WO2022222683A1 - 一种辅酶q10微乳液及其制备方法和应用 - Google Patents

一种辅酶q10微乳液及其制备方法和应用 Download PDF

Info

Publication number
WO2022222683A1
WO2022222683A1 PCT/CN2022/082838 CN2022082838W WO2022222683A1 WO 2022222683 A1 WO2022222683 A1 WO 2022222683A1 CN 2022082838 W CN2022082838 W CN 2022082838W WO 2022222683 A1 WO2022222683 A1 WO 2022222683A1
Authority
WO
WIPO (PCT)
Prior art keywords
coenzyme
microemulsion
emulsifier
mass
group
Prior art date
Application number
PCT/CN2022/082838
Other languages
English (en)
French (fr)
Inventor
朱小勇
李建东
严宏岳
陈志荣
程锦程
张其磊
李伟
吕天琪
王桂来
Original Assignee
浙江新和成股份有限公司
浙江大学
新昌新和成维生素有限公司
黑龙江新和成生物科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 浙江新和成股份有限公司, 浙江大学, 新昌新和成维生素有限公司, 黑龙江新和成生物科技有限公司 filed Critical 浙江新和成股份有限公司
Priority to US18/256,231 priority Critical patent/US20240016763A1/en
Publication of WO2022222683A1 publication Critical patent/WO2022222683A1/zh

Links

Images

Classifications

    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/52—Adding ingredients
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/06—Enzymes
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/04—Dispersions; Emulsions
    • A61K8/06—Emulsions
    • A61K8/068—Microemulsions
    • 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
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/35—Ketones, e.g. benzophenone
    • A61K8/355—Quinones
    • 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
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/86—Polyethers
    • 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
    • A61K8/92—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof
    • A61K8/922—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof of vegetable origin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/10—General cosmetic use

