CN111166760A - composition of beta-nicotinamide mononucleotide or precursor thereof, preparation method and application - Google Patents
composition of beta-nicotinamide mononucleotide or precursor thereof, preparation method and application Download PDFInfo
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- CN111166760A CN111166760A CN201911297235.0A CN201911297235A CN111166760A CN 111166760 A CN111166760 A CN 111166760A CN 201911297235 A CN201911297235 A CN 201911297235A CN 111166760 A CN111166760 A CN 111166760A
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- 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
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P17/18—Antioxidants, e.g. antiradicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
the invention relates to the field of biological medicine, and particularly discloses a β -nicotinamide mononucleotide or a precursor thereof, a preparation method and application thereof, wherein raw materials of the composition comprise, by weight, 0.001-25% of beta-nicotinamide mononucleotide or a precursor thereof, 0-20% of a transdermal absorption enhancer, 2-50% of auxiliary components and the balance of water.
Description
Technical Field
the invention belongs to the technical field of biological medicines, and particularly relates to a composition of β -Nicotinamide Mononucleotide (NMN) or a precursor β -Nicotinamide Ribose (NR) thereof, a preparation method and an application.
Background
With the increase of age, the body gradually shows the phenomenon of decline of the physiological function resistance, adaptability and the like of cells, tissues and organs. The general and skin functions of the human body gradually decrease with the increase of the body's age, resulting in aging, and the incidence of various internal and external diseases associated therewith increases, and the process of the decrease of the functions of these organs is based on the occurrence of cellular aging, i.e., cellular aging is the basis of the aging of the body.
One of the most significant changes in the body's cells as the body ages is the reduction in NAD + levels, linking the reduction in NAD + levels to various internal and external diseases associated with aging. NAD +, also known as coenzyme I, is known as nicotinamide adenine dinucleotide and is present in every cell and participates in thousands of reactions. NAD + can form NADH, a reducing agent and an electron donor, is involved in various cellular processes including oxidation and antioxidant systems, is involved in mitochondrial oxidative metabolic processes, acts as a signaling molecule to ensure cell survival and regulate energy metabolism, cell repair and circadian rhythm, and produces a regulating effect on physiological functions of various enzymes in the cell in the form of coenzymes, including deacetylase and poly-ADP-ribose polymerase (PARP). When the level of NAD + is reduced, the function of a series of processes in the cell is disturbed, so that the level of inflammation in the cell is increased, the function of mitochondria is disturbed, a plurality of enzyme functions dependent on NAD + are disturbed, the cell is metabolized abnormally, DNA is damaged, and the like, and finally the cell is aged.
β -Nicotinamide Mononucleotide (NMN) and β -Nicotinamide Riboside (NR), which are precursors of NAD +, providing such precursors of NAD + has prophylactic and therapeutic effects, alleviating age-related pathologies and disease states, as well as metabolic benefits, including promoting insulin secretion, as well as promoting insulin sensitivity, enhancing SIRTs family activity, reducing expression of inflammation-related genes, reducing oxidative stress, and improving cardiac rhythm, reducing inflammation in age-related adipose tissue, and improving systemic insulin sensitivity.
beta-nicotinamide mononucleotide has important physiological functions on human cells, can be naturally synthesized in the cells, can also be derived from various foods, including broccoli, cabbage, cucumber, green soy bean, avocado and the like, NMN is a precursor for synthesizing NAD + in a human body, and the physiological functions of the NMN are mainly embodied by improving the level of NAD +, NAD + in the cells not only serves as a coenzyme but also serves as a substrate for various signal reactions and participates in hundreds of reactions in 2013, David Sinclair issues a sentence on a Cell, a 22-month-old mouse (equivalent to 60 years old human) and a previous two-month-old mouse after improving NAD + by NMN for one week, and the research on improving aging indexes by NMN has similar levels on key indexes such as mitochondrial stability, muscle health and the like compared with a 6-month-old mouse (equivalent to 20 years old human).
