A tablet of coenzyme q10 with high bioavailability and a preparation method thereof

Abstract

The application 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 of the application comprises an active ingredient coenzyme Q10, a filler, a binder, a disintegrant, a lubricant and a high-molecular material; compared with the prior art, the coenzyme Q10 tablet prepared by mixing hydroxyethyl methyl cellulose and hydroxypropyl methyl cellulose succinate according to a certain mass ratio as a high-molecular carrier material has the advantages that the coenzyme Q10 tablet is rapidly dissolved in vitro, the drug stability can be improved, the coenzyme Q10 is rapidly absorbed in the body after oral administration, the oral bioavailability of the coenzyme Q10 is greatly improved, the preparation process is simple, the reproducibility is good, and the preparation is suitable for industrial production.

Description

TECHNICAL FIELD

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

[0002] Coenzyme Q10, also known as decenylquinone and ubiquinone, is a liposoluble quinone compound, which exists widely in animals, plants and microorganism cells. As an important hydrogen carrier in the respiratory chain, coenzyme Q10 is an important factor for energy generation and cell metabolism of organisms. Coenzyme Q10 is one of the most important antioxidants in organisms, which can scavenge free radicals, prevent oxidation of macromolecular substances such as proteins, lipids and DNA, and also can enhance the antioxidant capacity of tocopherols.

[0003]

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

[0005] (1) Coenzyme Q10 has a unique therapeutic effect in the treatment of cardiovascular diseases, and is commonly used for the adjuvant treatment of 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 for the treatment of acute and chronic hepatitis and subacute liver necrosis, and also has certain effects on other liver diseases.

[0007] (3) Coenzyme Q10 is used for the comprehensive treatment of cancer, can reduce some side effects caused by radiotherapy and chemotherapy, and has certain effects on the treatment of patients with advanced acute cancer.

[0008] (4) Coenzyme Q10 also has many other beneficial effects. It can be used for 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, and also has effects on delaying aging and improving immunity, and has irreplaceable effects and broad application prospects.

[0009] Coenzyme Q10 can be obtained from food, but sometimes the amount obtained from food cannot meet the body's needs, so coenzyme Q10 dietary supplement products can be consumed. Coenzyme Q10 is a water-insoluble macromolecular substance, and its absorption rate in the intestine is low, and the bioavailability of oral administration is low. In view of this situation, in recent years, a number of patents have disclosed formulations 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 completely achieve the desired effect.

[0010] Chinese patent CN101744288A describes a clear oral preparation containing coenzyme Q10 and its preparation method. The preparation of the oral preparation is roughly as follows: coenzyme Q10 0.1%~10%, emulsifier 0.5%~30%, co-emulsifier 5%~20%, stabilizer 0.5%~10%, and the balance is water. However, this invention only provides the stability data of coenzyme Q10 microemulsion at 25℃, and does not involve the stability at low temperature (-30℃~-10℃) and high temperature (100℃~130℃). Since coenzyme Q10 microemulsion needs to undergo high-temperature sterilization, cold storage and other extreme temperature environments in subsequent applications such as oral liquid, beverage, soft capsule, food, etc., the stability of the microemulsion in the existing technology under the above extreme temperature environment is insufficient, and it is easy to break emulsion, resulting in the destruction of its activity. Therefore, the performance of the current coenzyme Q10 microemulsion and its preparation process still need to be improved.

[0011] Chinese patent CN101053556A introduces coenzyme Q10 inclusion with hydroxypropyl-β-cyclodextrin as cyclodextrin, and coenzyme Q10 inclusion is prepared by drying. However, the weight ratio of hydroxypropyl-β-cyclodextrin to coenzyme Q10 in the above invention is large. During the drying process of the inclusion solution, the amount of water molecules decreases greatly, and the repulsive force on coenzyme Q10 also decreases greatly, destroying the stable environment of coenzyme Q10 existing in the cavity of cyclodextrin. Part of the coenzyme Q10 molecules are released from the cavity of cyclodextrin. Not only will coenzyme Q10 molecules combine with each other to form a precipitate, but also the inclusion rate of coenzyme Q10-cyclodextrin inclusion is low.