Definitions

  • the invention relates to a coenzyme Q10 microemulsion with small particle size, long-term storage stability under extreme temperature environment and high bioavailability, and a preparation method and application thereof. More specifically, it relates to the application of coenzyme Q10 microemulsion in beverage or oral liquid.
  • microemulsions for example, coenzyme Q10 oral emulsion used for medicine, coenzyme Q10 nano-microencapsulated emulsion used in cosmetics, and coenzyme Q10 clear oral emulsion used in food additives. Formulations and the like all relate to microemulsions.
  • Patent document 1 describes a kind of self-microemulsion and its preparation method, wherein the formula for preparing coenzyme Q10 self-microemulsion is roughly as follows: coenzyme Q10 5% to 20%, caprylic acid glyceride 5% to 20%, Span 601 % ⁇ 5%, Tween 60 15% ⁇ 25%, sodium stearate 1% ⁇ 5%, glycerin 20% ⁇ 30%, sorbitol 1% ⁇ 2%, water 8% ⁇ 15%.
  • the preparation method is as follows: adding coenzyme Q10 to caprylic acid glyceride, then adding emulsifier Span 60, avoiding light and evacuation and supplementing nitrogen for 3 times, heating and stirring until the solid material is completely dissolved; then adding a quantitative co-emulsifier glycerol, Then add the main emulsifier Tween 60 and sodium stearate; dissolve the sorbitol in pure water, and finally add it to the mixing system, heat it at about 65°C in the dark and avoid oxygen and stir until the system is uniform and transparent, and then keep the temperature for 10 to 30 minutes. , the final product is obtained after cooling.
  • the self-microemulsion product can be stored stably in the range of -10°C to 60°C, but the stability at low temperature (-30°C to -10°C) and high temperature (100°C to 130°C) is not involved.
  • Patent Document 2 describes a clear oral preparation containing coenzyme Q10 and a method for producing the same.
  • the formula for preparing the oral preparation is roughly as follows: coenzyme Q10 0.1%-10%, emulsifier 0.5%-30%, co-emulsifier 5%-20%, stabilizer 0.5%-10%, and the balance is water.
  • the preparation method is as follows: each raw material is weighed according to the formula, firstly dissolving coenzyme Q10 in an emulsifier and a co-emulsifier, adding it to water containing a stabilizer to form a uniform mixed solution, and preparing a final solution after high-speed shearing.
  • the method does not use an organic solvent, requires simple equipment, can prepare a uniform nano-dispersion system of coenzyme Q10 with a clear appearance, has good dispersibility, and can improve bioavailability, and the aqueous solution of coenzyme Q10 can be stably stored for more than one year.
  • this invention only gives the stability data of coenzyme Q10 microemulsion at 25°C, and does not involve the stability at low temperature (-30°C to -10°C) and high temperature (100°C to 130°C).
  • the coenzyme Q10 microemulsion needs to undergo extreme temperature environments such as high temperature sterilization and refrigerated storage in the subsequent applications of oral liquids, beverages, soft capsules, and food, and the current microemulsion in the prior art is in the above-mentioned extreme temperature environment. Insufficient stability, easy to break demulsification leading to the destruction of its activity. Therefore, the performance of the current coenzyme Q10 microemulsion and its preparation process still need to be improved.
  • Patent Document 3 describes a coenzyme Q10 oral emulsion and its preparation method.
  • the components and contents of the coenzyme Q10 oral emulsion are as follows: coenzyme Q10 is 0.1%-80%, medicinal oil is 1%-95%, emulsifier is 0.5%-30%, auxiliary emulsifier is 0%-10%, The antioxidant is 0.001% to 15%, and the balance is purified water. It is prepared by phase inversion emulsification method, PIT emulsification method, alternating liquid addition emulsification method, continuous emulsification method, low energy emulsification method and microfluidization method.
  • the prepared oral emulsion is centrifuged at a rotational speed of 3750 r/min for 30 minutes, without delamination, high bioavailability, good stability, and is easier to be taken by patients.
  • the invention does not relate to the stability of the coenzyme Q10 oral emulsion at normal temperature, low temperature (-30°C to -10°C) and high temperature (100°C to 130°C).
  • Patent Document 4 describes a coenzyme Q10 fish oil nanoemulsion and its preparation method and application.
  • the components and contents of the coenzyme Q10 fish oil nanoemulsion are as follows: coenzyme Q10 0.02%-25%, fish oil 0%-20%, emulsifier 0.5%-5%, vegetable oil 0%-20%, flavoring agent 0%-10% %, antioxidant 0%-0.5%, preservative 0%-0.5%, appropriate amount of pH adjuster, appropriate amount of purified water.
  • the particle size of the obtained emulsion is 300 nm to 550 nm, which does not involve the coenzyme Q10 fish oil nanoemulsion at room temperature and low temperature (-30 °C ⁇ -10 °C) and high temperature (100 °C ⁇ 130 °C) stability.
  • Patent Document 1 CN102423297B
  • Patent Document 2 CN101744288B
  • Patent Document 3 CN101015524A
  • Patent Document 4 CN107568731A
  • the present invention hopes to develop A coenzyme Q10 microemulsion with small particle size and improved extreme temperature stability, the preparation process is simple, and the above purpose can be achieved even without the aid of high-speed shearing, homogenization, ultrasound and other technical means.
  • the present invention also hopes that the microemulsion obtained by the above method has high clarity and transparency, a large microemulsion interval, remains clear and transparent after being diluted into oral liquid for high temperature sterilization, and has high bioavailability.
  • coenzyme Q10 is still in microemulsion. form, etc.
  • the coenzyme Q10 is first dissolved in the carrier oil, and then compounded with specific lipophilic and hydrophilic emulsifiers, and kept at a specific temperature to form an emulsified oil-water system to obtain a thermodynamically stable coenzyme Q10 microemulsion.
  • the present invention mainly includes the following aspects:
  • a coenzyme Q10 microemulsion characterized in that, based on the total amount of the coenzyme Q10 microemulsion, it comprises:
  • the particle size D V (90) of the coenzyme Q10 microemulsion is 20 nm ⁇ 80nm.
  • coenzyme Q10 microemulsion according to any one of [1] to [5], wherein the co-emulsifier is selected from the group consisting of glycerol, sorbitol, ethanol, polyethylene glycol-400 and polyethylene glycol At least one of the group consisting of ethylene glycol-800.
  • the anti-crystallizing agent is selected from the group consisting of tocopherol acetate, tocopherol, trihydroxystearin, At least one of the group consisting of chain triglycerides, povidone K30, povidone K12, and polyglycerol fatty acid esters.
  • the specific emulsifier is compounded, and the components are mixed and kept at a specific temperature to obtain a particle size D V (90) between 20 nm and 80 nm, which is clear and transparent, does not break demulsification, and has high bioavailability.
  • store the long-term stable coenzyme Q10 microemulsion under normal temperature and extreme temperature environment for example, at low temperature (-30°C to -10°C) and high temperature (100°C to 130°C)).
  • the microemulsion has a large microemulsion range and can maintain the microemulsion form after being diluted 100 times in an aqueous solution, so it is suitable for the fields of medicine, cosmetics and food, especially for beverages and oral liquids and other products. When used in beverages and oral liquids, it can still not break the demulsification after high temperature sterilization, and maintain a clear and transparent state.
  • the method of the present invention is simple in process and low in cost, and can even prepare a coenzyme Q10 microemulsion with a particle size of less than 100 nm without resorting to high-speed shearing, homogenization, ultrasound and other technical means.
  • Figures 1 to 4 are the three-phase diagrams of the microemulsion interval of the microemulsion system represented by Example 1, Comparative Example 1, Comparative Example 2, and Comparative Example 3, respectively, wherein the EM contains an emulsifier (including a lipophilic emulsifier, a hydrophilic emulsifier, a water-based emulsifier), co-emulsifier.
  • an emulsifier including a lipophilic emulsifier, a hydrophilic emulsifier, a water-based emulsifier
  • co-emulsifier co-emulsifier
  • the invention improves the emulsification ability through the compounding technology of a specific lipophilic emulsifier and a hydrophilic emulsifier, and provides a preparation method of a microemulsion with high stability and high content of coenzyme Q10.
  • the inventors have found through research that when using specific lipophilic and hydrophilic emulsifiers for compounding, firstly, the emulsifier system will adsorb on the oil-water interface to form a unique emulsifier complex.
  • the arrangement is compact and orderly, with high strength, which can well prevent the coalescence of the oil phase.
  • the group is cyclic), which can effectively disrupt the directional arrangement of the emulsifier molecules and increase the stability of the microemulsion.
  • the optimal HLB range in the system is expanded, which is no longer a separate point.
  • the inventors also found that the formation of the above microemulsion has the following characteristics: triglycerides with high solubility encapsulate the crystals of coenzyme Q10, and form an oil suspension under the action of an oil phase stabilizer (anti-crystallizing agent).