The transdermal drug delivery system is a novel drug delivery system, has the advantages of avoiding the metabolic burden of the liver and the kidney, keeping constant blood concentration, being convenient for drug delivery and the like, and has become one of the most rapidly developed hot development fields of pharmaceutical preparations due to more and more importance on the research and application of the transdermal drug delivery system at home and abroad.
the skin is a natural barrier and can resist the invasion of foreign substances, macromolecular substances hardly penetrate the skin, so that the molecular weight of the prepared medicament for percutaneous absorption is generally required to be less than 500-1000, the molecular weight of β -nicotinamide mononucleotide is 334.22, and the molecular weight is just in the range capable of percutaneous absorption, but no report is found whether the medicament can be absorbed through the skin so far, the administration of NMN is finished by injection or oral administration in the past, the external transdermal administration route and effect through transdermal absorption, and the improvement of the external administration on the whole human body and the function of the skin are not researched and reported.
Disclosure of Invention
the invention aims to provide a composition of β -nicotinamide mononucleotide or precursor β -nicotinamide ribose thereof, a preparation method and application thereof, and the composition is used for preparing a transdermal drug delivery preparation for improving internal functions of a human body and metabolism of the human body or preparing an external drug delivery preparation for improving epidermal functions of the human body and resisting skin aging.
The invention provides a technical scheme that:
the raw materials of the composition comprise, by weight, 0.001% -25% of beta-nicotinamide mononucleotide or beta-nicotinamide ribose serving as a precursor of the beta-nicotinamide mononucleotide, 0% -20% of a transdermal absorption enhancer, 2% -50% of an auxiliary component and the balance of water.
furthermore, the raw materials of the composition comprise, by weight, β -20% of beta-nicotinamide mononucleotide or a precursor thereof, namely beta-nicotinamide ribose, 5-15% of a transdermal absorption enhancer, 5-35% of an auxiliary component and the balance of water.
Further, the transdermal absorption enhancer is a natural transdermal enhancer or a synthetic transdermal enhancer, and the natural transdermal enhancer is one or more of essential oils, terpenes or lactones; the synthetic penetration enhancer is a unit and one or more of polyols, alkyl ketone, phospholipid and phosphate, organic acid and ester, phthaleins or surfactants.
Further, the auxiliary ingredients comprise one or more of skeleton ingredients, emulsifiers, comfortable moisturizing conditioning ingredients and preservative ingredients.
Further, the matrix component comprises one or more of the following substances: starch, vegetable gums, animal gelatin, sodium alginate, carrageenan, xanthan gum, polyacrylic acid, polyacrylate, copolymers of acrylic acid and acrylate, chitosan derivatives, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, guar gum and its derivatives, polyvinyl alcohol, polyvinyl acetate, ethylene/vinyl acetate copolymers, polyvinyl pyrrolidine, polyurethanes, polyisobutylene, long chain fatty alcohols, silicon dioxide.
Further, the emulsifier comprises one or more of the following: fatty acid soap, lauryl sodium sulfate, sodium dodecyl benzene sulfonate, N-dodecyl dimethylamine and other amine derivatives, quaternary ammonium salt, fatty acid monoglyceride, fatty acid triglyceride, sucrose fatty acid ester, phosphate, polyoxyethylene ether, polyoxypropylene ether, ethylene oxide and propylene oxide block copolymer, polyol fatty acid ester, SPAN series, TWEEN series, whey protein and lecithin.
Further, the comfort moisturizing conditioning ingredient comprises one or more of the following: propylene glycol, glycerol, n-butanol, isobutanol, white oil, squalane, vegetable oils, synthetic oils, polysiloxanes, hyaluronic acid and sodium salt, chitosan and derivatives thereof;
the preservative component comprises one or more of the following: benzoic acid and its salts, sorbic acid and its salts, dehydroacetic acid and its sodium salts, and parabens.
