CN113876698B - Coenzyme Q with high absorption utilization degree 10 Self-emulsifying composition and process for preparing same - Google Patents

Coenzyme Q with high absorption utilization degree 10 Self-emulsifying composition and process for preparing same Download PDF

Info

Publication number
CN113876698B
CN113876698B CN202111208573.XA CN202111208573A CN113876698B CN 113876698 B CN113876698 B CN 113876698B CN 202111208573 A CN202111208573 A CN 202111208573A CN 113876698 B CN113876698 B CN 113876698B
Authority
CN
China
Prior art keywords
coenzyme
oil
essence
self
preparation
Prior art date
Legal status (The legal status 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 status listed.)
Active
Application number
CN202111208573.XA
Other languages
Chinese (zh)
Other versions
CN113876698A (en
Inventor
张冉
陈卫平
张瑞国
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
CSPC Zhongnuo Pharmaceutical Taizhou Co Ltd
Original Assignee
CSPC Zhongnuo Pharmaceutical Taizhou Co Ltd
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 CSPC Zhongnuo Pharmaceutical Taizhou Co Ltd filed Critical CSPC Zhongnuo Pharmaceutical Taizhou Co Ltd
Publication of CN113876698A publication Critical patent/CN113876698A/en
Application granted granted Critical
Publication of CN113876698B publication Critical patent/CN113876698B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • 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
    • A61K9/08—Solutions
    • 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
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4875—Compounds of unknown constitution, e.g. material from plants or animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention provides coenzyme Q with high bioavailability for human 10 Nutritional supplement and/or adjuvant therapy self-emulsifying formulation compositions and methods of preparation. Comprises the following components in percentage by weight: 5 to 30 percent of coenzyme Q 10 60-95% of edible essence, 0-5% of edible oil and 0-5% of emulsifier, and the preparation method comprises the following steps: mixing all the liquid materials evenly, heating to 60-80 ℃, and slowly adding coenzyme Q 10 Pulverizing, stirring to obtain coenzyme Q 10 Completely dissolving to obtain coenzyme Q 10 And (5) liquid medicine. The obtained coenzyme Q 10 The medicinal liquid can be maintained in clear and transparent solution state at room temperature and has aromatic and pleasant smellAnd (4) taste. The obtained coenzyme Q 10 The liquid medicine can be stably dispersed in water and self-emulsified into transparent emulsion, thereby obviously improving the coenzyme Q 10 The bioavailability is more than 4 times. The obtained coenzyme Q 10 The liquid medicine has fragrant and pleasant smell, and can be directly taken orally, or be filled into capsule or soft capsule for swallowing, or extruded to obtain content for oral administration or chewing.