  • oil phase stabilizer anti-crystallizing agent
  • Add specific lipophilic and hydrophilic emulsifiers to compound, the head group of the lipophilic emulsifier is close to the oil suspension, and the lipophilic group of the emulsifier and the side chain of Q10 are interlocked with each other to form a spherical stable arrangement, which is attached to the oil. around the suspension.
  • hydrophilic emulsifier One end of the hydrophilic emulsifier is closely combined with the branched chain of the lipophilic emulsifier, acting as a "bridge". After adding pure water, the branched chain at the other end of the hydrophilic emulsifier and the water molecules adsorb each other, and the water molecules wrap around the emulsifier's periphery, finally forming an O/W type microemulsion.
  • the stability and bioavailability of the microemulsion are affected by the interaction between the components, and the type and ratio of the compounds affect the interaction between the components.
  • the inventors found that the compounds with the following characteristics can be used in the present invention, and the desired coenzyme Q10 microemulsion can be obtained after compounding.
  • the raw material coenzyme Q10 used in the present invention can be oxidized, reduced or a mixture of the two as needed, and the coenzyme Q10 can be obtained by any method, for example, organic synthesis method or microbial fermentation method.
  • the content of the coenzyme Q10 is 1% by mass to 20% by mass. More preferably, the content of coenzyme Q10 is 1% by mass to 15% by mass. Most preferably, the content of coenzyme Q10 is 1% by mass to 10% by mass.
  • the carrier oil of the present invention can use a carrier oil conventional in the art, as long as it can dissolve with coenzyme Q10 to form an oil phase.
  • the carrier oil is selected from the group consisting of caprylic acid glyceride, diethylene glycol monoethyl ether, glyceryl polyether, soybean lecithin and olive oil at least one of the group.
  • the content of the carrier oil is 1% by mass to 20% by mass. More preferably, the content of the carrier oil is 2% by mass to 10% by mass.
  • the lipophilic emulsifier of the present invention is polyglycerol castor. Alkyd esters.
  • the content of the polyglycerol ricinoleate is 2% by mass to 15% by mass based on the total amount of the microemulsion. More preferably, the content of the lipophilic emulsifier is 5% by mass to 10% by mass.
  • the hydrophilic emulsifier of the present invention is a polyoxyethylene ether emulsifier.
  • the polyoxyethylene ether emulsifier is selected from Polyoxyethylene sorbitan oleate (Tween-80), Polyoxyethylene sorbitan stearate (Tween-60), Polyoxyethylene sorbitan laurate (Tween-20 ) and at least one of the group consisting of polyoxyethylene hydrogenated castor oil.
  • the content of the hydrophilic emulsifier is 15% by mass to 30% by mass based on the total amount of the microemulsion. More preferably, the content of the hydrophilic emulsifier is 17% by mass to 24% by mass.
  • the co-emulsifier of the present invention is not limited, and any conventional co-emulsifier in the art can be used, as long as it can be used in combination with the emulsifier to help form the coenzyme Q10 microemulsion.
  • the co-emulsifier is selected from glycerol, sorbitol, ethanol, polyethylene glycol-400 (PEG-400) and polyethylene glycol At least one of the group consisting of ethylene glycol-800 (PEG-800). More preferably, the co-emulsifier is glycerol and/or sorbitol.
  • the total amount of coenzyme Q10 microemulsion is In total, the content of the co-emulsifier is 5% by mass to 25% by mass. More preferably, the content of the co-emulsifier is 7% by mass to 12% by mass.
  • the anti-crystallizing agent of the present invention is not limited, and any anti-crystallizing agent conventional in the art can be used, as long as it can be used in combination with an emulsifier and a co-emulsifier to help form a stable coenzyme Q10 microemulsion.
  • the anti-crystallization agent is selected from fertility Phenolic acetate, tocopherol, trihydroxystearin, medium chain triglycerides, povidone K30, povidone K12, polyglycerol fatty acid ester (THL-17) (purchased from Sakamoto Pharmaceutical, Japan), At least one of polyglycerol fatty acid ester (THL-15) (purchased from Sakamoto Pharmaceutical, Japan).
  • the content of the anti-crystallization agent is 0.5% by mass to 10% by mass, more preferably Typically, the content of the anti-crystallization agent is 2% by mass to 5% by mass.
  • the particle size D V (90) of the coenzyme Q10 microemulsion of the present invention is less than 100 nm, and the small particle size helps to form a uniform and clear microemulsion and improves transparency and bioavailability.
  • the particle size D V (90) is in the range of 20 nm to 80 nm, which can make the coenzyme Q10 microemulsion more clear and transparent, without demulsification, and with excellent stability under extreme temperature environments. More preferably, the particle size D V (90) is in the range of 30 nm to 75 nm, so that the coenzyme Q10 microemulsion can have more excellent stability and bioavailability under extreme temperature environment. Most preferably, the particle size D V (90) is in the range of 35 nm to 60 nm, and at this time, the aforementioned properties of the coenzyme Q10 microemulsion are more excellent.
  • the preparation of the coenzyme Q10 microemulsion of the present invention comprises the following steps:
  • coenzyme Q10, carrier oil and anti-crystallizing agent are stirred and dissolved in a water bath at 40°C to 70°C for 5 min to 10 min to form an oil phase;
  • the heat preservation process of the microemulsion is the process of re-emulsification and aging of the emulsifier. Selecting the appropriate heat preservation conditions is conducive to the formation of sol particles with uniform particle size, which can make the microemulsion system more stable.
  • Coenzyme Q10 microemulsion with particle size D V (90) ranging from 20 nm to 80 nm can be obtained by the above method.
  • the three-phase diagram is one of the common methods to study the distribution ratio of each component in the microemulsion.
  • the three phases in the microemulsion are emulsifier/co-emulsifier, oil phase (insoluble substances and polar organic substances), pure water .
  • pure water is added dropwise to the emulsifier/co-emulsifier and oil phase mixture by the Shah method, with the increase of the water amount, the system gradually changes from turbidity to clear, and then from clear to turbid, and records the components of the two changes.
  • the microemulsion interval of this system can be determined, and the optimal ratio of each component can be determined by screening in the microemulsion interval according to the required performance.
  • microemulsion interval From the size of the microemulsion interval, we can see the amount of water to expand the system.
  • the larger the microemulsion interval the more the microemulsion can maintain the microemulsion state after being diluted in downstream applications, and the more stable it is in extreme temperature environments. In a clear and transparent state, in particular, it is not easy to precipitate at low temperature, and it is not easy to become cloudy at high temperature.
  • the coenzyme Q10 microemulsion of the present invention can be used in the fields of medicine, cosmetics and food, and is especially suitable for beverages and oral liquids.
  • the preparation process of the microemulsion in the prior art is complicated, and the particle size is less than 100 nm only by means of high-speed shearing, homogenization, ultrasonic and other processes, and the obtained microemulsion is under extreme temperature environment (for example, low temperature (-30 °C ⁇ -10°C) and high temperature (100°C ⁇ 130°C)) the stability is poor.
  • the application of coenzyme Q10 microemulsion in the food field is also less, and the microemulsion is diluted into oral liquid, and problems such as turbidity and demulsification may occur.
  • the simplification of the preparation process can be achieved, and microscopic particles with a particle size D V (90) between 20 nm and 80 nm can be obtained.
  • D V particle size between 20 nm and 80 nm
  • the microemulsion is clear and transparent, does not break demulsification, has high bioavailability, can meet the performance requirements of medicines, cosmetics and food, and can even meet the requirements of preparation of oral liquids with relatively harsh conditions.
  • microemulsion sample was diluted 1:20 with distilled water and shaken gently to form a clear microemulsion. Then, the particle size distribution of the emulsion was measured with a MASTERSIZER 3000 laser particle size distribution analyzer (purchased from Malvern, UK), and the measurement temperature was 25°C.
  • the detection of the clarity and transparency is also called the demulsification test, and the type method is usually used to test the clarity and transparency.
  • the inspector Quickly pour the coenzyme Q10 microemulsion into the transparency meter cylinder.
  • the inspector observes vertically downward from the opening of the transparency meter, and slowly releases the microemulsion to the height of the microemulsion that can be clearly identified.
  • the microemulsion height is the transparency of the coenzyme Q10 microemulsion, generally More than 30cm is transparent. The measurement was repeated 3 times, and the results were averaged.
  • microemulsion samples and coenzyme Q10 raw materials were taken and placed for 15 days under the conditions of irradiation under 4500Lx light intensity, oxygenated filling (25 °C) and 60 °C (incubator) for 15 days.