The invention also provides a technical scheme that:
the preparation method of the composition comprises the steps of mixing the raw materials of the composition and stirring the mixture until the mixture is uniform.
The invention also provides a technical scheme that:
the composition is applied to the preparation of a transdermal drug delivery preparation for improving the internal functions of the human body and the metabolism of the human body, or the preparation of an external drug delivery preparation for improving the epidermal functions of the human body and resisting skin aging.
Further, the transdermal administration preparation or the external administration preparation is in a dosage form of spray, aqua, gel, emulsion, cream, ointment, salve or patch.
the composition of β -nicotinamide mononucleotide or precursor β -nicotinamide ribose provided by the invention can play a role in improving the internal function of a human body, improving the metabolism of the human body or improving the epidermal function of the human body, resisting skin inflammation, allergy and resisting skin aging after being absorbed by the human body in a transdermal administration or external administration mode, the burden of liver and kidney metabolism can be avoided and the constant blood concentration can be kept in the transdermal administration and external administration modes, and the administration is convenient.
Detailed Description
the composition of β -nicotinamide mononucleotide or precursor β -nicotinamide ribose thereof is prepared by mixing β -nicotinamide mononucleotide or precursor β -nicotinamide ribose thereof, a transdermal absorption enhancer, auxiliary components and water according to a certain proportion.
Wherein the transdermal absorption enhancer can be natural or synthetic transdermal enhancer, and the natural transdermal enhancer is essential oil, terpenes or lactone, such as Mentholum, oleum Menthae Dementholatum, Mentholum, Borneolum Syntheticum, oleum Eucalypti, rhizoma Ligustici Chuanxiong, fructus Amomi rotundus extract, terpineol, maple oil, oleum Cinnamomi, rhizoma Alpiniae Officinarum oil, flos Caryophylli volatile oil, and oleum Eucalypti; the synthetic penetration enhancer is a unit or a polyol, a ketone, a phospholipid and a phosphate, an organic acid and an ester, a phthalein amine or a surfactant, such as ethanol, ethylene glycol, propylene glycol, Azone (Azone ), oleic acid, linoleic acid, dimethyl sulfoxide, urea, pyrrolidone, sodium dodecyl sulfate and the like. The percutaneous absorption enhancer can be used singly or in combination of two or more.
The auxiliary component can be one or more of skeleton component, emulsifier, comfortable moisture keeping conditioning component, and antiseptic component.
The skeleton component comprises one or more of the following substances: starch, vegetable gums, animal gelatin, sodium alginate, carrageenan, xanthan gum, polyacrylic acid, polyacrylate, copolymers of acrylic acid and acrylate, chitosan derivatives, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, guar gum and its derivatives, polyvinyl alcohol, polyvinyl acetate, ethylene/vinyl acetate copolymers, polyvinyl pyrrolidine, polyurethanes, polyisobutylene, long chain fatty alcohols, silicon dioxide.
The emulsifier comprises one or more of the following: fatty acid soap, lauryl sodium sulfate, sodium dodecyl benzene sulfonate, N-dodecyl dimethylamine and other amine derivatives, quaternary ammonium salt, fatty acid monoglyceride, fatty acid triglyceride, sucrose fatty acid ester, phosphate, polyoxyethylene ether, polyoxypropylene ether, ethylene oxide and propylene oxide block copolymer, polyol fatty acid ester, SPAN series, TWEEN series, whey protein and lecithin.
The comfort moisturizing conditioning ingredient comprises one or more of the following: propylene glycol, glycerol, n-butanol, isobutanol, white oil, squalane, vegetable oils, synthetic oils, polysiloxanes, hyaluronic acid and sodium salt, chitosan and derivatives thereof.
The preservative component comprises one or more of the following: benzoic acid and its salts, sorbic acid and its salts, dehydroacetic acid and its sodium salts, and parabens.