[0012] Chinese patent CN109953967A discloses a process for coenzyme Q10 tablets. The technical solution is to use film coating as an enteric film coating premix for coenzyme Q10, which can obtain coenzyme Q10 tablets with high release rate. The prescription is as follows (1000 tablets): coenzyme Q10 tablets 185 million units, microcrystalline cellulose 50.0g, pregelatinized starch 30.0g, lactose 90.0g, polyvinylpyrrolidone 25ml, purified water, and magnesium stearate 0.5g. It is well known that coenzyme Q10 is easily decomposed by light. This patent does not verify its stability, but 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 rest is purified water, which is prepared by phase inversion emulsification method, PIT emulsification method, alternate liquid emulsification method, continuous emulsification method, low-energy emulsification method, microfluidization method, etc. However, the technology only uses the addition of auxiliary emulsifier to solve the stability problem of ordinary emulsion, and does not verify and mention the problems of easy oxidation of coenzyme Q10.

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

[0015] Therefore, the purpose of the present application is to overcome the shortcomings of the prior art, and to provide a high-bioavailability coenzyme Q10 tablet and its preparation method, which increases the solubility of coenzyme Q10 by adding appropriate excipients, not only improves the stability of the solution and reduces the content of related substances, but also improves the bioavailability of coenzyme Q10.

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

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

[0018] Further, the high molecular carrier material is a mixture of hydroxyethyl methyl cellulose and at least one of hydroxypropyl methyl cellulose succinate, hydroxypropyl methyl cellulose phthalate, acrylic resin, polyvinyl alcohol, polyvinyl pyrrolidone or polyacrylamide.

[0019] Further, the high molecular carrier material is a mixture of hydroxyethyl methyl cellulose and hydroxypropyl methyl cellulose succinate in a mass ratio of 1:(1-5).

[0020] Further, the raw materials include, in terms of weight fraction, 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 high molecular carrier material.

[0021] Further, 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] Further, the binder is selected from any one or more of pregelatinized starch, dextrin, carbomer, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose.

[0024] Further preferably, the binder is selected from any one or more of pregelatinized starch, dextrin, sodium carboxymethyl cellulose.

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

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

[0027] Further, the tablet lubricant is selected from any one or more of silicon dioxide, microfine silica, talc, glyceryl monostearate, glyceryl monostearate, glyceryl distearate, sodium docusate, 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, microfine silica, magnesium stearate and sodium stearyl fumarate.

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

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

[0031] The present application also provides a preparation method of a coenzyme Q10 tablet, comprising the following steps:

[0032] Step 1. Coenzyme Q10 raw material is pulverized by an air flow pulverizer, the feeding speed is 1 kg / h, the pulverizing pressure is 0.8 Mpa, and a cyclone separator is used for separation to obtain coenzyme Q10, which is ready for use;

[0033] Step 2. The filler, the binder, the disintegrant, the lubricant and the high molecular carrier material are respectively pulverized and passed through an 80-mesh sieve for standby use;

[0034] Step 3. The high molecular carrier material is added into a hot melt extrusion device for hot melt extrusion operation, the screw rotation speed is 180 rpm, the hot melt extrusion temperature is 150℃, and the feeding speed is 1 kg / h to obtain an extruded material, which is pulverized and passed through an 80-mesh sieve to obtain the high molecular carrier material;

[0035] Step 4. The prescription amount of coenzyme Q10 raw material, filler, binder, disintegrant, lubricant is weighed and added into a three-dimensional mixing device for mixing for 30 min, and then the polymer carrier material is added for further mixing for 15 min to obtain a mixture;

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

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

[0038] Further, the tabletting pressure in step 5 is 6-10 KN.

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

[0040] (1) The present application develops a coenzyme Q10 tablet taking coenzyme Q10 as an active ingredient, and the prescription of the auxiliary materials and the amount are optimized, and the prescription includes 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.