  • samples were taken on day 0, day 5, day 10, and day 15, respectively, and the content of coenzyme Q10 was determined by HPLC, and the labeled content (%) and appearance of coenzyme Q10 were investigated by light, oxygen, and temperature conditions. Impact.
  • High temperature The microemulsion samples were stored in a 120°C incubator for 0min, 10min, 15min, and 30min, and the samples were taken for measurement.
  • Preparation of coenzyme Q10 raw material sample solution Precisely weigh 0.1 g of coenzyme Q10 crystal and dissolve it in 100 mL of diethylene glycol monoethyl ether solution as a raw material sample.
  • microemulsion samples of Examples 1 to 6 code-named Sample 1, Sample 2, Sample 3, Sample 4, Sample 5, and Sample 6, were selected for animal experiments.
  • Experimental conditions laboratory feeding environment temperature of 25 ⁇ 3°C, relative humidity of 55% to 70%, daily free drinking and food intake (deionized water and standard feed), fasting for 12 hours before the experiment, and free drinking water.
  • the rats were operated in accordance with the international experimental guidelines for experimental animals, and the rats that were fasted for 12 h were divided into seven groups for every 10 rats by a completely random design.
  • Microemulsion samples 1 to 6 and raw material samples of the same dose were given to rats by gavage, respectively. , 3h, 6h, 10h, and 15h to collect plasma, put it into an anticoagulant centrifuge tube containing heparin, mix evenly, centrifuge, separate plasma, and use high performance liquid chromatography to detect plasma drug concentration after treatment.
  • the preparation method of the three-phase diagram is as follows: the temperature of the experimental process is controlled at 50 ° C, and then the coenzyme Q10 crystallization and anti-crystallization agent are dissolved in the carrier oil as the oil phase; the emulsifier (including lipophilic emulsifier, lipophilic Emulsifier) and co-emulsifier are mixed uniformly as EM phase; the oil phase and EM phase are in different mass ratios (1:1, 2:3, 1:2, 2:5, 3:7, 1:3, 2:7, 3:10, 1:4, 2:9, 5:12, 1:5, a total of 12 groups) weigh a certain mass and mix well; slowly add water to each group, record each A set of water consumption from turbidity to clarification and water consumption from clarification to turbidity again; draw a three-phase diagram according to the recorded oil phase, emulsifier/co-emulsifier, and water quantity data, and do two parallel experiments and take the average value as The point value to use when plotting.
  • the reagents and materials in the examples are of food grade or pharmaceutical grade, which can be obtained through commercial channels.
  • coenzyme Q10 is from Zhejiang Xinhecheng Co., Ltd., and other raw materials are commercially available products.
  • the coenzyme Q10 microemulsion of the present invention can be prepared by the above method, and its particle size D V (90) is shown in Table 1.
  • Example 2 to Example 6 Example 2 to Example 6 :
  • the coenzyme Q10 microemulsion was prepared according to the formula shown in Table 1, the content (mass %) of the components was calculated based on the total amount of the coenzyme Q10 microemulsion, and the temperature was kept at 90° C. to 120° C.
  • the particle size D V (90) of the prepared microemulsion is shown in Table 1.
  • the coenzyme Q10 microemulsion can be obtained according to the formulations of Examples 1 to 6, and its particle size D V (90) is between 20 nm and 80 nm.
  • the coenzyme Q10 microemulsion of Comparative Example 5 to Comparative Example 10 and Comparative Example 11 to Comparative Example 16 was prepared according to the holding temperature and holding time of Table 3 and Table 4 below with the same formula and preparation method as Example 1, and the microemulsion was measured.
  • Table 3 and Table 4 show that although the formula of the microemulsion is the same as that of Example 1, the particle size D V (90) of the microemulsion is affected by the difference of the holding temperature and holding time, and its value is all greater than 80 nm.
  • the experimental results show that the holding temperature and holding time have a great influence on the particle size of the microemulsion.
  • the holding time is preferably controlled to 0.5 h ⁇ Within the range of 1h, the holding temperature is controlled within the range of 90°C to 120°C.
  • the coenzyme Q10 microemulsion of Examples 1 to 6 was also tested for clarity and transparency (demulsification test) and stability testing.
  • the effects of temperature (60° C., incubator) on the stability of coenzyme Q10 microemulsion are shown in Table 5, Table 6, and Table 7, respectively.
  • Tables 5 to 7 show that the coenzyme Q10 microemulsion of Examples 1 to 6 under the conditions of light (4500Lx light), oxygenation (oxygenation filling, 25°C) and high temperature (60°C, incubator), the coenzyme Q10 microemulsion
  • the marked content and appearance of Q10 did not change significantly.
  • the measured results of the labeled content of coenzyme Q10 on the 5th, 10th, and 15th days did not change much, and were more stable than the labeled content of coenzyme Q10 in the raw material.
  • the appearance of the microemulsion is also clear and transparent, and there is no turbid demulsification phenomenon. Therefore, the coenzyme Q10 microemulsion of the present invention has better stability to light, oxygen and temperature, and can prolong the shelf life of the product.
  • the present application also conducted performance experiments on the coenzyme Q10 microemulsions of Examples 1 to 6 and Comparative Examples 1 to 4 under low temperature (-20°C) and high temperature (120°C) conditions to detect the label of Coenzyme Q10. Changes in content and appearance traits.
  • the experimental results at low temperature (-20°C) are shown in Table 8
  • the experimental results at high temperature (120°C) are shown in Table 9.
  • Tables 8 to 9 show that the Coenzyme Q10 microemulsions of Examples 1 to 6 have no significant changes in the labeled content and appearance of Coenzyme Q10 under the conditions of low temperature (-20° C.) and high temperature (120° C.). The appearance of the emulsion is clear and transparent, without the phenomenon of cloudy demulsification.
  • the coenzyme Q10 microemulsions of Comparative Examples 1 to 4 are unstable in a low temperature environment, and the crystals of Coenzyme Q10 will be precipitated in a short time, resulting in demulsification of the microemulsion system.
  • Comparative Examples 1 to 4 are also unstable at high temperature, and with the extension of storage time, the microemulsion is completely cloudy, and the microemulsion system is destroyed.
  • the data in the table shows that the microemulsion of the present invention has excellent extreme temperature environmental stability, and can meet the needs of the microemulsion in subsequent applications.
  • the data in Table 10 shows that after taking the oral liquid, compared with the raw material sample, the peak concentration Cmax values of the microemulsions of Examples 1 to 6 have a statistically significant advantage (P ⁇ 0.05), The AUC value is also significantly higher, and the fluctuation of the peak concentration is also smaller than that of the raw material.
  • the results show that the coenzyme Q10 microemulsion has high bioavailability, is rapidly absorbed in rats, can reach a higher plasma concentration, and has a higher drug safety.
  • the particle size D V (90) of the microemulsion of the present invention is between 20 nm and 80 nm, the smaller particle size can improve the uniformity of drug absorption, which is beneficial to drug absorption.
  • Example 1 and Comparative Examples 1 to 3 are respectively a certain point value in the microemulsion interval of FIGS. 1 to 4 .
  • the microemulsion interval shown in Figure 1 is relatively large, indicating that the microemulsion system where Example 1 is located has a large amount of water to expand, and can still maintain the microemulsion state after being diluted in downstream applications, and the microemulsion is extremely It is also more stable under the temperature environment, showing a clear and transparent state, not easy to precipitate at low temperature, and not easy to be turbid at high temperature.
  • the microemulsion systems shown in Figures 2 to 4, where Comparative Examples 1 to 3 are located have a small microemulsion range, indicating that the microemulsion system has a small amount of water to expand, and the microemulsion occurs in extreme temperature environments. or unstable conditions such as turbidity.
  • the invention also provides a preparation method of coenzyme Q10 microemulsion with simple equipment, low cost and easy operation.
  • the particle size D V (90) of the microemulsion prepared by this method is between 20nm and 80nm, is clear and transparent, does not break demulsification, has high bioavailability, and is stable for long-term storage under normal temperature and extreme temperature environment.
  • the microemulsion prepared by the invention is suitable for the fields of medicine, cosmetics and food, and is especially suitable for products such as beverages and oral liquids.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Food Science & Technology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Polymers & Plastics (AREA)
  • Nutrition Science (AREA)
  • Birds (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Dispersion Chemistry (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Emergency Medicine (AREA)
  • Dermatology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