The composition can be prepared into a transdermal administration preparation or an external administration preparation, and is absorbed by a human body in a transdermal administration or external administration mode, specifically, the dosage form of the transdermal administration preparation or the external administration preparation is embodied in the form of spray, aqueous solution, gel, emulsion, cream, ointment, salve or patch, and the dosage form can have different evolution and variation forms, nanogel, nanoemulsion, liposome preparation, liposome nano preparation, suspension preparation and the like.
The present invention is further illustrated by the following specific examples, which are not intended to limit the invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
Example 1: spray agent
comprises 1 wt% of beta-nicotinamide mononucleotide, 5 wt% of propylene glycol, 0.2 wt% of sodium benzoate and 93.8 wt% of deionized water.
the preparation method comprises mixing deionized water and propylene glycol, stirring, heating to 80 deg.C, holding for 15 min, cooling to 35 deg.C, adding β -nicotinamide mononucleotide and sodium benzoate, stirring to dissolve completely, cooling to 25 deg.C, and packaging into suitable spray container.
Example 2: aqueous preparation
comprises 5 wt% of β -nicotinamide mononucleotide, 10 wt% of propylene glycol, 2 wt% of water-soluble azone, 0.2 wt% of sodium hyaluronate, 0.1 wt% of sorbic acid and the balance of deionized water.
the preparation method comprises mixing deionized water and propylene glycol, stirring and heating to 80 deg.C, adding sodium hyaluronate, stirring to dissolve, maintaining for 15 min, cooling to 35 deg.C, adding β -nicotinamide mononucleotide, water-soluble azone and sorbic acid, stirring to dissolve completely, and canning into a suitable container.
Example 3: gel agent
comprises 15 wt% of β -nicotinamide mononucleotide, 10 wt% of propylene glycol, 2 wt% of water-soluble azone, 0.1 wt% of sodium hyaluronate, 0.3 wt% of carbomer (polyacrylic acid), 0.25 wt% of triethanolamine, 0.2 wt% of sodium benzoate and the balance of deionized water.
the preparation method comprises stirring deionized water, adding sodium hyaluronate, heating to 80 deg.C, stirring to dissolve completely, mixing propylene glycol and carbomer, stirring as much as possible, adding into the water solution, homogenizing for two minutes, adding triethanolamine, stirring slowly for 15 minutes, cooling to 40 deg.C, adding β -nicotinamide mononucleotide, water-soluble azone and sodium benzoate, stirring well, and canning into a suitable container.
Example 4: emulsion agent
comprises 10 wt% of β -nicotinamide mononucleotide, 5 wt% of β -nicotinamide ribose, 5 wt% of propylene glycol, 0.1 wt% of xanthan gum, 15 wt% of white oil, 5 wt% of oleic acid, 3 wt% of azone, 2 wt% of monoglyceride, 2 wt% of 16-18 alcohol, 0.3 wt% of K2000PLUS (1, 3-dihydroxymethyl-5, 5-dimethylhydantoine and 3-iodine-2-propynyl butyl carbamate), and the balance of deionized water.
the preparation method comprises the steps of mixing deionized water and propylene glycol in a first container, stirring and heating, adding xanthan gum, continuously stirring and heating to 80 ℃, continuously stirring until the xanthan gum is completely dissolved, mixing white oil and oleic acid in another container, stirring and heating, adding monooleate and 16-18 alcohol, heating to 80 ℃, transferring the mixed solution into the first container after the mixture is completely uniform, stirring and homogenizing for 2 minutes, keeping for 10 minutes, cooling to 40 ℃, adding β -nicotinamide mononucleotide, β -nicotinamide ribose, azone and K2000PLUS (1, 3-dihydroxymethyl-5, 5-dimethylhydantoin and 3-iodo-2-propynyl butyl carbamate), stirring uniformly, and canning into a proper container.
