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WO2020063262A1 - Application of 3'-deoxyinosine in preparation of drug, food or health product for multiple disease - Google Patents

Application of 3'-deoxyinosine in preparation of drug, food or health product for multiple disease Download PDF

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Publication number
WO2020063262A1
WO2020063262A1 PCT/CN2019/103929 CN2019103929W WO2020063262A1 WO 2020063262 A1 WO2020063262 A1 WO 2020063262A1 CN 2019103929 W CN2019103929 W CN 2019103929W WO 2020063262 A1 WO2020063262 A1 WO 2020063262A1
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Prior art keywords
deoxyinosine
preparation
drug
application
food
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Ceased
Application number
PCT/CN2019/103929
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French (fr)
Inventor
Xudong TANG
Rui Liu
Jianyi XU
Hongjuan WANG
Jingzhao ZHANG
Yanli Zhou
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenzhen Sunny Bio TechnologyCo Ltd
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Shenzhen Sunny Bio TechnologyCo Ltd
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Publication of WO2020063262A1 publication Critical patent/WO2020063262A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/13—Nucleic acids or derivatives thereof
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A61K31/708—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/60—Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/60—Sugars; Derivatives thereof
    • A61K8/606—Nucleosides; Nucleotides; Nucleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/18—Antioxidants, e.g. antiradicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/005—Antimicrobial preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/26—Preparation of nitrogen-containing carbohydrates
    • C12P19/28—N-glycosides
    • C12P19/38—Nucleosides
    • C12P19/40—Nucleosides having a condensed ring system containing a six-membered ring having two nitrogen atoms in the same ring, e.g. purine nucleosides
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention relates to the technical field of drug, and in particular to an application of 3'-deoxyinosine in the preparation of food, drug or health products for the prevention or treatment of hyperlipidemia or diet-induced obesity, to an application of 3'-deoxyinosine in the preparation of food, drug or health products for the prevention of hypertension or arteriosclerosis, and to an application of 3'-deoxyinosine in the preparation of skin care products.
  • Hyperlipidemia is one of the leading causes of cardio-cerebrovascular diseases, and there are up to 116 million patients with hyperlipidemia in China. Hyperlipidemic damage to human body is latent, gradual, progressive, and systemic. Its direct damage is to accelerate systemic atherosclerosis and hence results in numerous diseases. Also, proportions of hyperlipidemia-induced stroke, coronary heart disease (CHD) , myocardial infarction (MI) , and sudden cardiac death (SCD) have been increasing year by year.
  • CHD coronary heart disease
  • MI myocardial infarction
  • SCD sudden cardiac death
  • LSAs lipid-lowering agents
  • Hyperlipidemia has a plurality of pathogenic factors and complicated pathogenesis and relates to abnormal pathologies of multiple systems.
  • hyperlipidemia will cause disturbance of glucose metabolism and thus blood glucose elevation, resulting in numerous diseases, such as diabetes mellitus, chronic pancreatic damage and the like. Therefore, a better therapeutic drug and/or therapeutic regimen for hyperlipidemia is an actual need.
  • the present invention provides an application of 3'-deoxyinosine in the preparation of food, drug or health products for the prevention or treatment of hyperlipidemia.
  • An objective of the present invention is to further provide an application of 3'-deoxyinosine in other aspects.
  • the present invention provides the following technical solutions.
  • the present invention provides an application of 3'-deoxyinosine in the preparation of food, drug or health products for the prevention or treatment of hyperlipidemia.
  • the present invention further provides an application of 3'-deoxyinosine in the preparation of food, drug or health products for the prevention or treatment of diet-induced obesity.
  • the present invention further provides an application of 3'-deoxyinosine in the preparation of food, drug or health products for the prevention of hypertension.
  • the present invention further provides an application of 3'-deoxyinosine in the preparation of food, drug or health products for the prevention of arteriosclerosis.
  • the present invention further provides an application of 3'-deoxyinosine in the preparation of skin care products.
  • the preparation method of the 3'-deoxyinosine includes the following steps:
  • the mass ratio of the 3'-deoxyadenosine to the adenosine deaminase is (800-1200) : 1.
  • the step of the concentrating and then recrystallizing includes:
  • the heating temperature for dissolving the crystals is 35-40°C.
  • the mass fraction of the 3'-deoxyinosine is 0.01%-99.99%in the food, drug, and health products.
  • the food product exists in form of pastries, beverages, reconstitutable powders, and puffed foods.
  • the pharmaceutical dosage form includes granules, tablets, pulvis, capsules, oral liquids, injections, sprays, aerosols, dry powder inhalers, lotions, liniments, pastes, emulsions, patches, eye drops, nasal drops, suppositories, pills, microsphere agents, and tinctures.
  • the pharmaceutical dosage form includes sustained-release, controlled-release or targeting preparation.
  • the health product exists in form of granules, tablets, pulvis, capsules, oral liquids, injections, sprays, aerosols, dry powder inhalers, lotions, liniments, pastes, emulsions, patches, eye drops, nasal drops, suppositories, pills, microsphere agents, and tinctures.
  • the skin care product exists in form of essences, lotions, creams, facial masks, toners, and gels.
  • 3'-deoxyinosine functions as a significant blood fat regulator; results of 3'-deoxyinosine in the treatment of a rat model of combined hyperlipidemia have concluded that 3'-deoxyinosine can effectively lower levels of total cholesterol (TC) , triglyceride (TG) , and low density lipoprotein (LDL) cholesterol and further result in a significant rise in high density lipoprotein (HDL) cholesterol level in model rats. That is to say, 3'-deoxyinosine has a significant preventive or therapeutic effect on hyperlipidemia.
  • TC total cholesterol
  • TG triglyceride
  • LDL low density lipoprotein
  • 3'-deoxyinosine lowers levels of TC and TG in model rats of combined hyperlipidemia, compared with conventional antihyperlipidemic agents, fenofibrate and simvastatin, and that compared with the preceding two conventional agents, 3'-deoxyinosine further plays a more significant role in lowering the serum LDL level in model rats and has a serum LDL level rising effect which fenofibrate and simvastatin do not have.
  • 3'-deoxyinosine provided by the present invention has more superior pharmacological activity to the existing drugs in the preparation of food, drug or health products for the prevention or treatment of hyperlipidemia.
  • 3'-Deoxyadenosine also known as cordycepin
  • Cordycepin is a nucleic acid derivative of nitrogenous glycoside.
  • Cordycepin as one of the active nucleosides in Cordyceps, has significant pharmacological effects.
  • Current studies (Chinese Patent CN107737136A) have showed that 3'-deoxyadenosine/berberine hydrochloride composite can regulate blood lipid and body weight effectively.
