CN113876698A - Coenzyme Q with high absorption utilization degree10Self-emulsifying composition and process for preparing same - Google Patents

Coenzyme Q with high absorption utilization degree10Self-emulsifying composition and process for preparing same Download PDF

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CN113876698A
CN113876698A CN202111208573.XA CN202111208573A CN113876698A CN 113876698 A CN113876698 A CN 113876698A CN 202111208573 A CN202111208573 A CN 202111208573A CN 113876698 A CN113876698 A CN 113876698A
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coenzyme
oil
essence
self
preparation
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CN113876698B (en
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张冉
陈卫平
张瑞国
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CSPC Zhongnuo Pharmaceutical Taizhou Co Ltd
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CSPC Zhongnuo Pharmaceutical Taizhou Co Ltd
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Abstract

The invention provides coenzyme Q with high bioavailability for human10Nutritional supplement and/or adjuvant therapy self-emulsifying formulation compositions and methods of preparation. Comprises the following components in percentage by weight: 5 to 30% of coenzyme Q1060-95% of edible essence, 0-5% of edible oil and 0-5% of emulsifier, and the preparation method comprises the following steps: uniformly mixing all liquid materials, heating to 60-80 ℃, and slowly adding coenzyme Q10Pulverizing, stirring to obtain coenzyme Q10Completely dissolving to obtain coenzyme Q10And (5) liquid medicine. The obtained coenzyme Q10The medicinal liquid can be maintained in a clear and transparent solution state at room temperature and has aromatic and pleasant odor. The obtained coenzyme Q10The liquid medicine can be stably dispersed in water and self-emulsified into transparent emulsion, thereby obviously improving the coenzyme Q10The bioavailability is more than 4 times. The obtained coenzyme Q10The 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 degree10Self-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 smell10A self-emulsifying formulation.
Background
Coenzyme Q10Is a fat-soluble quinone ring compound with the chemical name of 2, 3-dimethoxy-5-methyl-6-decaisopentenyl benzoquinone. The melting point is 48-52 ℃, and the molecular formula is C59H90O4And the molecular weight is 862. Coenzyme Q10At room temperatureThe crystal powder is yellow or light orange yellow, 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 Q10Has long isoprene side chain, so it is easily soluble in chloroform, benzene and carbon tetrachloride, soluble in acetone, petroleum ether and ether, slightly soluble in ethanol, and insoluble in water and methanol.
Coenzyme Q10Coenzyme 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 Q10The biological activity of (A) is mainly derived from the redox characteristics of the quinone ring and the physicochemical properties of the side chain.
Coenzyme Q10The medicine has wide distribution in human body and high concentration in heart, liver, kidney, pancreas and other tissues and organs. Coenzyme Q in human body10Mainly by self-synthesis and exogenous supplementation. Coenzyme Q produced in vivo with age10Gradually decreasing; in addition, in pathological conditions, endogenous coenzyme Q10The 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 administration10Can be used as health food with dosage of 50 mg/day. However, in the United states, coenzyme Q10The dosage of the nutritional supplement is 30-100 mg/day, and the dosage of the nutritional supplement for improving diseases is 100-300 mg/day; in Japan, while the upper limit of the amount used is not determined, it is recommended that the daily amount does not exceed 300 mg; the upper limit for dietary supplements in belgium is 200 mg/day; in Australia, coenzyme Q10The dosage is 150 mg/day; other countries in Europe formally transferred coenzyme Q from 198510The dosage of the nutrient supplement is about 100-300 mg/day.
Coenzyme Q10Has multiple biological functionsMainly can prevent and/or assist the treatment: (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 Q10It 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 Q10The 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 used for dissolving and diluting, the fat-soluble characteristic of the oil is not changed, so the absorption effect is not good; due to coenzyme Q10The 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 Q10Exists in the content in the form of small crystals, and influences the dissolution and the absorption in the body.
Coenzyme Q10Large molecular weight, high melting point and water insolubility, which is common coenzyme Q10The 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 coenzyme Q10A method of bioavailability. At present, coenzyme Q10The bioavailability of the tablet and capsule products is only 1-2%, and the coenzyme Q10The oily soft capsule improves the absorptivity, and the bioavailability is only 2-3%. Many documents and patents report the use of self-emulsifying systems to increase coenzyme Q10But most about coenzyme Q10In the patent, for example, CN200480044829.6 is used for high concentration self-microemulsifying coenzyme Q for nutritional use10Preparation, CN 201410033991.3A high absorptionCoenzyme Q in yield10Self-emulsifying drug release system, preparation method and application thereof, and CN201510794514.3 self-emulsifying coenzyme Q10The preparation method and application of the oil agent have no clear explanation on bioavailability. And coenzyme Q in the formulations of these documents and patents10Is not high enough to satisfy coenzyme Q10The demand, user convenience and compliance are greatly reduced; if the coenzyme Q is increased10Due to coenzyme Q10Low solubility of coenzyme Q at room temperature10Exists 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 Q10The product is in the form of soft capsule, the contents are vegetable oil, surfactant and the like, the smell and taste are unpleasant, and although the product is wrapped by a rubber sheet, the product is disintegrated in the stomach and has unpleasant smell return in some people.
Coenzyme Q10The solubility in different solvents is shown in the following chart:
Table1 Solubility of coenzymeQ10in 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 high bioavailability and pleasant odor in a clear solution state at room temperature10The 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 solution10A self-emulsifying formulation.
The specific technical scheme of the invention is as follows:
coenzyme with high bioavailabilityQ10A self-emulsifying formulation composition consisting essentially of two components: coenzyme Q10, edible essence.
The coenzyme Q provided by the invention10The 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 to 30% of coenzyme Q1060-95% of edible essence, 0-5% of emulsifier and 0-5% of edible oil.
Preferably, a coenzyme Q with high bioavailability10The self-emulsifying preparation composition comprises the following components in percentage by weight: 5-15% of coenzyme Q1080-95% of edible essence, 0-2% of emulsifier and 0-3% of edible oil.
Still further preferably, a coenzyme Q with high bioavailability10The self-emulsifying preparation composition comprises the following components in percentage by weight: 8-12% of coenzyme Q1085-91% 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, shaddock 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 the terpene component (limonene) in the edible essence is 15-25%, and 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 adjuvant 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 triglycerides.
Another object of the present invention is to provide the above-mentioned coenzyme Q10Preparation method and application of the preparation are provided.
Coenzyme Q with high bioavailability10The preparation method of the self-emulsifying preparation comprises the following steps:
(1) coenzyme Q10Preparation of a liquid medicine: uniformly mixing edible essence, emulsifier and edible oil, heating to 60-80 ℃, slowly adding coenzyme Q10 powder, preserving heat, and stirring until the coenzyme Q10Completely dissolving to obtain coenzyme Q10And (5) liquid medicine.
(2) Coenzyme Q10Preparation of the preparation: the coenzyme Q prepared in the step (1)10The liquid medicine is further prepared into coenzyme Q10Soft capsule, coenzyme Q10Liquid hard capsule, coenzyme Q10Oral liquid and coenzyme Q10Any one of the drops, preferably coenzyme Q10Soft capsule or coenzyme Q10An oral liquid.
The invention has the beneficial effects that:
1. the coenzyme Q with high bioavailability of the invention10The 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 invention10The liquid medicine of the self-emulsifying preparation can be dispersed in water and self-emulsified into transparent nano emulsion, the particle size is within 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 invention10Self-emulsifying formulation, 50 mg/tablet of coenzyme Q for oral administration10The soft capsule is equivalent to oral administration of 200 mg/capsule of conventional coenzyme Q10The soft capsule has improved clinical effect and can improve coenzyme Q10The bioavailability is more than 4 times.
4. High content of the inventionCoenzyme Q10The medicinal liquid of the self-emulsifying preparation has fragrant and pleasant smell, and can be directly taken orally.
5. The high content coenzyme Q of the invention10The 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 plasma10Concentration versus time graph of
The axis of abscissa is time, unit: hours; the ordinate is coenzyme Q10Plasma concentration, unit: μ g/mL.
FIG. 2: example 13 coenzyme Q in rat plasma10Concentration (Cmax) vs.
Coenzyme Q in ordinate10Concentration, in. mu.g/mL.
FIG. 3: example 13 coenzyme Q in rat plasma10Area under concentration curve (AUC) vs.
Coenzyme Q in ordinate10Area under the concentration curve in units of μ g. mL-1·h。
FIG. 4: coenzyme Q in human plasma in example 1410Area under the curve (AUC) comparison graph of concentration 0-12 h.
Coenzyme Q in ordinate1Area under the 0 concentration curve in units of μ g. mL-1·h。
FIG. 5: example 14 coenzyme Q for human administration10Coenzyme Q in plasma on day 1510The concentration increase value.
Detailed Description
The invention discloses coenzyme Q with high bioavailability for human10The nutritional supplement and/or adjuvant therapy self-emulsifying preparation composition and the preparation method can be realized by combining the related principles of medicinal preparations and edible essences and properly improving the process parameters by taking the contents of the invention as reference by the technical personnel in the field. 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: 5 mL/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 Q10Self-emulsifying portLiquid medicine
(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:
(ii) coenzyme Q10Preparation 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 Q10Powder, stirring while keeping the temperature until the coenzyme Q10Completely dissolving, and making the whole system be orange red and uniform transparent liquid to obtain coenzyme Q10And (5) liquid medicine.
② coenzyme Q10Preparation of the preparation: cooling the liquid medicine obtained in the step I, and filling the liquid medicine into bottles to obtain the coenzyme Q10An 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 Q10Self-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 is 22%) 87％
Corn oil
1％
Tween 80 2％
(2) The preparation method comprises the following steps:
(ii) coenzyme Q10Preparation 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 Q10Powder, stirring while keeping the temperature until the coenzyme Q10Completely dissolving, and making the whole system be orange red and uniform transparent liquid to obtain coenzyme Q10And (5) liquid medicine.
② coenzyme Q10Preparation of the preparation: taking the liquid medicine prepared in the step I as the content of the soft capsule, and preparing the soft capsule, wherein the content of each soft capsule is 500mg, and the coenzyme Q10The content of (B) is 50 mg.
(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 Q10Self-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:
(ii) coenzyme Q10Preparation 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 Q10Powder, stirring while keeping the temperature until the coenzyme Q10Completely dissolving, and making the whole system be orange red and uniform transparent liquid to obtain coenzyme Q10And (5) liquid medicine.
② coenzyme Q10Preparation of the preparation: cooling the liquid medicine prepared in the step I, and filling the liquid medicine into a glass bottle with a dropper to obtain the auxiliary medicineEnzyme Q10Drops 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 Q10Self-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%) 88％
Corn oil
2％
(2) The preparation method comprises the following steps:
(ii) coenzyme Q10Preparation 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 Q10Powder, stirring while keeping the temperature until the coenzyme Q10Completely dissolving, and making the whole system be orange red and uniform transparent liquid to obtain coenzyme Q10And (5) liquid medicine.
② coenzyme Q10Preparation of the preparation: taking the liquid medicine prepared in the step I as the content of the soft capsule, and preparing the soft capsule, wherein the content of each soft capsule is 500mg, and the coenzyme Q10The content of (B) is 50 mg.
(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 Q10Self-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 is 19%) 85％
Medium chain triglycerides 5％
(2) The preparation method comprises the following steps:
(ii) coenzyme Q10Preparation 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 Q10Powder, stirring while keeping the temperature until the coenzyme Q10Completely dissolving, and making the whole system be orange red and uniform transparent liquid to obtain coenzyme Q10And (5) liquid medicine.
② coenzyme Q10Preparation of the preparation: taking the liquid medicine prepared in the step I as hard capsule contents to prepare liquid hard capsules, wherein the weight of each hard capsule content is 500mg, and the coenzyme Q10The content of (B) is 50 mg.
(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 Q10Self-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:
(ii) coenzyme Q10Preparation of a liquid medicine: heating the sweet orange oil essence with the prescription amount to 70 ℃, and slowly adding coenzyme Q10Powder, stirring while keeping the temperature until the coenzyme Q10Completely dissolving, and making the whole system be orange red and uniform transparent liquid to obtain coenzyme Q10And (5) liquid medicine.
② coenzyme Q10Preparation of the preparation: taking the liquid medicine prepared in the step I as the content of the soft capsule, and preparing the soft capsule, wherein the content of each soft capsule is 500mg, and the coenzyme Q10The content of (B) is 25 mg.
(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 Q10Self-emulsifying soft capsule
(1) The composition comprises the following components:
Figure BDA0003307919220000081
Figure BDA0003307919220000091
(2) the preparation method comprises the following steps:
(ii) coenzyme Q10Preparation 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 Q10Powder, stirring while keeping the temperature until the coenzyme Q10Completely dissolving, and making the whole system be orange red and uniform transparent liquid to obtain coenzyme Q10And (5) liquid medicine.
② coenzyme Q10Preparation of the preparation: taking the liquid medicine prepared in the step I as the content of the soft capsule, and preparing the soft capsule, wherein the content of each soft capsule is 500mg, and the coenzyme Q10The content of (B) is 150 mg.
(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 Q10Self-emulsifying oral liquid
(1) The composition comprises the following components:
Figure BDA0003307919220000092
(2) the preparation method comprises the following steps:
(ii) coenzyme Q10Preparation 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 Q10Powder, stirring while keeping the temperature until the coenzyme Q10Completely dissolved, and the whole system is orange red and uniform and transparentObtaining coenzyme Q from the liquid10And (5) liquid medicine.
② coenzyme Q10Preparation of the preparation: cooling the liquid medicine obtained in the step I, and filling the liquid medicine into bottles to obtain the coenzyme Q10An 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 Q10Self-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:
(ii) coenzyme Q10Preparation of a liquid medicine: mixing lemon oil essence, polyethylene glycol 400 and corn oil uniformly, heating to 60 deg.C, and slowly adding coenzyme Q10Powder, stirring while keeping the temperature until the coenzyme Q10Completely dissolving, and making the whole system be orange red and uniform transparent liquid to obtain coenzyme Q10And (5) liquid medicine.
② coenzyme Q10Preparation of the preparation: cooling the liquid medicine obtained in the step I, and filling the liquid medicine into bottles to obtain the coenzyme Q10An 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 Q10Self-emulsifying soft capsule
(1) The composition comprises the following components:
components Weight percent of
Coenzyme Q10 8％
Sweet orange oil essence (terpene component content 23%) 91％
Corn oil
1％
(2) The preparation method comprises the following steps:
(ii) coenzyme Q10Preparation of a liquid medicine: heating the sweet orange oil essence and corn oil of the prescription amount to 70 ℃, and slowly adding coenzyme Q10Powder, stirring while keeping the temperature until the coenzyme Q10Completely dissolved, the whole system is orange red and uniform transparent liquidObtaining coenzyme Q10And (5) liquid medicine.
② coenzyme Q10Preparation of the preparation: taking the liquid medicine prepared in the step I as the content of the soft capsule, and preparing the soft capsule, wherein the content of each soft capsule is 500mg, and the coenzyme Q10The content of (B) is 40 mg.
(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 Q10Self-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:
(ii) coenzyme Q10Preparation of a liquid medicine: mixing the prescription amount of medium chain triglyceride and tween 80, heating to 70 deg.C, and slowly adding coenzyme Q10Powder, stirring while keeping the temperature until the coenzyme Q10Completely dissolving, and making the whole system be orange red and uniform transparent liquid to obtain coenzyme Q10And (5) liquid medicine.
② coenzyme Q10Preparation of the preparation: taking the liquid medicine prepared in the step I as the content of the soft capsule, and preparing the soft capsule, wherein the content of each soft capsule is 500mg, and the coenzyme Q10The content of (B) is 50 mg.
(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 Q10Self-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:
(ii) coenzyme Q10Preparation of a liquid medicine: mixing soybean oil, soybean phospholipid and Cera flava, heating to 70 deg.C, and slowly adding coenzyme Q10Powder, stirring while keeping the temperature until the coenzyme Q10Completely dissolved, the whole systemIs orange semi-solid suspension to obtain coenzyme Q10And (5) liquid medicine.
② coenzyme Q10Preparation of the preparation: taking the liquid medicine prepared in the step I as the content of the soft capsule, and preparing the soft capsule, wherein the content of each soft capsule is 500mg, and the coenzyme Q10The content of (B) is 50 mg.
(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 Q10Self-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:
(ii) coenzyme Q10Preparation of a liquid medicine: heating the prescribed amount of medium chain triglycerides to 70 deg.C, slowly adding coenzyme Q10Powder, stirring while keeping the temperature until the coenzyme Q10Completely dissolving, and making the whole system be orange yellow semisolid suspension to obtain coenzyme Q10And (5) liquid medicine.
② coenzyme Q10Preparation of the preparation: using the liquid medicine prepared in the step I as soft glueThe capsule content is prepared into soft capsule, and the content weight of each soft capsule is 500mg, wherein the coenzyme Q10The content of (B) is 50 mg.
(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 flavor having terpene components was not used in the composition, the prepared soft capsules had poor self-emulsifying properties and stability and low bioavailability (see, specifically, example 11, example 12, and example 13).
Comparative example 4: coenzyme Q10Self-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:
(ii) coenzyme Q10Preparation of a liquid medicine: mixing the above essence and corn oil, heating to 70 deg.C, and slowly addingCoenzyme Q10Powder, stirring while keeping the temperature until the coenzyme Q10Completely dissolving, and making the whole system be orange red and uniform transparent liquid to obtain coenzyme Q10And (5) liquid medicine.
② coenzyme Q10Preparation of the preparation: taking the liquid medicine prepared in the step I as the content of the soft capsule, and preparing the soft capsule, wherein the content of each soft capsule is 500mg, and the coenzyme Q10The content of (B) is 50 mg.
(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 4 could not self-emulsify in water.
Comparative example 5: coenzyme Q10Self-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:
(ii) coenzyme Q10Preparation of a liquid medicine: mixing the above orange oil essence and corn oil, and heatingSlowly adding coenzyme Q at 70 DEG C10Powder, stirring while keeping the temperature until the coenzyme Q10Completely dissolving, and making the whole system be orange red and uniform transparent liquid to obtain coenzyme Q10And (5) liquid medicine.
② coenzyme Q10Preparation of the preparation: and (4) cooling the liquid medicine prepared in the step (i), and filling the liquid medicine into a bottle to obtain the coenzyme Q10 oral liquid. The obtained coenzyme Q10The 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, which are further detected as coenzyme Q10(ii) a When the content of terpene components in the sweet orange oil essence is more 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 Q10Self-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:
(ii) coenzyme Q10Preparation 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 Q10Powder, stirring while keeping the temperature until the coenzyme Q10Completely dissolving, and making the whole system be orange red and uniform transparent liquid to obtain coenzyme Q10And (5) liquid medicine.
② coenzyme Q10Preparation of the preparation: taking the liquid medicine prepared in the step I as the content of the soft capsule, and preparing the soft capsule, wherein the content of each soft capsule is 500mg, and the coenzyme Q10The content of (B) is 50 mg.
(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 Q10Self-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:
(ii) coenzyme Q10Preparation 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 Q10Powder, stirring while keeping the temperature until the coenzyme Q10Completely dissolving, and making the whole system be orange red and uniform transparent liquid to obtain coenzyme Q10And (5) liquid medicine.
② coenzyme Q10Preparation of the preparation: taking the liquid medicine prepared in the step I as the content of the soft capsule, and preparing the soft capsule, wherein the content of each soft capsule is 500mg, and the coenzyme Q10The content of (B) is 50 mg.
During the pelleting process, a large amount of coenzyme Q is discovered10Crystallization affecting each coenzyme Q10The 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 Q10Stability testing of self-emulsifying formulations
For the coenzyme Q prepared in examples 1 to 10 and comparative examples 1 to 710Stability tests were performed on the self-emulsifying formulations to see if phase separation, turbidity and crystallization occurred at different temperatures. Coenzyme Q10The 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 Q10Stability test results for self-emulsifying formulations
Figure BDA0003307919220000141
Figure BDA0003307919220000151
The stability test results in the above table show that the coenzyme Q obtained by the invention10The 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 Q10Self-emulsification test of self-emulsifying formulations
Coenzyme Q prepared in examples 1 to 10 and comparative examples 1 to 710After 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 invention10The 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 Q10Particle 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 invention10Animal 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 410Self-emulsifying formulations (code: sample 1, sample 2);
coenzyme Q prepared in comparative examples 2 and 310Self-emulsifying formulation (code: reference 1, reference 2).
(2) Test animals and groups:
the test animal is an SD male rat purchased from Beijing Wittingle laboratory animal technology Limited and has the 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 in every day.
(4) Oral administration and blood sample collection:
one week after acclimation feeding, gavage administration was started. The administration amount is 60mg/kg per time by intragastric administration at 8:00 morning and 20:00 evening every day. In the fourth day, fasting is not forbidden after gastric lavage at night, in the fifth day, after gastric lavage at 8:00 morning, blood is collected, the last administration is 0 hour, the sampling time points are 0, 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours, blood is collected in an anticoagulation tube, and after centrifugal separation, coenzyme Q is carried out on blood plasma10Detection 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 Q10And (6) detecting.
(6) And (4) analyzing results:
coenzyme Q at each time point10The plasma concentration was subtracted from the corresponding 0 hour plasma concentration to obtain coenzyme Q10Net plasma concentrations, as shown in figure 1.
As shown in FIG. 2, samples 1 and 2Highest net coenzyme Q of group10Highest net coenzyme Q of reference 1 and reference 2 groups at concentrations of 1.32 and 1.34. mu.g/mL, respectively10The concentrations were 0.18 and 0.30. mu.g/mL, respectively. Highest net coenzyme Q of sample group10The concentration is 4-7 times of that of the reference sample group.
As shown in FIG. 3, sample 1 and sample 2 combined coenzyme Q10The area under the concentration curve (AUC) was 4.24 and 4.17. mu.g.mL, respectively-1H, reference 1 and reference 2 clean coenzyme Q10The areas under the concentration curve were 1.11 and 0.30. mu.g.mL, respectively-1H, AUC of the sample group is 4-13 times of that of the reference sample group.
From this, it can be seen that the coenzyme Q prepared in examples 1 and 4 of the present invention10The bioavailability of the liquid preparation is coenzyme Q in comparative example 2 and comparative example 310The bioavailability of the preparation is more than 4 times.
Example 14: bioavailability test in human body
Coenzyme Q of the invention10Human body tests prove that the self-emulsifying preparation can obviously improve the coenzyme Q10The in vivo bioavailability, test procedures and results are as follows:
(1) sample preparation:
coenzyme Q prepared in example 410Soft capsules, 50mg coenzyme Q10Grains (sample);
coenzyme Q commercially available10Soft capsule (the auxiliary materials of the content are rice bran oil and soybean lecithin), 200mg coenzyme Q10Particle (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 period10And (4) products are similar.
(4) Oral administration and blood sample collection:
administering 1 coenzyme Q at 8:00 every day10Soft capsule is administered continuously for 2 weeks.
First of allCoenzyme Q is taken 8:00 in the morning10Collecting blood before soft capsule as basic blood sample, and taking coenzyme Q10Collecting blood 2, 4, 6, 8, 10, and 12 hr after soft capsule, centrifuging blood sample, collecting plasma, and processing coenzyme Q10Detection of (3).
Administering coenzyme Q8: 00 in the morning on the fifteenth day10Collecting blood before soft capsule as basic blood sample, and taking coenzyme Q10Collecting blood 2, 4, 6, 8, 10, and 12 hr after soft capsule, centrifuging blood sample, collecting plasma, and processing coenzyme Q10Detection 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 Q10And (6) detecting.
(6) And (4) analyzing results:
coenzyme Q of each human at each time point10Plasma 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 plasma10The average value of the area under the curve for 0 to 12 hours of concentration is shown in FIG. 4.
As can be seen from FIG. 4, coenzyme Q was observed in the male group10The mean plasma concentration and the area under the curve were higher than in the female group; coenzyme Q on days 1 and 1510Average area under plasma curve, self-made coenzyme Q10The female and male soft capsule (50 mg/capsule) samples were administered with commercially available coenzyme Q10The female group and the male group of the soft capsule (200 mg/capsule) reference sample are equivalent, namely the self-made coenzyme Q is shown10Soft capsule (50 mg/capsule) sample and commercial coenzyme Q10The bioavailability of the soft gelatin capsule (200 mg/capsule) reference sample in humans was comparable.
Coenzyme Q is taken by different groups of subjects10Coenzyme Q in plasma after 2 weeks (14 days) of preparation10The concentrations were all increased as shown in figure 5.
As can be seen from FIG. 5, administration of coenzyme Q10The soft capsule is prepared after 2 weeksSelf-made coenzyme Q10Coenzyme Q in plasma of female and male groups of Soft Capsule (50 mg/Capsule) samples10The concentration increase was higher in each case than in the female and male groups which had received the reference sample of a commercially available coenzyme Q10 soft capsule (200 mg/capsule).
From the above examples 13 and 14, it can be concluded that the coenzyme Q10 liquid medicine obtained by the present invention can significantly improve the bioavailability of coenzyme Q10 by more than 4 times.

Claims (10)

1. Coenzyme Q with high bioavailability10A self-emulsifying formulation composition characterized by consisting essentially of two components: coenzyme Q10And edible essence.
2. The coenzyme Q according to claim 110The self-emulsifying preparation composition is characterized by comprising the following components in percentage by weight: 5 to 30% of coenzyme Q1060-95% of edible essence, 0-5% of emulsifier and 0-5% of edible oil.
3. The coenzyme Q according to claim 210The self-emulsifying preparation composition is characterized in that the weight percentages of the components are preferably as follows: 5-15% of coenzyme Q1080-95% of edible essence, 0-2% of emulsifier and 0-3% of edible oil.
4. The coenzyme Q according to claim 310The self-emulsifying preparation composition is characterized in that the weight percentages of the components are further preferably as follows: 8-12% of coenzyme Q1085-91% of edible essence and 1-3% of edible oil.
5. The coenzyme Q as claimed in any of claims 1 to 410A self-emulsifying formulation composition characterized by: 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 orange 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.
6. The coenzyme Q as claimed in claim 510A self-emulsifying formulation composition characterized by: the content of terpene components in the edible essence is 15-25%, and preferably 20-25%.
7. The coenzyme Q as claimed in claim 510A self-emulsifying formulation composition characterized by: the edible essence contains adjuvants selected from one or more of tween, polyoxyethylene fatty acid ester, poloxamer, sucrose ester, span, monoglyceride, and polyethylene glycol, preferably tween.
8. The coenzyme Q according to claim 2 to 310A self-emulsifying formulation composition characterized by: the emulsifier is one or more selected from tween, polyoxyethylene fatty acid ester, poloxamer, sucrose ester, span, monoglyceride and polyethylene glycol; preferably, the emulsifier is tween.
9. The coenzyme Q as claimed in any of claims 2 to 410A self-emulsifying formulation composition characterized by: 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 triglycerides.
10. A highly bioavailable coenzyme Q according to any one of claims 1 to 910The preparation method of the self-emulsifying preparation is characterized by comprising the following steps:
(1) coenzyme Q10Preparation of a liquid medicine: uniformly mixing edible essence, emulsifier and edible oil material, heating to 60-80 ℃, and slowly adding coenzyme Q10Pulverizing, maintaining the temperature, stirring to coenzyme Q10Completely dissolving to obtain coenzyme Q10Liquid medicine;
(2) preparation of coenzyme Q10 preparation: further preparing the coenzyme Q10 liquid medicine prepared in the step (1) into any one of coenzyme Q10 soft capsules, coenzyme Q10 liquid hard capsules, coenzyme Q10 oral liquid and coenzyme Q10 drops, preferably coenzyme Q10 soft capsules or coenzyme Q10 oral liquid.
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