Example 5: cream preparation
comprises 20 wt% of β -nicotinamide mononucleotide, 5 wt% of glycerol, 0.3 wt% of xanthan gum, 15 wt% of white oil, 2 wt% of menthol, 5 wt% of azone, 2 wt% of monoglyceride, 5 wt% of 16-18 alcohol, 0.3 wt% of K2000PLUS (1, 3-dihydroxymethyl-5, 5-dimethylhydantoin and 3-iodo-2-propynyl butyl carbamate), and the balance of deionized water.
the preparation method comprises mixing deionized water and glycerol in a first container, stirring and heating, adding xanthan gum, continuously stirring and heating to 80 deg.C, continuously stirring and heating to completely dissolve xanthan gum, mixing white oil and menthol in another container, stirring and heating, adding monooleate and 16-18 alcohol, heating to 80 deg.C, transferring the mixed solution into the first container after completely homogenizing, mixing and stirring, homogenizing for 2 min, keeping for 10 min, cooling to 40 deg.C, adding β -nicotinamide mononucleotide, azone, K2000PLUS (1, 3-dihydroxymethyl-5, 5-dimethylhydantoin, 3-iodo-2-propynyl butyl carbamate), stirring, and canning into a proper container.
Example 6: adhesive agent
comprises 5 wt% of β -nicotinamide mononucleotide, 50 wt% of glycerol, 5.0 wt% of NP700 (sodium polyacrylate), 2.0 wt% of PVP2, 2 wt% of dihydroxyaluminium, 0.4 wt% of azone, 2.5 wt% of propylene glycol, 0.4 wt% of tartaric acid and the balance of deionized water.
the preparation method comprises the steps of uniformly stirring a mixed solution of NP 7005 g and 50g of glycerin, adding PVPK30, dihydroxyaluminum glycinate and azone, uniformly stirring and mixing to obtain a phase A, dissolving β -nicotinamide mononucleotide, propylene glycol and tartaric acid in water to obtain a phase B, mixing the phase A and the phase B, fully stirring to obtain a viscous semi-solid fluid, uniformly coating the viscous semi-solid fluid on non-woven fabrics after slightly standing for a period of time, covering a back lining, Cumin at room temperature for 24 hours, punching and packaging to obtain the non-woven fabrics.
Experimental example 1: relieving effect of transdermal drug delivery preparation on fatigue
the cream was applied twice a day, each time applied to the face, hands and forearms at 3-5 grams, and then gently massaged to complete absorption after application for four weeks, showing that 5 subjects experienced 1 with no noticeable sensation and the remaining 4 experienced varying degrees of relief from symptoms within three weeks.
Experimental example 2: external preparation for treating skin inflammation or allergy
10 patients with symptoms of skin inflammation or allergy were treated with the gel containing 15 wt% β -nicotinamide mononucleotide obtained in example 3 the gel was applied topically to the affected area at least twice a day, the dose was dependent on the area of the area, and was typically between 1 and 2 grams.
Experimental example 3: external preparation for relieving skin aging signs
6 subjects with signs of aging (canthus wrinkles) were treated with the emulsion obtained in example 4 containing 10 wt% β -nicotinamide mononucleotide and 5 wt% β -nicotinamide ribose, and the emulsion was applied twice a day, the wrinkled area of the face was coated, each time at around 1 gram, and after application, the skin was gently massaged to complete absorption, and the test time was four weeks, and observations showed that 6 subjects had different degrees of relief of signs of aging (wrinkles) symptoms in two weeks.
in summary, the β -nicotinamide mononucleotide and the precursor transdermal or external administration system and the preparation method and the application thereof of the invention have the advantages that the β -nicotinamide mononucleotide or the precursor thereof can be absorbed transdermally, the effect is exerted, and the overall function of the human body is improved.
In the description herein, the embodiments and terminology are used for the purpose of illustration and are not intended to be limiting of the invention, and the particular features, structures, materials, or characteristics described may be combined, varied, modified, substituted, or extended in any one or more of the embodiments or examples as appropriate.
Claims (10)
- the composition of β -nicotinamide mononucleotide or its precursor is characterized by that its raw material includes (by wt%) 0.001% -25% of β -nicotinamide mononucleotide or its precursor β -nicotinamide ribose, 0% -20% of percutaneous absorption promoter, 2% -50% of auxiliary component and the rest is water.
