High-bioavailability coenzyme Q10 tablet and preparation method thereof

Abstract

The invention relates to the technical field of oral solid preparations, in particular to a high-bioavailability coenzyme Q10 tablet and a preparation method thereof. The coenzyme Q10 tablet comprises an active component coenzyme Q10, a filler, an adhesive, a disintegrating agent, a lubricant and a high polymer material, compared with the prior art, hydroxyethyl methylcellulose and hydroxypropyl methylcellulose succinate are mixed according to a certain mass ratio to serve as a high polymer carrier material, the prepared coenzyme Q10 tablet can be rapidly dissolved out in vitro, and the coenzyme Q10 tablet has the advantages that the preparation process is simple, and the cost is low. Moreover, the stability of the medicine can be improved, the medicine can be rapidly absorbed in vivo after being orally taken, the oral bioavailability of the coenzyme Q10 is greatly improved, and a preparation process of the preparation is simple to operate, good in reproducibility and suitable for industrial production.

Description

Technical Field

[0001] The present application relates to the technical field of oral solid preparations, and in particular to a tablet of coenzyme Q10 with high bioavailability and a preparation method thereof. Background Art

[0002] Coenzyme Q10, also known as decenequinone and ubiquinone, is a fat-soluble quinone compound with the structure shown below. It is widely present in the cells of animals, plants and microorganisms. As an important hydrogen donor in the respiratory chain, coenzyme Q10 is an important factor in the energy generation and cell metabolism of biological cells. Coenzyme Q10 is one of the most important antioxidants in organisms. It can remove free radicals, prevent the oxidation of macromolecules such as proteins, lipids, and DNA, and enhance the antioxidant capacity of tocopherol.

[0003]

[0004] Coenzyme Q10 participates in energy production and activation in human cells. It is a natural antioxidant and cell metabolism initiator produced by cells themselves. It has the functions of protecting and restoring the integrity of biological membrane structure and stabilizing membrane potential. It is a non-specific immune enhancer of the body. Coenzyme Q10 is widely used. It is mainly used as an auxiliary drug for cardiovascular diseases, acute and chronic hepatitis and cancer. In addition, it also has auxiliary therapeutic effects on many diseases. Its main clinical applications are detailed as follows:

[0005] (1) Coenzyme Q10 has unique therapeutic effects in the treatment of cardiovascular diseases and is often used as an auxiliary treatment for ischemic heart disease, rheumatic heart disease, constrictive pericarditis, myocarditis, angina pectoris, arrhythmia, coronary heart disease, congestive heart failure and hypertension.

[0006] (2) Coenzyme Q10 can be used to treat acute and chronic hepatitis, subacute liver necrosis, and also has certain therapeutic effects on other liver diseases.

[0007] (3) It is used in the comprehensive treatment of cancer and can reduce certain side effects caused by radiotherapy and chemotherapy. It also has a certain effect in the clinical treatment of patients with advanced acute cancer.

[0008] (4) Coenzyme Q10 has many other beneficial effects. It can be used to treat hypercholesterolemia, sequelae of neck trauma, cerebrovascular disease, hemorrhagic shock, gastric ulcer, duodenal ulcer, scurvy, necrotizing periodontitis, emphysema, bronchial asthma, hearing impairment, aplastic anemia and other diseases. It also has an irreplaceable role and broad application prospects in delaying aging and improving immunity.

[0009] Coenzyme Q10 can be obtained from food, but sometimes the amount obtained from food cannot meet the needs of the human body, so coenzyme Q10 dietary supplement products can be consumed. Coenzyme Q10 is a water-insoluble macromolecule with low intestinal absorption rate and low oral bioavailability. In response to this situation, in recent years, many patents have disclosed formulas and processes for improving the bioavailability of coenzyme Q10, such as inclusion technology, microcapsule technology, liposomes, etc., but there are still some problems, and the particle size of the aqueous solution cannot fully achieve the ideal effect.

[0010] Chinese patent CN101744288A records a clear oral preparation containing coenzyme Q10 and its preparation method. The formula for preparing the oral preparation is roughly as follows: coenzyme Q10 0.1% to 10%, emulsifier 0.5% to 30%, co-emulsifier 5% to 20%, stabilizer 0.5% to 10%, and the balance is water. However, the invention only gives the stability data of the coenzyme Q10 microemulsion at 25°C, and does not involve the stability at low temperature (-30°C to -10°C) and high temperature (100°C to 130°C). Since the coenzyme Q10 microemulsion needs to undergo extreme temperature environments such as high temperature sterilization and refrigerated storage in subsequent applications such as oral liquid, beverage, soft capsule, and food, the microemulsion in the current prior art is not stable enough in the above extreme temperature environment, and it is easy to break the emulsion, resulting in its activity being destroyed. Therefore, the current coenzyme Q10 microemulsion performance and its preparation process still need to be improved.