Description

Coenzyme Q with high absorption utilization degree 10 Self-emulsifying composition and process for preparing same
Technical Field
The invention belongs to the technical field of nutritional supplement and/or adjuvant therapy preparation, in particular to a high-content coenzyme Q which can maintain high bioavailability in a clear solution state at room temperature and has pleasant smell 10 A self-emulsifying formulation.
Background
Coenzyme Q 10 Is a fat-soluble quinone ring compound with the chemical name of 2, 3-dimethoxy-5-methyl-6-decaisopentenyl benzoquinone. Its melting point is 48-52 deg.C, molecular formula is C 59 H 90 O 4 And the molecular weight is 862. Coenzyme Q 10 The crystal powder is yellow or light orange yellow at room temperature, is odorless and tasteless, is easily decomposed by light, and has a dark color (reddish substance), and is slightly influenced by temperature and humidity. Coenzyme Q 10 Has long isoprene side chain, so it is easily soluble in chloroform, benzene and carbon tetrachloride, soluble in acetone, petroleum ether and diethyl ether, slightly soluble in ethanol, and insoluble in water and methanol.
Coenzyme Q 10 Coenzyme of at least 3 kinds of mitochondrial enzymes (multienzyme complexes I, II and III), and its chemical structure is 2, 3-dimethoxy-5-methyl-1, 4 benzoquinone derivative with ten units of isoprene side chain connected to 6-carbon. Its quinone ring plays an important role in the oxidative respiratory chain in the transport of electrons and protons, not only essential for all life forms, but also in the formation of ATP, the main form of storage of energy in the body and the important basis on which all cellular functions are based to function normally. Coenzyme Q 10 The biological activity of (A) mainly comes fromDue to the redox characteristics of the quinone ring and the physicochemical properties of the side chains.
Coenzyme Q 10 The medicine is widely distributed in human bodies, and has high concentration in tissues and organs such as hearts, livers, kidneys, pancreases and the like. Coenzyme Q in human body 10 Mainly by self-synthesis and exogenous supplementation. Coenzyme Q produced in vivo with age 10 Gradually decreasing; in addition, in pathological conditions, endogenous coenzyme Q 10 The requirement of the machine body cannot be met. In these cases, an increased exogenous supplemental dose is required. 2009 approved coenzyme Q by national food and drug administration 10 Can be used as health food with dosage of 50 mg/day. However, in the United states, coenzyme Q 10 The dosage of the nutritional supplement is 30-100 mg/day, and the dosage of the nutritional supplement is 100-300 mg/day for improving diseases; in Japan, while the upper limit of the amount used is not determined, it is recommended that the daily amount does not exceed 300mg; the upper limit for dietary supplements in belgium is 200 mg/day; in Australia, coenzyme Q 10 The dosage is 150 mg/day; other European countries formally convert coenzyme Q from 1985 10 The nutritional supplement is administered in an amount of about 100-300 mg/day.
Coenzyme Q 10 Has multiple biological functions and can mainly prevent and/or assist in treating: (1) Cardiovascular diseases, such as heart failure, coronary heart disease, hypertension, arrhythmia, myocardial infarction, viral myocarditis, chronic cardiac insufficiency angina pectoris, arteriosclerosis, etc.; (2) Hepatitis, such as viral hepatitis, subacute hepatic necrosis, chronic active hepatitis; (3) The comprehensive treatment of cancer can reduce some adverse reactions caused by radiotherapy and chemotherapy and enhance immunity. Coenzyme Q 10 It can also prevent or reduce side effects of certain drugs, such as statins, such as lovastatin, pravastatin and cerivastatin, or cytostatic, such as doxorubicin.
Coenzyme Q 10 The lipid-soluble vitamin has good physiological effect, but the water insolubility of the vitamin makes the vitamin difficult to digest and absorb in human body. Although the oil is dissolved and diluted by using the oil agent, the fat solubility characteristic of the oil agent is not changed, so the oil agent absorbs the fatThe effect is not good; due to coenzyme Q 10 The problem of solubility in common edible oil, beeswax is required to be added as a suspension to keep the uniformity of materials in the content of the soft capsule, which brings inconvenience to the pill making of the capsule, the materials are thick and need to be kept warm, after the soft capsule is made, the temperature is reduced, the beeswax is solidified to form thick semisolid slurry, and coenzyme Q 10 Exists in the content in the form of small crystals, and influences the dissolution and the absorption in the body.
Coenzyme Q 10 Large molecular weight, high melting point and water insolubility, which is common coenzyme Q 10 The oral preparation is difficult to be absorbed by human body. In the last 20 years, some researchers have been working on finding a method for increasing the Q-factor of coenzyme 10 A method of bioavailability. At present, coenzyme Q 10 The bioavailability of the tablet and capsule products is only 1 to 2 percent, and the coenzyme Q 10 The oily soft capsule improves the absorptivity, and the bioavailability is only 2-3%. Many documents and patents report the use of self-emulsifying systems for increasing coenzyme Q 10 But most about coenzyme Q 10 In patents such as CN200480044829.6 for nutritional use, high concentration self-microemulsifying coenzyme Q 10 Preparation and CN201410033991.3 coenzyme Q with high absorption rate 10 Self-emulsifying medicine releasing system, preparation method and application thereof, CN201510794514.3 self-emulsifying coenzyme Q 10 The preparation method and application of the oil agent have no clear explanation on bioavailability. And coenzyme Q in the formulations of these documents and patents 10 Is not high enough to satisfy coenzyme Q 10 The demand, user convenience and compliance are greatly reduced; if the coenzyme Q is increased 10 Due to coenzyme Q 10 Low solubility of coenzyme Q at room temperature 10 Exists in a crystal state, and the capsule content of the compound takes a solid or semisolid state, so that the formation of a self-emulsifying system is influenced in water, and the bioavailability is influenced. Most of the coenzyme Q 10 The product is in the form of soft capsule, the contents are vegetable oil, surfactant, etc., the smell and taste are unpleasant, although the product is wrapped by rubber, but after disintegration in stomach, it is in some peopleThere is an unpleasant smell of the mouth.
Coenzyme Q 10 The solubility in different solvents is shown in the following chart:
Table1 Solubility of coenzymeQ 10 in arious solvent
Figure BDA0003307919220000021
in view of the above problems of the prior art, the present inventors have developed a coenzyme Q-rich composition having a high bioavailability and a pleasant odor, which can be maintained in a clear solution state at room temperature 10 The liquid medicine can be directly taken orally, or can be filled into capsules or soft capsules to be swallowed or extruded to obtain the content to be taken orally or chewed.
Disclosure of Invention
The object of the present invention is to overcome the drawbacks of the prior art by providing a coenzyme Q-rich solution which has a high bioavailability and a pleasant odor at room temperature and which can be maintained in a clear solution 10 A self-emulsifying formulation.
The specific technical scheme of the invention is as follows:
coenzyme Q with high bioavailability 10 A self-emulsifying formulation composition consisting essentially of two components: coenzyme Q10 and edible essence.
The coenzyme Q provided by the invention 10 The self-emulsifying preparation composition can be stably dispersed in two systems of water and oil, and can be self-emulsified into nano emulsion in a water phase.
A coenzyme Q10 self-emulsifying preparation composition with high bioavailability comprises the following components in percentage by weight: 5-30% of coenzyme Q 10 60-95% of edible essence, 0-5% of emulsifier and 0-5% of edible oil.
Preferably, a coenzyme Q with high bioavailability 10 The self-emulsifying preparation composition comprises the following components in percentage by weight: 5 to 15 percent of coenzyme Q 10 80-95% of edible essence, 0-2% of emulsifier and 0-3% of edible oil.
Still more preferably, a coenzyme Q having high bioavailability 10 Self-emulsifyingThe preparation composition comprises the following components in percentage by weight: 8-12% of coenzyme Q 10 85-91% of edible essence and 1-3% of edible oil.
The edible essence is water-soluble liquid essence, and is selected from one or more of sweet orange oil essence, pomelo peel oil essence, lemon oil essence, bergamot oil essence, tangerine oil essence and bitter orange oil essence; furthermore, the sweet orange oil essence, the shaddock peel oil essence, the lemon oil essence, the bergamot oil essence, the tangerine oil essence and the bitter orange oil essence are prepared from sweet orange oil, shaddock peel oil, lemon oil, bergamot oil, tangerine oil, bitter orange oil and edible essence auxiliary materials.
Further, the content of terpene component (limonene) in the edible essence is 15-25%, preferably 20-25%.
Still further, the auxiliary materials in the edible essence are selected from one or more of tween, polyoxyethylene fatty acid ester, poloxamer, sucrose ester, span, monoglyceride and polyethylene glycol. Preferably, the auxiliary material is tween 80.