- 2. the composition includes β -nicotinamide mononucleotide or its precursor as claimed in claim 1, wherein the raw material of the composition includes (by weight%) beta-nicotinamide mononucleotide or its precursor beta-nicotinamide ribose 0.5% -20%, transdermal absorption enhancer 5% -15%, auxiliary component 5% -35%, and water in balance.
- 3. the composition of beta-nicotinamide mononucleotide or its precursor according to claim 1, wherein the transdermal absorption enhancer is a natural penetration enhancer or a synthetic penetration enhancer, the natural penetration enhancer is one or more of essential oils, terpenes or lactones, and the synthetic penetration enhancer is one or more of unit and polyhydric alcohols, flavanones, phospholipids and phosphates, organic acids and esters, phthalamines or surfactants.
- 4. the composition of β -nicotinamide mononucleotide or its precursor of claim 1, characterized in that the adjunct ingredients include one or more of a backbone ingredient, an emulsifier, a comfort moisturizing conditioning ingredient, a preservative ingredient.
- 5. the composition of β -nicotinamide mononucleotide or a precursor thereof of claim 4, wherein said backbone component comprises one or more of starch, vegetable gums, animal gelatin, sodium alginate, carrageenan, xanthan gum, polyacrylic acid, polyacrylates, copolymers of acrylic acid and acrylates, chitosan derivatives, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, guar gum and derivatives thereof, polyvinyl alcohol, polyvinyl acetate, ethylene/vinyl acetate copolymers, polyvinyl pyrrolidine, polyurethane, polyisobutylene, long chain fatty alcohols, silicon dioxide.
- 6. the composition of claim 4, wherein the emulsifier comprises one or more of fatty acid soaps, sodium lauryl sulfate, sodium dodecylbenzene sulfonate, N-dodecyldimethylamine and other amine derivatives, quaternary ammonium salts, fatty acid monoglycerides, fatty acid glycerides, sucrose fatty acid esters, phosphates, polyoxyethylene ethers, polyoxypropylene ethers, block copolymers of ethylene oxide and propylene oxide, polyol fatty acid esters, SPAN series, TWEEN series, whey proteins, lecithins.
- 7. the composition of β -nicotinamide mononucleotide or precursors thereof of claim 4, wherein said comfort moisturizing conditioning ingredient comprises one or more of propylene glycol, glycerol, n-butanol, isobutanol, white oil, squalane, vegetable oils, synthetic oils, silicones, hyaluronic acid and sodium salts, chitosan and derivatives thereof;the preservative component comprises one or more of the following: benzoic acid and its salts, sorbic acid and its salts, dehydroacetic acid and its sodium salts, and parabens.
- 8. A process for the preparation of a composition as claimed in any one of claims 1 to 7, which comprises mixing the raw materials of the composition and stirring until homogeneous.
- 9. Use of the composition of any one of claims 1 to 7 for the preparation of a transdermal preparation for enhancing the internal functions of the human body and improving the metabolism of the human body, or for the preparation of an external preparation for enhancing the epidermal functions of the human body and preventing skin aging.
- 10. The use of claim 9, wherein the transdermal or topical formulation is in the form of a spray, aqueous solution, gel, emulsion, cream, ointment, salve, or patch.
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| CN111658621A (en) * | 2020-06-18 | 2020-09-15 | 深圳市旷逸生物科技有限公司 | Electret nicotinamide mononucleotide transdermal drug delivery patch and preparation method thereof |
| CN111838669A (en) * | 2020-08-07 | 2020-10-30 | 四川大学华西医院 | Nano composition for treating and improving vulnerable viscera, preparation method and application |
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| CN114432259A (en) * | 2022-01-12 | 2022-05-06 | 澳美制药(苏州)有限公司 | Electrolyte effervescent tablet and preparation method thereof |
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