[0011] Chinese patent CN101053556A introduces the method of using hydroxypropyl-β-cyclodextrin as cyclodextrin to contain coenzyme Q10, and preparing the coenzyme Q10 inclusion complex after drying. However, the weight ratio of hydroxypropyl-β-cyclodextrin to coenzyme Q10 in the above invention is large. However, in the process of drying the inclusion complex solution, the water molecules are greatly reduced, and the repulsive force on coenzyme Q10 is also greatly reduced, which destroys the stable environment of coenzyme Q10 in the cyclodextrin cavity, and a part of coenzyme Q10 molecules escape from the cyclodextrin cavity. Not only will the coenzyme Q10 molecules combine with each other to form precipitation, but the inclusion rate of coenzyme Q10-cyclodextrin inclusion complex is low.

[0012] Chinese patent CN109953967A discloses a process research of coenzyme Q10 tablets. The technical scheme is to use film coating as the enteric film coating premix of coenzyme Q10, which can obtain coenzyme Q10 tablets with high release rate. Its prescription is as follows (1000 tablets): 185,000 units of coenzyme Q10 tablets, 50.0g of microcrystalline cellulose, 30.0g of pregelatinized starch, 90.0g of lactose, 25ml of polyvinylpyrrolidone, appropriate amount of purified water, and 0.5g of magnesium stearate. It is well known that coenzyme Q10 is easily decomposed by light. The patent does not verify its stability, etc., and only uses coating technology to control its release rate.

[0013] Chinese patent CN101015524A discloses a coenzyme Q10 oral emulsion and its preparation method, the components and contents of which are as follows: coenzyme Q10 is 0.1%-80%, medicinal oil is 1%-95%, emulsifier is 0.5%-30%, auxiliary emulsifier is 0-10%, antioxidant is 0.001-15%, and the balance is purified water, which is prepared by phase inversion emulsification method, PIT emulsification method, alternating liquid addition emulsification method, continuous emulsification method, low-energy emulsification method, microfluidization method, etc. However, this technology only solves the problem of stability of ordinary emulsions by adding auxiliary emulsifiers, and does not verify and mention the problem of easy oxidation of coenzyme Q10.

[0014] Therefore, under the premise of ensuring the quality of the drug, selecting appropriate excipients and new preparation processes to control the dissolution of coenzyme Q10 while improving stability and bioavailability has positive significance for ensuring the efficacy and safety of clinical drugs. Summary of the invention

[0015] In view of this, the purpose of the present invention is to overcome the shortcomings of the prior art and provide a tablet of coenzyme Q10 with high bioavailability and a preparation method thereof, which increases the solubility of coenzyme Q10 by screening and adding reasonable excipients, thereby not only improving the stability of the solution and reducing the content of related substances, but also improving the bioavailability of coenzyme Q10.

[0016] In order to achieve the above object, the present invention provides the following technical solutions:

[0017] The invention provides a coenzyme Q10 tablet, which is composed of the following raw materials: coenzyme Q10, a filler, a binder, a disintegrant, a lubricant, and a polymer carrier material.

[0018] Furthermore, the polymer carrier material is formed by mixing hydroxyethyl methylcellulose with at least one of hydroxypropyl methylcellulose succinate, hydroxypropyl methylcellulose phthalate, acrylic resin, polyvinyl alcohol, polyvinyl pyrrolidone or polyacrylamide.

[0019] Furthermore, the polymer carrier material is prepared by mixing hydroxyethyl methylcellulose and hydroxypropyl methylcellulose succinate in a mass ratio of 1:(1-5).

[0020] Furthermore, the raw materials include, by weight: 10-30 parts of coenzyme Q10, 40-80 parts of filler, 4-10 parts of binder, 5-10 parts of disintegrant, 0.5-3 parts of lubricant, and 1-10 parts of polymer carrier material.

[0021] Furthermore, the filler is selected from any one or more of starch, sucrose, lactose, calcium sulfate, calcium phosphate, calcium carbonate, mannitol, sorbitol, and microcrystalline cellulose.

[0022] Further preferably, the filler is selected from any one or more of starch, lactose, calcium carbonate or microcrystalline cellulose.

[0023] Furthermore, the adhesive is selected from any one or more of pregelatinized starch, dextrin, carbomer, methyl cellulose, ethyl cellulose, and sodium carboxymethyl cellulose.

[0024] More preferably, the binder is selected from any one or more of pregelatinized starch, dextrin, and sodium carboxymethylcellulose.

[0025] Furthermore, the disintegrant is selected from any one or more of sodium carboxymethyl starch, povidone, copovidone, sodium alginate, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose and calcium carboxymethyl cellulose.

[0026] More preferably, the disintegrant is selected from any one or more of sodium carboxymethyl starch, copovidone, and sodium alginate.

[0027] Furthermore, the disintegrating lubricant is selected from any one or more of silicon dioxide, micropowdered silica gel, talc, glyceryl behenate, glyceryl monostearate, glyceryl distearate, docusate sodium, sodium palmitate, magnesium silicate, stearic acid, sodium stearate, calcium stearate, zinc stearate, magnesium stearate and sodium stearyl fumarate.

[0028] Further preferably, the lubricant is selected from any one or more of silicon dioxide, micropowder silica gel, magnesium stearate and sodium stearyl fumarate.

[0029] Furthermore, the particle size D90 of the coenzyme Q10 is ≤20 μm.

[0030] Furthermore, the tablet is a chewable tablet.

