WO2020063262A1 - Application de la 3'-désoxyinosine dans la préparation d'un médicament, d'un aliment ou d'un produit concernant la santé destinés à de multiples maladies - Google Patents
Application de la 3'-désoxyinosine dans la préparation d'un médicament, d'un aliment ou d'un produit concernant la santé destinés à de multiples maladies Download PDFInfo
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- deoxyinosine
- preparation
- drug
- application
- food
- Prior art date
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Classifications
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-
- 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.
Abstract
La présente invention concerne le domaine du médicament et plus particulièrement une application de la 3'-désoxyinosine dans la préparation d'aliments, de médicaments ou de produits concernant la santé pour la prévention ou le traitement de l'obésité induite par le régime alimentaire ou de l'hyperlipidémie, une application de la 3'-désoxyinosine dans la préparation d'aliments, de médicaments ou de produits concernant la santé pour la prévention de l'hypertension ou de l'artériosclérose, ainsi qu'une application de la 3'-désoxyinosine dans la préparation de produits de soin de la peau. Des études de la présente invention ont montré que la 3'-désoxyinosine jouait un rôle important dans le traitement de l'hyperlipidémie et dans la perte de poids de patients atteints d'obésité induite par le régime alimentaire, résolvant le préjudice technique existant. De plus, la 3'-désoxyinosine présente un effet plus large sur la prévention ou le traitement de l'hyperlipidémie par rapport aux médicaments existants. Parallèlement, la 3'-désoxyinosine est capable d'empêcher efficacement le développement de l'hypertension et de l'artériosclérose par diminution de la concentration sérique en lipides et en lipoprotéines de haute densité (HDL).
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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EP0738475A1 (fr) * | 1995-04-20 | 1996-10-23 | The Hokuren Federation Of Agricultural Cooperatives | Inhibiteur d'alpha-glucosidase, composition comprenant principalement du sucre et de l'inhibiteur ainsi que l'édulcorant, les aliments et les fourrages le contenant |
WO2000062736A2 (fr) * | 1999-04-06 | 2000-10-26 | East Carolina University | Oligonucleotide antisens a faible teneur en adenosine, compositions, kit et procede pour le traitement d'affections des voies aeriennes associees a la bronchoconstriction, a l'inflammation pulmonaire, aux allergies et a la depletion de surfactant |
CN109260217A (zh) * | 2018-09-30 | 2019-01-25 | 深圳松乐生物科技有限公司 | 3`-脱氧次黄嘌呤核苷在制备用于多种疾病药品、食品或保健品中的应用 |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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EP0738475A1 (fr) * | 1995-04-20 | 1996-10-23 | The Hokuren Federation Of Agricultural Cooperatives | Inhibiteur d'alpha-glucosidase, composition comprenant principalement du sucre et de l'inhibiteur ainsi que l'édulcorant, les aliments et les fourrages le contenant |
WO2000062736A2 (fr) * | 1999-04-06 | 2000-10-26 | East Carolina University | Oligonucleotide antisens a faible teneur en adenosine, compositions, kit et procede pour le traitement d'affections des voies aeriennes associees a la bronchoconstriction, a l'inflammation pulmonaire, aux allergies et a la depletion de surfactant |
CN109260217A (zh) * | 2018-09-30 | 2019-01-25 | 深圳松乐生物科技有限公司 | 3`-脱氧次黄嘌呤核苷在制备用于多种疾病药品、食品或保健品中的应用 |
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