  • the prior art further discloses an alternative 3'-deoxyadenosine analogue/berberine hydrochloride composite.
  • 3'-Deoxyinosine can be prepared by 3'-deoxyadenosine.
  • ADA adenosine deaminase
  • the present invention breaks down the technical prejudice in the art, investigates roles of 3'-deoxyinosine in such diseases as hyperlipidemia, diet-induced obesity, hypertension and arteriosclerosis, and has found that 3'-deoxyinosine has significant preventive or therapeutic effects on hyperlipidemia and diet-induced obesity. Meanwhile, it has good preventive effects on hypertension and arteriosclerosis. Therefore, 3'-deoxyinosine is used to prepare drugs for these diseases.
  • 3'-deoxyinosine in the treatment of model rats with diet-induced obesity can significantly lose weights of model rats with diet-induced obesity, significantly different from model rats, i.e., 3'-deoxyinosine has a good therapeutic effect on diet-induced obesity and loses weight effectively.
  • the present invention further provides an application of 3'-deoxyinosine in the preparation of skin care products, where the skin care products containing 3'-deoxyinosine play a role in improving metabolism, anti-aging, losing weight, boosting immunity, and antisepsis.
  • An embodiment of the present invention shows that 3'-deoxyinosine can be detected in a Franz cell 5 min after transdermal delivery across pig ear skin, suggesting that the present invention 3'-deoxyinosine, when used to prepare skin care products, can enter the body through percutaneous absorption, playing a role in improving metabolism, anti-aging, losing weight, boosting immunity, and antisepsis.
  • the present invention provides a biosynthesis method for preparing high purity 3'-deoxyinosine, which can obtain 3'-deoxyinosine with a purity of greater than 98%.
  • the present invention provides an application of 3'-deoxyinosine in the preparation of food, drug or health products for the prevention or treatment of hyperlipidemia.
  • 3'-deoxyinosine lowers levels of TC and TG in model rats of combined hyperlipidemia, compared with conventional antihyperlipidemic agents, fenofibrate and simvastatin, and that compared with the preceding two conventional agents, 3'-deoxyinosine further plays a more significant role in lowering the serum LDL level in model rats and has a serum LDL level rising effect which fenofibrate and simvastatin do not have.
  • 3'-deoxyinosine provided by the present invention has more superior pharmacological activity to the existing drugs in the preparation of food, drug or health products for the prevention or treatment of hyperlipidemia.
  • 3'-deoxyinosine lowers levels of TC and TG in the rat model of combined hyperlipidemia, compared with conventional antihyperlipidemic agents, fenofibrate and simvastatin, and that compared with the preceding two conventional agents, 3'-deoxyinosine further plays a more significant role in lowering the serum LDL level in model rats and has a serum LDL level rising effect which fenofibrate and simvastatin do not have.
  • 3'-deoxyinosine provided by the present invention has more superior pharmacological activity to the existing drugs in the preparation of food, drug or health products for the prevention or treatment of hyperlipidemia.
  • the 3'-deoxyinosine serve as the only active ingredient in the food, drug or health products for the prevention or treatment of hyperlipidemia, but also can play a preventive or therapeutic effect when compounded with other active substance as a composite.
  • the hyperlipidemia includes primary hyperlipidemia and secondary hyperlipidemia.
  • the effective dose of the 3'-deoxyinosine having a preventive or therapeutic effect on hyperlipidemia is preferably 6-100 mg/kg/day, and more preferably 50 mg/kg/day.
  • the present invention further provides an application of 3'-deoxyinosine in the preparation of food, drug or health products for the prevention or treatment of diet-induced obesity.
  • 3'-deoxyinosine in the treatment of model rats with diet-induced obesity can significantly lose weights of model rats with diet-induced obesity, significantly different from model rats, i.e., 3'-deoxyinosine has a good therapeutic effect on diet-induced obesity and loses weight effectively.
  • the 3'-deoxyinosine serve as the only active ingredient in the food, drug or health products for the prevention or treatment of diet-induced obesity, but also can play a preventive or therapeutic effect when compounded with other active substance as a composite.
  • the effective dose of the 3'-deoxyinosine having a preventive or therapeutic effect on diet-induced obesity is preferably 6-100 mg/kg/day, and more preferably 50 mg/kg/day.
  • the present invention further provides an application of 3'-deoxyinosine in the preparation of food, drug or health products for the prevention of hypertension.
  • Peripheral vascular resistance, arterial wall elasticity, and blood viscosity are important factors for the development of hypertension, which are closely related to hyperlipidemia.
  • Use of 3'-deoxyinosine can effectively lower serum levels of TC, TG and LDL and improve HDL level; it can effectively control changes in peripheral vascular resistance, arterial wall elasticity, and blood viscosity, thereby achieving the preventive effect on hypertension.
  • the 3'-deoxyinosine serve as the only active ingredient in the food, drug or health products for the prevention of hypertension, but also can play a preventive or therapeutic effect when compounded with other active substance as a composite.
  • the effective dose of the 3'-deoxyinosine having a preventive effect on hypertension is preferably 6-100 mg/kg/day, and more preferably 50 mg/kg/day.
  • the present invention further provides an application of 3'-deoxyinosine in the preparation of food, drug or health products for the prevention of arteriosclerosis.
  • Hyperlipidemia results in disorder of lipid metabolism, elevated blood viscosity, deposition of lipids in tunica intima, and gradual formation of small plaques, known as atherosclerosis.
  • use of 3'-deoxyinosine can play a role in effectively lowering serum levels of TC, TG and LDL and improving HDL level to effectively relieve deposition of lipids and prevent plaque formation, realizing the purpose of preventing arteriosclerosis.
  • the 3'-deoxyinosine serve as the only active ingredient in the food, drug or health products for the prevention of arteriosclerosis, but also can play a preventive or therapeutic effect when compounded with other active substance as a composite.
  • the effective dose of the 3'-deoxyinosine having a preventive effect on arteriosclerosis is preferably 6-100 mg/kg/day, and more preferably 50 mg/kg/day.
  • the present invention further provides an application of 3'-deoxyinosine in the preparation of skin care products.
  • the effective dose of the 3'-deoxyinosine as an active ingredient in skin care products is 0.5-2%, and more preferably 0.8-1.2%.
  • the 3'-deoxyinosine can be prepared by extraction or in vitro synthesis.
  • the 3'-deoxyinosine is prepared by in vitro biosynthesis in the present invention.
  • the biosynthesis of the 3'-deoxyinosine preferably includes the following steps:
  • enzymatic reaction which features short time and high efficiency, is performed in vitro at a simulated in vivo temperature, and the 3'-deoxyinosine can be synthesized on a large scale.
  • dissolving 3'-deoxyadenosine in water is to make it fully expose to and react with adenosine deaminase in a liquid solution, where the water serves as a solvent merely.
  • the dissolution is carried out at a 3'-deoxyadenosine: water mass-to-volume ratio of preferably 30-50 g: 1 L, and more preferably 40 g: 1 L.
