Drug sustained-release capsule for treating liver diseases as well as preparation method and application of drug sustained-release capsule

Abstract

The invention belongs to the field of pharmaceutical preparations, and provides a drug sustained-release capsule for treating liver diseases as well as a preparation method and application of the drug sustained-release capsule. The sustained-release capsule provided by the invention is prepared by filling a capsule with sustained-release pellets. The drug carried by the sustained release pellet is IMM-H014 (Immunoglobulin M-H014). The sustained-release pellet is prepared by coating a sustained-release layer on a drug-loaded pellet, and the drug-loaded pellet has the characteristic of delayed release, and is stable in dissolution rate and good in bioavailability. The traditional Chinese medicine composition is used for treating non-alcoholic fatty liver, hepatitis and drug-induced liver diseases.

Description

TECHNICAL FIELD

[0001] The present application relates to a pharmaceutical preparation and a preparation method thereof, in particular to an IMM-H014 sustained-release capsule for treating non-alcoholic fatty liver, hepatitis and drug-induced liver disease and a preparation method and use thereof, and belongs to the field of pharmaceutical preparations. BACKGROUND

[0002] Liver disease is one of the common diseases that seriously endanger people's health. At present, there are a large number of patients with liver damage and liver inflammation caused by various reasons, including viral hepatitis, drug-induced liver disease, alcoholic and non-alcoholic fatty liver disease, autoimmune liver disease, etc. Finding safe and effective drugs for preventing and treating liver disease has always been a hot spot for research institutes and pharmaceutical companies all over the world.

[0003] IMM-H014 is a kind of biphenyl compound, which is a cell defense core factor-nuclear factor NF-E2 related factor activator, can simultaneously resist inflammation and increase insulin sensitivity, and can be used for treating non-alcoholic fatty liver disease, hepatitis and drug-induced liver disease (Wu Song, Sun Hua, Zhang Wenxuan, et al. A class of bicyclic alcohol derivatives and their preparation and application: CN107488162A[P]).

[0004] The chemical name of IMM-H014 is: 7,7'-dimethoxy-5'-(morpholino methyl)-[4,4'-biphenyl[d][1,3]dioxolane]-5-carboxylic acid methyl ester.

[0005] Chemical structure

[0006]

[0007] The commonly used IMM-H014 is a methanesulfonate salt, and its solubility has pH dependence, and the solubility gradually decreases with the increase of pH.

[0008] Chinese invention patent CN107488162A discloses "a class of bicyclic alcohol derivatives and their preparation and application". The patent discloses the preparation and application of IMM-H014 methanesulfonate salt.

[0009] International patent PCT201911190936.4 (application number) discloses "application of levorotatory bicyclic morpholine and its pharmaceutically acceptable salt in preventing and / or treating liver disease and other drugs". The patent discloses the preparation and application of levorotatory IMM-H014 methanesulfonate salt.

[0010] From the rat pharmacokinetic study results can know, IMM-H014 in rats oral bioavailability is 96.3%, and the bioavailability is higher. The compound is absorbed faster in rats and dogs, and the peak concentration of blood drug is reached at 0.5h. The elimination half-life is shorter (the elimination half-life of oral administration in rats is about 1.8h, and the elimination half-life of oral administration in beagle dogs is about 3.5h).

[0011] The drug with short half-life needs to be administered at short intervals and multiple times. As a chronic disease treatment drug, it will reduce the compliance of patients to a certain extent and affect the application of the drug in the clinic. In order to improve the compliance of patients and reduce side effects, it is of important clinical value to develop IMM-H014 into a sustained-release capsule.

[0012] The filling in the IMM-H014 sustained-release capsule is active drug IMM-H014 or a pharmaceutically acceptable salt thereof sustained-release pellets, and the IMM-H014 sustained-release pellets sequentially comprise a blank core, a main drug layer containing IMM-H014 and a sustained-release coating layer from inside to outside. SUMMARY

[0013] An object of the present application is to provide a prolonged-release capsule composition of the biphenyl compound IMM-H014 or a pharmaceutically acceptable salt thereof, and also to provide a method for preparing the capsule and uses thereof.

[0014] The present application adopts the following technical solutions:

[0015] An IMM-H014 or a pharmaceutically acceptable salt thereof sustained-release capsule is prepared by filling sustained-release pellets into a capsule. The sustained-release pellets are composed of a blank core, a drug loading layer and a sustained-release layer. The drug loading layer is composed of IMM-H014 or a pharmaceutically acceptable salt thereof, a binder and an anti-adhesive agent. The sustained-release layer is composed of a sustained-release material and a pore-forming agent.

[0016] The IMM-H014 sustained-release capsule provided by the present application is obtained by mixing the sustained-release pellets with a lubricant and then filling the mixture into a capsule. The amount of the lubricant added is 0.9% of the weight of the sustained-release pellets. The lubricant is one or a mixture of more than one of talc, magnesium stearate, calcium stearate and stearic acid, and the preferred lubricant is talc.

[0017] The IMM-H014 sustained-release capsule provided by the present application is composed of the following raw materials in the following mass fractions: 5% to 25% of IMM-H014 or a pharmaceutically acceptable salt thereof, 50% to 100% of a blank core, 0.5% to 2.5% of a binder, 1.0% to 3.0% of an anti-adhesive agent, 5% to 15% of a sustained-release material and 0.1% to 0.7% of a pore-forming agent.

[0018] The IMM-H014 sustained-release capsule provided by the present application takes the blank pellet core selected from microcrystalline cellulose pellet core, sucrose pellet core, starch pellet core and silicon dioxide pellet core; preferably the microcrystalline cellulose pellet core. The pellet core particle size is 300-900 μm, preferably the pellet core particle size is 300-900 μm.

[0019] The IMM-H014 sustained-release capsule provided by the present application takes the drug-loading layer binder selected from hydroxypropyl methyl cellulose, polyvinyl pyrrolidone and hydroxypropyl cellulose; preferably the hydroxypropyl methyl cellulose, more preferably the viscosity of the hydroxypropyl methyl cellulose is E5 type hydroxypropyl methyl cellulose. The anti-adhesive agent is talc, colloidal silicon dioxide, magnesium stearate or magnesium silicate; preferably the talc.

[0020] The IMM-H014 sustained-release capsule provided by the present application takes the sustained-release material of the sustained-release layer selected from ethyl cellulose, acrylic resin and cellulose acetate; preferably the ethyl cellulose. The pore-forming agent is hydroxypropyl methyl cellulose, polyvinyl pyrrolidone or hydroxypropyl cellulose; preferably the hydroxypropyl methyl cellulose, more preferably the viscosity of the hydroxypropyl methyl cellulose is E5 type hydroxypropyl methyl cellulose.

[0021] The preparation method of the IMM-H014 sustained-release capsule provided by the present application comprises the following steps: taking the microcrystalline cellulose pellet core as the blank pellet core, adopting the fluidized bed bottom spraying to perform the drug loading, sequentially performing the drug-loading layer coating and the sustained-release layer coating to produce the sustained-release pellets, then adding the lubricant to the sustained-release pellets to perform the mixing, and then filling the capsules to obtain the IMM-H014 sustained-release capsule.

[0022] The preparation method of the IMM-H014 sustained-release capsule provided by the present application sequentially dissolves the IMM-H014 raw material, the binder and the anti-adhesive agent in the aqueous solution to prepare the drug-loading layer liquid during the drug-loading layer coating process. The fluidized bed bottom spraying is adopted to perform the drug loading to coat the drug-loading layer, the fluidized bed air inlet temperature is 35-45 ℃, and the steady-state material temperature is 30-40 ℃.

[0023] The preparation method of the IMM-H014 sustained-release capsule provided by the present application adds the pore-forming agent to the sustained-release material to prepare the sustained-release layer bottom spraying solution during the sustained-release layer coating process. The fluidized bed bottom spraying is adopted to perform the drug loading to coat the sustained-release layer, the fluidized bed air inlet temperature is 25-35 ℃, and the steady-state material temperature is 20-30 ℃. The sustained-release layer weight gain is 5%-15%, preferably the weight gain is 8%-12%.

[0024] Beneficial technical effects: The IMM-H014 sustained-release capsule and the IMM-H014 immediate-release capsule provided by the present application are subjected to the beagle dog in-vivo pharmacokinetic determination, and the results show that the IMM-H014 sustained-release capsule prepared by the present application can significantly reduce the Cmax of the drug, significantly prolong the MRT, and the AUC is equivalent. There is obvious sustained-release effect.

[0025] The following description is only part of the embodiments of the present application, and does not limit the present application in any way. Any simple modification, change, and equivalent result variation of the above embodiments according to the technical essence of the present application still falls within the protection scope of the technical solution of the present application. BRIEF DESCRIPTION OF DRAWINGS

[0026] Figure 1 In-vitro release curves of the control and the examples

[0027] Figure 2 Beagle dog pharmacokinetic curves of the control and the examples DETAILED DESCRIPTION

[0028] In-vitro release test and pharmacokinetic test of the IMM-H014 sustained-release capsules of the present application

[0029] The release test was performed according to the first method of the Chinese Pharmacopoeia.

[0030] Dissolution conditions: 750 ml of 0.1M hydrochloric acid solution was used as the dissolution medium, the rotation speed was 50 rpm, and after sampling at 0.5h, 1.0h, and 2.0h, 250 ml of 0.2M trisodium phosphate solution preheated to 37°C was immediately added, and the operation was continued according to the method, and sampling was performed at 3.0h, 4.0h, 5.0h, 6.0h, 8.0h, 10.0h, 12.0h, 16.0h, 20.0h, and 24.0h.

[0031] Test sample solution: an appropriate amount of dissolution solution was taken at each time point and filtered.

[0032] Control sample solution: an appropriate amount of IMM-H014 control sample was taken and dissolved in 0.1M hydrochloric acid to prepare a 0.025mg / ml solution.

[0033] Determination method: the test sample solution and the control sample solution were determined by ultraviolet-visible spectrophotometry at a wavelength of 230nm to determine the absorbance, and the cumulative release at each time point was calculated.

[0034] Pharmacokinetic test

[0035] The administration and sample collection were designed by double cycle random crossover test, the interval of two cycles was 7 days, 10 beagles were randomly divided into 2 groups, after fasting for 12 hours, IMM-H014 immediate-release tablets (10 mg / kg) or IMM-H014 sustained-release tablets (10 mg / kg) were orally administered. The forelimb venous blood 1-2 ml was extracted before administration (0 h) and 0.08, 0.17, 0.25, 0.33, 0.5, 0.75, 1, 2, 3, 5, 8, 12, 24, 36, 48 h after administration for immediate-release tablets; the forelimb venous blood 1-2 ml was extracted before administration (0 h) and 0.25, 0.5, 1, 2, 3, 5, 8, 12, 24, 36, 48 h after administration for sustained-release tablets. The blood plasma was separated after centrifugation at 4000 rpm for 10 min at 4 ℃, and stored at -20 ℃, and then analyzed for blood drug concentration.

[0036] Chromatographic conditions: Chromatographic column: Agilent InfinityLab Porshell 120 EC-C18 (2.1 x 50 mm, 2.7 μm); mobile phase A: 0.1% formic acid aqueous solution, mobile phase B: 0.1% formic acid acetonitrile; flow rate: 0.4 ml / min; injection volume: 1 μL; column temperature: 35 ℃; internal standard: carbamazepine; gradient elution was used, elution program: 0-2.50 min, 20% B→40% B; 2.50-2.51 min, 40% B→95% B; 2.51-3.5 min, 95% B; 3.5-3.51 min, 95% B→20% B; 3.51-4.5 min, 20% B.

[0037] Mass spectrometry conditions: LC interface used pneumatic assisted electrospray ionization source (ESI) conditions, detection mode: positive ion; drying gas: 150 ℃, nitrogen, 11 L / min; atomizing gas: nitrogen, 25 psi; sheath gas: 300 ℃, 11 L / min; capillary voltage: 3000 V; scan mode: multiple reaction monitoring (MRM); detection ion pair: m / z: 460.1→341.

[0038] Preparation of plasma standard curve and quality control sample: Take H014 working solution (100 μg / ml) and dilute it with 20% acetonitrile water solution step by step to prepare a series of standard solutions with concentrations of 0.005, 0.02, 0.05, 0.5, 1, 5, 10, 20, 40 and 80 μg / ml, respectively. Take 10 μl of each standard solution and add 90 μl of blank plasma, vortex for 30 s to prepare a series of plasma standard solutions with H014 concentrations of 0.5, 2, 5, 50, 100, 500, 1000, 2000, 4000 and 8000 ng / ml, respectively. Then add 300 μl of internal standard working solution (500 ng / ml), vortex for 2 min, centrifuge at 13000 rpm for 5 min at 4°C, and take the supernatant as the standard curve solution, which is then put into a sample bottle for determination. Take the inverse of the H014 concentration as the weight, and make a linear regression of the peak area ratio of H014 to internal standard versus the concentration ratio of H014 to internal standard. The standard curve equation is y = 0.9983x - 0.0101. The linear range of the drug in beagle dog plasma is 0.5-8000 μg / ml, and the correlation coefficient r2 is greater than 0.99. The concentrations of the quality control samples (biological sample concentrations) are 5, 500 and 4000 ng / ml, respectively.

[0039] Preparation of test sample: Take 100 μl of plasma sample and add 300 μl of internal standard working solution into a 1.5 ml centrifuge tube, vortex for 2 min, centrifuge at 13000 rpm for 5 min at 4°C, take 50 μl of supernatant into a sample vial, and mix with 950 μl of diluent for testing.

[0040] Preparation of IMM-H014 immediate-release capsules

[0041] Table 1 Formulation of test examples

[0042] Ingredients %(w / w) Preparation of 1200 pellets (g) IMM-H014 (mesylate salt) 12.5 30 Microcrystalline cellulose (102) 60 144 Pre-gelatinized starch 25.5 61.2 Colloidal silicon dioxide 0.5 1.2 Magnesium stearate 1.5 3.6

[0043] Mix IMM-H014 with microcrystalline cellulose, pregelatinized starch and the like in equal amounts by the incremental method until uniform. Add microfine silica gel and magnesium stearate and mix for 10 min. Fill into size 2 capsules with a loading of 200 mg. Perform in vitro release determination and beagle dog plasma concentration determination and drug metabolism kinetic parameter calculation according to the aforementioned test methods.

[0044] Examples 1-3: IMM-H014 sustained-release capsules

[0045] Table 2 Formulation of IMM-H014 sustained-release capsules (1200 capsules)

[0046]

[0047]

[0048] The IMM-H014 sustained-release capsules of Examples 1-3 were prepared according to the following steps:

[0049] The sustained-release pellets were produced by using microcrystalline cellulose as blank pellet cores, adopting fluidized bed bottom spraying to apply the drug, sequentially coating the drug-loaded layer and the sustained-release layer, adding lubricant to the sustained-release pellets, mixing, and then filling into capsules to obtain the IMM-H014 sustained-release capsules.

[0050] The coating process of the drug-loaded layer: the IMM-H014 raw material, hydroxypropyl methyl cellulose (E5), and talc were sequentially added to the aqueous solution to prepare the drug-loaded layer liquid, and the fluidized bed was used for bottom spraying, the fluidized bed inlet temperature was 35-45°C, and the steady-state material temperature was 30-40°C.

[0051] The coating process of the sustained-release layer: ethyl cellulose and hydroxypropyl methyl cellulose (E50) were dissolved in the aqueous solution to prepare the sustained-release layer bottom spraying solution, and the fluidized bed was used for bottom spraying, the fluidized bed inlet temperature was 25-35°C, and the steady-state material temperature was 20-30°C. The weight gain of the sustained-release layer was 8%-12%.

[0052] Test Example 1

[0053] The in-vitro release curves of the control example and Examples 1-3 were compared according to the aforementioned test method, and the results are shown in Tables 3-4, Figure 1 Table 3 Release rate of the control example

[0054] Time (h) Release (%) Time (h) Release (%) 0.00 0.0 1.0 99.5 0.08 62.3 1.5 99.6 0.17 91.0 2.0 99.7 0.25 95.0 3.0 99.7 0.33 96.4 4.0 99.8 0.50 97.6 6.0 99.8 0.75 98.5

[0055] Table 4 Release rate of the examples

[0056]

[0057] Test Example 2

[0058] The blood drug concentration of beagle dogs and the calculation of pharmacokinetic parameters of the control example and Examples 1-3 were determined according to the aforementioned test method. The results are shown in Table 5, Figure 2

[0059] Table 5 Pharmacokinetic results of the control example and the examples

[0060]

Claims

1. A sustained-release capsule of biphenyl compound IMM-H014 represented by the following structural formula: ###00001### wherein, ###00002### characterized in that, The IMM-H014 sustained-release capsules are prepared by filling sustained-release pellets into capsules, wherein the sustained-release pellets are prepared by coating drug-loaded pellets with a sustained-release layer; the sustained-release pellets comprise a. a blank pellet core, b. a drug-loaded layer containing IMM-H014, and c. a sustained-release coating layer, wherein the drug is the mesylate salt of IMM-H014; 2. The IMM-H014 sustained release capsule according to claim 1, wherein, The blank pill core is one of a microcrystalline cellulose pill core, a sucrose pill core, a starch pill core, and a silicon dioxide pill core.

3. The IMM-H014 sustained release capsule according to claim 1, wherein: The sustained-release micropills need to be mixed with a lubricant before filling and then filled into capsules; the amount of the lubricant added is 0.9% of the weight of the sustained-release micropills; the lubricant is one or a mixture of more than one of talc, magnesium stearate, calcium stearate, and stearic acid.

4. The IMM-H014 sustained release capsule according to claim 1, wherein The drug-carrying layer containing IMM-H014 is composed of IMM-H014, an adhesive and an anti-adhesive agent.

5. The IMM-H014 sustained release capsule according to claim 1, wherein The sustained-release coating layer is composed of sustained-release materials and pore-forming agents.

6. The IMM-H014 sustained release capsule according to claim 1, wherein The sustained-release micropills are composed of the following raw materials in parts by mass: 5% to 25% of IMM-H014 or a pharmaceutically acceptable salt thereof, 50% to 100% of blank pellet cores, 0.5% to 2.5% of a binder, 1.0% to 3.0% of an anti-adhesive agent, 5% to 15% of a sustained-release material, and 0.1% to 0.7% of a pore-forming agent.

7. The IMM-H014 sustained release capsule according to any one of claims 1 to 2, wherein, The blank pellet core is a microcrystalline cellulose pellet core with a particle size of 300 μm to 900 μm.

8. The IMM-H014 sustained release capsule according to claim 6, wherein: The binder is hypromellose, polyvinyl pyrrolidone or hydroxypropyl cellulose; the anti-adhesive agent is talc, colloidal silicon dioxide, magnesium stearate or magnesium silicate; the sustained-release material is ethyl cellulose, acrylic resin or cellulose acetate; and the pore-forming agent is hypromellose, polyvinyl pyrrolidone or hydroxypropyl cellulose.

9. The IMM-H014 sustained release capsule according to claim 8, wherein, The adhesive is hypromellose E5; the anti-adhesive agent is talc; the sustained-release material is ethyl cellulose; and the pore-forming agent is hypromellose E5.

10. A process for the preparation of IMM-H014 sustained release capsules as claimed in claim 1, wherein, The following steps are involved: Microcrystalline cellulose pellets were used as blank pellets, and drug application was performed by fluidized bed bottom spraying. The drug-loaded layer and sustained-release layer were coated in sequence to produce sustained-release micropellets. Lubricant was then added to the sustained-release micropellets, mixed, and then filled into capsules to obtain IMM-H014 sustained-release capsules.

11. A process for the preparation of IMM-H014 sustained release capsules as claimed in claim 10, wherein: During the drug-loading coating process, the IMM-H014 API, binder, and anti-adherent agent are sequentially dissolved in an aqueous solution to prepare a drug-loading solution. The drug-loading layer is sprayed onto the bottom of a fluidized bed. The fluidized bed inlet air temperature is 35-45°C, and the steady-state material temperature is 30-40°C.

12. A process for the preparation of IMM-H014 sustained release capsules as claimed in claim 10, wherein: During the sustained-release layer coating process, a pore-forming agent is added to the sustained-release material to prepare a sustained-release layer bottom spray solution; the sustained-release layer is coated by drug spraying on the fluidized bed bottom spray, the fluidized bed air inlet temperature is 25-35°C, and the steady-state material temperature is 20-30°C; the sustained-release layer is weighted by 5%-15%.

13. Use of the IMM-H014 sustained-release capsule according to any one of claims 1 to 9 in the preparation of a medicament for preventing and / or treating liver diseases.

14. The use according to claim 13, characterized in that The liver disease is selected from hepatitis A, hepatitis B, hepatitis C, drug-induced liver disease, alcoholic liver disease, non-alcoholic liver disease, autoimmune liver disease, liver fibrosis, cirrhosis or liver failure caused by progressive liver disease.

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