nucleotide analogue), and 50mg of AMP (cGMP).
Example 4
Composition 4-1 formulation (1 single dose):
7G of L-arginine, 7G of L-glutamine, 2.5G of collagen, 8.2G of carbohydrate, 1.5G of beta methyl-beta-hydroxybutyrate (calcium) salt, 300mg of vitamin C, 15mg of vitamin E, 200mg of ionized calcium, 9.5mg of ionized zinc, 1G of Omega-3 fatty acid, LNA oligonucleotide (sequence: AGTCTAACAGGCATTAGACAGAGAAGCTGAGCTCC, wherein G is a G-beta-D-O-LNA nucleotide analogue, C is a C-beta-D-O-LNA nucleotide analogue, A is an A-beta-D-O-LNA nucleotide analogue, and T is a T-beta-D-O-LNA nucleotide analogue) 300mg and cGAMP 200 mg.
Example 5
Composition 5-1 formulation (1 single dose):
7G of L-arginine, 7G of L-glutamine, 2.5G of collagen, 8.2G of carbohydrate, 1.5G of beta methyl-beta-hydroxybutyrate (calcium) salt, 300mg of vitamin C, 15mg of vitamin E, 200mg of ionized calcium, 9.5mg of ionized zinc, 1G of Omega-3 fatty acid, LNA oligonucleotide (sequence: AGTATCACAGGCATTAGACAGATAAGCTGAGCTAC, wherein G is a G-beta-D-O-LNA nucleotide analogue, C is a C-beta-D-O-LNA nucleotide analogue, A is an A-beta-D-O-LNA nucleotide analogue, and T is a T-beta-D-O-LNA nucleotide analogue) 300mg and cGAMP 200 mg.
Example 6
Composition 6-1 formulation (1 single dose):
7G of L-arginine, 7G of L-glutamine, 2.5G of collagen, 8.2G of carbohydrate, 1.5G of beta methyl-beta-hydroxybutyrate (calcium) salt, 300mg of vitamin C, 15mg of vitamin E, 200mg of ionized calcium, 9.5mg of ionized zinc, 1G of Omega-3 fatty acid, LNA oligonucleotide (sequence: AGTATCACAGGCATTAGACAGAGAAGCTGAGCTAC, wherein G is a G-beta-D-O-LNA nucleotide analogue, C is a C-beta-D-O-LNA nucleotide analogue, A is an A-beta-D-O-LNA nucleotide analogue, and T is a T-beta-D-O-LNA nucleotide analogue) 300mg and cGAMP 200 mg.
Test example 1
Animal experiment for detecting treatment effect of GAS5 LNA oligonucleotide
The method comprises the steps of preparing a nude mouse subcutaneous tumor forming model by tumor cells MCF-7 of a nude mouse (24-26 g), extracting 60 nude mouse models with basically consistent weights (the highest-lowest weight is less than 2g) after the model is successfully established, randomly dividing the nude mouse models into 6 groups, and keeping the same feeding conditions. The nude mouse models of each group were divided into groups on days 1, 2, 3, 4, 5, 6, and 7 by injecting drugs orally (each time, 0.1 single dose was injected and dissolved in 3-5ml of water for injection), experiment group 1 injected the example (X) sample, experiment group 2 injected the control (X) -1 sample (or example 4 sample), experiment group 3 injected the control (X) -2 sample (or example 5 sample), experiment group 4 injected the control (X) -3 sample (or example 6 sample), experiment group 5 injected the control (X) -4 sample, and control injected water, and the number of water for injection was the same in the above experiments. The animals were sacrificed 2 weeks after the last injection, tumor tissues were taken out, tumor weights and volumes were measured, and the weight reduction rate and volume reduction rate of each experimental group of tumor tissues were calculated, the weight reduction rate being (total tumor tissue weight of control group-total tumor tissue weight of experimental group) × 100%/total tumor tissue weight of control group, and the volume reduction rate being (total tumor tissue volume of control group-total tumor tissue volume of experimental group) × 100%/total tumor tissue volume of control group. The results are shown in Table 1.
Tables 1 to 1: the weight reduction rate and the volume reduction rate of the tumor tissue of the nude mouse model of each experimental group
Tumor tissue weight reduction ratio (%) Tumor tissue weight reduction ratio (%)
Examples 1 to 1 80.2 81.7
Comparative example 1-1 40.8 41.6
Comparative examples 1 to 2 45.3 44.8
Comparative examples 1 to 3 53.8 54.6
Comparative examples 1 to 4 34.7 31.9
Tables 1 to 2: the weight reduction rate and the volume reduction rate of the tumor tissue of the nude mouse model of each experimental group
Tumor tissue weight reduction ratio (%) Tumor tissue weight reduction ratio (%)
Example 2-1 93.3 92.8
Comparative example 2-1 47.3 48.8
Comparative example 2-2 48.7 49.6
Comparative examples 2 to 3 63.6 64.5
Comparative examples 2 to 4 39.4 38.8
Tables 1 to 3: the weight reduction rate and the volume reduction rate of the tumor tissue of the nude mouse model of each experimental group
Tumor tissue weight reduction ratio (%) Tumor tissue weight reduction ratio (%)
Example 3-1 68.9 69.5
Comparative example 3-1 32.5 33.2
Comparative example 3-2 35.3 34.8
Comparative examples 3 to 3 47.4 46.8
Comparative examples 3 to 4 28.5 29.2
Tables 1 to 4: the weight reduction rate and the volume reduction rate of the tumor tissue of the nude mouse model of each experimental group
Tumor tissue weight reduction ratio (%) Tumor tissue weight reduction ratio (%)
Example 1 80.5 81.2
Example 2 61.2 61.8
Example 3 52.2 51.8
Example 4 56.2 55.6
Test example 2
In this oral dosing test, 200 volunteer adult subjects with tumors (330 males and 270 females between 28 and 53 years of age) were tested. The groups were randomly divided into 2 groups. The groups take the medicines orally on days 1, 2, 3, 4, 5, 6 and 7 after grouping (1 single dose is given each time, dissolved by 50-100ml of water for injection, and the volume of water for injection is the same in the experiment), experiment group 1 takes the sample of the example (X) orally, and experiment group 2 takes the sample of the control example (X) -4 orally. Side effects (including halitosis, "heartburn" (heartburn), dyspepsia, constipation, bloating, diarrhea, etc.) were observed and counted 1 hour after the last oral administration. The results are shown in Table 2.
Table 2-1: incidence of side effects in each experimental group
Diarrhea (diarrhea) Stomach distention Constipation Dyspepsia Others The total incidence rate%
Examples 1 to 1 0 0 0 1 1 2
Comparative examples 1 to 4 1 2 1 3 3 10
Tables 2 to 2: incidence of side effects in each experimental group
Diarrhea (diarrhea) Stomach distention Constipation Dyspepsia Others The total incidence rate%
Example 2-1 2 1 1 1 3 8
Comparative examples 2 to 4 5 6 4 3 8 26
Tables 2 to 3: incidence of side effects in each experimental group
Diarrhea (diarrhea) Stomach distention Constipation Dyspepsia Others The total incidence rate%
Example 3-1 4 2 3 2 5 16
Comparative examples 3 to 4 8 6 9 7 16 46

Claims (10)

1. A highly safe antitumor pharmaceutical composition comprising L-arginine, L-glutamine, collagen, a carbohydrate, vitamin C, vitamin E, ionic calcium, ionic zinc, beta methyl-beta-hydroxybutyrate, Omega-3 fatty acid, and a nucleotide selected from the group consisting of an LNA oligonucleotide and cGAMP (cyclic-GMP-AMP), wherein the LNA oligonucleotide is selected from the group consisting of one of the following sequences:
a)AGTCTAACAGGCATTAGACAGATAAGCTGAGCTCC；
b)AGTCTAACAGGCATTAGACAGAGAAGCTGAGCTCC；
c)AGTATCACAGGCATTAGACAGATAAGCTGAGCTAC；
d)AGTATCACAGGCATTAGACAGAGAAGCTGAGCTAC，
wherein G is G-beta-D-oxy-LNA nucleotide analogue, C is C-beta-D-oxy-LNA nucleotide analogue, A is A-beta-D-oxy-LNA nucleotide analogue, and T is T-beta-D-oxy-LNA nucleotide analogue.
2. The pharmaceutical composition according to claim 1, wherein the ratio of L-arginine, L-glutamine, collagen, carbohydrate, beta-methyl-beta-hydroxybutyrate, Omega-3 fatty acid is 1:0.5 to 1.5:0.1 to 0.8:0.5 to 2:0.1 to 0.8:0.5 to 1.5:0.5 to 5 (weight ratio), or the total weight of L-arginine, L-glutamine, collagen, carbohydrate, beta-methyl-beta-hydroxybutyrate, Omega-3 fatty acid is 10 to 95% (weight ratio) of the total weight of the composition, or the individual amounts of L-arginine, L-glutamine, collagen, carbohydrate, beta-methyl-beta-hydroxybutyrate, Omega-3 fatty acid administered once are 3 to 15g of L-arginine, L-glutamine, carbohydrate, beta-methyl-beta-hydroxybutyrate, Omega-3 fatty acid administered once, 3-15g of L-glutamine, 1-5g of collagen, 3-20g of carbohydrate, 0.5-5 g of beta methyl-beta-hydroxybutyrate and 0.1-5g of Omega-3 fatty acid.
3. The pharmaceutical composition according to claim 1, wherein the ratio of vitamin C, vitamin E, ionized calcium and ionized zinc is 1: 0.01-0.2: 0.5-2: 0.01-0.2 (weight ratio), or the total weight of vitamin C, vitamin E, ionized calcium and ionized zinc is 0.05-10% (weight ratio) of the total weight of the whole composition, or the individual amounts of vitamin C, vitamin E, ionized calcium and ionized zinc administered once are respectively 50-1000mg of vitamin C, 5-60mg of vitamin E and 3-30mg of ionized calcium 50-500mg of ionized zinc.
4. The pharmaceutical composition according to claim 1, wherein the ratio of the LNA oligonucleotide to the cGAMP is 1: 0.01-10 (by weight), or the total weight of the LNA oligonucleotide and the cGAMP is 0.1-30 (by weight) of the total weight of the composition, or the amounts of the LNA oligonucleotide and the cGAMP to be administered at a single time are 5-1000mg, respectively.
5. The pharmaceutical composition according to claim 1, wherein the LNA oligonucleotide is used in the form of a plurality of pharmaceutically acceptable salts.
6. A pharmaceutical composition according to claim 5, wherein said salts comprise salts which can be formed with organic amino acids, with base addition salts and with metal cations, with cations formed from ammonia, N-dibenzylethylenediamine, D-glucamine, tetraethylammonium or ethylenediamine; or a combination thereof.
7. The pharmaceutical composition of claim 1, wherein the LNA oligonucleotide is selected from AGTCTAACAGGCATTAGACAGATAAGCTGAGCTCC, wherein G is a G- β -D-oxy-LNA nucleotide analog, C is a C- β -D-oxy-LNA nucleotide analog, a is an a- β -D-oxy-LNA nucleotide analog, and T is a T- β -D-oxy-LNA nucleotide analog.
8. The pharmaceutical composition according to claim 1, wherein the tumor comprises gastric cancer, lung cancer, colon cancer, liver cancer, prostate cancer, pancreatic cancer, lung cancer, breast cancer, testicular cancer, and cervical cancer.
9. Use of L-arginine, L-glutamine, collagen, carbohydrate, vitamin C, vitamin E, ionic calcium, ionic zinc, beta methyl-beta-hydroxybutyrate, Omega-3 fatty acid and a nucleotide in the manufacture of a medicament for use in the treatment of a tumour, wherein the medicament comprises L-arginine, L-glutamine, collagen, carbohydrate, vitamin C, vitamin E, ionic calcium, ionic zinc, beta methyl-beta-hydroxybutyrate, Omega-3 fatty acid and a nucleotide selected from the group consisting of an LNA oligonucleotide and cGAMP (cyclo-GMP-AMP), the LNA oligonucleotide being selected from the group consisting of one of the following sequences:
a)AGTCTAACAGGCATTAGACAGATAAGCTGAGCTCC；
b)AGTCTAACAGGCATTAGACAGAGAAGCTGAGCTCC；
c)AGTATCACAGGCATTAGACAGATAAGCTGAGCTAC；
d)AGTATCACAGGCATTAGACAGAGAAGCTGAGCTAC，
wherein G is G-beta-D-oxy-LNA nucleotide analogue, C is C-beta-D-oxy-LNA nucleotide analogue, A is A-beta-D-oxy-LNA nucleotide analogue, and T is T-beta-D-oxy-LNA nucleotide analogue.
10. A package comprising a pharmaceutical composition according to claims 1 to 8 and a label and/or package insert instructing administration of the composition to an individual to provide the composition.
CN201910644468.7A 2019-07-17 2019-07-17 Composition for resisting tumor Pending CN111714616A (en)

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