[0031] The present invention also provides a method for preparing a coenzyme Q10 tablet, comprising the following steps:

[0032] Step 1. The coenzyme Q10 raw material is crushed by a jet mill at a feed rate of 1 kg / h and a crushing pressure of 0.8 MPa, and separated by a cyclone separator to obtain coenzyme Q10 for later use;

[0033] Step 2. Grind the filler, binder, disintegrant, lubricant and polymer carrier material separately and pass through an 80-mesh sieve for later use;

[0034] Step 3. Add the polymer carrier material into a hot melt extrusion device for hot melt extrusion operation, the screw speed is 180 rpm, the hot melt extrusion temperature is 150 ° C, the feeding rate is 1 kg / h, and the extruded material is obtained. The extruded material is crushed and passed through an 80-mesh sieve to obtain the polymer carrier material;

[0035] Step 4. Weigh the prescribed amount of coenzyme Q10 raw material, filler, binder, disintegrant, and lubricant, add them into a three-dimensional mixing device and mix for 30 minutes, then add the polymer carrier material and continue mixing for 15 minutes to obtain a mixture;

[0036] Step 5. The mixture is compressed by a rotary tablet press to obtain coenzyme Q10 tablets with a tablet weight of 30 mg.

[0037] Furthermore, the particle size D90 of the coenzyme Q10 after crushing in step 1 is ≤20 μm.

[0038] Furthermore, in step 5, the tableting pressure is 6 to 10 KN.

[0039] Compared with the prior art, the present invention has the following beneficial effects:

[0040] (1) The present invention develops a coenzyme Q10 tablet with coenzyme Q10 as an active ingredient. The prescription comprises 10-30 parts of coenzyme Q10, 40-80 parts of a filler, 4-10 parts of a binder, 5-10 parts of a disintegrant, 0.5-3 parts of a lubricant, and 1-10 parts of a polymer carrier material by optimizing the screening of prescription excipients and dosages.

[0041] (2) The present invention mixes hydroxyethyl methylcellulose and hydroxypropyl methylcellulose succinate in a certain mass ratio and prepares a polymer carrier material through a hot melt extrusion process. The coenzyme Q10 tablet prepared by mixing the polymer carrier material with other auxiliary materials solves the problems of content uniformity and stability. Hydroxyethyl methylcellulose and hydroxypropyl methylcellulose succinate synergistically improve the stability of the tablet.

[0042] (3) The coenzyme Q10 tablets prepared by the present invention have good dissolution rate and dissolution effect. The dissolution rate in vitro within 30 minutes can reach more than 85%. The high dissolution rate and good dissolution effect greatly improve the oral bioavailability of coenzyme Q10. The preparation process of the preparation is simple to operate, has good reproducibility, and is suitable for industrial production. DETAILED DESCRIPTION

[0043] The following detailed description of the embodiments of the present invention provided in the examples is not intended to limit the scope of the invention claimed, but merely represents selected embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in the field without creative work are within the scope of protection of the present invention.

[0044] The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials described are commercially available unless otherwise specified.

[0045] Example 1 A coenzyme Q10 tablet, the composition and preparation process of which are as follows:

[0046] The components are shown in the following table:

[0047]

[0048]

[0049] The preparation process is as follows:

[0050] Step 1. The coenzyme Q10 raw material is crushed by a jet mill at a feed rate of 1 kg / h and a crushing pressure of 0.8 MPa. A cyclone separator is used for separation to obtain coenzyme Q10 with D90 ≤ 20 μm for standby use.

[0051] Step 2. Grind the filler, binder, disintegrant, lubricant and polymer carrier material separately and pass through an 80-mesh sieve for later use.

[0052] Step 3. Add hydroxyethyl methylcellulose and hydroxypropyl methylcellulose succinate in a mass ratio of 1:1 into a hot melt extrusion device for hot melt extrusion operation, the screw speed is 180 rpm, the hot melt extrusion temperature is 150°C, the feeding rate is 1 kg / h, and an extruded material is obtained. The extruded material is crushed and passed through an 80-mesh sieve to obtain a polymer carrier material.

[0053] Step 4. Weigh the prescribed amount of coenzyme Q10 raw material, filler, binder, disintegrant, and lubricant, add them into a three-dimensional mixing device and mix for 30 minutes, then add the polymer carrier material and continue mixing for 15 minutes to obtain a mixture.

[0054] Step 5. The mixture is compressed by a rotary tablet press at a compression pressure of 6 to 10 kN to obtain coenzyme Q10 tablets with a tablet weight of 30 mg.

[0055] Example 2 A coenzyme Q10 tablet, the composition and preparation process of which are as follows:

[0056] The components are shown in the following table:

[0057]

[0058] The preparation process is as follows:

[0059] Step 1. The coenzyme Q10 raw material is crushed by a jet mill at a feed rate of 1 kg / h and a crushing pressure of 0.8 MPa. A cyclone separator is used for separation to obtain coenzyme Q10 with D90 ≤ 20 μm for standby use.

[0060] Step 2. Grind the filler, binder, disintegrant, lubricant and polymer carrier material separately and pass through an 80-mesh sieve for later use.

[0061] Step 3. Add hydroxyethyl methylcellulose and hydroxypropyl methylcellulose succinate in a mass ratio of 1:3 into a hot melt extrusion device for hot melt extrusion operation, the screw speed is 180 rpm, the hot melt extrusion temperature is 150°C, the feeding rate is 1 kg / h, and an extruded material is obtained. The extruded material is crushed and passed through an 80-mesh sieve to obtain a polymer carrier material.

