Compound Glycyrrhizin Tablets and Preparation Method Thereof

Abstract

The present invention belongs to the field of pharmaceutical preparations, and particularly relates to a compound glycyrrhizin tablet and a preparation method thereof. The compound glycyrrhizin tablet comprises: 10-50 parts of ammonium glycyrrhizinate, 10-50 parts of glycine, 10-50 parts of methionine, 32-68 parts of a filler, 5-25 parts of sodium carboxymethylcellulose, 5-15 parts of low-substituted hydroxypropyl cellulose, and 0.5-5 parts of a lubricant; the compound glycyrrhizin tablet has high dissolution rate and good stability, adopts film coating, has quick disintegration, and the concentration change of the drug is relatively gentle.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and particularly relates to a compound glycyrrhizin tablet and a preparation method thereof. Background Art

[0002] Compound glycyrrhizin tablets are compound preparations composed of glycyrrhizin, glycine, and DL-methionine. They were mainly used for treating allergic skin in the early stage. Later, it was found that compound glycyrrhizin tablets have anti-inflammatory, immunomodulatory effects, inhibit experimental liver cell damage, inhibit virus proliferation, and inactivate viruses. They can be used to treat chronic liver diseases, improve abnormal liver function, as well as eczema, dermatitis, alopecia areata, etc. At present, the glycyrrhizin products already on the market in China are mainly injection solutions, and the problem with them is inconvenient administration. It is difficult for patients with chronic liver diseases to adhere to long-term injection administration, which affects the treatment effect.

[0003] Glycyrrhizin is unstable in nature. When preparing compound glycyrrhizin tablets, using ammonium glycyrrhizinate as the raw material, existing glycyrrhizin tablets generally have the defects of cumbersome preparation procedures and poor finished product stability. Therefore, in order to improve the above defects, further improve product stability, and ensure drug quality, it is urgent to develop a brand-new compound glycyrrhizin tablet preparation and preparation process.

[0004] The reference preparation compound glycyrrhizin tablet (Minone) is a sugar-coated tablet. The prescription process of sugar-coated tablets is relatively complex. When ensuring the strength of the tablets, it often affects the stability and dissolution rate of the tablet drugs. Summary of the Invention

[0005] The present invention provides a compound glycyrrhizin tablet and a preparation method thereof. The compound glycyrrhizin tablet has high dissolution rate, good stability, uses film coating, has fast disintegration, and the drug concentration changes relatively gently.

[0006] The present invention provides a compound glycyrrhizin tablet, which comprises, by weight: 10 - 50 parts of ammonium glycyrrhizinate, 10 - 50 parts of glycine, 10 - 50 parts of methionine, 32 - 68 parts of a filler, 5 - 25 parts of sodium carboxymethylcellulose, 5 - 15 parts of low-substituted hydroxypropyl cellulose, and 0.5 - 5 parts of a lubricant.

[0007] In this application, parts are in milligrams.

[0008] In some embodiments, the filler is one or more of calcium carbonate, calcium sulfate, microcrystalline cellulose, calcium hydrogen phosphate, mannitol, sorbitol, starch, dextrin, lactose, and glucose, preferably calcium carbonate and microcrystalline cellulose. In some preferred embodiments, the compound glycyrrhizin tablet comprises, by weight: 10 - 40 parts of calcium carbonate and 12 - 48 parts of microcrystalline cellulose.

[0009] In some embodiments, the lubricant is one or more of magnesium stearate, magnesium lauryl sulfate, polyethylene glycol, colloidal silicon dioxide, stearic acid, sodium stearyl fumarate, and talc powder, preferably magnesium stearate.

[0010] In some embodiments, the filler is calcium carbonate and microcrystalline cellulose, and the lubricant is magnesium stearate.

[0011] In some embodiments, based on parts by weight, the compound glycyrrhizin tablets comprise: 10 - 50 parts of ammonium glycyrrhizinate, 10 - 50 parts of glycine, 10 - 50 parts of methionine, 10 - 40 parts of calcium carbonate, 12 - 48 parts of microcrystalline cellulose, 5 - 25 parts of sodium carboxymethyl cellulose, 5 - 15 parts of low-substituted hydroxypropyl cellulose, and 0.5 - 5 parts of magnesium stearate.

[0012] In some embodiments, in the compound glycyrrhizin tablets, the sodium carboxymethyl cellulose is 15.00 parts and the low-substituted hydroxypropyl cellulose is 7.50 parts.

[0013] In some embodiments, based on parts by weight, the compound glycyrrhizin tablets comprise: 25.51 parts of ammonium glycyrrhizinate, 25.00 parts of glycine, 25.00 parts of methionine, 20.00 parts of calcium carbonate, 24.00 parts of microcrystalline cellulose, 15.00 parts of sodium carboxymethyl cellulose, 7.50 parts of low-substituted hydroxypropyl cellulose, and 1.00 parts of magnesium stearate.

[0014] In some embodiments, based on parts by weight, the compound glycyrrhizin tablets comprise: 25.51 parts of ammonium glycyrrhizinate, 25.00 parts of glycine, 25.00 parts of methionine, 20.00 parts of calcium carbonate, 24.00 parts of microcrystalline cellulose, 15.00 parts of sodium carboxymethyl cellulose, 7.50 parts of low-substituted hydroxypropyl cellulose, and 1.00 parts of magnesium stearate.

[0015] In some embodiments, the compound glycyrrhizin tablets comprise a tablet core and a film coating. Based on parts by weight, the components of the tablet core comprise: 10 - 50 parts of ammonium glycyrrhizinate, 32 - 68 parts of filler, 10 - 50 parts of glycine, 10 - 50 parts of methionine, 5 - 25 parts of sodium carboxymethyl cellulose, 5 - 15 parts of low-substituted hydroxypropyl cellulose, and 0.5 - 5 parts of lubricant; the components of the film coating comprise: 5 - 25 parts of hypromellose.

[0016] In some embodiments, by weight parts, the tablet core of the compound glycyrrhizin tablets comprises 10 - 50 parts of ammonium glycyrrhizinate, 10 - 50 parts of glycine, 10 - 50 parts of methionine, 10 - 40 parts of calcium carbonate, 12 - 48 parts of microcrystalline cellulose, 5 - 25 parts of sodium carboxymethyl cellulose, 5 - 15 parts of low-substituted hydroxypropyl cellulose, and 0.5 - 5 parts of magnesium stearate. In some preferred embodiments, by weight parts, the tablet core of the compound glycyrrhizin tablets is 10 - 50 parts of ammonium glycyrrhizinate, 10 - 50 parts of glycine, 10 - 50 parts of methionine, 10 - 40 parts of calcium carbonate, 12 - 48 parts of microcrystalline cellulose, 5 - 25 parts of sodium carboxymethyl cellulose, 5 - 15 parts of low-substituted hydroxypropyl cellulose, and 0.5 - 5 parts of magnesium stearate.

[0017] In some specific embodiments, by weight parts, the compound glycyrrhizin tablets are 25.51 parts of ammonium glycyrrhizinate, 25.00 parts of glycine, 25.00 parts of methionine, 20.00 parts of calcium carbonate, 24.00 parts of microcrystalline cellulose, 15.00 parts of sodium carboxymethyl cellulose, 7.50 parts of low-substituted hydroxypropyl cellulose, and 1.00 part of magnesium stearate; or,

[0018] the compound glycyrrhizin tablets are 25.51 parts of ammonium glycyrrhizinate, 25.00 parts of glycine, 25.00 parts of methionine, 20.00 parts of calcium carbonate, 24.00 parts of microcrystalline cellulose, 15.00 parts of sodium carboxymethyl cellulose, 7.50 parts of low-substituted hydroxypropyl cellulose, and 1.00 part of magnesium stearate.

[0019] In some embodiments, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose E5.

[0020] In some embodiments, by weight parts, the film coating components comprise: 5.00 - 25.00 parts of hydroxypropyl methylcellulose, 0.25 - 1.25 parts of polyethylene glycol, and 0.60 - 4.17 parts of titanium dioxide.

[0021] In some embodiments, the film coating is prepared from a coating solution, and the solid content of the coating solution is 10 - 15% (w / w), for example: 12.2%. In some embodiments, the coating solution comprises hydroxypropyl methylcellulose. In some embodiments, the coating solution comprises hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, and water. In some specific embodiments, the coating solution consists of hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, and water; preferably, the weight ratio of hydroxypropyl methylcellulose, polyethylene glycol, and titanium dioxide in the coating solution is 5.00 - 25.00:0.25 - 1.25:0.6 - 4.17, more preferably, the weight ratio of hydroxypropyl methylcellulose, polyethylene glycol, and titanium dioxide in the coating solution is 5.00 - 18.00:0.9:3.00, and the solid content of the coating solution is 12.2%.

[0022] In some embodiments, based on parts by weight, the film coating composition comprises: 5.00 - 18.00 parts of hypromellose, 0.90 part of polyethylene glycol, and 3.00 parts of titanium dioxide.

[0023] In some embodiments, in the compound glycyrrhizin tablets of a unit dose, the core composition is 25.51 mg of ammonium glycyrrhizinate, 25.00 mg of glycine, 25.00 mg of methionine, 20.00 mg of calcium carbonate, 24.00 mg of microcrystalline cellulose, 15.00 mg of sodium carboxymethylcellulose, 7.50 mg of low-substituted hydroxypropyl cellulose, and 1.00 mg of magnesium stearate;

[0024] The film coating composition is 5.00 mg - 18.00 mg of hypromellose E5, 0.90 mg of polyethylene glycol, and 3.00 mg of titanium dioxide.

[0025] In some specific embodiments, in the compound glycyrrhizin tablets of a unit dose, the core composition is 25.51 mg of ammonium glycyrrhizinate, 25.00 mg of glycine, 25.00 mg of methionine, 20.00 mg of calcium carbonate, 24.00 mg of microcrystalline cellulose, 15.00 mg of sodium carboxymethylcellulose E5, 7.50 mg of low-substituted hydroxypropyl cellulose, and 1.00 mg of magnesium stearate;

[0026] The film coating composition is 5.00 mg of hypromellose, 0.90 mg of polyethylene glycol, and 3.00 mg of titanium dioxide; or

[0027] The film coating composition is 18.00 mg of hypromellose E5, 0.90 mg of polyethylene glycol, and 3.00 mg of titanium dioxide.

[0028] The present invention also provides a method for preparing the above compound glycyrrhizin tablets, comprising:

[0029] Premixing: ammonium glycyrrhizinate, glycine, methionine, filler, sodium carboxymethylcellulose, and low-substituted hydroxypropyl cellulose;

[0030] Granulation: dry granulation;

[0031] Total mixing: mixing the granules obtained from granulation with a lubricant to obtain total mixed granules;

[0032] Tabletting: tabletting the total mixed granules to obtain a tablet core;

[0033] Coating: coating the tablet core.

[0034] In some embodiments, the glycine is a ground glycine material. In some embodiments, the preparation method further comprises: grinding glycine, screening through a sieve, and collecting to obtain the ground glycine material. In some embodiments, the preparation method further comprises: grinding glycine, screening through an 80-mesh sieve, and collecting to obtain the ground glycine material. In some embodiments, the ground glycine material is screened through a 32-mesh sieve before premixing.

[0035] In some embodiments, the premixing step specifically comprises:

[0036] Mixing ammonium glycyrrhizinate, calcium carbonate, sodium carboxymethylcellulose, and low-substituted hydroxypropyl cellulose to obtain premixed powder 1;

[0037] Mixing the prescribed amount of ground glycine, methionine, microcrystalline cellulose with the above-mentioned premixed powder 1 to obtain premixed powder 2.

[0038] In some embodiments, the preparation method further comprises: coating the tablet core with a coating solution after tabletting. In some embodiments, the coating step comprises: coating the tablet core with a coating solution obtained by mixing hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, and water. In some embodiments, the coating step comprises: coating the tablet core with a coating solution having a solid content of 10 - 15% (w / w) obtained by mixing hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, and water.

[0039] In some embodiments, the preparation method specifically comprises:

[0040] Grinding: Grinding glycine, screening through an 80-mesh sieve, and collecting to obtain ground glycine 1; Screening ground glycine 1 through a 32-mesh sieve to obtain ground glycine 2;

[0041] Premixing: Mixing ammonium glycyrrhizinate, calcium carbonate, sodium carboxymethylcellulose, and low-substituted hydroxypropyl cellulose to obtain premixed powder 1; Mixing ground glycine 2, methionine, microcrystalline cellulose with the above-mentioned premixed powder 1 to obtain premixed powder 2;

[0042] Granulation: Dry granulation;

[0043] Total mixing: Mixing the granules obtained from granulation with a lubricant to obtain total mixed granules:

[0044] Tabletting: Tabletting the total mixed granules to obtain a tablet core;

[0045] Coating:

[0046] Mixing hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, and water to obtain a coating solution with a solid content of 12.2% (w / w);

[0047] Control the inlet air temperature at 50 - 70°C, and the outlet air reaches 40°C. Spray the core tablet with the coating solution and dry for 10 - 20 minutes.

[0048] The beneficial effects of the present invention are as follows:

[0049] In this application, for the compound glycyrrhizin tablets, sodium carboxymethyl cellulose, a binder with disintegration effect, and low-substituted hydroxypropyl cellulose, a disintegrant with viscosity-increasing effect, are selected as excipients and act together. By optimizing the dosages, the obtained compound glycyrrhizin tablets have good fluidity, compressibility, disintegration degree, and dissolution rate. The tablet raw materials have good fluidity and compressibility, without the need to use organic solvents, and without granulation and drying steps; further, film coating is used to improve the disintegration degree. Hydroxypropyl methylcellulose with viscosity-increasing effect is used as the film coating component, and hydroxypropyl methylcellulose E5 with appropriate viscosity is selected, and the film coating formulation is optimized to further ensure the disintegration, dissolution rate, and stability of the compound glycyrrhizin tablets. The compound glycyrrhizin tablets of this application have good long-term stability and can be used and stored for a long time.

[0050] The compound glycyrrhizin tablets of this application are ordinary tablets, which not only shorten the disintegration time but also avoid the too fast rate after the drug enters the blood, resulting in too high a peak blood drug concentration. It effectively ensures that the drug concentration changes gently, does not cause violent concentration peak fluctuations, and can maintain the curative effect for a longer time.

[0051] Based on the optimized prescription, dry granulation can be used in this application, which improves the stability of the compound glycyrrhizin tablets compared with wet granulation, has no special requirements for equipment, has a simple preparation method, and low production cost, and is suitable for large-scale production. Further, in the preparation method, glycine is first pulverized, passed through an 80-mesh sieve, and then passed through a 32-mesh sieve and premixed, which ensures the uniformity of the premixed powder and thus improves the uniformity of the compound glycyrrhizin tablet product. Detailed implementation manners

[0052] The following are further detailed descriptions of the present invention in combination with embodiments, but it is not a limitation to the present invention. Any equivalent substitution in the art made in accordance with the disclosed content of the present invention belongs to the protection scope of the present invention.

[0053] In this application, the terms "comprise", "include" and "contain" and their equivalents should be understood in an open and non-exclusive sense, that is, "including but not limited to", meaning that in addition to the listed elements, components and steps, other unspecified elements, components and steps can also be covered. In this article, unless otherwise clearly specified in the context, the singular term covers plural referents and vice versa.

[0054] The term "pharmaceutically acceptable" means that a carrier, vehicle, diluent, excipient, and / or the salt formed is generally chemically or physically compatible with the other components of a pharmaceutical dosage form and physiologically compatible with the recipient, without undue toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0055] The term "treatment" means administering a compound or preparation described in the present application to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes inhibiting the progression of the disease or disorder and alleviating the disease or disorder.

[0056] In this text, parts can be in milligrams.

[0057] In the present application, pharmaceutical excipients or reagents can all be from commercial sources.

[0058] In the present application, unless otherwise specified, "%" in the examples of the present application refers to mass percentage.

[0059] Unless otherwise specified in the examples, the reaction temperature is 20 - 30 °C.

[0060] Examples 1 - 5

[0061] The amounts of each raw material in each tablet of Examples 1 - 5 are shown in Table 2. The preparation method of Example 1 is as follows. The differences between Examples 2 - 5 and Example 1 are only in the disintegrants, and the preparation methods refer to the preparation method of Example 1.

[0062] Preparation method of compound glycyrrhizin tablets in Example 1

[0063] Batch: 10000 tablets / batch

[0064] (1) Crushing

[0065] Crush glycine using an air-cooled crusher with a 80-mesh sieve, collect to obtain crushed glycine material.

[0066] (2) Weighing and mixing

[0067] Weigh and mix according to the prescription amount, and weigh and mix the raw materials after conversion according to requirements.

[0068] (3) Premixing

[0069] Mix ammonium glycyrrhizinate, calcium carbonate, sodium carboxymethylcellulose, and low-substituted hydroxypropyl cellulose (L-HPC) in the hopper of a mixer at a rotation speed of 10 rpm for 20 min to obtain premixed powder 1.

[0070] Crush glycine (sieved through a 32-mesh sieve before mixing), methionine, microcrystalline cellulose and the above mixture in the hopper of a mixer at a rotation speed of 10 rpm for 20 min to obtain premixed powder 2.

[0071] (4)Granulation

[0072] Get a 0.8-mm sizing screen and install it on a dry granulator.

[0073] Perform dry granulation according to the parameters in Table 1:

[0074] Table 1 Granulation parameters

[0075]

[0076] (5)Total mixing

[0077] Mix the granules and the externally added magnesium stearate in a hopper mixer at a rotation speed of 10 rpm for 5 min to obtain the total mixed granules;

[0078] (6)Tabletting

[0079] Get a round punching die and install it on a tabletting machine.

[0080] According to the contents of glycyrrhizinate, glycine and methionine in the inspection report of the total mixed granules of compound glycyrrhizin tablets, calculate the tablet weights of glycyrrhizinate, glycine and methionine to be pressed respectively,

[0081] Control the tablet weight: ±7.5%

[0082] Control the hardness of the plain tablets: 20 - 70 N.

[0083] (7)Coating

[0084] Coating solution preparation: Weigh purified water into a heat-insulated stirring tank, slowly add polyethylene glycol 6000 to the purified water under continuous stirring, after complete dissolution, add hypromellose (LV) and continue stirring until evenly mixed, let it stand until clear, then add titanium dioxide (sieved through a 40-mesh sieve before addition) and stir evenly to prepare a coating solution with a solid content of 12.2% (w / w) for standby.

[0085] Start preheating the coating pan, set the inlet air temperature to 60 ± 10 °C, and when the outlet air temperature reaches 40 °C, the preheating is completed.

[0086] Gently pour the cores of compound glycyrrhizin tablets into a high-efficiency coating pan to preheat the tablets.

[0087] Open the door of the coating pan, install the spray gun, infusion tube and compressed air tube, set the inlet air temperature to 60 ± 10 °C, control the tablet bed temperature at 45 ± 10 °C, control the main machine rotation speed at 2 - 12 rpm, and control the peristaltic pump rotation speed ≤ 40 rpm to start coating.

[0088] During the coating process, the operator takes samples to detect the coating weight gain. After stopping the spraying of the liquid, continue heating and drying for 10 - 20 minutes.

[0089] Table 2 Tablet Prescription

[0090]

[0091] Examples 6 - 12

[0092] The differences between Examples 6 - 12 and Example 1 are only in the binder and disintegrant. The amounts of each raw material are shown in Table 3, and the preparation method refers to the preparation method of Example 1.

[0093] Table 3 Tablet Prescription

[0094]

[0095] Examples 13 - 16

[0096] The differences between Examples 13 - 15 and Example 1 are only in the coating material. The amounts of each raw material are shown in Table 4, and the preparation method refers to the preparation method of Example 1.

[0097] The difference between Example 16 and Example 1 is only in the coating material and the preparation steps of the coating solution. The preparation method refers to the preparation method of Example 1. Coating solution preparation steps for Example 16: Weigh purified water into a heat - insulated stirring tank, add hypromellose (LV) and continuously stir until evenly mixed. After standing until clear, add titanium dioxide (sieved through a 40 - mesh sieve before addition) and stir evenly to prepare a coating solution with a solid content of 11.7% (w / w), and set aside.

[0098] Table 4 Tablet Prescription

[0099]

[0100] Examples 17 - 22

[0101] The differences between Examples 17 - 22 and Example 1 are only in the dosages of the components (filler, binder, disintegrant). The amounts of each raw material are shown in Table 5, and the preparation method refers to the preparation method of Example 1.

[0102] Table 5 Tablet Prescription

[0103]

[0104] Examples 23 - 24

[0105] The differences between Examples 23 - 24 and Example 1 are only in the dosages of the coating layer components. The amounts of each raw material are shown in Table 6, and the preparation method refers to the preparation method of Example 1.

[0106] Table 6 Tablet Prescription

[0107]

[0108] Examples 25 - 30

[0109] The differences between Examples 25 - 30 and Example 1 are only in the dosages of the components. The amounts of each raw material are shown in Table 7. The preparation method refers to the preparation method of Example 1.

[0110] Table 7 Tablet Prescription

[0111]

[0112] Effect Example 1

[0113] Examine the angle of repose, hardness, friability, and dissolution of the reference samples.

[0114] 1. Samples:

[0115] Compound glycyrrhizin tablets prepared with reference to Examples 1 - 23 of the present invention;

[0116] Control Example 1: Reference preparation compound glycyrrhizin tablets (Minone).

[0117] 2. Methods:

[0118] The dissolution curve was determined by the method for the determination of dissolution and release in General Chapter 0931 of the Fourth Part of the Chinese Pharmacopoeia 2020 Edition.

[0119] Dissolution detection method: Refer to the method for the determination of dissolution and release (the second paddle method in General Chapter 0931 of the Fourth Part of the Chinese Pharmacopoeia 2020 Edition) for determination.

[0120] Dissolution conditions: Dissolution medium is water, the rotation speed is 50 revolutions per minute. Operate according to the law and sample at 45 minutes.

[0121] Test solution: Take the dissolution solution, filter it, and take the subsequent filtrate as the test solution.

[0122] Reference solution: Take an appropriate amount of the reference substance, accurately weigh it, dissolve and dilute it with the solvent [62% methanol] to prepare a solution containing about 16.7 μg of the main component per 1 ml.

[0123] Determination method: Inject the test solution and the reference solution into the liquid chromatograph respectively, and record the chromatogram. Calculate the dissolution amount per tablet by the external standard method based on the peak area.

[0124] 3. The inspection results are shown in Table 8.

[0125] Table 8 Inspection Results of Angle of Repose, Hardness, Friability, and Dissolution

[0126]

[0127] As can be seen from Examples 1 to 22 and Comparative Example 1, compared with the reference preparation, the compound glycyrrhizin tablets of the present invention have better hardness, lower friability, good compressibility, and better dissolution degrees of monoammonium glycyrrhizinate, glycine, and methionine.

[0128] As can be seen from Examples 1 to 12, by using sodium carboxymethyl cellulose, which has a disintegrating effect, and low-substituted hydroxypropyl cellulose, which has a viscosity-increasing disintegrating effect, as excipients and allowing them to act together, the obtained compound glycyrrhizin tablets have good fluidity (the smallest angle of repose), the highest hardness, the lowest friability, good compressibility, and good dissolution degrees of monoammonium glycyrrhizinate, glycine, and methionine.

[0129] The compound glycyrrhizin tablets of the present invention are film-coated. As can be seen from Examples 1, 13 to 15, the type of hypromellose in the coating solution has an impact on hardness, friability, and dissolution degree. It is preferred to use hypromellose E5 and hypromellose E3, and the effect of using hypromellose E5 is the best.

[0130] As can be seen from Examples 1 and 16, compared with not adding polyethylene glycol 6000 to the coating solution, the present invention has slight advantages in terms of the angle of repose, friability, and dissolution degree of glycine.

[0131] As can be seen from Examples 1, 17 to 22, the dosages of calcium carbonate, microcrystalline cellulose, sodium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose of the present invention have an impact on the angle of repose, hardness, friability, and dissolution degree. In particular, as can be seen from Example 1 and Example 21, the dosages of sodium carboxymethyl cellulose and low-substituted hydroxypropyl cellulose have a significant impact on hardness, friability, and dissolution degree. Example 1 (15.00 parts of sodium carboxymethyl cellulose and 7.50 parts of low-substituted hydroxypropyl cellulose) has the best effect, with the best fluidity (the smallest angle of repose), the highest hardness, the lowest friability, good compressibility, and good dissolution degrees of monoammonium glycyrrhizinate, glycine, and methionine.

[0132] As can be seen from Examples 1, 23, and 24, the dosage of hypromellose has an impact on the dissolution degrees of monoammonium glycyrrhizinate, glycine, and methionine. Examples 1 and 24 (5.00 parts to 18.00 parts of hypromellose) have higher dissolution degrees.

[0133] Effect Example 2

[0134] Examine the disintegration time of the reference sample

[0135] Sample:

[0136] Compound glycyrrhizin tablets prepared with reference to Examples 1 to 23 of the present invention;

[0137] Comparative Example 1: Reference preparation compound glycyrrhizin tablets (Minone);

[0138] Comparative Example 2: Compound glycyrrhizin tablets were prepared with reference to Example 1 of CN117899039A;

[0139] Comparative Example 3: Compound glycyrrhizin tablets were prepared with reference to Example 1 of CN108186655A;

[0140] Comparative Example 4: Compound glycyrrhizin tablets were prepared with reference to Example 1 of CN106692086B;

[0141] Comparative Example 5: Compound glycyrrhizin tablets were prepared with reference to Prescription 1 of CN103845350A;

[0142] Comparative Example 6: Compound glycyrrhizin tablets were prepared with reference to Example 1 of CN1857288A;

[0143] Comparative Example 7: Compound glycyrrhizin tablets were prepared with reference to Example 1 of CN1586490A.

[0144] 2. Method:

[0145] Disintegration time detection method: It was determined with reference to the disintegration limit inspection method in General Principles 0931 and 0921, Part III of the Chinese Pharmacopoeia 2020 Edition.

[0146] 3. The investigation results are shown in Table 9-10.

[0147] Table 9 Investigation Results of Disintegration Time

[0148]

[0149] Table 10 Investigation Results of Disintegration Time

[0150]

[0151] Effect Example 3: Stability Test

[0152] The stability of the samples was investigated through accelerated tests and long-term tests.

[0153] Samples

[0154] Compound glycyrrhizin tablets prepared with reference to Example 1 of the present invention;

[0155] Comparative Example 1: Reference preparation compound glycyrrhizin tablets (Minone).

[0156] 2. The stability test results are shown in Table 11.

[0157] Table 11 Stability Test Results (Temperature 40±2°C, Relative Humidity 75±5%)

[0158]

[0159] The compound glycyrrhizin tablets of the present invention have good long-term stability, which is superior to the reference preparation, and is helpful for long-term use and storage.

[0160] Effect Example 4:

[0161] Determination of drug bioavailability:

[0162] 1. Experimental method

[0163] 1.1 Test materials

[0164] The sample prepared according to Example 1;

[0165] Comparative Example 1: Reference preparation compound glycyrrhizin tablets (Minone);

[0166] Comparative Example 8: Compound glycyrrhizin dispersible tablets prepared by referring to Example 1 of CN101288651A;

[0167] Comparative Example 9: Compound glycyrrhizin dispersible tablets prepared by referring to Prescription 5 of CN1919185A.

[0168] 1.2 Test equipment

[0169] LC-MS / MS instrument model: Triple Quad 4500, AB Sciex (USA).

[0170] 1.3 Research subjects

[0171] 24 Beagle dogs, half male and half female, weighing 8±2 kg, as shown in Table 12.

[0172] 2. Experimental method

[0173] After Beagle dogs were orally administered with the samples of Example 1 of the present invention, the samples of Comparative Example 1, the samples of Comparative Example 8, and the samples of Comparative Example 9 at the same dose (1 tablet) once, the concentration levels of the active ingredients in plasma and their basic pharmacokinetic characteristics were measured, and the differences in the main parameters Cmax, Tmax, AUClast, etc. were compared to evaluate their bioavailability.

[0174] Blood sampling points: Before administration, 0.5h, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 8, 9, 10, 12, 14, 16, 24h.

[0175] Blood sample treatment and storage: Take 2 mL of blood from the anterior limb vein, place it in an EDTA-K2 anticoagulant tube, centrifuge at 4500 r / min for 10 min, separate 50 μL of plasma into a centrifuge tube, and freeze it in a -80°C refrigerator.

[0176] Sample analysis: Take 50 μL of plasma, add 150 μL of a 50:50 (methanol:water) v / v solution, and mix well; centrifuge at 12,000 rpm for 10 min, take 100 μL of the supernatant into an EP tube, add 100 μL of a 50:50 (methanol:water) v / v solution and mix evenly, and take 5 μL for analysis by LC-MS / MS.

[0177] Table 12 Research subjects, dosage, and administration route

[0178]

[0179] 3. Test results

[0180] The in vivo activity data are shown in Table 13.

[0181] Table 13 In vivo activity data

[0182]

[0183] Patents CN101288651A and CN1919185A disclose dispersible tablets with a short disintegration time limit. As demonstrated by Comparative Examples 8 and 9, too short a disintegration time results in rapid drug release, a significantly shortened Tmax, a significantly increased Cmax, and thus an increased risk of adverse reactions. Moreover, the drug concentration drops rapidly and the t1 / 2 is short, requiring frequent administration. In Comparative Examples 8 and 9, the drug concentration fluctuates greatly compared to Example 1 of the present invention and the reference preparation, and the drug efficacy is unstable or the risk of side effects increases.

[0184] Compared with Comparative Example 1, Example 1 of the present invention has a slightly higher Tmax, a slightly higher Cmax, and a longer t1 / 2. Based on the disintegration time and the results of the long-term stability test of Example 1 and Comparative Example 1, it can be seen that although the disintegration time of Example 1 is shortened, the Tmax of the drug is slightly higher and the t1 / 2 is extended, indicating that the change in drug concentration is relatively gentle, without causing a sharp peak concentration fluctuation, and can maintain the efficacy for a longer time.

[0185] For purposes of description and disclosure, all patents, patent applications, and other publications are hereby expressly incorporated herein by reference. These publications are provided only because their disclosures predate the filing date of the present application. All statements regarding the dates of these documents or the content thereof are based on information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the content thereof. Moreover, in any country, any reference to these publications in this application does not constitute an admission that such publication is part of the common general knowledge in the art.

[0186] Those skilled in the art will recognize that the scope of the present application is not limited to the various specific embodiments and examples described above, but rather various modifications, substitutions, or recombinations can be made without departing from the spirit of the present application, which all fall within the scope of protection of the present application.

Claims

1. A compound glycyrrhizin tablet, characterized in that, The compound glycyrrhizin tablets comprise a tablet core and a film coating; in a unit dose of the compound glycyrrhizin tablets, the components of the tablet core are 25.51 mg of ammonium glycyrrhizinate, 25.00 mg of glycine, 25.00 mg of methionine, 20.00 mg of calcium carbonate, 24.00 mg of microcrystalline cellulose, 15.00 mg of sodium carboxymethylcellulose, 7.50 mg of low-substituted hydroxypropyl cellulose and 1.00 mg of magnesium stearate; the components of the film coating are 18.00 mg of hypromellose E5, 0.90 mg of polyethylene glycol and 3.00 mg of titanium dioxide.

2. The preparation method of the compound glycyrrhizin tablets according to claim 1, characterized in that, Comprising: Premixing: ammonium glycyrrhizinate, glycine, methionine, calcium carbonate, microcrystalline cellulose, sodium carboxymethylcellulose and low-substituted hydroxypropyl cellulose; Granulation: dry granulation; Overall mixing: the granules obtained from the granulation are mixed with magnesium stearate to obtain overall mixed granules; Tabletting: the overall mixed granules are tabletted to obtain a tablet core; Coating: the tablet core is coated.

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