The emulsifier is one or more of tween, polyoxyethylene fatty acid ester, poloxamer, sucrose ester, span, monoglyceride and polyethylene glycol. Preferably, the emulsifier is tween 80.
The edible oil is one or more selected from sunflower oil, soybean oil, corn oil, olive oil, palm oil, coconut oil and medium chain triglyceride. Preferably, the edible oil is corn oil or medium chain triglyceride.
Another object of the present invention is to provide the above-mentioned coenzyme Q 10 Preparation method and application of the preparation are provided.
Coenzyme Q with high bioavailability 10 The preparation method of the self-emulsifying preparation comprises the following steps:
(1) Coenzyme Q 10 Preparation of a liquid medicine: mixing edible essence, emulsifier and edible oil uniformly, heating to 60-80 deg.C, slowly adding coenzyme Q10 powder, keeping temperature, stirring until coenzyme Q 10 Completely dissolving to obtain coenzyme Q 10 And (5) liquid medicine.
(2) Coenzyme Q 10 Preparation of the formulationPreparing: the coenzyme Q prepared in the step (1) 10 The liquid medicine is further prepared into coenzyme Q 10 Soft capsule, coenzyme Q 10 Liquid hard capsule and coenzyme Q 10 Oral liquid and coenzyme Q 10 Any one of the drops, preferably coenzyme Q 10 Soft capsule or coenzyme Q 10 An oral liquid.
The beneficial effects of the invention are:
1. the coenzyme Q with high bioavailability of the invention 10 The medicinal liquid of the self-emulsifying preparation can be kept in a clear and transparent liquid state at room temperature, and has high stability.
2. The coenzyme Q with high bioavailability of the invention 10 The medicinal liquid of the self-emulsifying preparation can be dispersed in water and self-emulsified into transparent nano emulsion, the particle size is in the range of 20-200 nm, the self-emulsifying effect is ensured, and the bioavailability is provided.
3. The coenzyme Q with high bioavailability provided by the invention 10 Self-emulsifying preparation, 50 mg/granule coenzyme Q for oral administration 10 The soft capsule is equivalent to oral administration of 200 mg/capsule of conventional coenzyme Q 10 The soft capsule has improved clinical effect and can improve coenzyme Q 10 The bioavailability is more than 4 times.
4. The high content coenzyme Q of the invention 10 The liquid medicine of the self-emulsifying preparation has fragrant and pleasant smell and can be directly taken orally.
5. The high content coenzyme Q of the invention 10 The preparation method of the self-emulsifying preparation is simple, easy to realize industrial production, economic and environment-friendly.
Drawings
FIG. 1: example 13 coenzyme Q in rat plasma 10 Concentration versus time graph of
The abscissa axis is time, unit: hours; the ordinate is coenzyme Q 10 Plasma concentration, unit: μ g/mL.
FIG. 2: example 13 coenzyme Q in rat plasma 10 Concentration (Cmax) is plotted against time.
Coenzyme Q in ordinate 10 Concentration, in. Mu.g/mL.
FIG. 3: example 13 coenzyme Q in rat plasma 10 Under the concentration curveProduct (AUC) vs. graph.
Coenzyme Q in ordinate 10 Area under the concentration curve in units of μ g. ML -1 ·h。
FIG. 4: coenzyme Q in human plasma in example 14 10 Area under the curve (AUC) comparison graph of concentration 0-12 hours.
Coenzyme Q in ordinate 1 Area under the 0 concentration curve in units of μ g. ML -1 ·h。
FIG. 5 is a schematic view of: example 14 coenzyme Q for human administration 10 Coenzyme Q in plasma on day 15 10 The concentration is increased.
Detailed Description
The invention discloses coenzyme Q with high bioavailability for human 10 The nutritional supplement and/or adjuvant therapy self-emulsifying preparation composition and the preparation method can be realized by appropriately improving the process parameters by combining the related principles of medicinal preparations and edible essences according to the content of the invention. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the scope of the invention.
For a better understanding of the invention, and not as a limitation on the scope thereof, all numbers expressing quantities, percentages, and other numerical values used in this application are to be understood as being modified in all instances by the term "about". At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.
Sweet orange oil, lemon oil: the terpene component content is above 90%, and is from Shanghai Jiuzi industries, inc.
Sweet orange oil essence: the sweet orange oil and the accessory Tween are mixed to prepare the water-soluble essence containing 15 to 25 percent of terpene components.
Lemon oil essence: the lemon oil and the accessory Tween are mixed to prepare the water-soluble essence containing 15 to 25 percent of terpene components
The detection method of terpene components (calculated by limonene) in the edible essence comprises the following steps: and (4) measuring by gas chromatography.
The chromatographic conditions and the system applicability test are performed by using a quartz capillary column: zebron ZB-Wax column (30 ml. Times.0.53 mm ID. Times.1.0 mm dF) surface coated with 100% polyethylene glycol; flow rate of carrier gas: 5mL/min; column temperature: the temperature of the sample inlet is 220 ℃ and the temperature of the detector is 220 ℃. The number of theoretical plates should not be less than 6000 calculated as limonene peak.
Preparation of control solution A proper amount of limonene control was precisely weighed, placed in a brown measuring flask, and added with acetone to make a solution containing 0.8mg per 1 mL.
Preparation of test solution A proper amount of the content (about 40mg of limonene) under the condition of different filling amounts of the test solution is precisely weighed, placed in a 50mL brown measuring flask, dissolved and diluted to scale by adding acetone, shaken up and centrifuged to obtain the test solution.
The determination method comprises precisely sucking 1mL of each of the reference solution and the sample solution, injecting into a gas chromatograph, determining, and calculating.
Wherein the modes are conventional methods unless otherwise specified; the reagents and materials, unless otherwise specified, are food grade or pharmaceutical grade and are commercially available.
Example 1: coenzyme Q 10 Self-emulsifying oral liquid
(1) The composition comprises the following components:
components Weight percent of
Coenzyme Q 10 10％
Sweet orange oil essence (terpene component content is 24%) 83％
Medium chain triglycerides 5％
Tween 80 2％
(2) The preparation method comprises the following steps:
(1) coenzyme Q 10 Preparation of a liquid medicine: uniformly mixing the sweet orange oil essence, the medium chain triglyceride and the Tween 80 according to the prescription amount, heating to 60 ℃, and slowly adding the coenzyme Q 10 Pulverizing, stirring while keeping the temperature until the coenzyme Q 10 Completely dissolving, making the whole system be orange red and uniform transparent liquid to obtain coenzyme Q 10 And (5) liquid medicine.
(2) Coenzyme Q 10 Preparation of the preparation: cooling the liquid medicine prepared in the step (1) and then bottling the liquid medicine to obtain the coenzyme Q 10 An oral liquid.
(3) Self-emulsification detection:
1g of the product is added into 100mL of purified water, and the mixture is slightly shaken to obtain an orange transparent aqueous solution, so that the water dispersibility of the product is good.
Example 2: coenzyme Q 10 Self-emulsifying soft capsule
(1) The composition comprises the following components:
components Weight percent of
Coenzyme Q 10 10％
Sweet orange oil essence (terpene component content 22%) 87％
Corn oil
1％
Tween 80 2％
(2) The preparation method comprises the following steps:
(1) coenzyme Q 10 Preparation of a liquid medicine: uniformly mixing the sweet orange oil essence, the corn oil and the Tween 80 according to the prescription amount, heating to 70 ℃, and slowly adding the coenzyme Q 10 Powder, stirring while keeping the temperature until the coenzyme Q 10 Completely dissolving, and making the whole system be orange red and uniform transparent liquid to obtain coenzyme Q 10 And (5) liquid medicine.
(2) Coenzyme Q 10 Preparation of the preparation: taking the liquid medicine prepared in the step (1) as the content of the soft capsule, and preparing the soft capsule, wherein the content of each soft capsule is 500mg, and the coenzyme Q 10 The content of (B) is 50mg.
(3) Self-emulsification detection:
1g of the product is added into 100mL of purified water and slightly shaken to obtain an orange transparent aqueous solution, so that the water dispersibility of the product is good.
Example 3: coenzyme Q 10 Self-emulsifying drops
(1) The composition comprises the following components:
components Weight percent of
Coenzyme Q 10 15％
Lemon oil essence (terpene component content 23%) 82％
Corn oil
1％
Tween 80 2％
(2) The preparation method comprises the following steps:
(1) coenzyme Q 10 Preparation of a liquid medicine: uniformly mixing the lemon oil essence, the corn oil and the Tween 80 according to the prescription amount, heating to 80 ℃, and slowly adding the coenzyme Q 10 Pulverizing, stirring while keeping the temperature until the coenzyme Q 10 Completely dissolving, and making the whole system be orange red and uniform transparent liquid to obtain coenzyme Q 10 And (5) liquid medicine.