本发明提供了一种辅酶Q10微乳液及其制备方法和应用。该辅酶Q10微乳液由包含辅酶Q10，载体油，抗结晶剂，亲脂性乳化剂，亲水性乳化剂，助乳化剂和水的组分制备得到。该微乳液的粒径DV(90)在20nm～80nm之间，澄清透明，不破乳，生物利用度高，在常温和极端温度环境下储存长期稳定。该微乳液适用于药物、化妆品和食品领域，尤其适用于饮料和口服液等产品。本发明还提供一种设备简单、成本低廉、易操作的辅酶Q10微乳液制备方法。

Description

一种辅酶Q10微乳液及其制备方法和应用 技术领域
本发明涉及一种粒径小、在极端温度环境下储存长期稳定、生物利用度高的辅酶Q10微乳液及其制备方法和应用。更具体地，涉及辅酶Q10微乳液在饮料或口服液中的应用。
背景技术
现有技术中对于微乳液的制备方法及其用途方面的研究较多，例如，用于医药的辅酶Q10口服乳剂、用于化妆品的辅酶Q10纳米微囊乳液、用于食品添加剂的辅酶Q10澄清口服制剂等均涉及微乳液。
专利文献1中记载了一种自微乳及其制备方法，其中制备辅酶Q10自微乳的配方大致如下：辅酶Q10 5％～20％，辛癸酸甘油酯5％～20％，司盘601％～5％，吐温60 15％～25％，硬脂酸钠1％～5％，甘油20％～30％，山梨醇1％～2％，水8％～15％。其制备方法如下：将辅酶Q10加到辛癸酸甘油酯中，再加入乳化剂司盘60，避光抽空补氮3次后加热搅拌至固体物料完全溶解；然后加入定量的助乳化剂甘油，再将主乳化剂吐温60和硬脂酸钠加入；将山梨醇溶解于纯水中，最后加到混合体系中，避光隔氧加热65℃左右搅拌直至体系均一透明，再保温10min～30min，降温后得到最终产品。该自微乳产品在-10℃～60℃范围内能稳定保存，但并未涉及在低温(-30℃～-10℃)和高温(100℃～130℃)下的稳定性。
专利文献2中记载了一种含有辅酶Q10的澄清口服制剂及其制备方法。制备该口服制剂的配方大致为如下：辅酶Q10 0.1％～10％，乳化剂0.5％～30％，助乳化剂5％～20％，稳定剂0.5％～10％，余量为水。其制备方法如下：按配方量称取各原料，将辅酶Q10先溶于乳化剂与助乳化剂中，加入含有稳定剂的水中形成均匀混合液中，高速剪切后制备出最终溶液。该方法不使用有机溶剂，所需设备简单，可制备出外观澄清的辅酶Q10均匀纳米分散体系，分散性好，可提高生物利用度，该辅酶Q10水溶液可稳定保存一年以上。但该发明只给出了辅酶Q10微乳液在25℃下的稳定性数据，并未涉及在低温(-30℃～-10℃)和高温(100℃～130℃)下的稳定性情况。由于辅酶Q10微乳液在后续的口服液、饮料、软胶囊、食品等应用中，需要经历高温灭菌、冷藏保存等极 端温度环境，而目前现有技术中的微乳液在上述极端温度环境下的稳定性不足，容易破乳导致其活性遭到破坏。因此，目前的辅酶Q10微乳液性能及其制备工艺仍需改进。
专利文献3中记载了一种辅酶Q10口服乳剂及其制备方法。该辅酶Q10口服乳剂的组分和含量如下：辅酶Q10为0.1％～80％，药用油为1％～95％，乳化剂为0.5％～30％，辅助乳化剂为0％～10％，抗氧剂为0.001％～15％，余量为纯化水。采用转相乳化法，PIT乳化法，交替加液乳化法，连续式乳化法，低能乳化法和微流化法等方法制备。制备的口服乳剂在3750r/min的转速下离心30分钟，无分层现象，生物利用度高，稳定性好，更易被患者服用。但该发明并未涉及辅酶Q10口服乳剂在常温、低温(-30℃～-10℃)和高温(100℃～130℃)下的稳定性。
专利文献4中记载了一种辅酶Q10鱼油纳米乳液及其制备方法与应用。该辅酶Q10鱼油纳米乳液的组分和含量如下：辅酶Q10 0.02％～25％，鱼油0％～20％，乳化剂0.5％～5％，植物油0％～20％，矫味剂0％～10％，抗氧剂0％～0.5％，防腐剂0％～0.5％，pH调节剂适量，纯化水适量。该辅酶Q10鱼油纳米乳液的制备过程中采用了剪切和高压均质等操作，所得乳液的粒径在300nm～550nm，并未涉及辅酶Q10鱼油纳米乳液在常温、低温(-30℃～-10℃)和高温(100℃～130℃)下的稳定性。
现有技术文献
专利文献1：CN102423297B
专利文献2：CN101744288B
专利文献3：CN101015524A
专利文献4：CN107568731A
发明内容
发明要解决的问题
针对现有技术中辅酶Q10微乳液存在的极端温度环境下(例如，在低温(-30℃～-10℃)和高温(100℃～130℃)下)稳定性不足等缺点，本发明希望开发一种粒径较小、具有改善的极端温度稳定性的辅酶Q10微乳液，其制备工艺简单，甚至无需借助高速剪切、均质、超声等技术手段也能达到上述目的。
本发明还希望由上述方法获得的微乳液具有澄清透明度高，微乳区间大，稀释到口服液中高温杀菌后仍保持澄清透亮，生物利用度高，用于食品中时辅酶Q10仍然以微乳形式存在等特点。
用于解决问题的方案
本发明首先将辅酶Q10溶于载体油中，然后采用特定的亲脂性和亲水性乳化剂进行复配，在特定温度下保温，最终形成乳化油水体系，得到热力学稳定的辅酶Q10微乳液。
本发明主要包括如下方面：
[1]、一种辅酶Q10微乳液，其特征在于，以所述辅酶Q10微乳液的总量计，其包括：
1质量％～20质量％的辅酶Q10，1质量％～20质量％的载体油，0.5质量％～10质量％的抗结晶剂，2质量％～15质量％的亲脂性乳化剂，15质量％～30质量％的亲水性乳化剂，5质量％～25质量％的助乳化剂，和30质量％～65质量％的水，所述辅酶Q10微乳液的粒径D V(90)为20nm～80nm。
[2]、根据[1]所述的辅酶Q10微乳液，其特征在于，所述亲脂性乳化剂包含聚甘油蓖麻醇酸酯。
[3]、根据[1]或[2]所述的辅酶Q10微乳液，其特征在于，所述亲水性乳化剂包含聚氧乙烯醚类乳化剂。
[4]、根据[1]～[3]中任一项所述的辅酶Q10微乳液，其特征在于，所述载体油选自由辛癸酸甘油酯、二乙二醇单乙醚、甘油聚醚、大豆磷脂和橄榄油组成的组中的至少一种。
[5]、根据[3]或[4]所述的辅酶Q10微乳液，其特征在于，所述聚氧乙烯醚类乳化剂选自由聚氧乙烯失水山梨醇油酸酯、聚氧乙烯失水山梨醇硬脂酸酯、聚氧乙烯失水山梨醇月桂酸酯和聚氧乙烯氢化蓖麻油组成的组中的至少一种。
[6]、根据[1]～[5]中任一项所述的辅酶Q10微乳液，其特征在于，所述助乳化剂选自由甘油、山梨醇、乙醇、聚乙二醇-400和聚乙二醇-800组成的组中的至少一种。
[7]、根据[1]～[6]中任一项所述的辅酶Q10微乳液，其特征在于，所述抗结晶剂选自由生育酚醋酸酯、生育酚、三羟基硬脂精、中链甘油三酸酯、聚维酮K30、聚维酮K12、聚甘油脂肪酸酯组成的组中的至少一种。
[8]、根据[1]～[7]中任一项所述的辅酶Q10微乳液的制备方法，其特征在于，所述制备方法包括：
使用辅酶Q10、载体油和抗结晶剂形成油相；
将亲脂性乳化剂和亲水性乳化剂加入所述油相中；
所述油相混合均匀后，进一步加入助乳化剂，搅拌混合均匀后滴加水，继续搅拌至整个体系均一透明，90℃～120℃下保温0.5h～1h，由此得到所述辅酶Q10微乳液。
[9]、根据[1]～[7]中任一项所述的辅酶Q10微乳液在制备药物、化妆品和食品中的应用。
[10]、根据[9]所述的应用，其特征在于，所述应用为制备饮料或口服液。
发明的效果
本发明通过对特定的乳化剂进行复配，各组分混合后在特定温度下进行保温，可以获得粒径D V(90)在20nm～80nm之间，澄清透明，不破乳，生物利用度高，在常温和极端温度环境下(例如，在低温(-30℃～-10℃)和高温(100℃～130℃)下)储存长期稳定的辅酶Q10微乳液。该微乳液的微乳区间大，能够在水溶液中稀释100倍后仍保持微乳形式，因此适用于药物、化妆品和食品领域，尤其适用于饮料和口服液等产品。用于饮料和口服液时，高温杀菌后仍能不破乳，保持澄清透明状态。
此外，本发明方法工艺简单，成本低廉，甚至无需借助高速剪切、均质、超声等技术手段也可制备粒径小于100nm的辅酶Q10微乳液。
附图说明
图1～图4分别为实施例1、比较例1、比较例2、比较例3所代表的微乳体系的微乳区间三相图，其中，EM包含乳化剂(包括亲脂性乳化剂、亲水性乳化剂)、助乳化剂。
具体实施方式
以下对本发明的辅酶Q10微乳液的特点、配方、制备方法及其应用进行详细介绍。
<本发明的辅酶Q10微乳液的特点>
本发明通过特定的亲脂性乳化剂、亲水性乳化剂复配技术，提高乳化能力，提供一种稳定性高、辅酶Q10含量高的微乳液的制备方法。
本发明人经过研究发现，使用特定的亲脂性和亲水性两大类乳化剂进行复配时，首先，乳化剂体系会在油水界面上吸附形成独特的乳化剂复合物，该复合物结构上排列紧密有序，具有较高的强度，可以很好地防止油相聚结。其次，当两种特定结构的乳化剂亲水基团的构象不同时，具有亲水基团构象互补效应(例如，单甘脂的亲水基团是线性的，而蔗糖脂肪酸酯的亲水基团是环状的)，能有效地打乱乳化剂分子的定向排列，增加微乳液稳定性。另外，特定的亲脂性乳化剂和亲水性乳化剂复配后，使得体系中最佳HLB区间扩大，不再是一个单独的点。