[0062] Step 4. Weigh the prescribed amount of coenzyme Q10 raw material, filler, binder, disintegrant, and lubricant, add them into a three-dimensional mixing device and mix for 30 minutes, then add the polymer carrier material and continue mixing for 15 minutes to obtain a mixture.

[0063] Step 5. The mixture is compressed by a rotary tablet press at a compression pressure of 6 to 10 kN to obtain coenzyme Q10 tablets with a tablet weight of 30 mg.

[0064] Example 3 A coenzyme Q10 tablet, the composition and preparation process of which are as follows:

[0065] The components are shown in the following table:

[0066]

[0067] The preparation process is as follows:

[0068] Step 1. The coenzyme Q10 raw material is crushed by a jet mill at a feed rate of 1 kg / h and a crushing pressure of 0.8 MPa. A cyclone separator is used for separation to obtain coenzyme Q10 with D90 ≤ 20 μm for standby use.

[0069] Step 2. Grind the filler, binder, disintegrant, lubricant and polymer carrier material separately and pass through an 80-mesh sieve for later use.

[0070] Step 3. Add hydroxyethyl methylcellulose and hydroxypropyl methylcellulose succinate in a mass ratio of 1:5 into a hot melt extrusion device for hot melt extrusion operation, the screw speed is 180 rpm, the hot melt extrusion temperature is 150°C, the feeding rate is 1 kg / h, and an extruded material is obtained. The extruded material is crushed and passed through an 80-mesh sieve to obtain a polymer carrier material.

[0071] Step 4. Weigh the prescribed amount of coenzyme Q10 raw material, filler, binder, disintegrant, and lubricant, add them into a three-dimensional mixing device and mix for 30 minutes, then add the polymer carrier material and continue mixing for 15 minutes to obtain a mixture.

[0072] Step 5. The mixture is compressed by a rotary tablet press at a compression pressure of 6 to 10 kN to obtain coenzyme Q10 tablets with a tablet weight of 30 mg.

[0073] Example 4 A coenzyme Q10 tablet, the composition and preparation process of which are as follows:

[0074] The components are shown in the following table:

[0075]

[0076] The preparation process is as follows:

[0077] Step 1. The coenzyme Q10 raw material is crushed by a jet mill at a feed rate of 1 kg / h and a crushing pressure of 0.8 MPa. A cyclone separator is used for separation to obtain coenzyme Q10 with D90 ≤ 20 μm for standby use.

[0078] Step 2. Grind the filler, binder, disintegrant, lubricant and polymer carrier material separately and pass through an 80-mesh sieve for later use.

[0079] Step 3. Add hydroxyethyl methylcellulose and hydroxypropyl methylcellulose succinate in a mass ratio of 1:2 into a hot melt extrusion device for hot melt extrusion operation, the screw speed is 180 rpm, the hot melt extrusion temperature is 150°C, the feeding rate is 1 kg / h, and an extruded material is obtained. The extruded material is crushed and passed through an 80-mesh sieve to obtain a polymer carrier material.

[0080] Step 4. Weigh the prescribed amount of coenzyme Q10 raw material, filler, binder, disintegrant, and lubricant, add them into a three-dimensional mixing device and mix for 30 minutes, then add the polymer carrier material and continue mixing for 15 minutes to obtain a mixture.

[0081] Step 5. The mixture is compressed by a rotary tablet press at a compression pressure of 6 to 10 kN to obtain coenzyme Q10 tablets with a tablet weight of 30 mg.

[0082] Example 5 A coenzyme Q10 tablet, the composition and preparation process of which are as follows:

[0083] The components are shown in the following table:

[0084]

[0085] The preparation process is as follows:

[0086] Step 1. The coenzyme Q10 raw material is crushed by a jet mill at a feed rate of 1 kg / h and a crushing pressure of 0.8 MPa. A cyclone separator is used for separation to obtain coenzyme Q10 with D90 ≤ 20 μm for standby use.

[0087] Step 2. Grind the filler, binder, disintegrant, lubricant and polymer carrier material separately and pass through an 80-mesh sieve for later use.

[0088] Step 3. Add hydroxyethyl methylcellulose and hydroxypropyl methylcellulose succinate in a mass ratio of 1:3 into a hot melt extrusion device for hot melt extrusion operation, the screw speed is 180 rpm, the hot melt extrusion temperature is 150°C, the feeding rate is 1 kg / h, and an extruded material is obtained. The extruded material is crushed and passed through an 80-mesh sieve to obtain a polymer carrier material.

[0089] Step 4. Weigh the prescribed amount of coenzyme Q10 raw material, filler, binder, disintegrant, and lubricant, add them into a three-dimensional mixing device and mix for 30 minutes, then add the polymer carrier material and continue mixing for 15 minutes to obtain a mixture.

[0090] Step 5. The mixture is compressed by a rotary tablet press at a compression pressure of 6 to 10 kN to obtain coenzyme Q10 tablets with a tablet weight of 30 mg.