  • the solution after dissolving 3'-deoxyadenosine is mixed with adenosine deaminase.
  • the mass ratio of the 3'-deoxyadenosine to the adenosine deaminase is preferably 800-1200: 1, and more preferably 1000: 1.
  • the adenosine deaminase is preferably raw material with an enzyme activity of 150-200 U/mg; the 3'-deoxyadenosine is preferably raw material with a purity of greater than 98% (HPLC grade) .
  • sources of the 3'-deoxyadenosine and the adenosine deaminase are not particularly limited, and commercially available products that meet the preceding condition can be used.
  • a mixture of 3'-deoxyadenosine and adenosine deaminase reacts for 0.8-2 h at 35-40°C, and the 3'-deoxyadenosine is catalytically deaminized by the adenosine deaminase and transformed into 3'-deoxyinosine.
  • the reaction temperature is preferably 37-38°C; preferably, in the present invention, the reaction time is preferably 1-1.2 h. In the present invention, the reaction temperature is preferably maintained by means of water bath heating.
  • reaction solution is concentrated until a small amount of crystals are precipitated, which are heated to dissolve; after the precipitated crystals are redissolved, they are recrystallized at 3-6°C; after 10-16 h, the recrystallized crystals are collected, i.e., 3'-deoxyinosine is obtained.
  • the way of concentration is not particularly limited, which is preferably vacuum concentration.
  • the pressure of the vacuum concentration is 0.05-0.09 MPa, and more preferably 0.07 MPa; the temperature of the vacuum concentration is 30-50°C, and more preferably 40°C.
  • the reheating temperature is preferably 40-50°C, and more preferably 45°C. Remove from the heat once the precipitated crystals disappear.
  • the recrystallization temperature is preferably 4°C.
  • the standing time of the recrystallization is preferably 12 h, allowing 3'-deoxyinosine to separate out from the solution fully.
  • the resultant 3'-deoxyinosine is purified by means of recrystallization, thereby obtaining HPLC grade 3'-deoxyinosine with a purity of not less than 98%.
  • the food product exists in form of, including but not limited to, pastries, beverages, reconstitutable powders, and puffed foods.
  • the pharmaceutical dosage form includes, but not limited to, granules, tablets, pulvis, capsules, oral liquids, injections, sprays, aerosols, dry powder inhalers, lotions, liniments, pastes, emulsions, patches, eye drops, nasal drops, suppositories, pills, microsphere agents, and tinctures.
  • the pharmaceutical dosage form can also be sustained-release, controlled-release or targeting preparation.
  • the health product exists in form of, including but not limited to, granules, tablets, pulvis, capsules, oral liquids, injections, sprays, aerosols, dry powder inhalers, lotions, liniments, pastes, emulsions, patches, eye drops, nasal drops, suppositories, pills, microsphere agents, and tinctures.
  • the skin care product exists in form of, including but not limited to, essences, lotions, creams, facial masks, toners, and gels.
  • appropriate adjuvants and excipients are selected according to different preparation forms and requirements of food, drug, health, or skin care products.
  • the 3'-deoxyinosine content is 0.01-99.99% (mass percent) , and more preferably 0.1-45.00%in the food, drug, health, or skin care products.
  • This experiment is to verify the preventive or therapeutic effect of 3'-deoxyinosine on hyperlipidemia.
  • Rats were fed adaptively for one week and weighed. Twenty laboratory animals were randomized into two groups of 10 animals. The blank control group was given diets, and the model group was given high-fat diets. After feeding for four consecutive weeks and fasting for 12 h, rats were weighed and docked for blood collection 1 h after the last administration.
  • Forty model rats of combined hyperlipidemia were prepared according to the foregoing modeling method.
  • the prepared model animals were divided into four groups of 10 animals: a blank group, an administration group, a positive drug fenofibrate group, and a positive drug simvastatin group, respectively, where the blank group was given high-fat diets, the administration group was given high-fat diets and 50 mg/kg/day 3'-deoxyinosine, the positive drug fenofibrate group was given high-fat diets and fenofibrate, and the positive drug simvastatin group was given high-fat diets and simvastatin.
  • 3'-Deoxyinosine, fenofibrate and simvastatin could significantly lower TC level, and there was a slight difference among groups; 3'-deoxyinosine, fenofibrate and simvastatin could significantly lower TG level, and there was a slight difference among groups; 3'-deoxyinosine could significantly lower LDL level, and the other two administration groups were not significantly different from the model group; 3'-deoxyinosine could significantly elevate HDL level, and the other two administration groups were not significantly different from the model group.
  • 3'-deoxyinosine With respect to lowering hyperlipidemic parameters, TC and TG levels, 3'-deoxyinosine has comparable efficacy to positive drugs fenofibrate and simvastatin; 3'-deoxyinosine can reduce LDL level, which is superior to positive drugs fenofibrate and simvastatin; moreover, 3'-deoxyinosine can significantly elevate HDL level, whereas such effect has not been found in fenofibrate and simvastatin yet.
  • This experiment is to verify the preventive or therapeutic effect of 3'-deoxyinosine on diet-induced obesity.
  • Rats were fed adaptively for one week and weighed. Twenty laboratory animals were randomized into two groups of 10 animals. The blank control group was given diets, and the model group was given high-fat diets. After feeding for four consecutive weeks and fasting for 12 h, rats were weighed and docked for blood collection 1 h after the last administration. Blood was retained for 2 h at room temperature. After centrifugation for 30 min at 3000 r/min, serum was collected for the detection of four serum lipid parameters: TC, TG, LDL, and HDL; and, intraperitoneal white fat was removed for weighing after rats were sacrificed under anesthesia. Results showed that rat body weight, TC, TG, and LDL increased significantly and HDL decreased significantly in the model group compared with the blank group. Modeling was successful.
  • Forty model rats of diet-induced obesity were prepared according to the foregoing modeling method.
  • the prepared model animals were divided into four groups of 10 animals: a blank group, a high-dose administration group, a middle dose administration group, and a low-dose administration group, respectively, where the blank group was given high-fat diets, and the high-, middle-, and low-dose administration groups were given 85.5, 50, and 12.5 mg/kg/day 3'-deoxyinosine in addition to high-fat diets.
  • rats were weighed 1 h after the last administration. After sacrifice, intraperitoneal white fat was removed and hepatectomy was performed.
  • 3'-deoxyinosine can significantly lose weights of rats with diet-induced obesity, showing a significant difference from the blank group, where the middle-dose group exhibit most significantly.
  • Embodiment 4 3'-Deoxyinosine tablets
  • Embodiment 5 3'-Deoxyinosine facial mask
  • Non-woven fabric was immersed in a mixture of water, 5-15%glycerol, 0.2-1.0%mannitol, 0.3-0.5%sodium polyglutamate, 0.2-0.5% ⁇ -glucose, 0.02-0.12%sodium hyaluronate, 0.3-5%3'-deoxyinosine, and 0.5-1.5%yeast extract, and a 3'-deoxyinosine facial mask was prepared.
  • Embodiment 6 Edible 3'-deoxyinosine powder
  • 3'-Deoxyinosine (1-4%) was added as food raw material to corn starch, and an edible 3'-deoxyinosine powder was prepared.