本发明人还发现，上述微乳液的形成具有如下特点：溶解度高的甘油三酯将辅酶Q10结晶包裹其中，在油相稳定剂(抗结晶剂)的作用下，形成油悬液。加入特定的亲脂性、亲水性乳化剂复配，亲脂性乳化剂的头基与油悬液靠近，乳化剂的亲油基与Q10的侧链相互嵌合，形成球形稳定排列，附着在油悬液周围。亲水性乳化剂一端与亲油性乳化剂的支链紧密结合，起到“桥梁”作用。加入纯水后，亲水性乳化剂另一端的支链与水分子相互吸附，水分子包裹在乳化剂的外围，最终形成O/W型微乳液。
<配方>
微乳液的稳定性和生物可利用率等性质受各组分间相互作用的影响，化合物的种类和配比影响组分间的相互作用。本发明人研究后发现，具有如下特征的化合物可用于本发明，配混后可获得所需的辅酶Q10微乳液。
本发明中使用的原料辅酶Q10根据需要可使用氧化型、还原型或者二者的混合物，所述辅酶Q10可通过任何方法获得，例如，有机合成法或者微生物发酵法。配方中，以辅酶Q10微乳液的总量计，优选地，辅酶Q10的含量为1质量％～20质量％。更优选地，辅酶Q10的含量为1质量％～15质量％。最优选地，辅酶Q10的含量为1质量％～10质量％。
本发明的载体油可使用本领域常规的载体油，只要其可以与辅酶Q10溶解形成油相。从形成稳定均一的混合油相和防止辅酶Q10抗氧化性降低的角度，优选地，载体油选自由辛癸酸甘油酯、二乙二醇单乙醚、甘油聚醚、大豆磷脂和橄榄油组成的组中的至少一种。以辅酶Q10微乳液的总量计，优选 地，载体油的含量为1质量％～20质量％。更优选地，载体油的含量为2质量％～10质量％。
从复配时在油水界面上易于吸附形成乳化剂复合物，且该复合物排列紧密有序，具有较高的强度，防止油相聚结的角度，本发明的亲脂性乳化剂为聚甘油蓖麻醇酸酯。从有助于形成粒径D V(90)小于100nm的微乳液，并且所述微乳液澄清透明、不破乳、生物利用度高、极端温度环境下稳定性优异的角度，优选地，以辅酶Q10微乳液的总量计，聚甘油蓖麻醇酸酯的含量为2质量％～15质量％。更优选地，亲脂性乳化剂的含量为5质量％～10质量％。
本发明的亲水性乳化剂为聚氧乙烯醚类乳化剂。从复配时在油水界面上易于吸附形成乳化剂复合物，且该复合物排列紧密有序，具有较高的强度，防止油相聚结的角度，优选地，聚氧乙烯醚类乳化剂选自由聚氧乙烯失水山梨醇油酸酯(吐温-80)、聚氧乙烯失水山梨醇硬脂酸酯(吐温-60)、聚氧乙烯失水山梨醇月桂酸酯(吐温-20)和聚氧乙烯氢化蓖麻油组成的组中的至少一种。从有助于形成粒径D V(90)小于100nm的微乳液、并且所述微乳液澄清透明、不破乳、生物利用度高、极端温度环境下稳定性优异的角度，优选地，以辅酶Q10微乳液的总量计，亲水性乳化剂的含量为15质量％～30质量％。更优选地，亲水性乳化剂的含量为17质量％～24质量％。
本发明的助乳化剂不受限制，可使用本领域常规的任何助乳化剂，只要其可以与乳化剂配合使用，有助于形成辅酶Q10微乳液即可。从与混合油相、乳化剂体系较好混合，形成稳定均一的微乳液的角度，优选地，助乳化剂选自由甘油、山梨醇、乙醇、聚乙二醇-400(PEG-400)和聚乙二醇-800(PEG-800)组成的组中的至少一种。更优选地，助乳化剂为甘油和/或山梨醇。从有助于形成粒径D V(90)小于100nm的微乳液、并且所述微乳液澄清透明、不破乳、极端温度环境下稳定性优异的角度，优选地，以辅酶Q10微乳液的总量计，助乳化剂的含量为5质量％～25质量％。更优选地，助乳化剂的含量为7质量％～12质量％。
本发明的抗结晶剂不受限制，可使用本领域常规的任何抗结晶剂，只要其可以与乳化剂、助乳化剂配合使用，有助于形成稳定的辅酶Q10微乳液即可。从提高微乳液的稳定性，使其在较宽的温度范围内(零摄氏度以上)不使辅酶Q10结晶析出，有利于人体吸收，提高生物利用度的角度，优选地，抗结晶剂选自生育酚醋酸酯、生育酚、三羟基硬脂精、中链甘油三酸酯、聚维 酮K30、聚维酮K12、聚甘油脂肪酸酯(THL-17)(购自坂本药业，日本)、聚甘油脂肪酸酯(THL-15)(购自坂本药业，日本)中的至少一种。从更好地实现减少辅酶Q10的结晶析出和提高微乳液的稳定性的角度，优选地，以辅酶Q10微乳液的总量计，抗结晶剂的含量为0.5质量％～10质量％，更优选地，抗结晶剂含量为2质量％～5质量％。
本发明的辅酶Q10微乳液的粒径D V(90)小于100nm，该小粒径有助于形成均一澄清的微乳液，提高透明度和生物利用度。优选地，粒径D V(90)在20nm～80nm的范围，可使辅酶Q10微乳液更澄清透明、不破乳、在极端温度环境下稳定性优异。更优选地，粒径D V(90)在30nm～75nm的范围，可使辅酶Q10微乳液具有更优异的极端温度环境下的稳定性和生物利用度。最优选地，粒径D V(90)在35nm～60nm的范围，此时辅酶Q10微乳液的前述性能更优异。
<本发明的辅酶Q10微乳液的制备方法>
本发明的辅酶Q10微乳液的制备包括如下步骤：
(1)使用辅酶Q10、载体油和抗结晶剂形成油相；
优选地，将辅酶Q10、载体油和抗结晶剂在40℃～70℃水浴下搅拌溶解5min～10min，形成油相；
(2)将亲脂性乳化剂和亲水性乳化剂加入所述油相中；优选地，每加入一种乳化剂磁力搅拌5min～10min；
(3)上述油相混合均匀后，进一步加入助乳化剂，搅拌混合均匀后滴加水，继续搅拌至整个体系均一透明，90℃～120℃下保温0.5h～1h，由此得到所述辅酶Q10微乳液。
本发明发现，各组分添加完毕后，将所述混合物在90℃～120℃下保温0.5h～1h对微乳液的稳定性尤为重要。微乳液的保温过程是乳化剂的再次乳化和陈化的过程，选择适当的保温条件有利于形成粒径均匀的溶胶粒子，可以使微乳液体系更加稳定。
通过上述方法可获得粒径D V(90)在20nm～80nm之间的辅酶Q10微乳液。
<微乳液的微乳区间三相图>
三相图是研究微乳液中各组分配比关系的常见方法之一，一般微乳液中所说的三相为乳化剂/助乳化剂、油相(难溶性物质和极性有机物)、纯水。采用Shah法向乳化剂/助乳化剂和油相混合物中滴加纯水时，随水量的增加，体系由浑浊逐渐变为澄清，再由澄清变为浑浊，记录两次变化时的各组分的比 例数据，形成三相图后，就可确定此体系的微乳区间，进一步根据所需性能在微乳区间中筛选确定各组分的最优配比。
由微乳区间的大小可以看出体系的增容水量的多少，微乳区间越大，则微乳液在下游应用中稀释后越能保持微乳状态，并且在极端温度环境下越能保持稳定，呈现澄清透明的状态，特别是，在低温下不易析出，高温下不易浑浊。
<应用>
本发明的辅酶Q10微乳液可用于药物、化妆品和食品领域，尤其适用于饮料和口服液。
现有技术中的微乳液制备过程复杂，需借助高速剪切、均质、超声等工艺才能达到粒径小于100nm，并且，所得的微乳液在极端温度环境下(例如，低温(-30℃～-10℃)和高温(100℃～130℃)下)的稳定性较差。此外，辅酶Q10微乳液在食品领域中的应用也较少，微乳液稀释到口服液中还会出现浑浊破乳等问题。
本发明通过对特定的乳化剂进行复配，将混合后的各组分在特定温度下进行保温处理，可实现制备工艺的简化，获得粒径D V(90)在20nm～80nm之间的微乳液。该微乳液澄清透明，不破乳，生物利用度高，可以满足药物、化妆品和食品性能的需要，甚至可以满足条件较为苛刻的口服液制备的需要。
以下介绍本发明的辅酶Q10微乳液的性能检测的方法。
<粒径D V(90)的检测>
将微乳液样品用蒸馏水以1：20的比例稀释、轻轻摇匀，形成澄清的微乳。然后，用MASTERSIZER 3000激光粒度分布仪(购自Malvern公司，英国)测定乳液的粒径分布，测定温度为25℃。
<澄清透明度的检测>
该澄清透明度的检测也称作破乳试验，通常采用铅字法检测澄清透明度。
将辅酶Q10微乳液快速倒入透明度计筒内，检验人员从透明度计的筒口垂直向下观察，缓慢放出微乳液至刚好能清楚辨认其底部铅字的微乳液高度为辅酶Q10微乳液的透明度，一般大于30cm为透明。重复测量3次，结果取平均值。
<稳定性检测>
取微乳液样品和辅酶Q10原料，分别在4500Lx光照强度下照射、充氧灌装(25℃)和60℃(恒温箱)的条件下放置15天进行实验。在这些实验中，分别于第0天、第5天、第10天、第15天取样，用HPLC法测定辅酶Q10含量，考察光照、氧气、温度条件对辅酶Q10标示含量(％)和外观形状的影响。
<极端温度环境下的稳定性检测>
低温：将微乳液样品置于-20℃医用冰箱中15天，分别于第0天、第5天、第10天、第15天取样测定，用HPLC法测定辅酶Q10含量，考察低温环境对辅酶Q10标示含量(％)和外观性状的影响。