(2) Coenzyme Q 10 Preparation of the preparation: cooling the liquid medicine prepared in the step (1), and filling the liquid medicine into a glass bottle with a dropper to obtain the coenzyme Q 10 Drops are prepared.
(3) Self-emulsification detection:
1g of the product is added into 100mL of purified water and slightly shaken to obtain an orange transparent aqueous solution, so that the water dispersibility of the product is good.
Example 4: coenzyme Q 10 Self-emulsifying soft capsule
(1) The composition comprises the following components:
components Weight percent of
Coenzyme Q 10 10％
Sweet orange oil essence (terpene component content 21%) 88％
Corn oil
2％
(2) The preparation method comprises the following steps:
(1) coenzyme Q 10 Preparation of a liquid medicine: uniformly mixing the sweet orange oil essence and the corn oil according to the prescription amount, heating to 70 ℃, and slowly adding the coenzyme Q 10 Powder, stirring while keeping the temperature until the coenzyme Q 10 Completely dissolving, and making the whole system be orange red and uniform transparent liquid to obtain coenzyme Q 10 And (5) liquid medicine.
(2) Coenzyme Q 10 Preparation of the preparation: taking the liquid medicine prepared in the step (1) as the content of the soft capsule, and preparing the soft capsule, wherein the content of each soft capsule weighs 500mg, and the coenzyme Q is contained in the soft capsule 10 The content of (B) is 50mg.
(3) Self-emulsification detection:
1g of the product is added into 100mL of purified water and slightly shaken to obtain an orange transparent aqueous solution, so that the water dispersibility of the product is good.
Example 5: coenzyme Q 10 Self-emulsifying liquid hard capsule
(1) The composition comprises the following components:
components Weight percent of
Coenzyme Q 10 10％
Sweet orange oil essence (terpene component content 19%) 85％
Medium chain triglycerides 5％
(2) The preparation method comprises the following steps:
(1) coenzyme Q 10 Preparation of a liquid medicine: uniformly mixing the sweet orange oil essence and the medium-chain triglyceride according to the prescription amount, heating to 60 ℃, and slowly adding coenzyme Q 10 Powder, stirring while keeping the temperature until the coenzyme Q 10 Completely dissolving, and making the whole system be orange red and uniform transparent liquid to obtain coenzyme Q 10 And (5) liquid medicine.
(2) Coenzyme Q 10 Preparation of the preparation: taking the liquid medicine prepared in the step (1) as hard capsule contents to prepare liquid hard capsules, wherein the weight of each hard capsule content is 500mg, and the coenzyme Q 10 The content of (B) is 50mg.
(3) Self-emulsification detection:
1g of the product is added into 100mL of purified water and slightly shaken to obtain an orange transparent aqueous solution, so that the water dispersibility of the product is good.
Example 6: coenzyme Q 10 Self-emulsifying soft capsule
(1) The composition comprises the following components:
components Weight percent of
Coenzyme Q 10 5％
Sweet orange oil essence (terpene component content is 15%) 95％
(2) The preparation method comprises the following steps:
(1) coenzyme Q 10 Preparation of a liquid medicine: heating the sweet orange oil essence with the prescription amount to 70 ℃, and slowly adding coenzyme Q 10 Powder, stirring while keeping the temperature until the coenzyme Q 10 Completely dissolving, and making the whole system be orange red and uniform transparent liquid to obtain coenzyme Q 10 And (5) liquid medicine.
(2) Coenzyme Q 10 Preparation of the preparation: taking the liquid medicine prepared in the step (1) as the content of the soft capsule, and preparing the soft capsule, wherein the content of each soft capsule is 500mg, and the coenzyme Q 10 The content of (B) is 25mg.
(3) Self-emulsification detection:
1g of the product is added into 100mL of purified water and slightly shaken to obtain an orange transparent aqueous solution, so that the water dispersibility of the product is good.
Example 7: coenzyme Q 10 Self-emulsifying soft capsule
(1) The composition comprises the following components:
Figure BDA0003307919220000081
Figure BDA0003307919220000091
(2) The preparation method comprises the following steps:
(1) coenzyme Q 10 Preparation of a liquid medicine: heating the formula amount of sweet orange oil essence, medium chain triglyceride and tween 80 to 70 deg.C, slowly adding coenzyme Q 10 Powder, stirring while keeping the temperature until the coenzyme Q 10 Completely dissolved, the whole system is orange red and uniform transparent liquid, and the auxiliary material is obtainedEnzyme Q 10 And (5) liquid medicine.
(2) Coenzyme Q 10 Preparation of the preparation: taking the liquid medicine prepared in the step (1) as the content of the soft capsule, and preparing the soft capsule, wherein the content of each soft capsule weighs 500mg, and the coenzyme Q is contained in the soft capsule 10 The content of (B) is 150mg.
(3) Self-emulsification detection:
1g of the product is added into 100mL of purified water and slightly shaken to obtain an orange transparent aqueous solution, so that the water dispersibility of the product is good.
Example 8: coenzyme Q 10 Self-emulsifying oral liquid
(1) The composition comprises the following components:
Figure BDA0003307919220000092
(2) The preparation method comprises the following steps:
(1) coenzyme Q 10 Preparation of a liquid medicine: uniformly mixing sweet orange oil essence and lemon oil essence according to the prescription amount, heating to 60 ℃, and slowly adding coenzyme Q 10 Pulverizing, stirring while keeping the temperature until the coenzyme Q 10 Completely dissolving, and making the whole system be orange red and uniform transparent liquid to obtain coenzyme Q 10 And (5) liquid medicine.
(2) Coenzyme Q 10 Preparation of the preparation: cooling the liquid medicine prepared in the step (1) and then filling the liquid medicine into a bottle to obtain the coenzyme Q 10 An oral liquid.
(3) Self-emulsification detection:
1g of the product is added into 100mL of purified water, and the mixture is slightly shaken to obtain an orange transparent aqueous solution, so that the water dispersibility of the product is good.
Example 9: coenzyme Q 10 Self-emulsifying oral liquid
(1) The composition comprises the following components:
components Weight percent of
Coenzyme Q 10 15％
Lemon oil essence (terpene component content 25%) 80％
Polyethylene glycol 400 3％
Corn oil
2％
(2) The preparation method comprises the following steps:
(1) coenzyme Q 10 Preparation of a liquid medicine: mixing lemon oil essence, polyethylene glycol 400 and corn oil uniformly, heating to 60 deg.C, and slowly adding coenzyme Q 10 Pulverizing, stirring while keeping the temperature until the coenzyme Q 10 Completely dissolving, and making the whole system be orange red and uniform transparent liquid to obtain coenzyme Q 10 And (5) liquid medicine.
(2) Coenzyme Q 10 Preparation of the preparation: cooling the liquid medicine prepared in the step (1) and then filling the liquid medicine into a bottle to obtain the coenzyme Q 10 An oral liquid.
(3) Self-emulsification detection:
1g of the product is added into 100mL of purified water, and the mixture is slightly shaken to obtain an orange transparent aqueous solution, so that the water dispersibility of the product is good.
Example 10: coenzyme Q 10 Self-emulsifying soft capsule
(1) The composition comprises the following components:
components Weight percent of
Coenzyme Q 10 8％
Sweet orange oil essence (terpene component content 23%) 91％
Corn oil
1％
(2) The preparation method comprises the following steps:
(1) coenzyme Q 10 Preparing a liquid medicine: heating the sweet orange oil essence and corn oil of the prescription amount to 70 ℃, and slowly adding coenzyme Q 10 Powder, stirring while keeping the temperature until the coenzyme Q 10 Completely dissolving, and making the whole system be orange red and uniform transparent liquid to obtain coenzyme Q 10 And (5) liquid medicine.
(2) Coenzyme Q 10 Preparation of the preparation: taking the liquid medicine prepared in the step (1) as the content of the soft capsule, and preparing the soft capsule, wherein the content of each soft capsule is 500mg, and the coenzyme Q 10 The content of (B) is 40mg.
(3) Self-emulsification detection:
1g of the product is added into 100mL of purified water and slightly shaken to obtain an orange transparent aqueous solution, so that the water dispersibility of the product is good.
Comparative example 1: coenzyme Q 10 Self-emulsifying soft capsule
(1) The composition comprises the following components:
components Weight percent of
Coenzyme Q 10 10％
Medium chain triglycerides 20％
Tween 80 70％
(2) The preparation method comprises the following steps:
(1) coenzyme Q 10 Preparation of a liquid medicine: mixing the prescription amount of medium chain triglyceride and tween 80, heating to 70 deg.C, and slowly adding coenzyme Q 10 Powder, stirring while keeping the temperature until the coenzyme Q 10 Completely dissolving, and making the whole system be orange red and uniform transparent liquid to obtain coenzyme Q 10 And (5) liquid medicine.
(2) Coenzyme Q 10 Preparation of the preparation: taking the liquid medicine prepared in the step (1) as the content of the soft capsule, and preparing the soft capsule, wherein the content of each soft capsule is 500mg, and the coenzyme Q 10 The content of (B) is 50mg.