[0041] (2) The present application mixes hydroxyethyl methyl cellulose and hydroxypropyl methyl cellulose succinate according to a certain mass ratio to prepare a polymer carrier material by hot melt extrusion process, and the coenzyme Q10 tablet prepared by mixing the polymer carrier material with other auxiliary materials solves the problems of content uniformity and stability, and the hydroxyethyl methyl cellulose and hydroxypropyl methyl cellulose succinate cooperatively improve the stability of the tablet.

[0042] (3) The coenzyme Q10 tablet prepared by the present application has good dissolution rate and dissolution effect, and the dissolution rate in vitro for 30 min can reach more than 85%, the dissolution rate is high and the dissolution effect is good, which greatly improves the oral bioavailability of coenzyme Q10, the preparation process is simple, the reproducibility is good, and it is suitable for industrial production. DETAILED DESCRIPTION

[0043] The following detailed description of the embodiments of the present application provided in the examples is not intended to limit the scope of the claimed application, but only represents selected embodiments of the application. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative labor are within the scope of protection of the present application.

[0044] The experimental methods described in the following examples are all conventional methods unless otherwise specified, and the reagents and materials can be obtained from commercial channels unless otherwise specified.

[0045] Example 1 A coenzyme Q10 tablet, its components and preparation process 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 pulverized by an air flow pulverizer, the feeding speed is 1 kg / h, the pulverizing pressure is 0.8 Mpa, and a cyclone separator is used for separation to obtain coenzyme Q10 with D90≤20 μm for standby.

[0051] Step 2. The filler, binder, disintegrant, lubricant and high molecular carrier material are respectively pulverized and passed through an 80 mesh sieve for standby.

[0052] Step 3. The hydroxyethyl methyl cellulose and hydroxypropyl methyl cellulose succinate are added to a hot melt extrusion device in a mass ratio of 1:1 for hot melt extrusion operation, the screw rotation speed is 180 rpm, the hot melt extrusion temperature is 150°C, and the feeding speed is 1 kg / h to obtain extruded material. The extruded material is pulverized and passed through an 80 mesh sieve to obtain the high molecular carrier material.

[0053] Step 4. The prescription amount of coenzyme Q10 raw material, filler, binder, disintegrant and lubricant are weighed and added to a three-dimensional mixing device for mixing for 30 min, and then the high molecular carrier material is added for further mixing for 15 min to obtain a mixture.

[0054] Step 5. The mixture is compressed by a rotary tablet press, the tabletting pressure is 6-10 KN to obtain coenzyme Q10 tablets with a tablet weight of 30 mg.

[0055] Example 2 A coenzyme Q10 tablet, its components and preparation process 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 pulverized by an air flow pulverizer, the feeding speed is 1 kg / h, the pulverizing pressure is 0.8 Mpa, and a cyclone separator is used for separation to obtain coenzyme Q10 with D90≤20 μm for standby.

[0060] Step 2. The filler, binder, disintegrant, lubricant and high molecular carrier material are respectively pulverized and passed through an 80 mesh sieve for standby.

[0061] Step 3. Hydroxyethyl methyl cellulose and hydroxypropyl methyl cellulose succinate were added into a hot melt extrusion device according to a mass ratio of 1:3 for hot melt extrusion operation, the screw rotation speed was 180 rpm, the hot melt extrusion temperature was 150°C, and the feeding speed was 1 kg / h, to obtain extruded material. The extruded material was crushed and sieved through an 80-mesh sieve to obtain the high molecular carrier material.

[0062] Step 4. The prescription amount of coenzyme Q10 raw material, filler, binder, disintegrant, and lubricant were weighed and added into a three-dimensional mixing device for mixing for 30 min, and then the high molecular carrier material was added for further mixing for 15 min to obtain a mixture.

[0063] Step 5. The mixture was compressed into tablets using a rotary tablet press, and the tabletting pressure was 6-10 KN to obtain coenzyme Q10 tablets with a tablet weight of 30 mg.

[0064] Example 3: A coenzyme Q10 tablet, the components 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 was pulverized using an airflow pulverizer, the feeding speed was 1 kg / h, the pulverization pressure was 0.8 MPa, and a cyclone separator was used for separation to obtain coenzyme Q10 with a D90 of ≤20 μm for standby use.

[0069] Step 2. The filler, binder, disintegrant, lubricant, and high molecular carrier material were respectively pulverized and sieved through an 80-mesh sieve for standby use.

[0070] Step 3. Hydroxyethyl methyl cellulose and hydroxypropyl methyl cellulose succinate were added into a hot melt extrusion device according to a mass ratio of 1:5 for hot melt extrusion operation, the screw rotation speed was 180 rpm, the hot melt extrusion temperature was 150°C, and the feeding speed was 1 kg / h, to obtain extruded material. The extruded material was crushed and sieved through an 80-mesh sieve to obtain the high molecular carrier material.

[0071] Step 4. The prescription amount of coenzyme Q10 raw material, filler, binder, disintegrant, and lubricant were weighed and added into a three-dimensional mixing device for mixing for 30 min, and then the high molecular carrier material was added for further mixing for 15 min to obtain a mixture.

[0072] Step 5. The mixture was compressed into tablets using a rotary tablet press, and the tabletting pressure was 6-10 KN to obtain coenzyme Q10 tablets with a tablet weight of 30 mg.

[0073] Example 4 A coenzyme Q10 tablet, its components and preparation process 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 pulverized by an air flow pulverizer, the feeding speed is 1 kg / h, the pulverizing pressure is 0.8 Mpa, and a cyclone separator is used for separation to obtain coenzyme Q10 with D90≤20 μm for standby.

[0078] Step 2. The filler, binder, disintegrant, lubricant and high molecular carrier material are respectively pulverized and passed through an 80 mesh sieve for standby.

[0079] Step 3. The hydroxyethyl methyl cellulose and hydroxypropyl methyl cellulose succinate are added to a hot melt extrusion device according to a mass ratio of 1:2 for hot melt extrusion operation, the screw rotation speed is 180 rpm, the hot melt extrusion temperature is 150°C, and the feeding speed is 1 kg / h to obtain extruded material, which is pulverized and passed through an 80 mesh sieve to obtain the high molecular carrier material.

[0080] Step 4. The prescription amount of coenzyme Q10 raw material, filler, binder, disintegrant and lubricant are weighed and added to a three-dimensional mixing device for mixing for 30 min, and then the high molecular carrier material is added for further mixing for 15 min to obtain a mixture.

[0081] Step 5. The mixture is compressed by a rotary tablet press, the tablet pressing pressure is 6-10 KN to obtain coenzyme Q10 tablets with a tablet weight of 30 mg.

[0082] Example 5 A coenzyme Q10 tablet, its components and preparation process 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 pulverized by an air flow pulverizer, the feeding speed is 1 kg / h, the pulverizing pressure is 0.8 Mpa, and a cyclone separator is used for separation to obtain coenzyme Q10 with D90≤20 μm for standby.

[0087] Step 2. The filler, binder, disintegrant, lubricant and high molecular carrier material are respectively pulverized and passed through an 80 mesh sieve for standby.

[0088] Step 3. Hydroxyethyl methyl cellulose and hydroxypropyl methyl cellulose succinate were added into a hot melt extrusion device according to a mass ratio of 1:3 for hot melt extrusion operation, the screw rotation speed was 180 rpm, the hot melt extrusion temperature was 150°C, and the feeding speed was 1 kg / h, to obtain extruded material. The extruded material was crushed and sieved through an 80-mesh sieve to obtain the high molecular carrier material.

[0089] Step 4. The prescription amount of coenzyme Q10 raw material, filler, binder, disintegrant, and lubricant were weighed and added into a three-dimensional mixing device for mixing for 30 min, and then the high molecular carrier material was added for further mixing for 15 min, to obtain a mixture.

[0090] Step 5. The mixture was compressed into tablets using a rotary tablet press, and the tabletting pressure was 6-10 KN, to obtain coenzyme Q10 tablets with a tablet weight of 30 mg.

[0091] Example 6 A coenzyme Q10 tablet, the components 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 was pulverized using an airflow pulverizer, the feeding speed was 1 kg / h, the pulverization pressure was 0.8 MPa, and a cyclone separator was used for separation, to obtain coenzyme Q10 with a D90 of ≤20 μm, for standby use.

[0097] Step 2. The filler, binder, disintegrant, lubricant, and high molecular carrier material were respectively pulverized and sieved through an 80-mesh sieve for standby use.

[0098] Step 3. Hydroxyethyl methyl cellulose and hydroxypropyl methyl cellulose succinate were added into a hot melt extrusion device according to a mass ratio of 1:4 for hot melt extrusion operation, the screw rotation speed was 180 rpm, the hot melt extrusion temperature was 150°C, and the feeding speed was 1 kg / h, to obtain extruded material. The extruded material was crushed and sieved through an 80-mesh sieve to obtain the high molecular carrier material.

[0099] Step 4. The prescription amount of coenzyme Q10 raw material, filler, binder, disintegrant, and lubricant were weighed and added into a three-dimensional mixing device for mixing for 30 min, and then the high molecular carrier material was added for further mixing for 15 min, to obtain a mixture.

[0100] Step 5. The mixture was compressed into tablets using a rotary tablet press, and the tabletting pressure was 6-10 KN, to obtain coenzyme Q10 tablets with a tablet weight of 30 mg.

[0101] A coenzyme Q10 tablet, its components and preparation process 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 pulverized by an air flow pulverizer, the feeding speed is 1 kg / h, the pulverizing pressure is 0.8 Mpa, and a cyclone separator is used for separation, to obtain coenzyme Q10 with 80≤D90≤150 μm, ready for use.

[0106] Step 2. The filler, binder, disintegrant, lubricant and high molecular carrier material are respectively pulverized and passed through an 80 mesh sieve for standby use.

[0107] Step 3. Hydroxyethyl methyl cellulose and hydroxypropyl methyl cellulose succinate are added to a hot melt extrusion device in a mass ratio of 1:1 for hot melt extrusion operation, the screw rotation speed is 180 rpm, the hot melt extrusion temperature is 150°C, and the feeding speed is 1 kg / h, to obtain extruded material. The extruded material is pulverized and passed through an 80 mesh sieve to obtain the high molecular carrier material.

[0108] Step 4. The prescription amount of coenzyme Q10 raw material, filler, binder, disintegrant and lubricant are weighed and added to a three-dimensional mixing device for mixing for 30 min, and then the high molecular carrier material is added for further mixing for 15 min, to obtain a mixture.

[0109] Step 5. The mixture is compressed by a rotary tablet press, the tabletting pressure is 6-10 KN, to obtain coenzyme Q10 tablets with a tablet weight of 30 mg.

[0110] A coenzyme Q10 tablet, its components and preparation process are as follows:

[0111] Compared with Example 1, the mass ratio of the high molecular 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 pulverized by an air flow pulverizer, the feeding speed is 1 kg / h, the pulverizing pressure is 0.8 Mpa, and a cyclone separator is used for separation, to obtain coenzyme Q10 with D90≤20 μm, ready for use.

[0115] Step 2. The filler, binder, disintegrant, lubricant and high molecular carrier material were respectively crushed and passed through an 80-mesh sieve for use.

[0116] Step 3. The hydroxyethyl methyl cellulose and hydroxypropyl methyl cellulose succinate were added to a hot melt extrusion device in a mass ratio of 1:8 for hot melt extrusion operation, the screw rotation speed was 180 rpm, the hot melt extrusion temperature was 150°C, and the feeding speed was 1 kg / h, to obtain an extruded material. The extruded material was crushed and passed through an 80-mesh sieve to obtain the high molecular carrier material.

[0117] Step 4. The prescription amount of coenzyme Q10 raw material, filler, binder, disintegrant and lubricant were weighed and added to a three-dimensional mixing device for mixing for 30 min, and then the high molecular carrier material was added for further mixing for 15 min to obtain a mixed material.

[0118] Step 5. The mixed material was compressed into tablets using a rotary tablet press with a tabletting pressure of 6-10 KN to obtain coenzyme Q10 tablets with a tablet weight of 30 mg.

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

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

[0121] Raw material components Specific components Components in wt% Coenzyme Q10 Coenzyme Q10 (D90 ≤ 20 μm) 20 Filler Starch 60 Binder Pre-gelatinized starch 7 Disintegrant Carboxymethyl starch sodium 8 Lubricant Silicon dioxide 2 High molecular carrier material / /

[0122] The preparation process is as follows:

[0123] Step 1. The coenzyme Q10 raw material was crushed using an air flow crusher with a feeding speed of 1 kg / h and a crushing pressure of 0.8 Mpa, and separated using a cyclone separator to obtain coenzyme Q10 with a D90≤20 μm for use.

[0124] Step 2. The filler, binder, disintegrant and lubricant were respectively crushed and passed through an 80-mesh sieve for use.

[0125] Step 3. The prescription amount of coenzyme Q10 raw material, filler, binder, disintegrant and lubricant were weighed and added to a three-dimensional mixing device for mixing for 30 min to obtain a mixed material.

[0126] Step 4. The mixed material was compressed into tablets using a rotary tablet press with a tabletting pressure of 6-10 KN to obtain coenzyme Q10 tablets with a tablet weight of 30 mg.

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

[0128] Compared with Example 1, the composition of the high molecular 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 pulverized by an air flow pulverizer, the feeding speed is 1 kg / h, the pulverizing pressure is 0.8 Mpa, and a cyclone separator is used for separation to obtain coenzyme Q10 with D90≤20 μm, which is ready for use.

[0133] Step 2. The filler, binder, disintegrant, lubricant and high molecular carrier material are respectively pulverized and passed through an 80 mesh sieve for use.

[0134] Step 3. The hydroxyethyl methyl cellulose and polyacrylamide are added to a hot melt extrusion device in a mass ratio of 1:1 for hot melt extrusion operation, the screw rotation speed is 180 rpm, the hot melt extrusion temperature is 150°C, and the feeding speed is 1 kg / h to obtain an extruded material, which is pulverized and passed through an 80 mesh sieve to obtain a high molecular carrier material.

[0135] Step 4. The prescription amount of coenzyme Q10 raw material, filler, binder, disintegrant, lubricant and high molecular carrier material are weighed and added to a three-dimensional mixing device for mixing for 30 min, and then the high molecular carrier material is added and mixed for another 15 min to obtain a mixture.

[0136] Step 5. The mixture is compressed by a rotary tablet press, the tabletting pressure is 6-10 KN, and coenzyme Q10 tablets with a tablet weight of 30 mg are obtained.

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

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

[0139] Raw material components Specific components Components in wt% Coenzyme Q10 Coenzyme Q10 (D90 ≤ 20 μm) 20 Filler Starch 60 Binder Pre-gelatinized starch 7 Disintegrant Carboxymethyl starch sodium 8 Lubricant Silicon dioxide 2 High molecular carrier material Hydroxyethyl methyl cellulose 5

[0140] The preparation process is as follows:

[0141] Step 1. The coenzyme Q10 raw material is pulverized by an air flow pulverizer, the feeding speed is 1 kg / h, the pulverizing pressure is 0.8 Mpa, and a cyclone separator is used for separation to obtain coenzyme Q10 with D90≤20 μm, which is ready for use.

[0142] Step 2. The filler, binder, disintegrant, lubricant and high molecular carrier material are respectively pulverized and passed through an 80 mesh sieve for use.

[0143] Step 3. Hydroxyethyl methyl cellulose is added to a hot melt extrusion device for hot melt extrusion operation, the screw rotation speed is 180 rpm, the hot melt extrusion temperature is 150°C, and the feeding speed is 1 kg / h, to obtain extruded material, which is crushed and sieved through an 80-mesh sieve to obtain the high molecular carrier material.

[0144] Step 4. The prescription amount of coenzyme Q10 raw material, filler, binder, disintegrant, lubricant is weighed and added to a three-dimensional mixing device for mixing for 30 min, and then the high molecular carrier material is added for further mixing for 15 min to obtain a mixture.

[0145] Step 5. The mixture is compressed into tablets using a rotary tablet press, and the tabletting pressure is 6-10 KN to obtain coenzyme Q10 tablets with a tablet weight of 30 mg.

[0146] Comparative Example 6: A coenzyme Q10 tablet, the components and preparation process of which 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 pulverized by an air flow pulverizer, the feeding speed is 1 kg / h, the pulverizing pressure is 0.8 MPa, and a cyclone separator is used for separation to obtain coenzyme Q10 with D90≤20 μm for standby use.

[0151] Step 2. The filler, binder, disintegrant, lubricant, and high molecular carrier material are respectively pulverized and sieved through an 80-mesh sieve for standby use.

[0152] Step 3. Hydroxyethyl methyl cellulose and hydroxypropyl methyl cellulose succinate are added to a hot melt extrusion device for hot melt extrusion operation at a mass ratio of 1:1, the screw rotation speed is 180 rpm, the hot melt extrusion temperature is 150°C, and the feeding speed is 1 kg / h, to obtain extruded material, which is crushed and sieved through an 80-mesh sieve to obtain the high molecular carrier material.

[0153] Step 4. The prescription amount of coenzyme Q10 raw material, filler, binder, disintegrant, lubricant is weighed and added to a three-dimensional mixing device for mixing for 30 min, and then the high molecular carrier material is added for further mixing for 15 min to obtain a mixture.

[0154] Step 5. The mixture is compressed into tablets using a rotary tablet press, and the tabletting pressure is 6-10 KN to obtain coenzyme Q10 tablets with a tablet weight of 30 mg.

[0155] Effect Example 1: Content uniformity test

[0156] According to the 2020 edition of Chinese Pharmacopoeia four uniformity of content inspection method (general 0941).

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

[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, 20 more test samples should be taken for retesting.

[0161] In the above formula, L is the 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 determined, and the results are shown in Table 1.

[0163] Table 1 Content uniformity

[0164] Test 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] As can be seen from the above table, the content uniformity of the coenzyme Q10 tablets provided by the present application meets the requirements and is much smaller than the specified requirements. The micro tablets prepared by the present application have good content uniformity, and the composition of the high molecular carrier material has a greater impact 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 determination method (Chinese Pharmacopoeia 2020 edition four general 0931 second method).

[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 0931 second method), take 900 mL of pH=4.5 acetate buffer solution containing 0.25% sodium dodecyl sulfate as the dissolution medium, paddle method 75 revolutions per minute, according to the operation, according to the sampling time, the dissolution curve determination data is shown in Table 2:

[0169] Table 2 Dissolution test

[0170] Test group 10 min 20 min 30 min 60 min 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 of Table 2, the tablets of Examples 1-6 can reach more than 85% dissolution in vitro in 30 min, and the dissolution in 1 h is basically close to 100%, which can be completely released after rapid disintegration, indicating that the coenzyme Q10 tablets prepared by the present application have good dissolution rate and dissolution effect, high bioavailability, and are more beneficial to human body absorption.

[0172] In addition, the dissolution of Comparative Examples 1-6 at 30 min is significantly lower than that of the example group, and as shown in Comparative Example 1, the particle size of the coenzyme Q10 raw material has a greater impact on the final dissolution, and Comparative Examples 3-5 show that the high molecular carrier material has a greater impact 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 Pharmaceutical and Preparation (Guiding Principles for Stability Testing of Raw Pharmaceutical and Preparation, Chinese Pharmacopoeia 2020 Edition, Part IV, Guiding Principles for Stability Testing of Raw Pharmaceutical and Preparation, Pharmaceutical Preparations), the accelerated test was carried out under the accelerated conditions of 40℃ / RH 75% for 3 months, and the related substances (total impurities, %) were determined, and the results are shown in Table 3.

[0175] Table 3 Stability Test Results

[0176]

[0177] From the stability test results of Table 3, the tablets of Examples 1-6 have little change in related substances (compared with 0 days) after 3 months of accelerated test, indicating high long-term stability. The related substances of Comparative Examples 1-6 are significantly higher than those of the examples of the present application in the third month, indicating that the composition and content of the excipients of the drug have a greater impact on the stability of the tablets, and in particular, the high molecular carrier material plays a crucial role in the stability of the entire drug system.

[0178] Effect Example 4: Bioavailability Test

[0179] Forty SD rats, half male and half female, weighing 220±20g, were evenly divided into 5 groups, 8 rats in each group, namely Example 1, 6 groups and Comparative Example 1, 3, 4 groups, and were given intragastrically. The test animals were fasted for 6h before administration, and the administration amount was 50mg / kg of coenzyme Q10, and 1.5ml of blood was taken from the orbit at 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, 12h, 4000rpm centrifugation for 10min, 0.5ml of supernatant was taken, 1.5ml of methanol was added, 5min was stirred, 8000rpm centrifugation for 10min, 10μl of supernatant was taken, and the concentration of coenzyme Q10 in the blood sample was detected by high performance liquid chromatography. The pharmacokinetic parameters are as follows in Table 4.

[0180] Table 4 Pharmacokinetic parameters

[0181]

[0182] The rat pharmacokinetics showed that the coenzyme Q10 tablets prepared by the present application not only showed good dissolution in the in vitro dissolution experiment, but also had good absorption in rats. The preparations prepared in Example 1 and Example 6 of the present application could detect higher blood drug concentrations. Compared with Comparative Examples 1, 3 and 4, the Cmax, AUC0-t and AUC0-∞ of the coenzyme Q10 tablets prepared by the present application were significantly improved, indicating that the coenzyme Q10 tablets prepared by the present application significantly improved the absorption rate and bioavailability of coenzyme Q10. max and bioavailability AUC 0-12 The above results showed that the formula and process design of the sample of the present application were reasonable. The added excipients, especially the high molecular carrier material, could effectively promote the dissolution of coenzyme Q10 and improve the stability of the drug. After taking the drug, the human body could rapidly absorb the effective drug. The sample of the present application could meet the market demand.

[0183] The above results showed that the formula and process design of the sample of the present application were reasonable. The added excipients, especially the high molecular carrier material, could effectively promote the dissolution of coenzyme Q10 and improve the stability of the drug. After taking the drug, the human body could rapidly absorb the effective drug. The sample of the present application could meet the market demand.

[0184] Based on the above description, those skilled in the art will understand that the present disclosure can be implemented in different specific forms without changing the technical spirit and essential characteristics thereof. Therefore, it should be understood that the above embodiments are not limiting in all aspects, but are illustrative. The scope of the present disclosure is limited by the appended claims, not by the description before them, and therefore all changes and modifications falling within the boundaries and scope of the claims, or the equivalents of such boundaries and scope, are intended to be covered by the claims.

Claims

1. A coenzyme Q10 tablet, characterized in that, It is composed of the following raw materials: 10-30 parts coenzyme Q10, 40-80 parts filler, 4-10 parts binder, 5-10 parts disintegrant, 0.5-3 parts lubricant, and 1-10 parts polymeric carrier material; wherein, The filler is selected from any one or more of starch, lactose, calcium carbonate, or microcrystalline cellulose; The adhesive is selected from any one or more of pregelatinized starch, dextrin, and sodium carboxymethyl cellulose. The disintegrant is selected from any one or more of sodium carboxymethyl starch, copovidone, and sodium alginate; The lubricant is selected from any one or more of silica, micronized silica gel, magnesium stearate and sodium stearate fumarate; The polymeric carrier material is composed of hydroxyethyl methyl cellulose and hydroxypropyl methyl cellulose succinate mixed in a mass ratio of 1:(1-5); The particle size D90 of the coenzyme Q10 is ≤20μm.

2. The tablet according to claim 1, characterized in that, The tablets are chewable tablets.

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