高温：将微乳液样品在120℃恒温箱储存0min、10min、15min、30min，取样测定，用HPLC法测定辅酶Q10含量，考察高温环境对辅酶Q10标示含量(％)和外观性状的影响。
<生物利用度的检测>
辅酶Q10原料样溶液的配制：精密称取0.1g辅酶Q10结晶溶于100mL二乙二醇单乙醚溶液中，作为原料样。
选取实施例1～6的微乳液样品，代号为样品1、样品2、样品3、样品4、样品5、样品6，进行动物性实验。
实验条件：实验室饲养环境温度25±3℃，相对湿度55％～70％，每日自由饮水摄食(去离子水和标准饲料)，其在实验前禁食12h，自由饮水。
实验动物与分组：70只8周龄健康SPF级雄性SD大鼠，由湖北省实验动物研究中心提供，体重为220g～230g。
按照国际实验动物的实验准则对大鼠进行操作，采用完全随机设计将禁食12h的大鼠每10只分为一组，共七组。
口服给药及样品采集、处理：分别对大鼠灌胃给予相同剂量(15mg/kg：辅酶Q10含量)的微乳液样品1～6和原料样，给药后分别于5min、15min、30min、1h、3h、6h、10h、15h采集血浆，放入含肝素的抗凝离心管中，混合均匀后离心，分离血浆，处理后用高效液相色谱法检测血浆药物浓度。
根据血药浓度结果，应用统计分析软件进行统计学拟合分析，计算血药浓度，结果以平均值±标准差表示。
<辅酶Q10的含量检测>
参考《中国药典》2015版辅酶Q10含量检测方法。
<微乳液的微乳区间三相图的制作>
三相图的制作方法如下：将实验过程的温度控制在50℃，然后，将辅酶Q10结晶、抗结晶剂溶解于载体油中，作为油相；将乳化剂(包括亲脂性乳化剂、亲油性乳化剂)和助乳化剂混合均匀，作为EM相；将油相与EM相按照不同的质量比(1:1，2:3，1:2，2:5，3:7，1:3，2:7，3:10，1:4，2:9，5:12，1:5，共12组)各称取一定质量，混合均匀；将水缓慢滴加到每一组中，记录每一组由浑浊变澄清时的用水量和由澄清再次变浑浊时的用水量；根据记录的油相、乳化剂/助乳化剂、水量数据绘制三相图，做两次平行实验取平均值作为绘图时所用的点值。
<实施例>
以下通过实施例对本发明进行具体描述和说明，但是，本发明不限于此。
如无特殊说明，实施例中的试剂和材料均为食品级或医药级，均可以通过商业途径获得。其中，辅酶Q10均来自于浙江新和成股份有限公司，其它原料均为市售产品。
实施例1：
将10质量％的辅酶Q10、3质量％的辛癸酸甘油酯和5质量％的生育酚醋酸酯在50℃水浴下磁力搅拌溶解10min，形成油相；
将15质量％的聚甘油蓖麻醇酸酯、30质量％的吐温-80加入油相中，每加入一种乳化剂磁力搅拌10min；
所述油相混合均匀后，加入5质量％的乙醇，磁力搅拌混合均匀后，添加水，边滴加水边磁力搅拌，直至整个体系均一透明。滴加结束后搅拌0.5h，90℃保温0.5h。
经上述方法可制备得到本发明的辅酶Q10微乳液，其粒径D V(90)如表1所示。
实施例2～实施例6：
以与实施例1相同的方式，按照表1中所示的配方配制辅酶Q10微乳液，组分的含量(质量％)以所述辅酶Q10微乳液的总量计，保温温度在90℃～120℃的范围内、保温时间在0.5h～1h的范围内改变，制备得到的微乳液的粒径D V(90)示于表1中。
表1
Figure PCTCN2022082838-appb-000001
由表1中的数据可知，按照实施例1～实施例6的配方可以获得辅酶Q10微乳液，其粒径D V(90)在20nm～80nm之间。
比较例1～比较例4：
以与实施例1相同的方式，按照如下表2的配方和保温条件制备比较例1～比较例4的辅酶Q10微乳液，同时测定其粒径D V(90)。
表2
Figure PCTCN2022082838-appb-000002
由表2中的数据可知，虽然比较例1～比较例4的其他组分、保温温度和保温时间与实施例1相同，但由于仅添加一种亲脂性乳化剂或亲水性乳化剂，制备得到的辅酶Q10微乳液的粒径偏高。该实验结果表明，只有将特定的乳化剂按照特定的比例组合使用才能制备出粒径D V(90)在20nm～80nm之间的辅酶Q10微乳液。
比较例5～比较例10和比较例11～比较例16：
以与实施例1相同的配方和制备方式，按照下表3和表4的保温温度和保温时间制备比较例5～比较例10和比较例11～比较例16的辅酶Q10微乳液，并测定微乳液的粒径D V(90)。
表3
Figure PCTCN2022082838-appb-000003
表4
Figure PCTCN2022082838-appb-000004
表3和表4显示，虽然微乳液的配方与实施例1相同，但由于保温温度和保温时间不同，微乳液的粒径D V(90)受到影响，其值均大于80nm。该实验结果表明，保温温度和保温时间对微乳液的粒径影响较大，为获得粒径D V(90)在20nm～80nm范围内的辅酶Q10微乳液，优选将保温时间控制到0.5h～1h的范围内，保温温度控制到90℃～120℃的范围内。
本申请还对实施例1～实施例6的辅酶Q10微乳液进行了澄清透明度的检测(破乳试验)和稳定性检测，考察光照(4500Lx光照)、氧气(充氧灌装，25℃)、温度(60℃，恒温箱)对辅酶Q10微乳液的稳定性的影响，分别示于表5、表6、表7中。
表5
Figure PCTCN2022082838-appb-000005
表6
Figure PCTCN2022082838-appb-000006
表7
Figure PCTCN2022082838-appb-000007
表5～表7显示，实施例1～实施例6的辅酶Q10微乳液在光照(4500Lx光照)、充氧(充氧灌装，25℃)和高温(60℃，恒温箱)条件下，辅酶Q10的标示含量和外观形状均没有显著变化。具体而言，辅酶Q10的标示含量在第5天、第10天、第15天测定的结果变化不大，比原料中辅酶Q10的标示含量更稳定。此外，微乳液的外观也呈现出澄清透明，无浑浊破乳现象。因此，本发明的辅酶Q10微乳液对光照、氧气、温度的稳定性较好，可延长产品的保存期。
此外，本申请还对实施例1～实施例6、比较例1～比较例4的辅酶Q10微乳液进行了低温(-20℃)和高温(120℃)条件下的性能实验，检测辅酶Q10标示含量和外观性状的变化。其中，低温(-20℃)的实验结果示于表8，高温(120℃)的实验结果示于表9。
表8
Figure PCTCN2022082838-appb-000008
表9
Figure PCTCN2022082838-appb-000009
表8～表9显示，实施例1～实施例6的辅酶Q10微乳液在低温(-20℃)和高温(120℃)条件下，辅酶Q10标示含量和外观性状均没有显著变化，其中，微乳液的外观呈现澄清透明，无浑浊破乳的现象。而比较例1～比较例4的辅酶Q10微乳液在低温环境下不稳定性，短时间内辅酶Q10结晶就会析出，导致微乳体系破乳。另外，比较例1～比较例4在高温下的外观也不稳定，随储存时间的延长，微乳液完全浑浊，微乳液体系被破坏。表中数据说明本发明的微乳液具有优异的极端温度环境稳定性，可满足微乳液在后续应用中的需要。
为考察辅酶Q10微乳液的生物利用度，本申请对实施例1～实施例6的辅酶Q10微乳液进行了该方面的实验，表10显示了大鼠经口服给药样品平均血药浓度-时间(mean±SD，n＝10)(μg/L)的结果。
表10
Figure PCTCN2022082838-appb-000010
表10中的数据显示，服用口服液后，与原料样相比，实施例1～实施例6的微乳液的峰浓度C max值具有统计学意义上的显著高的优势(P<0.05)，AUC值也明显较高，峰浓度的波动也小于原料样。该结果表明辅酶Q10微乳液的生物利用度高，在大鼠体内吸收快，可以达到较高的血浆浓度，用药安全性也较高。此外，由于本发明的微乳液粒径D V(90)在20nm～80nm之间，因此该较小粒径可提高药物吸收的均匀性，有利于药物吸收。
此外，本申请还分别使用实施例1、比较例1～比较例3的微乳液组分在不 同组分的配比下，按照前述方法制作三相图，分别示于图1～图4。实施例1、比较例1～比较例3的具体配方分别为图1～图4的微乳区间中的某一点值。
可以看出，图1所示的微乳区间较大，说明实施例1所在的微乳液体系的增容水量大，在下游应用中被稀释后仍能保持微乳状态，并且该微乳液在极端温度环境下也越稳定，呈现澄清透明的状态，低温下不易析出，高温下不易浑浊。与其相比，比较例1～比较例3所在的图2～图4的微乳体系，其微乳区间较小，说明该微乳液体系的增容水量小，微乳液在极端温度环境下出现析出或浑浊等不稳定情况。
产业上的可利用性
本发明还提供一种设备简单、成本低廉、易操作的辅酶Q10微乳液制备方法。由该方法制备的微乳液的粒径D V(90)在20nm～80nm之间，澄清透明，不破乳，生物利用度高，在常温和极端温度环境下储存长期稳定。本发明制备的微乳液适用于药物、化妆品和食品领域，尤其适用于饮料和口服液等产品。

Claims (10)

  1. 一种辅酶Q10微乳液，其特征在于，以所述辅酶Q10微乳液的总量计，其包括：
    1质量％～20质量％的辅酶Q10，1质量％～20质量％的载体油，0.5质量％～10质量％的抗结晶剂，2质量％～15质量％的亲脂性乳化剂，15质量％～30质量％的亲水性乳化剂，5质量％～25质量％的助乳化剂，和30质量％～65质量％的水，所述辅酶Q10微乳液的粒径D V(90)为20nm～80nm。
  2. 根据权利要求1所述的辅酶Q10微乳液，其特征在于，所述亲脂性乳化剂包含聚甘油蓖麻醇酸酯。
  3. 根据权利要求1或2所述的辅酶Q10微乳液，其特征在于，所述亲水性乳化剂包含聚氧乙烯醚类乳化剂。
  4. 根据权利要求1～3中任一项所述的辅酶Q10微乳液，其特征在于，所述载体油选自由辛癸酸甘油酯、二乙二醇单乙醚、甘油聚醚、大豆磷脂和橄榄油组成的组中的至少一种。
  5. 根据权利要求3或4所述的辅酶Q10微乳液，其特征在于，所述聚氧乙烯醚类乳化剂选自由聚氧乙烯失水山梨醇油酸酯、聚氧乙烯失水山梨醇硬脂酸酯、聚氧乙烯失水山梨醇月桂酸酯和聚氧乙烯氢化蓖麻油组成的组中的至少一种。
  6. 根据权利要求1～5中任一项所述的辅酶Q10微乳液，其特征在于，所述助乳化剂选自由甘油、山梨醇、乙醇、聚乙二醇-400和聚乙二醇-800组成的组中的至少一种。
  7. 根据权利要求1～6中任一项所述的辅酶Q10微乳液，其特征在于，所述抗结晶剂选自由生育酚醋酸酯、生育酚、三羟基硬脂精、中链甘油三酸酯、聚维酮K30、聚维酮K12、聚甘油脂肪酸酯组成的组中的至少一种。
  8. 根据权利要求1～7中任一项所述的辅酶Q10微乳液的制备方法，其特征在于，所述制备方法包括：
    使用辅酶Q10、载体油和抗结晶剂形成油相；
    将亲脂性乳化剂和亲水性乳化剂加入所述油相中；
    所述油相混合均匀后，进一步加入助乳化剂，搅拌混合均匀后滴加水，继续搅拌至整个体系均一透明，90℃～120℃下保温0.5h～1h，由此得到所述辅酶Q10微乳液。
  9. 根据权利要求1～7中任一项所述的辅酶Q10微乳液在制备药物、化妆品和食品中的应用。
  10. 根据权利要求9所述的应用，其特征在于，所述应用为制备饮料或口服液。
PCT/CN2022/082838 2021-04-23 2022-03-24 一种辅酶q10微乳液及其制备方法和应用 WO2022222683A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US18/256,231 US20240016763A1 (en) 2021-04-23 2022-03-24 Coenzyme q10 microemulsion, preparation method therefor and use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110441892.9A CN113509437B (zh) 2021-04-23 2021-04-23 一种辅酶q10微乳液及其制备方法和应用
CN202110441892.9 2021-04-23

Publications (1)

Publication Number Publication Date
WO2022222683A1 true WO2022222683A1 (zh) 2022-10-27

Family

ID=78062730

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/082838 WO2022222683A1 (zh) 2021-04-23 2022-03-24 一种辅酶q10微乳液及其制备方法和应用

Country Status (3)

Country Link
US (1) US20240016763A1 (zh)
CN (1) CN113509437B (zh)
WO (1) WO2022222683A1 (zh)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113509437B (zh) * 2021-04-23 2022-11-04 浙江新和成股份有限公司 一种辅酶q10微乳液及其制备方法和应用
CN114569573A (zh) * 2022-03-09 2022-06-03 重庆师范大学 一种自微乳化制备辅酶q10维生素e软胶囊的方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060134085A1 (en) * 2003-01-17 2006-06-22 Rumi Yamaguchi Compositions containing coenzyme q10
US20060275358A1 (en) * 2005-06-01 2006-12-07 Cardinal Health Australia 401 Pty. Ltd. Self-microemulsifying dosage forms of low solubility active ingredients such as co-enzyme Q10
WO2009022798A2 (en) * 2007-07-26 2009-02-19 Daewoong Pharmaceutical Co., Ltd. Self-microemulsifying drug delivery system composition containing coenzyme q10 and method for preparing the same
CN106727441A (zh) * 2016-12-29 2017-05-31 厦门金达威生物科技有限公司 水溶性纳米缓释功能性辅酶q10微胶囊及其制备方法与应用
CN113509437A (zh) * 2021-04-23 2021-10-19 浙江新和成股份有限公司 一种辅酶q10微乳液及其制备方法和应用

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101744288B (zh) * 2010-01-27 2013-07-10 神舟天辰科技实业有限公司 一种含有辅酶q10的澄清口服制剂及其制备方法
JP2013032301A (ja) * 2011-08-01 2013-02-14 Shizuokaken Koritsu Daigaku Hojin コエンザイムｑ１０含有組成物
CN102423297B (zh) * 2011-12-23 2013-11-20 厦门金达威集团股份有限公司 一种自微乳液及其制备方法
CN105963254B (zh) * 2016-06-28 2019-03-22 北京素维生物科技有限公司 一种辅酶q10药物组合物及其制备工艺

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060134085A1 (en) * 2003-01-17 2006-06-22 Rumi Yamaguchi Compositions containing coenzyme q10
US20060275358A1 (en) * 2005-06-01 2006-12-07 Cardinal Health Australia 401 Pty. Ltd. Self-microemulsifying dosage forms of low solubility active ingredients such as co-enzyme Q10
WO2009022798A2 (en) * 2007-07-26 2009-02-19 Daewoong Pharmaceutical Co., Ltd. Self-microemulsifying drug delivery system composition containing coenzyme q10 and method for preparing the same
CN106727441A (zh) * 2016-12-29 2017-05-31 厦门金达威生物科技有限公司 水溶性纳米缓释功能性辅酶q10微胶囊及其制备方法与应用
CN113509437A (zh) * 2021-04-23 2021-10-19 浙江新和成股份有限公司 一种辅酶q10微乳液及其制备方法和应用

Also Published As

Publication number Publication date
CN113509437B (zh) 2022-11-04
US20240016763A1 (en) 2024-01-18
CN113509437A (zh) 2021-10-19

Similar Documents

Publication Publication Date Title
WO2022222683A1 (zh) 一种辅酶q10微乳液及其制备方法和应用
DK2254600T3 (en) New Preparations and Uses thereof
EP3316860B1 (en) Delivery systems for propofol
EP1249230B1 (de) Coenzym Q10 enthaltende Mikroemulsion-Prekonzentrate und Mikroemulsionen
CN104257632B (zh) 一种虾青素固体脂质纳米粒及其制备方法
WO2022160971A1 (zh) 一种含有难溶性药物的浓缩液以及由其制备的乳剂
CN101744288B (zh) 一种含有辅酶q10的澄清口服制剂及其制备方法
WO2016177346A1 (zh) 一种卡巴他赛脂肪乳注射剂及其制备方法和用途
CN101703468A (zh) 维生素e油纳米乳制剂与制备方法
WO2022061870A1 (zh) 维生素k2微胶囊及其制备方法和在制备防治心脑血管疾病的药物中的应用
CN104523606B (zh) 自组装法制备棉酚及其衍生物普朗尼克纳米粒子的方法
CN111643451B (zh) 一种注射用和厚朴酚自乳化微乳制剂及其制备方法
CN108553417B (zh) 一种蛇床子素自乳化释药系统及其制备方法与用途
WO2020253709A1 (zh) 一种脂溶性营养药透明水分散液的制备方法
CN109692155A (zh) 一种聚醚类抗生素不饱和脂肪酸复合物油溶液剂的制备方法和应用
CN109248144B (zh) 一种透明的脂质乳剂
Zahid et al. Cytotoxicity of VCO Microemulsion Developed Using Non-Ionic Surfactants Mixture against Normal L6 Cell and Optimisation its Formulation Containing Curcumin
CN113855631B (zh) 和厚朴酚口服自微乳剂及其制备方法
Ho et al. Preparation and in vivo pharmacokinetic evaluation of stable microemulsion system of cholecalciferol
EP3190898B1 (en) Ubidecarenone composition
DK3191444T3 (en) Recrystallization of ubidecarenone for improved bioavailability
CN102727670A (zh) 一种水包油型特拉唑嗪、葡萄籽油纳米乳抗高血压药物
WO2021167481A1 (ru) Мицелированный раствор фуллеренов, способ его получение и применение
CN104274499A (zh) 一种水包油型复方米诺环素抗菌药物
CN102727862A (zh) 一种盐酸地拉普利、川芎油纳米乳抗高血压药物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22790792

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 18256231

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22790792

Country of ref document: EP

Kind code of ref document: A1