(3) Self-emulsification detection:
this product, 1g, was added to 100mL of purified water and shaken vigorously to give a cloudy orange-yellow aqueous emulsion, from which it was seen that comparative example 1 had poor water dispersibility.
Comparative example 2: coenzyme Q 10 Self-emulsifying soft capsule
(1) The composition comprises the following components:
components Weight percent of
Coenzyme Q10 10％
Soybean oil 45％
Soybean lecithin 40％
Beeswax (Cera flava) 5％
(2) The preparation method comprises the following steps:
(1) coenzyme Q 10 Preparation of a liquid medicine: mixing soybean oil, soybean phospholipid and Cera flava, heating to 70 deg.C, and slowly adding coenzyme Q 10 Powder, stirring while keeping the temperature until the coenzyme Q 10 Completely dissolving, and making the whole system be orange yellow semisolid suspension to obtain coenzyme Q 10 And (5) liquid medicine.
(2) Coenzyme Q 10 Preparation of the preparation: taking the liquid medicine prepared in the step (1) as the content of the soft capsule, and preparing the soft capsule, wherein the content of each soft capsule is 500mg, and the coenzyme Q 10 The content of (B) is 50mg.
(3) Self-emulsification detection:
1g of this product was added to 100mL of purified water, vigorously shaken, allowed to stand for immediate separation, and the content floated semisolid on water, and no uniform emulsion could be obtained, from which it was seen that comparative example 2 could not self-emulsify in water.
Comparative example 3: coenzyme Q 10 Self-emulsifying soft capsule
(1) The composition comprises the following components:
components Weight percent of
Coenzyme Q 10 10％
Medium chain triglycerides 90％
(2) The preparation method comprises the following steps:
(1) coenzyme Q 10 Preparation of a liquid medicine: heating the prescribed amount of medium chain triglycerides to 70 deg.C, slowly adding coenzyme Q 10 Powder, stirring while keeping the temperature until the coenzyme Q 10 Completely dissolving to obtain orange semisolid suspension as whole system to obtain coenzyme Q 10 And (5) liquid medicine.
(2) Coenzyme Q 10 Preparation of the preparation: taking the liquid medicine prepared in the step (1) as the content of the soft capsule, and preparing the soft capsule, wherein the content of each soft capsule weighs 500mg, and the coenzyme Q is contained in the soft capsule 10 The content of (B) is 50mg.
(3) Self-emulsification detection:
this product, 1g, was added to 100mL of purified water, shaken vigorously, allowed to stand and separate immediately, and the content oil floated on water, and a uniform emulsion could not be obtained, whereby it was seen that comparative example 3 could not self-emulsify in water.
And (4) conclusion: as can be seen from comparative examples 1 to 3, when the flavoring essence having a terpene component was not used in the composition, the prepared soft capsules had poor self-emulsifying properties and stability and low bioavailability (see, specifically, examples 11, 12, and 13).
Comparative example 4: coenzyme Q 10 Self-emulsifying soft capsule
(1) The composition comprises the following components:
components Weight percent of
Coenzyme Q 10 10％
Sweet orange oil essence (terpene component content of 29%) 88％
Corn oil
2％
(2) The preparation method comprises the following steps:
(1) coenzyme Q 10 Preparing a liquid medicine: uniformly mixing the sweet orange oil essence and the corn oil according to the prescription amount, heating to 70 ℃, and slowly adding the coenzyme Q 10 Powder, stirring while keeping the temperature until the coenzyme Q 10 Completely dissolving, and making the whole system be orange red and uniform transparent liquid to obtain coenzyme Q 10 And (5) liquid medicine.
(2) Coenzyme Q 10 Preparation of the preparation: taking the liquid medicine prepared in the step (1) as the content of the soft capsule, and preparing the soft capsule, wherein the content of each soft capsule is 500mg, and the coenzyme Q 10 The content of (B) is 50mg.
(3) Self-emulsification detection:
this product, 1g, was added to 100mL of purified water, shaken vigorously, allowed to stand and separate immediately, and the content floated oily on water, and no uniform emulsion could be obtained, from which it was seen that comparative example 4 was not self-emulsifiable in water.
Comparative example 5: coenzyme Q 10 Self-emulsifying oral liquid
(1) The composition comprises the following components:
components Weight percent of
Coenzyme Q 10 10％
Sweet orange oil essence (terpene component content is 12%) 88％
Corn oil
2％
(2) The preparation method comprises the following steps:
(1) coenzyme Q 10 Preparation of a liquid medicine: uniformly mixing the sweet orange oil essence and the corn oil according to the prescription amount, heating to 70 ℃, and slowly adding the coenzyme Q 10 Pulverizing, stirring while keeping the temperature until the coenzyme Q 10 Completely dissolving, and making the whole system be orange red and uniform transparent liquid to obtain coenzyme Q 10 And (5) liquid medicine.
(2) Coenzyme Q 10 Preparation of the preparation: and (2) cooling the liquid medicine prepared in the step (1) and then filling the liquid medicine into a bottle to obtain the coenzyme Q10 oral liquid. The obtained coenzyme Q 10 The crystal is gradually separated out by oral liquid and light detection.
(3) Self-emulsification detection:
1g of the product is added into 100mL of purified water and slightly shaken to obtain orange transparent water emulsion, so that the water dispersibility of the product is good.
And (4) conclusion: as can be seen from comparative examples 4 to 5, when the terpene component content of the orange oil flavor is less than 15% (e.g., 12% in comparative example 5), the self-emulsified oral liquid prepared has condensed orange yellow crystals, and furtherDetected as coenzyme Q 10 (ii) a When the terpene component content of the sweet orange oil essence is higher than 25% (e.g. 29% of comparative example 4), the self-emulsifying capsule prepared has poor self-emulsifying property and cannot be uniformly dispersed in water.
Comparative example 6: coenzyme Q 10 Self-emulsifying soft capsule
(1) The composition comprises the following components:
components Weight percent of
Coenzyme Q 10 10％
Sweet orange oil essence (terpene component content of 21%) 55％
Medium chain triglycerides 35％
(2) The preparation method comprises the following steps:
(1) coenzyme Q 10 Preparation of a liquid medicine: uniformly mixing the sweet orange oil essence and the medium-chain triglyceride according to the prescription amount, heating to 70 ℃, and slowly adding coenzyme Q 10 Powder, stirring while keeping the temperature until the coenzyme Q 10 Completely dissolving, and making the whole system be orange red and uniform transparent liquid to obtain coenzyme Q 10 And (5) liquid medicine.
(2) Coenzyme Q 10 Preparation of the preparation: taking the liquid medicine prepared in the step (1) as the content of the soft capsule, and preparing the soft capsule, wherein the content of each soft capsule is 500mg, and the coenzyme Q 10 The content of (B) is 50mg.
(3) Self-emulsification detection:
this product, 1g, was added to 100mL of purified water, shaken vigorously, allowed to stand, and gradually separated into layers, and the oily contents floated on water, and a uniform emulsion could not be obtained, whereby it was seen that comparative example 6 could not be completely self-emulsified in water.
Comparative example 7: coenzyme Q 10 Self-emulsifying soft capsule
(1) The composition comprises the following components:
components Weight percent of
Coenzyme Q 10 10％
Sweet orange oil essence (terpene component content of 21%) 55％
Corn oil 35％
(2) The preparation method comprises the following steps:
(1) coenzyme Q 10 Preparation of a liquid medicine: uniformly mixing the sweet orange oil essence and the corn oil according to the prescription amount, heating to 70 ℃, and slowly adding the coenzyme Q 10 Powder, stirring while keeping the temperature until the coenzyme Q 10 Completely dissolving, and making the whole system be orange red and uniform transparent liquid to obtain coenzyme Q 10 And (5) liquid medicine.
(2) Coenzyme Q 10 Preparation of the preparation: taking the liquid medicine prepared in the step (1) as the content of the soft capsule, and preparing the soft capsule, wherein the content of each soft capsule weighs 500mg, and the coenzyme Q is contained in the soft capsule 10 The content of (B) is 50mg.
During the pelleting process, a large amount of coenzyme Q is discovered 10 Crystallization affecting each coenzyme Q 10 The uniformity of the product content is difficult to control.
(3) Self-emulsification detection:
this product, 1g, was added to 100mL of purified water, shaken vigorously, allowed to stand, and gradually separated into layers, and the oily contents floated on water, and a uniform emulsion could not be obtained, whereby it was seen that comparative example 7 could not be completely self-emulsified in water.
And (4) conclusion: as can be seen from comparative examples 6 to 7, when the amount of the essence of sweet orange oil is less than 60% (e.g., 55% of comparative examples 6 to 7), the self-emulsifying soft gelatin capsule prepared has poor emulsifying properties and is not uniformly dispersed in water.
Example 11: coenzyme Q 10 Stability testing of self-emulsifying formulations
