CN112370442B - Coenzyme Q10 drug delivery system and preparation method thereof - Google Patents
Coenzyme Q10 drug delivery system and preparation method thereof Download PDFInfo
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- 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
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- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- 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
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- 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
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- 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
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B02—CRUSHING, PULVERISING, OR DISINTEGRATING; PREPARATORY TREATMENT OF GRAIN FOR MILLING
- B02C—CRUSHING, PULVERISING, OR DISINTEGRATING IN GENERAL; MILLING GRAIN
- B02C17/00—Disintegrating by tumbling mills, i.e. mills having a container charged with the material to be disintegrated with or without special disintegrating members such as pebbles or balls
- B02C17/10—Disintegrating by tumbling mills, i.e. mills having a container charged with the material to be disintegrated with or without special disintegrating members such as pebbles or balls with one or a few disintegrating members arranged in the container
Abstract
The invention discloses a coenzyme Q10 drug delivery system and a preparation method thereof, wherein the coenzyme Q10 drug delivery system consists of coenzyme Q10, a protein carrier, a surfactant, a stabilizer and a lubricant, stainless steel balls are used as grinding media, raw materials and the stainless steel balls are added into a ball milling tank for co-grinding reaction, and after the reaction is finished, the stainless steel balls are separated out to obtain the coenzyme Q10 drug delivery system. By adopting the technology, the invention can prolong the circulation time of the coenzyme Q10 in vivo, improve the oral absorption of the medicine, improve the transmembrane transport capacity of the medicine and be beneficial to further exerting the effect of the coenzyme Q10 in heart health care. The medicine delivery system of coenzyme Q10 is prepared by adopting a mechanochemical ball milling method, the operation is simple, the process route is short, no solvent or heating is needed in the preparation process, and the loss rate of coenzyme Q10 is reduced in the process. The stability of the prepared coenzyme Q10 drug delivery system is obviously improved, namely the coenzyme Q10.
Description
Technical Field
The invention belongs to the technical field of development of pharmaceutical preparations and health care products, and particularly relates to a coenzyme Q10 drug delivery system and a preparation method thereof, wherein the coenzyme Q10 drug delivery system taking protein as a carrier is prepared by mechanochemical ball milling.
Background
Coenzyme Q10 is a fat-soluble quinone compound widely present in organisms, the number of side chain isoprene units of coenzyme Q varies from one source to another, and 10 isoprene units are present in humans and mammals, so that coenzyme Q10 (Redox Biology, 2015, 4: 289) is named. Coenzyme Q10 is mainly present in mitochondrial inner membrane, is involved in electron transfer chain (a main energy generation mechanism) in oxidative phosphorylation process, is an activator of cell respiration and cell metabolism, has antioxidant effect, and can eliminate free radical generated in cell metabolism and improve immunity. Coenzyme Q10 is widely used in the fields of clinical therapy, food and cosmetics, and is mainly used for cardiovascular diseases such as sexual heart failure, hypertension and endothelial dysfunction in the field of clinical therapyClinica Chimica Acta，2015，450：83-89）。
With the deeper and deeper knowledge of coenzyme Q10, the application of coenzyme Q10 is more and more extensive. However, coenzyme Q10 is a hydrophobic molecule, has poor water solubility, is easily decomposed by light, is easily chemically degraded, and has low oral bioavailability (Food Hydrocolloids，2020, 103: 105651), so current formulation research is mainly focused on improving the solubility and stability of coenzyme Q10 to improve its bioavailability. The coenzyme Q10 preparation types mainly comprise liposome, solid dispersion, nanoemulsion and the like. For example, the film dispersion method is adopted by Huibin LiSaudi to prepare the CoQ10 long-circulating liposome, so that the stability of the medicament is improved, but the medicament-loading rate is less; the FiammettaNigroa takes 2% w/w of coumarone oil of coenzyme Q10 as an oil phase, and the Q10 nanoemulsion is prepared by an ultrasonic method, so that the solubility is improved, but the emulsifier has slight toxicity to a certain extent; Jin-SeokChoi et al prepared coenzyme Q10 solid dispersion by hot melt method using poloxamer 407 (Kolliphor P407) as main solubilizer, polyvinylpyrrolidone (Kollidon 17) as co-solubilizer, Aerosil 200 as carrier, and improved solubility but was unstable when stored for a long time.
The coenzyme Q10 drug delivery system can improve the water solubility and stability of the coenzyme Q10, prolong the circulation time of the coenzyme Q10 in vivo, improve the oral absorption of the drug and improve the bioavailability of the drug. The invention adopts a mechanochemical ball milling method to prepare the drug delivery system, can increase the contact area of the drug, the carrier and the auxiliary materials, and stimulate the chemical reaction between the effective components and a small amount of solid-phase reagents, thereby the drug is uniformly dispersed in the drug delivery system.
Disclosure of Invention
In view of the above problems in the prior art, the present invention is directed to a coenzyme Q10 drug delivery system and a method for preparing the same, and the present invention develops a coenzyme Q10 drug delivery system, which improves the water solubility, stability and bioavailability of coenzyme Q10.
The idea of the invention is as follows: the coenzyme Q10, a protein carrier and other auxiliary materials are ground together, and the coenzyme Q10 and the protein act under the action of high-energy mechanical force to form a drug delivery system.
The coenzyme Q10 drug delivery system is characterized by consisting of coenzyme Q10, a protein carrier, a surfactant, a stabilizer and a lubricant, and the weight parts are as follows: 101-6 parts of coenzyme Q, 25-35 parts of protein carrier, 4.45-4.55 parts of surfactant, 0.35-0.45 part of stabilizer and 0.05-0.055 part of lubricant.
The coenzyme Q10 drug delivery system is characterized in that the weight portions are as follows: 102-5 parts of coenzyme Q, 28-32 parts of protein carrier, 4.45-4.55 parts of surfactant, 0.35-0.45 part of stabilizer and 0.05-0.055 part of lubricant.
The coenzyme Q10 drug delivery system is characterized in that the protein carrier is one or more of soy protein, protamine, hemoglobin, alcohol-soluble corn protein, pea protein and whey protein, and protamine or soy protein is preferred.
The coenzyme Q10 drug delivery system is characterized in that the lubricant is one or a mixture of more of silica gel micropowder, tricalcium phosphate, talcum powder and magnesium stearate, and the silica gel micropowder is preferred.
The coenzyme Q10 drug delivery system is characterized in that the stabilizer is one or a mixture of more of 2, 6-di-tert-butyl-4-methylphenol, DL tocopherol, vitamin C palmitate and tea polyphenol, and 2, 6-di-tert-butyl-4-methylphenol is preferred.
The coenzyme Q10 drug delivery system is characterized in that the surfactant is poloxamer, monoglyceride and diglyceride, disodium glycyrrhizinate, sodium caseinate, sucrose ester or tea saponin, and poloxamer is preferred.
The preparation method of the coenzyme Q10 drug delivery system is characterized in that coenzyme Q10, a protein carrier, a surfactant, a stabilizer and a lubricant are added into a ball milling tank according to a feeding ratio, then stainless steel ball milling beads are added as a milling medium, the ball milling tank is placed into a ball mill for ball milling, a co-milling reaction is carried out at a certain rotating speed, and after the reaction is finished, a drug is separated from the stainless steel ball milling beads, so that the coenzyme Q10 drug delivery system is obtained.
The preparation method of the coenzyme Q10 drug delivery system is characterized in that the diameter of the stainless steel ball milling beads is 5mm-25mm, preferably 5-15mm, and the number of the added stainless steel ball milling beads is 15-85, preferably 64, based on the volume of a ball milling tank of 500 mL.
The preparation method of the coenzyme Q10 drug delivery system is characterized in that the ball mill adopts a planetary ball mill, and the ball milling time is 0.5-8h, preferably 2-4 h; the rotation speed of the ball mill is 50-400r/min, preferably 200 r/min.
Specifically, the invention recommends that the method is carried out according to the following steps:
adding 101-6 parts of coenzyme Q, 25-35 parts of protein carriers, 0.35-0.45 part of stabilizing agent, 0.05-0.055 part of lubricating agent, 4.45-4.55 parts of surfactant and 15-85 stainless steel balls with the diameter of 1.5cm into a 500mL stainless steel ball mill, carrying out grinding reaction at the speed of 50-400r/min for 0.5-8 hours, and separating the medicament from the stainless steel balls after the reaction is finished to obtain the coenzyme Q10 medicament delivery system.
Compared with the prior art, the novel coenzyme Q10 drug delivery system is prepared by adopting a mechanochemical grinding method, and the beneficial effects are mainly represented by the following steps:
(1) the coenzyme Q10 drug delivery system prepared by adopting the limited technology can improve the solubility of the coenzyme Q10, prolong the circulation time of the coenzyme Q10 in vivo, improve the oral absorption of the drug and improve the transmembrane transport capacity of the drug;
(2) compared with other dosage forms, the drug delivery system can remarkably improve the solubility of the coenzyme Q10 in water, the in-vivo bioavailability and the drug concentration thereof in the heart, and is beneficial to further exerting the effect of the coenzyme Q10 in heart health care;
(3) the method for preparing the coenzyme Q10 drug delivery system by adopting the mechanochemical ball milling method has the advantages of simple operation, short process route, no need of solvent and heating in the preparation process, and reduced loss rate of coenzyme Q10 in the whole preparation process;
(5) the coenzyme Q10 drug delivery system prepared by the invention has obviously improved stability of coenzyme Q10.
Drawings
FIG. 1 is a graph of the thermostability of coenzyme Q10;
FIG. 2 is a graph of coenzyme Q10 blood concentration versus time;
FIG. 3 tissue distribution map of coenzyme Q10.
Detailed Description
The technical solutions of the present invention are further illustrated by the following specific examples, but the scope of the present invention is not limited thereto.
Example 1
Adding coenzyme Q102 g, protamine 32g, superfine silica gel powder 0.055g, 2, 6-di-tert-butyl-4-methylphenol (BHT) 0.35g, poloxamer 4.45g and 64 stainless steel ball milling beads with the diameter of 15mm into a 500mL stainless steel ball milling tank, carrying out grinding reaction at 200rpm for 4 hours, and separating the medicine from the stainless steel ball milling beads after the reaction is finished to obtain the coenzyme Q10 medicine delivery system.
Example 2
Adding coenzyme Q101 g, 30g of soybean protein, 0.05g of talcum powder, 0.35g of DL tocopherol, 4.55g of mono-diglycerol stearate and 64 stainless steel balls with the diameter of 15mm into a 500mL stainless steel ball mill tank, grinding at 200rpm for reaction for 4 hours, and separating the medicament from the stainless steel balls after the reaction is finished to obtain the coenzyme Q10 medicament delivery system.
Example 3
Adding coenzyme Q106 g, casein and hemoglobin 25g, tricalcium phosphate 0.05g, vitamin palmitate 0.45g, disodium glycyrrhizinate and sodium caseinate 4.45g, and stainless steel balls with the diameter of 25mm 64 into a 500mL stainless steel ball mill, grinding at 100rpm for reaction for 4 hours, and separating the medicine from the stainless steel balls after the reaction is finished to obtain the coenzyme Q10 medicine delivery system.
Example 4
Adding coenzyme Q106 g, alcohol-soluble corn protein and whey protein 30g, magnesium stearate 0.055g, tea polyphenol 0.35g, sucrose ester and tea saponin 4.55g, and stainless steel balls with diameter of 5mm 15 into a 500mL stainless steel ball mill tank, grinding at 400rpm for reaction for 8 hours, and separating the drug from the stainless steel balls after the reaction to obtain the coenzyme Q10 drug delivery system.
Example 5
Adding coenzyme Q103 g, protamine 25g, talcum powder and micropowder silica gel 0.055g, 2, 6-di-tert-butyl-4-methylphenol (BHT) 0.35g, poloxamer 4.55g and 85 stainless steel balls with diameter of 15mm into a 500mL stainless steel ball mill, carrying out grinding reaction at 50rpm for 0.5 hour, and separating the medicine from the stainless steel balls after the reaction is finished to obtain the coenzyme Q10 medicine delivery system.
Example 6
Method for quantitative determination of coenzyme Q10
Accurately weighing 3.1mg coenzyme Q10 standard substance, adding absolute ethanol for dissolving, and fixing the volume to 10ml with absolute ethanol to obtain standard stock solution with mass concentration of 0.5mg/ml, and storing in-20C refrigerator for later use. Accurately transferring 1ml of standard stock solution at room temperature, adding absolute ethyl alcohol to dissolve the stock solution and fixing the volume to 10ml to obtain standard use solution with the mass concentration of 50 ug/ml. Standard solutions 0.1.0.2, 0.4, 0.8, 1.2, and 1.6ml were taken, and the volume was adjusted to 10ml with absolute ethanol to obtain a standard series, and the peak area of the standard series was measured under the following HPLC conditions to obtain a standard curve of coenzyme Q10 (y =0.3681 x-0.0642, R2= 0.9998).
The HPLC conditions were as follows:
a chromatographic column: ODS-C184.6 x 150 mm, 5 μm,
mobile phase: methanol: ethanol = 1: 1,
flow rate: 1 mL/min of the mixture is added,
column temperature: 35 ℃, sample introduction: the water content of the water is 10 mu L,
detection wavelength: 275nm
The solution to be measured was diluted with ethanol to within the peak area range of the standard curve and the dilution factor V was recorded, the peak area PA of the solution was measured using HPLC, and the concentration c (ug/ml) of coenzyme Q10 in the solution to be measured was calculated according to the following formula.
And calculating the concentration of the complex forming a saturated solution in water according to a standard curve method to obtain the solubility of the coenzyme Q10.
Example 7
Method for measuring equilibrium solubility of coenzyme Q10
The coenzyme Q10 drug delivery system prepared in examples 1-5 and the coenzyme Q10 bulk drug 4g each were placed in 4 100ml erlenmeyer flasks, 50ml distilled water was added to disperse the drug uniformly, the erlenmeyer flasks were placed in a water bath shaker at 37 ℃ and 180 rpm for 12h to dissolve the coenzyme Q10 sufficiently, and after the dissolution was completed, a microporous membrane was used to filter the saturated solution, the method described in example 6 was used to determine the concentration of the coenzyme Q10 saturated solution by HPLC, which is the equilibrium solubility of examples 1-5, and the results are shown in Table 1.
Table 1: examples 1-5 solubility in pure aqueous solution
The experimental results in table 1 show that the coenzyme Q10 drug delivery systems of the 5 embodiments of the invention all have solubilization effects, and the coenzyme Q10 drug delivery system described in example 1 has the best solubilization effect.
Example 8
Coenzyme Q10 thermostability assay:
the effect of the delivery systems described in examples 1-5 on the thermostability of coenzyme Q10 was determined in a forced heat disruption manner due to the poor thermostability of coenzyme Q10. 4g of the samples of the embodiments 1 to 5 and the coenzyme Q10 raw material medicines are respectively placed in a culture dish, the culture dish is heated in a 60 ℃ oven, 0.1g of the samples are accurately weighed in 0, 0.5, 1, 2, 4, 8, 16, 24, 36, 48, 96 and 216 hours respectively, the samples are placed in a 100ml volumetric flask to be constant in volume with absolute ethyl alcohol, the obtained solution is subjected to HPLC (high performance liquid chromatography) to measure the concentration of the coenzyme Q10 according to the method described in the embodiment 6, the content of the coenzyme Q10 is calculated according to the following formula, the content of the coenzyme Q10 at different time points is plotted, the result is shown in FIG. 1, and as can be seen from FIG. 1, compared with the raw material medicines, the uniform range of the embodiments 1 to 5 of the invention improves the stability of the coenzyme Q10, wherein the embodiment 1 has the best stability increasing effect.
Example 9
Through examination of examples 7 and 8, examples 1 and 2 can both improve solubility and stability well, and the bioavailability study was further conducted as described above.
Determination of bioavailability of coenzyme Q10:
1) animal administration and sampling method
18 SD male rats were housed for 5 days and acclimatized. Rats were subjected to 12-hour light and dark cycles under controlled temperature and relative humidity conditions, fasted for 12h before dosing and fasted for 3h after dosing, with free access to water. Rats were randomly assigned to 3 groups of 6 animals each and weighed and labeled. The first group of gavage examples 1 was prepared with coenzyme Q10 solution (drug concentration 1.8mg/ml, dosage 18mg/kg), the second group of gavage examples 2 was prepared with coenzyme Q10 solution (drug concentration 1.8mg/ml, dosage 18mg/kg), and the third group was prepared with coenzyme Q10 (Meishiwei Q-Sorb 200 mg) drug solution (drug concentration 1.8mg/ml, dosage 18 mg/kg). After administration, 2Ml of orbital blood samples of rats in each group was collected by capillary at 0, 0.5, 1, 2, 3, 6, 8, 10, and 24 hours, placed in heparinized centrifuge tubes, and sacrificed immediately 24 hours after blood collection. Centrifuging at 13000r/min for 10min, collecting upper layer plasma, storing at-80 deg.C in refrigerator, and thawing at room temperature for 2 hr before measurement.
2) Blood sample processing method
Placing 1.0ml of blood plasma in a 15ml polypropylene centrifuge tube, adding 1ml of methanol for deproteinization, carrying out vortex mixing for 1min, adding 4.0ml of n-hexane, carrying out vortex mixing for 1min, carrying out 13000rmp/min centrifugation for 10min, transferring an n-hexane layer into a 15ml stoppered test tube, adding 6.0ml of n-hexane into the centrifuge tube twice, extracting twice according to the steps, combining n-hexane extract liquid into the 15ml stoppered test tube, blowing the n-hexane solvent by using nitrogen flow under the condition of 40C water bath, adding 100ul of absolute ethyl alcohol into residues for dissolving, taking 20ul of the residues, and carrying out HPLC analysis according to the coenzyme Q10 content analysis method described in example 6 to obtain a blood concentration curve. The time course is shown in figure 2, and the results of the bioavailability parameters of the coenzyme Q10 are shown in table 2.
Table 2: bioavailability parameter of coenzyme Q10
As can be seen from the results of fig. 2 and table 2, the bioavailability of coenzyme Q10 in example 1 and example 2 was greatly improved compared to the commercial product, and in particular, the bioavailability was improved by 2.17 times compared to the commercial product in example 1, and the maximum blood concentration value in example 1 was also the maximum. The peak time of the blood concentration of the three medicines is 2 hours after administration. In conclusion, the coenzyme in example 1 has the highest bioavailability and the best effect.
Example 10
Coenzyme Q10 in vivo tissue distribution experimental method: 12 SD male rats were housed for 5 days and acclimatized. Rats were subjected to a 12 hour light-dark cycle under controlled temperature and relative humidity conditions. Rats were randomly divided into three groups of four rats, a first group of intragastric administration of the solution of example 2 (7 days, drug concentration 1.8mg/ml, dosage 18mg/kg), a second group of intragastric administration of a commercial coenzyme Q10 (Meishiwei Q-Sorb 200 mg) product (7 days, drug concentration 1.8mg/ml, dosage 18mg/kg), and a third group of free access to food and water daily (7 days). After 7 days, all animals were sacrificed by dislocation of cervical vertebrae, and liver, spleen, kidney, lung, heart and other organs were weighed. An amount of PBS was added, PH = 7.4. The frozen stock was rapidly stored with liquid nitrogen (-20 ℃ C.). The specimen still needs to be kept at the temperature of 2-8 ℃ after being melted. An amount of PBS (pH 7.4) was added and the specimen was homogenized with a homogenizer. The mixture was centrifuged for 20 minutes (3000 rpm), and the supernatant was collected. Putting 1.0ml of supernatant into a 15ml polypropylene centrifuge tube, adding Iml methanol for deproteinization, carrying out vortex mixing for 1min, adding 4.0ml of n-hexane, carrying out vortex mixing for 1min, carrying out 13000rmp/min centrifugation for 10min, transferring an n-hexane layer into a 15ml test tube with a plug, adding 6.0ml of n-hexane into the centrifuge tube twice, extracting twice according to the steps, combining n-hexane extract liquid into the 15ml test tube with the plug, blowing the n-hexane solvent by using nitrogen flow under the condition of 40C water bath, adding 100ul of absolute ethyl alcohol into residues for dissolving, taking 20ul of the mixture, and carrying out HPLC analysis according to the coenzyme Q10 content analysis method described in the embodiment 6 to obtain the concentration of the coenzyme Q10 between tissues. The results of the distribution of the components are shown in figure 3,
as can be seen from FIG. 3, the distribution of coenzyme Q10 in the tissues is greatly improved in examples 1 and 2 and the commercial product compared with the blank control. Example 1, coenzyme Q10 was highest in heart, spleen, lung, and kidney, indicating that both examples 1 and 2 improve the utilization of coenzyme Q10 in tissues.
Claims (4)
1. The coenzyme Q10 medicine delivery composition is characterized by comprising the following raw materials in parts by weight: 102 parts of coenzyme Q, 32 parts of protamine, 4.45 parts of surfactant, 0.35 part of stabilizer and 0.055 part of lubricant; the preparation process comprises the following steps: adding all raw materials into a 500mL stainless steel ball milling tank, adding 64 stainless steel ball milling beads with the diameter of 15mm, carrying out grinding reaction at 200rpm for 4 hours, and separating the drug from the stainless steel ball milling beads after the reaction is finished to obtain the coenzyme Q10 drug delivery composition.
2. The coenzyme Q10 delivery composition according to claim 1, wherein the lubricant is one or more selected from the group consisting of silica gel, tricalcium phosphate, talc, and magnesium stearate.
3. The coenzyme Q10 drug delivery composition according to claim 1 or 2, wherein the stabilizer is one or more of 2, 6-di-tert-butyl-4-methylphenol, DL tocopherol, vitamin C palmitate and tea polyphenol.
4. The coenzyme Q10 delivery composition according to claim 1 or 2, wherein the surfactant is poloxamer, diglycerol stearate, disodium glycyrrhizinate, sodium caseinate, sucrose ester or tea saponin.
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