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Abstract

The present invention relates to the field of drug, provides an application of 3'-deoxyinosine in the preparation of food, drug or health products for the prevention or treatment of diet-induced obesity or hyperlipidemia, provides an application of 3'-deoxyinosine in the preparation of food, drug or health products for the prevention of hypertension or arteriosclerosis, and further provides an application of 3'-deoxyinosine in the preparation of skin care products. Studies of the present invention have indicated that 3'-deoxyinosine plays a significant role in treating hyperlipidemia and reducing weights of patients with diet-induced obesity, overcoming the existing technical prejudice. Moreover, 3'-deoxyinosine has a more extensive effect on preventing or treating hyperlipidemia compared with the existing medications. Meanwhile, 3'-deoxyinosine is able to effectively prevent the development of hypertension and arteriosclerosis by reducing serum lipid content and high-density lipoprotein (HDL) content.

Description

APPLICATION OF 3’-DEOXYINOSINE IN PREPARATION OF DRUG, FOOD OR HEALTH PRODUCT FOR MULTIPLE DISEASE
The present application claims priority to Chinese Patent Application No. 201811157346.7 filed on September 30, 2018 and entitled "APPLICATION of 3'-DEOXYINOSINE IN PREPARATION OF DRUG, FOOD OR HEALTH PRODUCT FOR MULTIPLE DISEASE" , which is incorporated herein by reference in its entirety.
TECHNICAL FIELD
The present invention relates to the technical field of drug, and in particular to an application of 3'-deoxyinosine in the preparation of food, drug or health products for the prevention or treatment of hyperlipidemia or diet-induced obesity, to an application of 3'-deoxyinosine in the preparation of food, drug or health products for the prevention of hypertension or arteriosclerosis, and to an application of 3'-deoxyinosine in the preparation of skin care products.
BACKGROUND
Approximately 12 million people die of cardio-cerebrovascular diseases worldwide every year. Hyperlipidemia is one of the leading causes of cardio-cerebrovascular diseases, and there are up to 116 million patients with hyperlipidemia in China. Hyperlipidemic damage to human body is latent, gradual, progressive, and systemic. Its direct damage is to accelerate systemic atherosclerosis and hence results in numerous diseases. Also, proportions of hyperlipidemia-induced stroke, coronary heart disease (CHD) , myocardial infarction (MI) , and sudden cardiac death (SCD) have been increasing year by year. Currently, conventional lipid-lowering agents (LLAs) are predominantly to lower cholesterol and triglyceride, including reductase inhibitors, statins, fibrates, nicotinic acids and the like, but these agents will cause severe side effects, such as liver injury, palpitation, and rhabdomyolysis, during clinical medication. In China, patients with hyperlipidemia still use imported or generic drugs, apart from a few traditional Chinese medicines.
Drugs with a single action site are generally difficult to achieve satisfactory efficacy because hyperlipidemia has a plurality of pathogenic factors and complicated pathogenesis and relates to abnormal pathologies of multiple systems. In addition, hyperlipidemia will cause disturbance of glucose metabolism and thus blood glucose elevation, resulting in numerous diseases, such as diabetes mellitus, chronic pancreatic damage and the like. Therefore, a better therapeutic drug and/or therapeutic regimen for hyperlipidemia is an actual need.
SUMMARY
To solve the problem of insufficient efficacy of antihyperlipidemic agents in the prior art, the present invention provides an application of 3'-deoxyinosine in the preparation of food, drug or health products for the prevention or treatment of hyperlipidemia.
An objective of the present invention is to further provide an application of 3'-deoxyinosine in other aspects.
In order to solve the above problems, the present invention provides the following technical solutions.
The present invention provides an application of 3'-deoxyinosine in the preparation of food, drug or health products for the prevention or treatment of hyperlipidemia.
The present invention further provides an application of 3'-deoxyinosine in the preparation of food, drug or health products for the prevention or treatment of diet-induced obesity.
The present invention further provides an application of 3'-deoxyinosine in the preparation of food, drug or health products for the prevention of hypertension.
The present invention further provides an application of 3'-deoxyinosine in the preparation of food, drug or health products for the prevention of arteriosclerosis.
The present invention further provides an application of 3'-deoxyinosine in the preparation of skin care products.
Preferably, the preparation method of the 3'-deoxyinosine includes the following steps:
dissolving 3'-deoxyadenosine in water and mixing with adenosine deaminase, reacting for 0.8-2 h at 37℃, concentrating and then recrystallizing, to obtain a crystal, i.e., the 3'-deoxyinosine.
Preferably, the mass ratio of the 3'-deoxyadenosine to the adenosine deaminase is (800-1200) : 1.
Preferably, the step of the concentrating and then recrystallizing includes:
concentrating a reacted solution until crystals are precipitated, reheating the crystals to dissolve, standing for 10-16 h at 3-6℃ for recrystallization, and separating the crystals, to obtain the 3'-deoxyinosine.
Preferably, the heating temperature for dissolving the crystals is 35-40℃.
Preferably, the mass fraction of the 3'-deoxyinosine is 0.01%-99.99%in the food, drug, and health products.
Preferably, the food product exists in form of pastries, beverages, reconstitutable powders, and puffed foods.
Preferably, the pharmaceutical dosage form includes granules, tablets, pulvis, capsules, oral liquids, injections, sprays, aerosols, dry powder inhalers, lotions, liniments, pastes, emulsions, patches, eye drops, nasal drops, suppositories, pills, microsphere agents, and tinctures.
Preferably, the pharmaceutical dosage form includes sustained-release, controlled-release or targeting preparation.
Preferably, the health product exists in form of granules, tablets, pulvis, capsules, oral liquids,  injections, sprays, aerosols, dry powder inhalers, lotions, liniments, pastes, emulsions, patches, eye drops, nasal drops, suppositories, pills, microsphere agents, and tinctures.
Preferably, the skin care product exists in form of essences, lotions, creams, facial masks, toners, and gels.
Compared with the prior art, the technical solutions provided by the present invention have the following advantages:
Studies of the present invention have indicated that 3'-deoxyinosine functions as a significant blood fat regulator; results of 3'-deoxyinosine in the treatment of a rat model of combined hyperlipidemia have concluded that 3'-deoxyinosine can effectively lower levels of total cholesterol (TC) , triglyceride (TG) , and low density lipoprotein (LDL) cholesterol and further result in a significant rise in high density lipoprotein (HDL) cholesterol level in model rats. That is to say, 3'-deoxyinosine has a significant preventive or therapeutic effect on hyperlipidemia. Meanwhile, studies of the present invention have further indicated that there is no significant difference in pharmacological action when 3'-deoxyinosine lowers levels of TC and TG in model rats of combined hyperlipidemia, compared with conventional antihyperlipidemic agents, fenofibrate and simvastatin, and that compared with the preceding two conventional agents, 3'-deoxyinosine further plays a more significant role in lowering the serum LDL level in model rats and has a serum LDL level rising effect which fenofibrate and simvastatin do not have. Thus, 3'-deoxyinosine provided by the present invention has more superior pharmacological activity to the existing drugs in the preparation of food, drug or health products for the prevention or treatment of hyperlipidemia.
3'-Deoxyadenosine, also known as cordycepin, is a nucleic acid derivative of nitrogenous glycoside. Cordycepin, as one of the active nucleosides in Cordyceps, has significant pharmacological effects. Current studies (Chinese Patent CN107737136A) have showed that 3'-deoxyadenosine/berberine hydrochloride composite can regulate blood lipid and body weight effectively. The prior art further discloses an alternative 3'-deoxyadenosine analogue/berberine hydrochloride composite.
3'-Deoxyinosine can be prepared by 3'-deoxyadenosine. However, some studies of this field have indicated that the role of adenosine deaminase (ADA) results in transformation of 3'-deoxyadenosine into 3'-deoxyinosine, thereby becoming less effective (LUO Shanshan. Study on separation of main medicinal components form Cordyceps kushuensis Kob. and their biological activity [D] . Shandong University, 2006. ) . The present invention breaks down the technical prejudice in the art, investigates roles of 3'-deoxyinosine in such diseases as hyperlipidemia, diet-induced obesity, hypertension and arteriosclerosis, and has found that 3'-deoxyinosine has significant preventive or therapeutic effects on hyperlipidemia and  diet-induced obesity. Meanwhile, it has good preventive effects on hypertension and arteriosclerosis. Therefore, 3'-deoxyinosine is used to prepare drugs for these diseases.
Studies of the present invention have indicated that 3'-deoxyinosine in the treatment of model rats with diet-induced obesity can significantly lose weights of model rats with diet-induced obesity, significantly different from model rats, i.e., 3'-deoxyinosine has a good therapeutic effect on diet-induced obesity and loses weight effectively.
The present invention further provides an application of 3'-deoxyinosine in the preparation of skin care products, where the skin care products containing 3'-deoxyinosine play a role in improving metabolism, anti-aging, losing weight, boosting immunity, and antisepsis.
An embodiment of the present invention shows that 3'-deoxyinosine can be detected in a Franz cell 5 min after transdermal delivery across pig ear skin, suggesting that the present invention 3'-deoxyinosine, when used to prepare skin care products, can enter the body through percutaneous absorption, playing a role in improving metabolism, anti-aging, losing weight, boosting immunity, and antisepsis.
In a preferred technical solution, the present invention provides a biosynthesis method for preparing high purity 3'-deoxyinosine, which can obtain 3'-deoxyinosine with a purity of greater than 98%.
DETAILED DESCRIPTION
The present invention provides an application of 3'-deoxyinosine in the preparation of food, drug or health products for the prevention or treatment of hyperlipidemia.
In the present invention, the structural formula of 3'-deoxyinosine is shown in Formula I:
Figure PCTCN2019103929-appb-000001
Studies of the present invention have indicated that results of 3'-deoxyinosine in the treatment of a rat model of combined hyperlipidemia have concluded that 3'-deoxyinosine can effectively lower levels of total cholesterol (TC) , triglyceride (TG) , and low density lipoprotein (LDL) cholesterol and further result in a significant rise in high density lipoprotein (HDL) cholesterol level in model rats. That is to say, 3'-deoxyinosine has a significant preventive or therapeutic effect on hyperlipidemia.
Meanwhile, studies of the present invention have further indicated that there is no significant  difference in pharmacological action when 3'-deoxyinosine lowers levels of TC and TG in model rats of combined hyperlipidemia, compared with conventional antihyperlipidemic agents, fenofibrate and simvastatin, and that compared with the preceding two conventional agents, 3'-deoxyinosine further plays a more significant role in lowering the serum LDL level in model rats and has a serum LDL level rising effect which fenofibrate and simvastatin do not have. Thus, 3'-deoxyinosine provided by the present invention has more superior pharmacological activity to the existing drugs in the preparation of food, drug or health products for the prevention or treatment of hyperlipidemia.
Studies of the present invention have indicated that results of 3'-deoxyinosine in the treatment of the rat model of combined hyperlipidemia have concluded that 3'-deoxyinosine can effectively lower levels of total cholesterol (TC) , triglyceride (TG) , and low density lipoprotein (LDL) cholesterol and further result in a significant rise in high density lipoprotein (HDL) cholesterol level. That is to say, 3'-deoxyinosine has a significant preventive or therapeutic effect on hyperlipidemia.
Meanwhile, studies of the present invention have further indicated that there is no significant difference in pharmacological action when 3'-deoxyinosine lowers levels of TC and TG in the rat model of combined hyperlipidemia, compared with conventional antihyperlipidemic agents, fenofibrate and simvastatin, and that compared with the preceding two conventional agents, 3'-deoxyinosine further plays a more significant role in lowering the serum LDL level in model rats and has a serum LDL level rising effect which fenofibrate and simvastatin do not have. Thus, 3'-deoxyinosine provided by the present invention has more superior pharmacological activity to the existing drugs in the preparation of food, drug or health products for the prevention or treatment of hyperlipidemia.
In the present invention, not only can the 3'-deoxyinosine serve as the only active ingredient in the food, drug or health products for the prevention or treatment of hyperlipidemia, but also can play a preventive or therapeutic effect when compounded with other active substance as a composite.
In the present invention, the hyperlipidemia includes primary hyperlipidemia and secondary hyperlipidemia.
Preferably, in the present invention, the effective dose of the 3'-deoxyinosine having a preventive or therapeutic effect on hyperlipidemia is preferably 6-100 mg/kg/day, and more preferably 50 mg/kg/day.
The present invention further provides an application of 3'-deoxyinosine in the preparation of food, drug or health products for the prevention or treatment of diet-induced obesity.
Studies of the present invention have indicated that 3'-deoxyinosine in the treatment of model  rats with diet-induced obesity can significantly lose weights of model rats with diet-induced obesity, significantly different from model rats, i.e., 3'-deoxyinosine has a good therapeutic effect on diet-induced obesity and loses weight effectively.
In the present invention, not only can the 3'-deoxyinosine serve as the only active ingredient in the food, drug or health products for the prevention or treatment of diet-induced obesity, but also can play a preventive or therapeutic effect when compounded with other active substance as a composite.
Preferably, in the present invention, the effective dose of the 3'-deoxyinosine having a preventive or therapeutic effect on diet-induced obesity is preferably 6-100 mg/kg/day, and more preferably 50 mg/kg/day.
The present invention further provides an application of 3'-deoxyinosine in the preparation of food, drug or health products for the prevention of hypertension.