For the coenzyme Q prepared in examples 1 to 10 and comparative examples 1 to 7 10 Stability tests were performed on the self-emulsifying formulations to see if phase separation, turbidity and crystallization occurred at different temperatures. Coenzyme Q 10 The liquid formulations were stored in thermostats at 10 ℃, 25 ℃ and 37 ℃ and after one week the samples were visually checked for stability. The results are shown in table 1:
TABLE 1 different coenzymes Q 10 Stability test results for self-emulsifying formulations
Figure BDA0003307919220000141
/>
Figure BDA0003307919220000151
The results of the stability tests in the above table show that the coenzyme Q obtained by the invention 10 The liquid preparation can be kept stable at a lower temperature and a wider temperature range, the transparency of the system is kept good, and the phenomena of phase separation and crystallization precipitation are avoided.
Example 12: coenzyme Q 10 Self-emulsification test of self-emulsifying formulations
Coenzyme Q prepared in examples 1 to 10 and comparative examples 1 to 7 10 After the self-emulsifying preparation was left at 25 ℃ for one week, 1g of each sample was added to 100mL of purified water, shaken, and the dispersibility in water was observed to examine the particle size of the solution. The results show that:
(1) Dispersibility in water: coenzyme Q obtained by the invention 10 The liquid preparation can be self-emulsified in water and has good dispersibility.
(2) The particle size of the solution is shown in Table 2.
TABLE 2 different coenzymes Q 10 Particle size detection result of liquid preparation in water
Examples Dispersibility in water Particle size (nm)
Example 1 Transparent homogeneous liquid 123
Example 2 Transparent homogeneous liquid 176
Example 3 Transparent homogeneous liquid 46
Example 4 Transparent homogeneous liquid 27
Example 5 Transparent homogeneous liquid 188
Example 6 Transparent homogeneous liquid 20
Example 7 Transparent homogeneous liquid 190
Example 8 Transparent homogeneous liquid 29
Example 9 Transparent homogeneous liquid 38
Example 10 Transparent homogeneous liquid 22
Comparative example 1 Suspension homogeneous liquid 1654
Comparative example 2 Semi-solid floating shape ——
Comparative example 3 Oil-like floating state ——
Comparative example 4 Oil-like floating state ——
Comparative example 5 Transparent homogeneous liquid 191
Comparative example 6 Oil-like floating state ——
Comparative example 7 Oil-like floating state ——
Example 13: bioavailability test in rats
Coenzyme Q of the invention 10 Animal experiments prove that the self-emulsifying preparation can obviously improve the in vivo bioavailability of the coenzyme Q10, and the experimental steps and results are as follows:
(1) Sample preparation:
coenzyme Q prepared in example 1 and example 4 10 Self-emulsifying formulations (code: sample 1, sample 2);
coenzyme Q prepared in comparative examples 2 and 3 10 Self-emulsifying formulation (code: reference 1, reference 2).
(2) Test animals and groups:
the test animal is SD male rat bought from Beijing Wittingle laboratory animal technology Limited and has weight of 280-320 g. Each 8 rats were in 1 group for a total of 4 groups.
(3) The test conditions are as follows:
the environment temperature is 23-25 ℃, the relative humidity is 40-60%, and purified water and standard feed can be freely taken every day.
(4) Oral administration and blood sample collection:
one week after acclimation feeding, gavage administration was started. The administration amount is 60mg/kg each time by intragastric administration at 8% in the morning and 20% in the evening. Fasting is not forbidden after the lavage at night on the fourth day, blood sampling is started after 8:00 in the morning on the fifth day, blood is sampled in an anticoagulation tube by taking the last administration as 0 hour and taking sampling time points as 0, 1, 2,3, 4, 5, 6, 8, 10, 12 and 24 hours, and blood plasma is taken after centrifugal separation and is subjected to coenzyme Q 10 Detection of (3).
(5) Sample detection:
collecting centrifuged plasma 200 μ L, adding 400 μ L anhydrous ethanol, oscillating for 10 s, adding 5mL n-hexane, oscillating for 5 min, centrifuging at 3000rpm for 10 min, transferring the upper layer to clean centrifuge tube, evaporating, adding 100 μ L anhydrous ethanol for dissolving, and performing HPLC to obtain coenzyme Q 10 And (6) detecting.
(6) And (4) analyzing results:
coenzyme Q at each time point 10 The plasma concentration was subtracted from the corresponding 0 hour plasma concentration to obtain coenzyme Q 10 Net plasma concentrations, as shown in figure 1.
As shown in FIG. 2, the highest net coenzyme Q of the groups of sample 1 and sample 2 10 Highest net coenzyme Q of reference 1 and reference 2 groups at concentrations of 1.32 and 1.34. Mu.g/mL, respectively 10 The concentrations were 0.18 and 0.30. Mu.g/mL, respectively. Highest net coenzyme Q of sample group 10 The concentration is 4 to 7 times of the reference sample group.
As shown in FIG. 3, sample 1 and sample 2 combined coenzyme Q 10 The area under the concentration curve (AUC) was 4.24 and 4.17. Mu.g.mL, respectively -1 H, reference 1 and reference 2 clean coenzyme Q 10 The areas under the concentration curve were 1.11 and 0.30. Mu.g.mL, respectively -1 H, AUC of the sample group is 4 to 13 times that of the reference group.
From this, it can be seen that the coenzyme Q prepared in examples 1 and 4 of the present invention 10 The bioavailability of the liquid preparation is coenzyme Q in comparative example 2 and comparative example 3 10 The bioavailability of the preparation is more than 4 times.
Example 14: bioavailability test in human body
Coenzyme Q of the invention 10 Human body tests prove that the self-emulsifying preparation can obviously improve the coenzyme Q 10 The in vivo bioavailability, test procedures and results are as follows:
(1) Sample preparation:
coenzyme Q prepared in example 4 10 Soft capsules, 50mg coenzyme Q 10 Grains (sample);
coenzyme Q commercially available 10 Soft capsule (the auxiliary materials of the content are rice bran oil and soybean lecithin), 200mg coenzyme Q 10 Particle (reference).
(2) Test population and grouping:
the test population is 30-50 years old, and the healthy adult male comprises 20 people and the healthy adult female comprises 20 people. Groups were divided into 4 groups of 10 persons each according to age and gender.
(3) The test conditions are as follows:
without changing original living habit, normal diet and work, coenzyme Q should not be taken during the period 10 And (4) products are similar.
(4) Oral administration and blood sample collection:
1 coenzyme Q is taken 8 10 Soft capsule is administered continuously for 2 weeks.
Coenzyme Q was administered 8 10 Collecting blood before soft capsule as basic blood sample, and taking coenzyme Q 10 Collecting blood 2, 4, 6, 8, 10, and 12 hr after soft capsule, centrifuging, collecting blood plasma, and processing coenzyme Q 10 Detection of (3).
Administration of coenzyme Q at 8 10 Collecting blood before soft capsule as basic blood sample, and taking coenzyme Q 10 Collecting blood 2, 4, 6, 8, 10, and 12 hr after soft capsule, centrifuging blood sample, collecting plasma, and processing coenzyme Q 10 Detection of (3).
(5) Sample detection:
collecting centrifuged plasma 200 μ L, adding 400 μ L anhydrous ethanol, oscillating for 10 s, adding 5mL n-hexane, oscillating for 5 min, centrifuging at 3000rpm for 10 min, transferring the upper layer to clean centrifuge tube, evaporating, adding 100 μ L anhydrous ethanol for dissolving, and performing HPLC to obtain coenzyme Q 10 And (6) detecting.
(6) And (4) analyzing results:
coenzyme Q of each human at each time point 10 Plasma concentrations (in. Mu.g/mL) were plotted against time to determine the area under the curve (AUC), and coenzyme Q was calculated for each group of plasma 10 The average of the area under the curve for concentrations 0 to 12 hours is shown in FIG. 4.
As can be seen from FIG. 4, coenzyme Q was observed in the male group 10 The mean plasma concentration and the area under the curve were higher than in the female group; coenzyme Q on days 1 and 15 10 Average area under plasma curve, self-made coenzyme Q 10 The female and male soft capsule (50 mg/capsule) samples were administered with commercially available coenzyme Q 10 The female group and the male group of the soft capsule (200 mg/capsule) reference sample are equivalent, namely the self-made coenzyme Q is shown 10 Soft capsule (50 mg/capsule) sample and commercial coenzyme Q 10 The bioavailability of the soft gelatin capsule (200 mg/capsule) reference sample in humans was comparable.
Coenzyme Q is taken by different groups of subjects 10 Coenzyme Q in plasma after 2 weeks (14 days) of preparation 10 The concentrations were all increased as shown in figure 5.
As can be seen from FIG. 5, administration of coenzyme Q 10 Making coenzyme Q into soft capsule after 2 weeks 10 Coenzyme Q in plasma of female and male groups of Soft Capsule (50 mg/Capsule) samples 10 The concentration increase values were higher in the female group and the male group, respectively, than in the reference sample which had been administered with a commercially available coenzyme Q10 soft capsule (200 mg/capsule).
As can be seen from the above examples 13 and 14, the bioavailability of coenzyme Q10 in the liquid medicine of the present invention can be significantly increased by 4 times or more.