[0091] Example 6 A coenzyme Q10 tablet, the composition and preparation process of which are as follows:

[0092] The components are shown in the following table:

[0093]

[0094]

[0095] The preparation process is as follows:

[0096] Step 1. The coenzyme Q10 raw material is crushed by a jet mill at a feed rate of 1 kg / h and a crushing pressure of 0.8 MPa. A cyclone separator is used for separation to obtain coenzyme Q10 with D90 ≤ 20 μm for standby use.

[0097] Step 2. Grind the filler, binder, disintegrant, lubricant and polymer carrier material separately and pass through an 80-mesh sieve for later use.

[0098] Step 3. Add hydroxyethyl methylcellulose and hydroxypropyl methylcellulose succinate in a mass ratio of 1:4 into a hot melt extrusion device for hot melt extrusion operation, the screw speed is 180 rpm, the hot melt extrusion temperature is 150°C, the feeding rate is 1 kg / h, and an extruded material is obtained. The extruded material is crushed and passed through an 80-mesh sieve to obtain a polymer carrier material.

[0099] Step 4. Weigh the prescribed amount of coenzyme Q10 raw material, filler, binder, disintegrant, and lubricant, add them into a three-dimensional mixing device and mix for 30 minutes, then add the polymer carrier material and continue mixing for 15 minutes to obtain a mixture.

[0100] Step 5. The mixture is compressed by a rotary tablet press at a compression pressure of 6 to 10 kN to obtain coenzyme Q10 tablets with a tablet weight of 30 mg.

[0101] Comparative Example 1 A coenzyme Q10 tablet, the composition and preparation process of which are as follows:

[0102] Compared with Example 1, the particle size of coenzyme Q10 is larger, and the specific components are shown in the following table:

[0103]

[0104] The preparation process is as follows:

[0105] Step 1. The coenzyme Q10 raw material is crushed by a jet mill at a feed rate of 1 kg / h and a crushing pressure of 0.8 MPa. A cyclone separator is used for separation to obtain coenzyme Q10 with 80≤D90≤150 μm for standby use.

[0106] Step 2. Grind the filler, binder, disintegrant, lubricant and polymer carrier material separately and pass through an 80-mesh sieve for later use.

[0107] Step 3. Add hydroxyethyl methylcellulose and hydroxypropyl methylcellulose succinate in a mass ratio of 1:1 into a hot melt extrusion device for hot melt extrusion operation, the screw speed is 180 rpm, the hot melt extrusion temperature is 150°C, the feeding rate is 1 kg / h, and an extruded material is obtained. The extruded material is crushed and passed through an 80-mesh sieve to obtain a polymer carrier material.

[0108] Step 4. Weigh the prescribed amount of coenzyme Q10 raw material, filler, binder, disintegrant, and lubricant, add them into a three-dimensional mixing device and mix for 30 minutes, then add the polymer carrier material and continue mixing for 15 minutes to obtain a mixture.

[0109] Step 5. The mixture is compressed by a rotary tablet press at a compression pressure of 6 to 10 kN to obtain coenzyme Q10 tablets with a tablet weight of 30 mg.

[0110] Comparative Example 2 A coenzyme Q10 tablet, whose components and preparation process are as follows:

[0111] Compared with Example 1, the mass ratio of the polymer carrier material is different, and the specific components are shown in the following table:

[0112]

[0113] The preparation process is as follows:

[0114] Step 1. The coenzyme Q10 raw material is crushed by a jet mill at a feed rate of 1 kg / h and a crushing pressure of 0.8 MPa. A cyclone separator is used for separation to obtain coenzyme Q10 with D90 ≤ 20 μm for standby use.

[0115] Step 2. Grind the filler, binder, disintegrant, lubricant and polymer carrier material separately and pass through an 80-mesh sieve for later use.

[0116] Step 3. Add hydroxyethyl methylcellulose and hydroxypropyl methylcellulose succinate in a mass ratio of 1:8 into a hot melt extrusion device for hot melt extrusion operation, the screw speed is 180 rpm, the hot melt extrusion temperature is 150°C, the feeding rate is 1 kg / h, and an extruded material is obtained. The extruded material is crushed and passed through an 80-mesh sieve to obtain a polymer carrier material.

[0117] Step 4. Weigh the prescribed amount of coenzyme Q10 raw material, filler, binder, disintegrant, and lubricant, add them into a three-dimensional mixing device and mix for 30 minutes, then add the polymer carrier material and continue mixing for 15 minutes to obtain a mixture.

[0118] Step 5. The mixture is compressed by a rotary tablet press at a compression pressure of 6 to 10 kN to obtain coenzyme Q10 tablets with a tablet weight of 30 mg.

[0119] Comparative Example 3 A coenzyme Q10 tablet, whose components and preparation process are as follows:

[0120] Compared with Example 1, no polymer carrier material was added, and the specific components are shown in the following table:

[0121] Raw material components specific ingredients Each component is measured in wt%, Coenzyme Q10 Coenzyme Q10 (D90≤20μm) 20 Fillers starch 60 Adhesives Pregelatinized starch 7 Disintegrants Sodium starch glycolate 8 Lubricants Silicon dioxide 2 Polymer carrier materials / /

[0122] The preparation process is as follows:

[0123] Step 1. The coenzyme Q10 raw material is crushed by a jet mill at a feed rate of 1 kg / h and a crushing pressure of 0.8 MPa. A cyclone separator is used for separation to obtain coenzyme Q10 with D90 ≤ 20 μm for standby use.

[0124] Step 2. Grind the filler, binder, disintegrant and lubricant separately and pass through an 80-mesh sieve for later use.

[0125] Step 3. Weigh the prescribed amount of coenzyme Q10 raw material, filler, binder, disintegrant, and lubricant, add them into a three-dimensional mixing device and mix for 30 minutes to obtain a mixture.

[0126] Step 4. The mixture is compressed by a rotary tablet press at a compression pressure of 6 to 10 kN to obtain coenzyme Q10 tablets with a tablet weight of 30 mg.

[0127] Comparative Example 4 A coenzyme Q10 tablet, whose components and preparation process are as follows:

[0128] Compared with Example 1, the composition of the polymer carrier material is different, and the specific components are shown in the following table:

[0129]

[0130]

[0131] The preparation process is as follows:

[0132] Step 1. The coenzyme Q10 raw material is crushed by a jet mill at a feed rate of 1 kg / h and a crushing pressure of 0.8 MPa. A cyclone separator is used for separation to obtain coenzyme Q10 with D90 ≤ 20 μm for standby use.

[0133] Step 2. Grind the filler, binder, disintegrant, lubricant and polymer carrier material separately and pass through an 80-mesh sieve for later use.

[0134] Step 3. Add hydroxyethyl methyl cellulose and polyacrylamide in a mass ratio of 1:1 into a hot melt extrusion device for hot melt extrusion operation, the screw speed is 180 rpm, the hot melt extrusion temperature is 150°C, the feeding rate is 1 kg / h, and an extruded material is obtained. The extruded material is crushed and passed through an 80-mesh sieve to obtain a polymer carrier material.

[0135] Step 4. Weigh the prescribed amount of coenzyme Q10 raw material, filler, binder, disintegrant, and lubricant, add them into a three-dimensional mixing device and mix for 30 minutes, then add the polymer carrier material and continue mixing for 15 minutes to obtain a mixture.

[0136] Step 5. The mixture is compressed by a rotary tablet press at a compression pressure of 6 to 10 kN to obtain coenzyme Q10 tablets with a tablet weight of 30 mg.

[0137] Comparative Example 5 A coenzyme Q10 tablet, whose components and preparation process are as follows:

[0138] Compared with Example 1, the composition of the polymer carrier material is different, and the specific components are shown in the following table:

[0139] Raw material components specific ingredients Each component is measured in wt%, Coenzyme Q10 Coenzyme Q10 (D90≤20μm) 20 Fillers starch 60 Adhesives Pregelatinized starch 7 Disintegrants Sodium starch glycolate 8 Lubricants Silicon dioxide 2 Polymer carrier materials Hydroxyethyl methylcellulose 5

[0140] The preparation process is as follows:

[0141] Step 1. The coenzyme Q10 raw material is crushed by a jet mill at a feed rate of 1 kg / h and a crushing pressure of 0.8 MPa. A cyclone separator is used for separation to obtain coenzyme Q10 with D90 ≤ 20 μm for standby use.

[0142] Step 2. Grind the filler, binder, disintegrant, lubricant and polymer carrier material separately and pass through an 80-mesh sieve for later use.

[0143] Step 3. Add hydroxyethyl methyl cellulose to a hot melt extrusion device for hot melt extrusion operation, the screw speed is 180 rpm, the hot melt extrusion temperature is 150°C, the feeding rate is 1 kg / h, and an extruded material is obtained. The extruded material is crushed and passed through an 80-mesh sieve to obtain a polymer carrier material.

[0144] Step 4. Weigh the prescribed amount of coenzyme Q10 raw material, filler, binder, disintegrant, and lubricant, add them into a three-dimensional mixing device and mix for 30 minutes, then add the polymer carrier material and continue mixing for 15 minutes to obtain a mixture.

[0145] Step 5. The mixture is compressed by a rotary tablet press at a compression pressure of 6 to 10 kN to obtain coenzyme Q10 tablets with a tablet weight of 30 mg.

[0146] Comparative Example 6 A coenzyme Q10 tablet, whose components and preparation process are as follows:

[0147] Compared with Example 1, the content of each component is different, and the specific components are shown in the following table:

[0148]

[0149] The preparation process is as follows:

[0150] Step 1. The coenzyme Q10 raw material is crushed by a jet mill at a feed rate of 1 kg / h and a crushing pressure of 0.8 MPa. A cyclone separator is used for separation to obtain coenzyme Q10 with D90 ≤ 20 μm for standby use.

[0151] Step 2. Grind the filler, binder, disintegrant, lubricant and polymer carrier material separately and pass through an 80-mesh sieve for later use.

[0152] Step 3. Add hydroxyethyl methylcellulose and hydroxypropyl methylcellulose succinate in a mass ratio of 1:1 into a hot melt extrusion device for hot melt extrusion operation, the screw speed is 180 rpm, the hot melt extrusion temperature is 150°C, the feeding rate is 1 kg / h, and an extruded material is obtained. The extruded material is crushed and passed through an 80-mesh sieve to obtain a polymer carrier material.