Peripheral vascular resistance, arterial wall elasticity, and blood viscosity are important factors for the development of hypertension, which are closely related to hyperlipidemia. Use of 3'-deoxyinosine can effectively lower serum levels of TC, TG and LDL and improve HDL level; it can effectively control changes in peripheral vascular resistance, arterial wall elasticity, and blood viscosity, thereby achieving the preventive effect on hypertension.
In the present invention, not only can the 3'-deoxyinosine serve as the only active ingredient in the food, drug or health products for the prevention of hypertension, but also can play a preventive or therapeutic effect when compounded with other active substance as a composite.
Preferably, in the present invention, the effective dose of the 3'-deoxyinosine having a preventive effect on hypertension is preferably 6-100 mg/kg/day, and more preferably 50 mg/kg/day.
The present invention further provides an application of 3'-deoxyinosine in the preparation of food, drug or health products for the prevention of arteriosclerosis.
Hyperlipidemia results in disorder of lipid metabolism, elevated blood viscosity, deposition of lipids in tunica intima, and gradual formation of small plaques, known as atherosclerosis. In the present invention, use of 3'-deoxyinosine can play a role in effectively lowering serum levels of TC, TG and LDL and improving HDL level to effectively relieve deposition of lipids and prevent plaque formation, realizing the purpose of preventing arteriosclerosis.
In the present invention, not only can the 3'-deoxyinosine serve as the only active ingredient in the food, drug or health products for the prevention of arteriosclerosis, but also can play a preventive or therapeutic effect when compounded with other active substance as a composite.
Preferably, in the present invention, the effective dose of the 3'-deoxyinosine having a preventive effect on arteriosclerosis is preferably 6-100 mg/kg/day, and more preferably 50  mg/kg/day.
The present invention further provides an application of 3'-deoxyinosine in the preparation of skin care products.
Studies of the present invention have indicated that the effective dose of the 3'-deoxyinosine as an active ingredient in skin care products is 0.5-2%, and more preferably 0.8-1.2%.
In the present invention, the 3'-deoxyinosine can be prepared by extraction or in vitro synthesis.
In order to obtain higher purity 3'-deoxyinosine, the 3'-deoxyinosine is prepared by in vitro biosynthesis in the present invention.
In the present invention, the biosynthesis of the 3'-deoxyinosine preferably includes the following steps:
dissolving 3'-deoxyadenosine in water and mixing with adenosine deaminase, reacting for 0.8-2 h at 37℃, concentrating and then recrystallizing, to obtain a crystal, i.e., 3'-deoxyinosine.
In the present invention, using a property that 3'-deoxyadenosine can be deaminized by adenosine deaminase, enzymatic reaction, which features short time and high efficiency, is performed in vitro at a simulated in vivo temperature, and the 3'-deoxyinosine can be synthesized on a large scale.
In the present invention, dissolving 3'-deoxyadenosine in water is to make it fully expose to and react with adenosine deaminase in a liquid solution, where the water serves as a solvent merely. In the present invention, the dissolution is carried out at a 3'-deoxyadenosine: water mass-to-volume ratio of preferably 30-50 g: 1 L, and more preferably 40 g: 1 L.
In the present invention, the solution after dissolving 3'-deoxyadenosine is mixed with adenosine deaminase. In the present invention, the mass ratio of the 3'-deoxyadenosine to the adenosine deaminase is preferably 800-1200: 1, and more preferably 1000: 1.
In the present invention, the adenosine deaminase is preferably raw material with an enzyme activity of 150-200 U/mg; the 3'-deoxyadenosine is preferably raw material with a purity of greater than 98% (HPLC grade) . In the present invention, sources of the 3'-deoxyadenosine and the adenosine deaminase are not particularly limited, and commercially available products that meet the preceding condition can be used.
In the present invention, a mixture of 3'-deoxyadenosine and adenosine deaminase reacts for 0.8-2 h at 35-40℃, and the 3'-deoxyadenosine is catalytically deaminized by the adenosine deaminase and transformed into 3'-deoxyinosine. Preferably, in the present invention, the reaction temperature is preferably 37-38℃; preferably, in the present invention, the reaction time is preferably 1-1.2 h. In the present invention, the reaction temperature is preferably maintained by means of water bath heating.
After completion of the reaction, in the present invention reaction solution is concentrated until a small amount of crystals are precipitated, which are heated to dissolve; after the precipitated crystals are redissolved, they are recrystallized at 3-6℃; after 10-16 h, the recrystallized crystals are collected, i.e., 3'-deoxyinosine is obtained.
In the present invention, the way of concentration is not particularly limited, which is preferably vacuum concentration. When the vacuum concentration is performed, the pressure of the vacuum concentration is 0.05-0.09 MPa, and more preferably 0.07 MPa; the temperature of the vacuum concentration is 30-50℃, and more preferably 40℃.
In the present invention, the reheating temperature is preferably 40-50℃, and more preferably 45℃. Remove from the heat once the precipitated crystals disappear.
In the present invention, the recrystallization temperature is preferably 4℃. In the present invention, the standing time of the recrystallization is preferably 12 h, allowing 3'-deoxyinosine to separate out from the solution fully.
In the present invention, the resultant 3'-deoxyinosine is purified by means of recrystallization, thereby obtaining HPLC grade 3'-deoxyinosine with a purity of not less than 98%.
In the present invention, the food product exists in form of, including but not limited to, pastries, beverages, reconstitutable powders, and puffed foods.
In the present invention, the pharmaceutical dosage form includes, but not limited to, granules, tablets, pulvis, capsules, oral liquids, injections, sprays, aerosols, dry powder inhalers, lotions, liniments, pastes, emulsions, patches, eye drops, nasal drops, suppositories, pills, microsphere agents, and tinctures.
In the present invention, the pharmaceutical dosage form can also be sustained-release, controlled-release or targeting preparation.
In the present invention, the health product exists in form of, including but not limited to, granules, tablets, pulvis, capsules, oral liquids, injections, sprays, aerosols, dry powder inhalers, lotions, liniments, pastes, emulsions, patches, eye drops, nasal drops, suppositories, pills, microsphere agents, and tinctures.
In the present invention, the skin care product exists in form of, including but not limited to, essences, lotions, creams, facial masks, toners, and gels.
In the present invention, appropriate adjuvants and excipients are selected according to different preparation forms and requirements of food, drug, health, or skin care products.
In the present invention, the 3'-deoxyinosine content is 0.01-99.99% (mass percent) , and more preferably 0.1-45.00%in the food, drug, health, or skin care products.
In order to further illustrate the present invention, the technical solutions provided by the  present invention are described in detail below in connection with embodiments, but these embodiments should not be understood as limiting the claimed scope of the present invention.
Embodiment 1
Synthesis of 3'-deoxyinosine:
Twenty grams of 3'-deoxyadenosine was weighed, dissolved in 500 mL of pure water, then mixed with 20.0 mg of adenosine deaminase, heated in water bath for 1 h at 37℃, and concentrated under vacuum at 0.07 MPa and 40℃ until a small amount of crystals were precipitated. The crystals were reheated to dissolve at 37℃, and stood for 12 h at 4℃ to obtain recrystals, i.e., 3'-deoxyinosine (HPLC grade≥98%) .
Embodiment 2
This experiment is to verify the preventive or therapeutic effect of 3'-deoxyinosine on hyperlipidemia.
1. Modeling
Twenty clean grade male SD rats, weighing 180-200 g, were purchased from the Laboratory Animal Center, Academy of Military Medical Sciences of the PLA, with the Laboratory Animal Use Permit number of SCXK2015-0001. Standard diets for rat (LAD0020, Trophic Animal Feed High-Tech Co., Ltd. ) and 60%high-fat diets for rat (model diet of combined hyperlipidemia, Trophic Animal Feed High-Tech Co., Ltd. ) were available.
Rats were fed adaptively for one week and weighed. Twenty laboratory animals were randomized into two groups of 10 animals. The blank control group was given diets, and the model group was given high-fat diets. After feeding for four consecutive weeks and fasting for 12 h, rats were weighed and docked for blood collection 1 h after the last administration.
Blood was retained for 2 h at room temperature. After centrifugation for 30 min at 3000 r/min, serum was collected for the detection of four serum lipid parameters: TC, TG, LDL, and HDL; and, intraperitoneal white fat was removed for weighing after rats were sacrificed under anesthesia. Results showed that rat body weight, TC, TG, and LDL increased significantly and HDL decreased significantly in the model group compared with the blank group. Modeling was successful.
2. Sample detection
Forty model rats of combined hyperlipidemia were prepared according to the foregoing modeling method. The prepared model animals were divided into four groups of 10 animals: a blank group, an administration group, a positive drug fenofibrate group, and a positive drug simvastatin group, respectively, where the blank group was given high-fat diets, the administration group was given high-fat diets and 50 mg/kg/day 3'-deoxyinosine, the positive drug fenofibrate group was given high-fat diets and fenofibrate, and the positive drug simvastatin  group was given high-fat diets and simvastatin.
After each group was fed for four consecutive weeks and fasted for 12 h, rats were weighed and docked for blood collection 1 h after the last administration. Blood was retained for 2 h at room temperature. After centrifugation for 30 min at 3000 r/min, serum was collected for the detection of four serum lipid parameters: TC, TG, LDL, and HDL.
3. Results
3'-Deoxyinosine, fenofibrate and simvastatin could significantly lower TC level, and there was a slight difference among groups; 3'-deoxyinosine, fenofibrate and simvastatin could significantly lower TG level, and there was a slight difference among groups; 3'-deoxyinosine could significantly lower LDL level, and the other two administration groups were not significantly different from the model group; 3'-deoxyinosine could significantly elevate HDL level, and the other two administration groups were not significantly different from the model group.
4. Conclusion
With respect to lowering hyperlipidemic parameters, TC and TG levels, 3'-deoxyinosine has comparable efficacy to positive drugs fenofibrate and simvastatin; 3'-deoxyinosine can reduce LDL level, which is superior to positive drugs fenofibrate and simvastatin; moreover, 3'-deoxyinosine can significantly elevate HDL level, whereas such effect has not been found in fenofibrate and simvastatin yet.
Embodiment 3
This experiment is to verify the preventive or therapeutic effect of 3'-deoxyinosine on diet-induced obesity.
1. Laboratory animals and diets
Thirty clean grade male SD rats, weighing 180-200 g, were purchased from the Laboratory Animal Center, Academy of Military Medical Sciences of the PLA, with the Laboratory Animal Use Permit number of SCXK2015-0001. Standard diets for rat (LAD0020, Trophic Animal Feed High-Tech Co., Ltd. ) and 60%high-fat diets for rat (Research diets D12492, 60%cal, Research Diets, U.S. ) were available.
2. Modeling of rats with diet-induced obesity
Rats were fed adaptively for one week and weighed. Twenty laboratory animals were randomized into two groups of 10 animals. The blank control group was given diets, and the model group was given high-fat diets. After feeding for four consecutive weeks and fasting for 12 h, rats were weighed and docked for blood collection 1 h after the last administration. Blood was retained for 2 h at room temperature. After centrifugation for 30 min at 3000 r/min, serum was collected for the detection of four serum lipid parameters: TC, TG, LDL, and HDL; and,  intraperitoneal white fat was removed for weighing after rats were sacrificed under anesthesia. Results showed that rat body weight, TC, TG, and LDL increased significantly and HDL decreased significantly in the model group compared with the blank group. Modeling was successful.
3. Sample detection
Forty model rats of diet-induced obesity were prepared according to the foregoing modeling method. The prepared model animals were divided into four groups of 10 animals: a blank group, a high-dose administration group, a middle dose administration group, and a low-dose administration group, respectively, where the blank group was given high-fat diets, and the high-, middle-, and low-dose administration groups were given 85.5, 50, and 12.5 mg/kg/day 3'-deoxyinosine in addition to high-fat diets. After feeding for 30 consecutive days and fasting for 12 h, rats were weighed 1 h after the last administration. After sacrifice, intraperitoneal white fat was removed and hepatectomy was performed.
4. Results
As illustrated in Table 1, 3'-deoxyinosine can significantly lose weights of rats with diet-induced obesity, showing a significant difference from the blank group, where the middle-dose group exhibit most significantly.
Table 1 Body weight changes in rats receiving different treatments
Figure PCTCN2019103929-appb-000002
Embodiment 4 3'-Deoxyinosine tablets
Four grams of 3'-deoxyinosine was mixed with 96 g of magnesium stearate. After wet granulation, drying and tableting, oral tablets with a strength of 4 g/tablet were obtained. Oral tablets containing 3'-deoxyinosine tablets 0.03-4 g/tablet were prepared.
Embodiment 5 3'-Deoxyinosine facial mask
Non-woven fabric was immersed in a mixture of water, 5-15%glycerol, 0.2-1.0%mannitol, 0.3-0.5%sodium polyglutamate, 0.2-0.5%β-glucose, 0.02-0.12%sodium hyaluronate, 0.3-5%3'-deoxyinosine, and 0.5-1.5%yeast extract, and a 3'-deoxyinosine facial mask was prepared.
Embodiment 6 Edible 3'-deoxyinosine powder
3'-Deoxyinosine (1-4%) was added as food raw material to corn starch, and an edible  3'-deoxyinosine powder was prepared.
The above description of the embodiment is only for helping to understand the method of the present invention and its core idea. It should be noted that, several improvements and modifications may be made by persons of ordinary skill in the art without departing from the principle of the present invention, and these improvements and modifications should also be considered within the protection scope of the present invention. Various modifications to these embodiments are readily apparent to persons skilled in the art, and the generic principles defined herein may be practiced in other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not limited to the embodiments shown herein but falls within the widest scope consistent with the principles and novel features disclosed herein.

Claims (15)

  1. An application of 3'-deoxyinosine in the preparation of food, drug or health products for the prevention or treatment of hyperlipidemia.
  2. An application of 3'-deoxyinosine in the preparation of food, drug or health products for the prevention or treatment of diet-induced obesity.
  3. An application of 3'-deoxyinosine in the preparation of food, drug or health products for the prevention of hypertension.
  4. An application of 3'-deoxyinosine in the preparation of food, drug or health products for the prevention of arteriosclerosis.
  5. An application of 3'-deoxyinosine in the preparation of skin care products.
  6. The application according to any one of claims 1 to 5, wherein the preparation method of the 3'-deoxyinosine comprises the following steps:
    dissolving 3'-deoxyadenosine in water and mixing with adenosine deaminase, reacting for 0.8-2 h at 37℃, concentrating and then recrystallizing, to obtain a crystal, i.e., the 3'-deoxyinosine.
  7. The application according to claim 6, wherein the mass ratio of the 3'-deoxyadenosine to the adenosine deaminase is (800-1200) : 1.
  8. The application according to claim 6, wherein the step of the concentrating and then recrystallizing comprises:
    concentrating the reacted solution until crystals are precipitated, reheating the crystals to dissolve, standing for 10-16 h at 3-6℃ for recrystallization, and separating the crystals, to obtain the 3'-deoxyinosine.
  9. The application according to claim 8, wherein the heating temperature for dissolving the crystals is 35-40℃.
  10. The application according to any one of claims 1 to 5, wherein the mass fraction of the 3'-deoxyinosine is 0.01%-99.99%in the food, drug, health, or skin care products.
  11. The application according to any one of claims 1 to 4, wherein the food product exists in form of pastries, beverages, reconstitutable powders, and puffed foods.
  12. The application according to any one of claims 1 to 4, wherein the pharmaceutical dosage form comprises granules, tablets, pulvis, capsules, oral liquids, injections, sprays, aerosols, dry powder inhalers, lotions, liniments, pastes, emulsions, patches, eye drops, nasal drops, suppositories, pills, microsphere agents, and tinctures.
  13. The application according to any one of claims 1 to 4, wherein the pharmaceutical dosage form comprises sustained-release, controlled-release or targeting preparation.
  14. The applications according to claims 1 to 4, wherein the health product exists in form of  granules, tablets, pulvis, capsules, oral liquids, injections, sprays, aerosols, dry powder inhalers, lotions, liniments, pastes, emulsions, patches, eye drops, nasal drops, suppositories, pills, microsphere agents, and tinctures.
  15. The application according to claim 5, wherein the skin care product exists in form of essences, lotions, creams, facial masks, toners, and gels.
PCT/CN2019/103929 2018-09-30 2019-09-02 Application of 3'-deoxyinosine in preparation of drug, food or health product for multiple disease Ceased WO2020063262A1 (en)

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Publication number Priority date Publication date Assignee Title
CN116531396A (en) * 2023-04-26 2023-08-04 昆山市中医医院 Application of 2'-deoxyinosine in the treatment of autoimmune encephalitis

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CN109260217A (en) * 2018-09-30 2019-01-25 深圳松乐生物科技有限公司 3`- deoxyinosine nucleosides is in preparation for the application in a variety of disease drugs, food or health care product

Citations (3)

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Publication number Priority date Publication date Assignee Title
EP0738475A1 (en) * 1995-04-20 1996-10-23 The Hokuren Federation Of Agricultural Cooperatives Alpha-glucosidase inhibitor, composition principally comprising sugar and containing the same, sweetener, food and feed
WO2000062736A2 (en) * 1999-04-06 2000-10-26 East Carolina University Low adenosine anti-sense oligonucleotide, compositions, kit and method for treatment of airway disorders associated with bronchoconstriction, lung inflammation, allergy(ies) and surfactant depletion
CN109260217A (en) * 2018-09-30 2019-01-25 深圳松乐生物科技有限公司 3`- deoxyinosine nucleosides is in preparation for the application in a variety of disease drugs, food or health care product

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Publication number Priority date Publication date Assignee Title
EP0738475A1 (en) * 1995-04-20 1996-10-23 The Hokuren Federation Of Agricultural Cooperatives Alpha-glucosidase inhibitor, composition principally comprising sugar and containing the same, sweetener, food and feed
WO2000062736A2 (en) * 1999-04-06 2000-10-26 East Carolina University Low adenosine anti-sense oligonucleotide, compositions, kit and method for treatment of airway disorders associated with bronchoconstriction, lung inflammation, allergy(ies) and surfactant depletion
CN109260217A (en) * 2018-09-30 2019-01-25 深圳松乐生物科技有限公司 3`- deoxyinosine nucleosides is in preparation for the application in a variety of disease drugs, food or health care product

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116531396A (en) * 2023-04-26 2023-08-04 昆山市中医医院 Application of 2'-deoxyinosine in the treatment of autoimmune encephalitis

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