Claims (10)

1. A coenzyme Q10 self-emulsifying preparation composition with high bioavailability is characterized by mainly comprising two components: coenzyme Q10, edible essence; the weight percentage of each component is as follows: 5-30% of coenzyme Q10, 60-95% of edible essence, 0-5% of emulsifier and 0-5% of edible oil; the edible essence is water-soluble liquid essence, and is selected from one or more of sweet orange oil essence, shaddock peel oil essence, lemon oil essence, bergamot oil essence, tangerine oil essence and bitter orange oil essence; the sweet orange oil essence, the shaddock peel oil essence, the lemon oil essence, the bergamot oil essence, the tangerine oil essence and the bitter orange oil essence are prepared from sweet orange oil, shaddock peel oil, lemon oil, bergamot oil, tangerine oil, bitter orange oil and edible essence auxiliary materials; the content of terpene components in the edible essence is 15-25%; the auxiliary material in the edible essence is tween.
2. The coenzyme Q10 self-emulsifying formulation composition according to claim 1, which comprises the following components in percentage by weight: 5-15% of coenzyme Q10, 80-95% of edible essence, 0-2% of emulsifier and 0-3% of edible oil.
3. The coenzyme Q10 self-emulsifying formulation composition according to claim 2, characterized in that the weight percentages of the components are: 8-12% of coenzyme Q10, 85-91% of edible essence and 1-3% of edible oil.
4. The coenzyme Q10 self-emulsifying formulation composition according to claim 1, characterized in that: the terpene component content in the edible essence is 20-25%.
5. The coenzyme Q10 self-emulsifying formulation composition according to claim 2, characterized in that: the emulsifier is one or more selected from tween, polyoxyethylene fatty acid ester, poloxamer, sucrose ester, span, monoglyceride and polyethylene glycol.
6. The coenzyme Q10 self-emulsifying formulation composition according to claim 5, characterized in that: the emulsifier is tween.
7. The coenzyme Q10 self-emulsifying formulation composition according to claim 2 or 3, characterized in that: the edible oil is one or more selected from sunflower oil, soybean oil, corn oil, olive oil, palm oil, coconut oil and medium chain triglyceride.
8. The coenzyme Q10 self-emulsifying formulation composition according to claim 7, characterized in that: the edible oil is corn oil or medium chain triglyceride.
9. A method for preparing a highly bioavailable coenzyme Q10 self-emulsifying formulation composition according to any one of claims 1 to 8, comprising the steps of:
(1) Preparing coenzyme Q10 liquid medicine: uniformly mixing edible essence, emulsifier and edible oil material, heating to 60-80 ℃, slowly adding coenzyme Q10 powder, preserving heat, and stirring until the coenzyme Q10 is completely dissolved to obtain coenzyme Q10 liquid medicine;
(2) Preparation of coenzyme Q10 preparation: and (2) further preparing the coenzyme Q10 liquid medicine prepared in the step (1) into any one of a coenzyme Q10 soft capsule, a coenzyme Q10 liquid hard capsule, a coenzyme Q10 oral liquid and a coenzyme Q10 drop.
10. The method of claim 9, wherein the step (2) of preparing the coenzyme Q10 preparation: and (2) further preparing the coenzyme Q10 liquid medicine prepared in the step (1) into a coenzyme Q10 soft capsule or a coenzyme Q10 oral liquid.
CN202111208573.XA 2021-09-30 2021-10-18 Coenzyme Q with high absorption utilization degree 10 Self-emulsifying composition and process for preparing same Active CN113876698B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202111159013 2021-09-30
CN202111159013X 2021-09-30