[0153] Step 4. Weigh the prescribed amount of coenzyme Q10 raw material, filler, binder, disintegrant, and lubricant, add them into a three-dimensional mixing device and mix for 30 minutes, then add the polymer carrier material and continue mixing for 15 minutes to obtain a mixture.

[0154] Step 5. The mixture is compressed by a rotary tablet press at a compression pressure of 6 to 10 kN to obtain coenzyme Q10 tablets with a tablet weight of 30 mg.

[0155] Effect Example 1: Content Uniformity Test

[0156] According to the content uniformity test method of Part IV of the 2020 edition of the "Chinese Pharmacopoeia" (General Rule 0941).

[0157] Unless otherwise specified, take 10 samples of the test product and determine the relative content xi of each single dose with the labeled amount as 100 according to the method specified under each variety, and calculate the mean value and standard deviation S and the absolute value A of the difference between the indicated value and the mean

[0158] If A+2.2S≤L, the content uniformity of the test sample meets the requirements;

[0159] If A+S>L, it does not meet the requirements;

[0160] If A+2.2S>L and A+S≤L, another 20 samples should be taken for retesting.

[0161] In the above formula, L is a specified value, unless otherwise specified, L = 15.0.

[0162] Referring to the above method, the content uniformity of the tablets prepared in Examples 1-6 and Comparative Examples 1-6 was measured. The results are shown in Table 1.

[0163] Table 1 Content uniformity

[0164] Experimental Group Content uniformity Example 1 7.2 Example 2 6.8 Example 3 7.5 Example 4 7.8 Example 5 8.0 Example 6 7.4 Comparative Example 1 13.5 Comparative Example 2 12.1 Comparative Example 3 16.8 Comparative Example 4 10.4 Comparative Example 5 11.5 Comparative Example 6 12.3

[0165] It can be seen from the above table that the content uniformity of the coenzyme Q10 tablets provided by the present invention meets the regulations and is far less than the prescribed requirements. The microtablets prepared by the present invention have good content uniformity, and the composition of the polymer carrier material has a greater influence on the content uniformity of the final tablets.

[0166] Effect Example 2: Dissolution Test

[0167] Method: The dissolution was determined according to the dissolution and release method (Method 2, Part 4, General Rules 0931, Chinese Pharmacopoeia 2020 Edition).

[0168] Take the corresponding tablets in Examples 1-6 and Comparative Examples 1-6, and according to the dissolution and release determination method (Chinese Pharmacopoeia 2020 Edition Four General Rules 0931 Second Method), take 900 mL of pH = 4.5 acetate buffer solution containing 0.25% sodium dodecyl sulfate as the dissolution medium, the paddle method is 75 revolutions per minute, operate according to the law, take the solution for determination according to the sampling time, and the dissolution curve determination data are shown in Table 2:

[0169] Table 2 Dissolution test

[0170] Experimental Group 10min 20min 30min 60min Example 1 33.2 65.8 87.5 98.6 Example 2 29.5 67.4 89.6 99.3 Example 3 32.4 70.1 88.4 99.6 Example 4 31.6 68.4 85.3 98.4 Example 5 33.4 70.6 86.9 97.8 Example 6 34.1 65.2 85.1 99.5 Comparative Example 1 24.2 59.1 75.1 90.2 Comparative Example 2 28.5 60.3 77.8 86.4 Comparative Example 3 18.5 36.6 55.2 78.5 Comparative Example 4 22.4 58.6 78.0 92.4 Comparative Example 5 24.3 60.4 75.5 90.5 Comparative Example 6 32.5 55.4 72.4 88.5

[0171] From the dissolution test results in Table 2, it can be seen that the tablets of Examples 1 to 6 can achieve a dissolution rate of more than 85% in vitro within 30 minutes, and the dissolution rate within 1 hour is basically close to 100%. They can quickly disintegrate and release all the coenzyme Q10 tablets after taking them, indicating that the coenzyme Q10 tablets prepared by the present invention have good dissolution rate and dissolution effect, high bioavailability, and are more conducive to human absorption.

[0172] In addition, the dissolution rate of Comparative Examples 1-6 at 30 min was significantly lower than that of the Example Group, and it can be seen from Comparative Example 1 that the particle size of the coenzyme Q10 raw material has a greater influence on the final dissolution rate. Comparative Examples 3-5 show that the polymer carrier material has a greater influence on the dissolution of the drug, and the dissolution effect is poor.

[0173] Effect Example 3: Stability Test

[0174] According to the requirements of the Guiding Principles for Stability Testing of Raw Materials and Preparations (Guiding Principles of the Fourth Part of the 2020 Edition of the Chinese Pharmacopoeia 9001 Guiding Principles for Stability Testing of Raw Materials and Preparations Pharmaceutical Preparations), the product was placed under accelerated conditions of 40°C / RH75% for 3 months, and the related substances (total impurities, %) were determined. The results are shown in Table 3:

[0175] Table 3 Stability test results

[0176]

[0177] From the stability test results in Table 3, it can be seen that the tablets of Examples 1 to 6 have a small change in the relevant substances after the 3-month accelerated test (compared with 0 day), indicating high long-term stability. The relevant substances of Comparative Examples 1-6 are significantly higher than those of the embodiments of the present invention in the 3rd month, indicating that the auxiliary material composition and content of the drug have a great influence on the stability of the tablets, especially the polymer carrier material plays a vital role in the stability of the entire drug system.

[0178] Effect Example 4: Bioavailability Determination

[0179] 40 SD rats, half male and half female, weighing 220±20g, were divided into 5 groups, 8 rats in each group, namely, Example 1 and 6 groups and Comparative Example 1, 3, and 4 groups, and were administered by gavage. The experimental animals were fasted for 6 hours before administration, and the dosage was 50 mg / kg in terms of coenzyme Q10. 1.5 ml of blood was collected from the orbit at 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, and 12h, respectively, and centrifuged at 4000rpm for 10min. 0.5 ml of the supernatant was taken, 1.5 ml of methanol was added, vortexed for 5min, centrifuged at 8000rpm for 10min, and 10 μl of the supernatant was taken. The concentration of coenzyme Q10 in the blood sample was detected by high performance liquid chromatography. The pharmacokinetic parameters are shown in Table 4.

[0180] Table 4 Pharmacokinetic parameters

[0181]

[0182] The pharmacokinetics of rats showed that the coenzyme Q10 tablets prepared by the present invention not only showed good dissolution in the in vitro dissolution experiment, but also had good absorption in rats. The preparations prepared in Examples 1 and 6 of the present invention could detect higher blood drug concentrations. Compared with Comparative Examples 1, 3 and 4, both in C max and bioavailability AUC 0-12 The above results show that the coenzyme Q10 tablets prepared by the present invention significantly improve the absorption rate and bioavailability of coenzyme Q10.

[0183] The above results show that the formula and process design of the samples of the embodiments of the present invention are reasonable, the added excipients, especially the polymer carrier material, can effectively promote the dissolution of coenzyme Q10 and improve the stability of the drug. The human body can quickly absorb the effective drug after taking the drug. The samples of the present invention can meet market demand.

[0184] Based on the above description, it will be appreciated by those skilled in the art that the present disclosure may be implemented in different specific forms without changing its technical spirit and essential features. Therefore, it should be understood that the above-mentioned embodiments are not restrictive in all aspects, but illustrative. The scope of the present disclosure is limited by the appended claims, rather than by the preceding description thereof, and therefore all changes and modifications fall within the boundaries and scope of the claims, or the equivalents of such boundaries and scope are therefore intended to be covered by the claims.

Claims

1. A coenzyme Q10 tablet, characterized in that: The invention is composed of the following raw materials: coenzyme Q10, a filler, a binder, a disintegrant, a lubricant, and a polymer carrier material.

2. The tablet according to claim 1, characterized in that The polymer carrier material is formed by mixing hydroxyethyl methylcellulose with at least one of hydroxypropyl methylcellulose succinate, hydroxypropyl methylcellulose phthalate, acrylic resin, polyvinyl alcohol, polyvinyl pyrrolidone or polyacrylamide.

3. The tablet according to claim 2, characterized in that The polymer carrier material is prepared by mixing hydroxyethyl methylcellulose and hydroxypropyl methylcellulose succinate in a mass ratio of 1:(1-5).

4. The tablet according to any one of claims 1 to 3, characterized in that The raw materials include, by weight, 10-30 parts of coenzyme Q10, 40-80 parts of filler, 4-10 parts of binder, 5-10 parts of disintegrant, 0.5-3 parts of lubricant, and 1-10 parts of polymer carrier material.

5. The tablet according to claim 4, characterized in that The filler is selected from any one or more of starch, sucrose, lactose, calcium sulfate, calcium phosphate, calcium carbonate, mannitol, sorbitol, and microcrystalline cellulose; preferably, the filler is selected from any one or more of starch, lactose, calcium carbonate, or microcrystalline cellulose.

6. The tablet according to claim 4, characterized in that The binder is selected from any one or more of pregelatinized starch, dextrin, carbomer, methyl cellulose, ethyl cellulose, and sodium carboxymethyl cellulose; preferably, the binder is selected from any one or more of pregelatinized starch, dextrin, and sodium carboxymethyl cellulose.

7. The tablet according to claim 4, characterized in that The disintegrant is selected from any one or more of sodium starch glycolate, povidone, copovidone, sodium alginate, low-substituted hydroxypropyl cellulose, croscarmellose sodium and calcium carboxymethyl cellulose; preferably, the disintegrant is selected from any one or more of sodium starch glycolate, copovidone and sodium alginate.

8. The tablet according to claim 4, characterized in that The disintegrating lubricant is selected from any one or more of silicon dioxide, micropowder silica gel, talc, glyceryl behenate, glyceryl monostearate, glyceryl distearate, docusate sodium, sodium palmitate, magnesium silicate, stearic acid, sodium stearate, calcium stearate, zinc stearate, magnesium stearate and sodium stearyl fumarate; preferably, the lubricant is selected from any one or more of silicon dioxide, micropowder silica gel, magnesium stearate and sodium stearyl fumarate.

9. The tablet according to any one of claims 1 to 8, characterized in that The particle size D90 of the coenzyme Q10 is ≤20 μm.

10. The tablet according to claim 1, characterized in that The tablet is a chewable tablet.

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