Publications (2)

Publication Number Publication Date
CN113876698A CN113876698A (en) 2022-01-04
CN113876698B true CN113876698B (en) 2023-04-18

Family

ID=79003279

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202111208573.XA Active CN113876698B (en) 2021-09-30 2021-10-18 Coenzyme Q with high absorption utilization degree 10 Self-emulsifying composition and process for preparing same

Country Status (1)

Country Link
CN (1) CN113876698B (en)

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003041632A2 (en) * 2001-11-14 2003-05-22 Texas Tech University Eutectic-based self-nanoemulsified drug delivery system
JP2008520563A (en) * 2004-11-16 2008-06-19 バイオアバイラビリティ，インク． High concentration self-microemulsifying coenzyme Q10 preparation for nutritional use
JP5176352B2 (en) * 2006-04-06 2013-04-03 大正製薬株式会社 Ubidecalenone-containing composition for internal use
CN101658510B (en) * 2008-08-25 2011-08-10 沈阳皓天万嘉医药科技有限公司 Coenzyme Q10 self-emulsifying microcapsules and preparation method thereof
JP5999765B2 (en) * 2012-12-07 2016-09-28 バイオアバイラビリティ，インク． High concentration self-microemulsifying coenzyme Q10 preparation for nutritional use
CN103859395B (en) * 2014-01-24 2015-08-26 天津科技大学 A kind of ubiquinone of high-absorbility 10self-emulsifying drug delivery system and preparation method thereof and application

Also Published As

Publication number Publication date
CN113876698A (en) 2022-01-04

Similar Documents

Publication Publication Date Title
US10314793B2 (en) Solubilized CoQ-10
JP4758898B2 (en) Solubilized CoQ-10
AU2018100110A4 (en) Ubiquinone And Ubiquinol Compositions, And Methods Relating Thereto
JP4423447B2 (en) Osteoporosis preventive and therapeutic agent
CN101534807A (en) Pharmaceutical and nutraceutical products comprising vitamin k2
WO2006003909A1 (en) Fat combustion accelerator
CA2988478C (en) Solid dispersions of coenzyme q10
US20120141446A1 (en) Oral Nutritional Supplement Delivery System
JPS60224629A (en) Inhibitor composition for in vivo lipoperoxide formation
WO2009136587A1 (en) Anti-fatigue composition
CN113876698B (en) Coenzyme Q with high absorption utilization degree 10 Self-emulsifying composition and process for preparing same
AU2004249023A1 (en) Movement physiology improver
Stolk et al. Serum levels of 8‐methoxypsoralen: difference between two oral methods of administration
JP3479986B2 (en) Composition for preventing alcoholic liver injury
JPS5953421A (en) Agent for lowering or suppressing the increase of cholesterol level
JP5683768B2 (en) Composition containing coenzyme Q10
Ciceri et al. Solid dispersions of Coenzyme Q 10
CA3173107A1 (en) Composition comprising antimicrobial agent and its uses
JP2001187734A (en) Type 2 helper t cell differentiation inhibitor
JP2009107951A (en) Calcium absorption promoter
Patrick Resveratrol benefits health in many ways-Dr. Patrick Sept 2019
JP2004002452A (en) Formulation for prophylaxis of alcoholic hepatopathy

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant