An antiviral drug composition and its preparation process and application

Abstract

The present invention discloses an antiviral drug composition and its preparation process and application, wherein the antiviral drug composition comprises the following components: (i) Compound I, or its monohydrate, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable long-chain ester, and (ii) a biodegradable biocompatible polymer; wherein component (i) exists in the composition in both crystalline and amorphous forms. The preparation method adopted by the present invention can obtain a drug composition with controllable drug crystal form and content, the drug content of the composition is high, the encapsulation rate is high, there is no delayed release period, no burst release, the release is stable in vitro and in vivo, and the release can be sustained for at least 28 days.

Description

Technical Field

[0001] The invention belongs to the field of medicine, and specifically relates to a pharmaceutical composition for sustained release of antiviral drugs and a preparation process and application thereof. Background Art

[0002] Compound I is a therapeutic drug for chronic hepatitis B. In the initial 1 to 2 years of use, it is prescribed in units of 1 to 3 months. After HBV is stabilized, it is prescribed in units of 6 months, and the drug needs to be taken for life. When chronic hepatitis B patients stop anti-hepatitis B treatment, there are reports of severe acute hepatitis attacks, which require close monitoring from clinical and laboratory tests, and follow-up for at least several months. The formulations of Compound I that have been marketed need to be taken every day; in addition, meals will affect the absorption of Compound I, and it needs to be taken on an empty stomach, which is inconvenient; after stopping the drug, the efficacy will rebound, leading to serious adverse consequences such as disease recurrence and poor prognosis.

[0003]

[0004] Therefore, there is an urgent need to develop a sustained-release preparation of Compound I to prolong the drug release time, reduce the number of dosing times, and improve patients' compliance with medication, thereby effectively reducing recurrence or drug resistance caused by missed medication or discontinuation of medication; improving bioavailability and reducing adverse drug reactions. Summary of the invention

[0005] The present invention provides a sustained and slow-release antiviral drug composition, which improves the medication compliance of patients, thereby effectively reducing the probability of relapse or drug resistance due to missed medication or discontinuation of medication.

[0006] The present invention provides an antiviral drug composition having the advantages of high content, high encapsulation rate, no delayed release period, small release fluctuation and easy control of residual solvent.

[0007] The present invention creatively discovered that the crystal form of compound I has a great influence on the release of the pharmaceutical composition. When the drug in the pharmaceutical composition exists in a crystalline or amorphous form, the release rate of the pharmaceutical composition is significantly different. The present invention can obtain a pharmaceutical composition with an ideal release rate by controlling the ratio of amorphous and crystalline forms of compound I. Furthermore, if the crystals in the pharmaceutical composition exist in a certain crystal habit, the pharmaceutical composition has a more ideal release behavior.

[0008] The present invention provides an antiviral pharmaceutical composition, comprising the following components: (i) Compound I, or a monohydrate thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable long-chain ester thereof; and (ii) a biodegradable and biocompatible polymer; wherein the component (i) exists in the composition in both crystalline and amorphous forms;

[0009]

[0010] Among them, pharmaceutically acceptable salts of Compound I include but are not limited to the hydrochloride, bromate, sulfate, phosphate, methanesulfonate, pamoate and triphosphate of Compound I.

[0011] Among them, the pharmaceutically acceptable long-chain esters of Compound I include but are not limited to stearate, arachidate, behenate, laurate, myristate, pentadecanoate, palmitate and heptadecanoate of Compound I.

[0012] Wherein, the crystal form of component (i) has XRD characteristic diffraction peaks at 5.3±0.2°, 15.6±0.2°, 17.4±0.2°, 19.7±0.2°, 25.0±0.2°, 25.5±0.2°, 26.3±0.2°, and 27.6±0.2°; preferably, the crystal of component (i) shows a plate-like or columnar crystal habit under a microscope, or a mixture of plate-like and columnar crystal habits; preferably, the crystal of component (i) shows a plate-like crystal habit under a microscope. Wherein, component (i) in the form of plate-like crystals has the strongest XRD diffraction peak at 15.6±0.2°, and component (i) in the form of columnar crystals has the strongest XRD diffraction peak at 17.4±0.2°.

[0013] In some embodiments, component (i) is present as amorphous and crystalline components in a ratio of 70-90:10-30 by mass, preferably 75-85:15-25, and more preferably 80:20 by mass.

[0014] In some embodiments, the particle size of component (i) in the crystalline form, D90, is 15 μm or less.

[0015] In some embodiments, the biodegradable and biocompatible polymer is any one or a combination of poly(lactide-glycolide) (PLGA), polylactide and polycaprolactone; in the poly(lactide-glycolide), the molar ratio of lactide to glycolide is 50:50 to 95:5, preferably 65:45 to 90:10, and more preferably 75:25 to 85:15.

[0016] In some embodiments, the intrinsic viscosity of the biodegradable and biocompatible polymer is 0.20 dl / g to 0.65 dl / g, preferably 0.30 dl / g to 0.45 dl / g, and more preferably 0.30 dl / g to 0.40 dl / g.

[0017] In some embodiments, the weight average molecular weight of the biodegradable and biocompatible polymer is 20,000 Da to 60,000 Da, preferably 28,000 Da to 45,000 Da, and more preferably 28,000 Da to 35,000 Da.

[0018] In some embodiments, the mass of component (i) is 15% to 35% of the total mass of the antiviral pharmaceutical composition, preferably 20% to 35%, more preferably 20% to 30%, and more preferably 25% to 30%.

[0019] In some embodiments, the antiviral drug composition is in the form of granules or powders, with a particle size D50 of 50 μm to 100 μm, preferably 55 μm to 90 μm; further, the particle size D10 is 20 μm to 60 μm; further, the particle size D90 is 105 μm to 150 μm.

[0020] In some embodiments, the antiviral drug composition is in the form of microspheres.

[0021] The present invention compares the in vitro and in vivo release behaviors of the antiviral drug composition, and studies the absorption, distribution, metabolism and excretion of compound I in vivo, and finds that when the drug composition is released at a specific rate in vitro, it can also achieve a smooth release in vivo.

[0022] The use of the antiviral pharmaceutical composition in the preparation of a product for preventing and / or treating chronic hepatitis B, or for preventing and / or treating chronic hepatitis B combined with decompensated cirrhosis is within the protection scope of the present invention.

[0023] The clinical application of the antiviral pharmaceutical composition is within the protection scope of the present invention.

[0024] The antiviral pharmaceutical composition is clinically used for preventing and / or treating chronic hepatitis B patients.

[0025] The antiviral pharmaceutical composition is clinically used for preventing and / or treating patients with chronic hepatitis B complicated with decompensated liver cirrhosis.

[0026] The method for using the antiviral pharmaceutical composition is also within the protection scope of the present invention.

[0027] The dosage form of the antiviral pharmaceutical composition is an injection, including but not limited to an intramuscular injection and / or a subcutaneous injection.

[0028] The antiviral pharmaceutical composition is administered to patients after being dispersed and suspended in an aqueous excipient.

[0029] The antiviral pharmaceutical composition is dispersed or suspended in an aqueous excipient at a concentration of 20 mg / ml or more (based on API) and administered to patients, preferably dispersed or suspended in an aqueous excipient at a concentration of 20-50 mg / ml.

[0030] In some embodiments, the aqueous excipient has a viscosity of 20 mPa.s to 100 mPa.s at 20°C.

[0031] The aqueous excipient includes but is not limited to viscosity enhancers, wetting agents, osmotic pressure regulators, and pH regulators. The viscosity enhancers include but are not limited to sodium carboxymethyl cellulose, sodium alginate, and gelatin; the wetting agents include but are not limited to polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80; the osmotic pressure regulators include but are not limited to glucose, sodium chloride, phosphate, and citrate; the pH regulators include but are not limited to hydrochloric acid, sulfuric acid, citric acid, sodium hydroxide, potassium hydroxide, sodium bicarbonate, disodium hydrogen phosphate, and sodium dihydrogen phosphate.

[0032] The antiviral drug composition is dispersed and suspended by an aqueous excipient and then administered to a patient using a 0.6# to 1.0# needle.

[0033] The antiviral pharmaceutical composition is administered to a patient at a dose of 0.3 mg / day or more.

[0034] The antiviral drug composition is injected into the patient's body once every 1 to 3 months.

[0035] The antiviral drug composition continuously provides Compound I for at least 28 days, such as 28 days, 30 days, 56 days, 60 days, and 84 days, and the blood concentration of Compound I is above 0.1 ng / mL, preferably above 0.2 ng / mL, and more preferably above 0.3 ng / mL.

[0036] The preparation process of the antiviral pharmaceutical composition is also within the scope of protection of the present invention, and in some embodiments, comprises the following steps:

[0037] a) preparing component (i) and a biodegradable and biocompatible polymer into a solid dispersion, wherein component (i) exists in an amorphous form in the solid dispersion;

[0038] b) adding the solid dispersion prepared in step a) and component (i) in crystalline form into an organic solvent to obtain a suspension;

[0039] c) dispersing the suspension obtained in step b) in a hydrophilic polymer aqueous solution to form micron-sized emulsion droplets;

[0040] d) removing the organic solvent in the emulsion droplets, filtering, washing and drying to obtain a sustained-release composition.

[0041] In some embodiments, the amorphous component (i) in step a) accounts for 70% to 90% of the total mass of component (i).

[0042] In some embodiments, the solid dispersion in step a) is prepared by hot melt extrusion; wherein the temperature of hot melt extrusion is 80°C to 110°C, preferably 90°C to 100°C.

[0043] In some embodiments, the preparation method of the solid dispersion described in step a) is a dissolution-freeze drying method, specifically, component (i) and a biodegradable and biocompatible polymer are dissolved in a co-solvent, and then freeze-dried to obtain; the co-solvent includes any one or a combination of dimethyl sulfoxide, dimethylformamide, dimethylacetamide, dichloromethane, chloroform, acetone, ethanol, acetonitrile, and ethyl acetate; the freeze-drying process is to pre-freeze the obtained solution at below -25°C for 4 hours; then evacuate, keep it for 24 hours, and then heat it to 25°C at a rate of 5°C / hour to obtain a solid dispersion.

[0044] In some embodiments, the organic solvent in step b) is a non-good solvent for component (i), in which component (i) is slightly soluble, very slightly soluble, almost insoluble or insoluble; specifically, the organic solvent includes any one or a combination of dichloromethane, ethyl acetate, methanol, ethanol, isopropanol, acetone, diethyl ether and n-heptane, preferably dichloromethane.

[0045] In some embodiments, the dispersion method in step c) is any one of ultrasound, vortex, homogenization, high-pressure homogenization and stirring.

[0046] In some embodiments, the hydrophilic polymer in step c) is polyvinyl alcohol and / or polyvinyl pyrrolidone.

[0047] In some embodiments, the encapsulation efficiency of the composition in step d) is 75% to 90%.

[0048] In some embodiments, the drug loading rate of the composition in step d) is 15% to 35%.

[0049] Different from the currently disclosed technical methods, the technology disclosed in the present invention can prepare a sustained-release preparation of compound I with a specific crystal form and a controllable ratio of different crystal forms.

[0050] Beneficial effects: Compared with the prior art, the present invention has the following characteristics and advantages:

[0051] (1) The antiviral pharmaceutical composition provided by the present invention contains both amorphous and crystalline forms of Compound I, and the preparation method adopted enables the ratio of different crystalline forms in the antiviral pharmaceutical composition to be controllable.

[0052] (2) The antiviral drug composition provided by the present invention has a high drug content, a high encapsulation rate, no delayed release period, no burst release, a smooth release in vivo and in vitro, and can continuously release Compound I for at least 28 days. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] Figure 1 These are the XRD test patterns in Example 6, a is the XRD test pattern of the Compound I API (API) with plate-like crystal habit, b is the XRD test pattern of the Compound I API (API) with columnar crystal habit, and c is the XRD test pattern of PLGA.

[0054] Figure 2 These are microscope images of the API in Example 7; a is a microscope image of the Compound I API with plate-like crystal habit, and b is a microscope image of the Compound I API with columnar crystal habit.

[0055] Figure 3 These are some microscopic images of microspheres in Example 9; a is prescription 1-1, b is prescription 1-2, and c is prescription 2-3.

[0056] Figure 4 are in vivo release diagrams; a is the in vivo release diagram of prescription 2-1, b is the in vivo release diagram of prescription 2-3, and c is the in vivo release diagram of prescription 2-5.

[0057] Figure 5 This is the blood drug concentration-time curve of repeated administration of prescription 2-3. DETAILED DESCRIPTION

[0058] The present invention can be better understood according to the following examples. However, it is easy for those skilled in the art to understand that the contents described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention described in detail in the claims.

[0059] In the following examples, compound I1 and compound I2 are the same substance, both are compound I, but the addition processes are different. Compound I1 refers to compound I added in the hot melt extrusion step; compound I2 refers to compound I added in the non-hot melt extrusion step.

[0060] In the following examples, the theoretical content is the total amount of Compound I in the entire prescription when the materials are added; the measured content is the actual measured content of Compound I in the product.

[0061] Unless otherwise specified, the PLGA described in the following embodiments is: PLGA model is 75 / 25, the marked viscosity is 0.30 dl / g, and the molecular weight is 28000 Da.

[0062] Unless otherwise specified, the dispersion described in the following embodiments is high-speed homogenization.

[0063] In the following embodiments, the detection methods involved are as follows:

[0064] (1) The content and proportion of the crystalline form of Compound I in each composition of Example 1 and Example 2 were determined by using XRD for quantitative determination using ZnO as the internal standard.

[0065] Amorphous Compound I content = measured total Compound I content - crystalline Compound I content.

[0066] The proportion of amorphous compound I in API = amorphous compound I content / measured total compound I content*100%.

[0067] (2) Microsphere particle size distribution

[0068] A laser particle size tester was used to measure the particle size distribution of sustained-release microspheres. The pump speed was 40%, the measurement time was 90s, the waiting time was 30s, the PIDS was set to "on", and the number of measurements was 1. During the measurement, an appropriate amount of sustained-release microspheres was taken, an appropriate amount of surfactant solution was added, and then 1mL of water was added and mixed. Turn on the instrument, add the sample to the sample pool until the shading degree is 8-12%, record the measurement results, perform 3 parallel measurements, and take the average value. Among them, D10 means that the number of particles smaller than this particle size accounts for 10% of the total, D50 represents the intermediate particle size, that is, the number of particles smaller than this particle size accounts for 50% of the total, and D90 means that the number of particles smaller than this particle size accounts for 90% of the total.

[0069] (3) Content determination and microsphere encapsulation efficiency determination

[0070] Take 20 mg of the accurately weighed drug composition, add 7 mL of acetonitrile and ultrasonically dissolve it, then add an appropriate amount of methanol to ultrasonically dissolve it, and dilute it to 25 mL with methanol. Accurately measure 1 mL and place it in a 20 mL volumetric flask, dilute it to the scale with mobile phase A (acetonitrile-water-trifluoroacetic acid (1:99:0.1)), and shake it well. Pour an appropriate amount into a centrifuge tube, centrifuge (10000 rpm, 10 min), and take the supernatant. Prepare two copies in parallel.

[0071] The same method was used to prepare the standard solution of Compound I. The content of Compound I tablets in the US Pharmacopoeia was determined by HPLC.

[0072] Encapsulation efficiency = actual content / theoretical content*100%.

[0073] (4) In vitro release

[0074] Test method: 30 mg of microspheres were accurately weighed, and 200 mL of PBS with a pH value of 7.4 was added as the release medium. The release experiment was carried out in a 37°C water bath shaker. The shaker speed was 50 rpm. At a fixed time, the sample was taken out and allowed to stand, and then the supernatant was taken and passed through a 0.22 μm microporous filter membrane. At the same time, fresh release medium was added. The sample was determined by the content determination method, and the release rate was calculated. Each batch of microspheres was tested in triplicate.

[0075] (5) In vivo release of each pharmaceutical composition in Example 2

[0076] The daily dosage of compound I for adults is 1.0 mg, and the adult body weight is 60 kg, that is, the adult dosage is 0.01667 mg / kg / day. The dosage conversion coefficient for beagle dogs and humans is 1.72, so the dosage for beagle dogs is 0.02867 mg / kg / day. The target product of compound I microspheres for injection is administered once every four weeks, so the single dosage is 0.8028 mg / kg. The above dosage conversions are all calculated based on active ingredients. Blood was drawn from each beagle before administration, 1h, 24h, 4d after administration, and then every 4 days, and then tested.

[0077] Example 1: Preparation of sustained-release pharmaceutical composition of Compound I (Compound I without hot-melt extrusion and Compound I fully hot-melt extrusion)

[0078] The compound I in this example has a plate-like crystal habit.

[0079] Prescription 1-1: Weigh 3.500 g of PLGA and 1.500 g of compound I2. Add PLGA and compound I2 to 30.00 g of dichloromethane and stir to obtain a suspension of compound I / PLGA / dichloromethane. Add the suspension to a 1.0% polyvinyl alcohol aqueous solution at 4°C and mechanically stir at 2000 rpm for emulsification for 5-10 min. Then raise the temperature to 40°C to volatilize the organic solvent, filter and collect the microspheres, wash the microspheres with water for injection, and freeze-dry to obtain a sustained-release pharmaceutical composition of compound I.

[0080] Prescription 1-2: Weigh 3.000g of compound I1 and 7.000g of PLGA, mix well, and hot-melt extrude at 90°C to 110°C using a hot-melt extruder to obtain a hot-melt extrudate of compound I1 / PLGA. Weigh 5.000g of the hot-melt extrudate of compound I1 / PLGA, add it to 30.00g of dichloromethane, and stir to obtain a suspension of compound I / PLGA / dichloromethane. Add the suspension to a 1.0% polyvinyl alcohol aqueous solution at 4°C, and mechanically stir and emulsify at 2000rpm for 5-10min. Then raise the temperature to 40°C to volatilize the organic solvent, filter and collect the microspheres, wash the microspheres with water for injection, and freeze-dry to obtain a sustained-release pharmaceutical composition of compound I.

[0081] Prescription 1-2-1: Take the hot melt extrudate of Compound I1 / PLGA in Prescription 1-2, crush it, sieve to collect particles between 500 mesh and 100 mesh, wash it with water for injection, and freeze-dry it to obtain a Compound I pharmaceutical composition.

[0082] Prescription 1-3: Weigh 3.000g of compound I1 and 7.000g of PLGA, mix well, and hot-melt extrude at 80°C to 89°C using a hot-melt extruder to obtain a hot-melt extrudate of compound I1 / PLGA. Weigh 5.000g of the hot-melt extrudate of compound I1 / PLGA, add it to 30.00g of dichloromethane, and stir to obtain a suspension of compound I / PLGA / dichloromethane. Add the suspension to a 1.0% aqueous solution of polyvinyl alcohol at 4°C, and mechanically stir and emulsify at 2000rpm for 5-10min. Then raise the temperature to 40°C to volatilize the organic solvent, filter and collect the microspheres, wash the microspheres with water for injection, and freeze-dry to obtain a sustained-release pharmaceutical composition of compound I.

[0083] Prescription 1-4 is a repeated test of Prescription 1-3.

[0084] The test results are as follows:

[0085] Table 1

[0086]

[0087] Table 2

[0088]

[0089]

[0090] Table 3

[0091]

[0092] Table 4

[0093]

[0094]

[0095] Comparison points:

[0096] Through the content, release rate and XRD data analysis of prescriptions 1-1, 1-2, 1-3 and 1-4 in Example 1, it can be seen that:

[0097] API was directly prepared into microspheres without hot-melt extrusion, and the microsphere encapsulation efficiency was low (see prescription 1-1 in Table 3), and there was a burst release phenomenon (see prescription 1-1 in Table 4). XRD detection showed that compound I in the pharmaceutical composition was almost entirely crystalline.

[0098] The API was completely hot-melt extruded, with a high encapsulation rate, but delayed release (see release data of formulation 1-2 in Table 4). XRD detection showed that all compound I in the pharmaceutical composition was amorphous.

[0099] Through XRD detection, it can be found that by reducing the extrusion temperature of the hot melt extrusion process step (80°C to 89°C) (Formulation 1-3), the compound I in the pharmaceutical composition exists partly in crystalline form and partly in amorphous form, with high encapsulation efficiency and no delayed release. However, this process step is difficult to repeat (Formulation 1-4), and the ratio of compound I in crystalline form and amorphous form varies from batch to batch, which cannot be accurately controlled and is not conducive to quality control.

[0100] The release data analysis of the formulations 1-2 and 1-2-1 in Example 1 shows that the composition prepared by crushing the hot-melt extrudate has a larger burst release.

[0101] Furthermore, the present invention unexpectedly discovered that better quality control can be achieved by adding Compound I to the microsphere preparation step by hot melt extrusion and without hot melt extrusion respectively. Compound I1 that has undergone the hot melt extrusion process step exists in an amorphous form, and Compound I2 that has not undergone the hot melt extrusion process step exists in a crystalline form, and the batch-to-batch difference is very small.

[0102] Example 2: Preparation of sustained-release pharmaceutical compositions (API in different proportions by hot-melt extrusion or dissolution-freeze drying)

[0103] The compound I in this example has a plate-like crystal habit, and the formula is shown in Table 5.

[0104] Step A: Weigh the prescribed amount of compound I1 and the prescribed amount of PLGA according to the weight in Table 5, mix them, and hot-melt extrude them at 95°C±5°C using a hot-melt extruder to obtain a hot-melt extrudate of compound I1 / PLGA for later use. This process is used in prescriptions 2-1 to 2-5.

[0105] Alternatively, the compound I1 and the PLGA in the prescription amount are weighed according to the weight in the prescription table, and dimethyl sulfoxide (9 times the weight of the total weight of the compound I1 and PLGA) and dichloromethane (1 times the weight) are added to dissolve them, and the resulting solution is pre-frozen at below -25°C for 4 hours; then vacuumed, kept for 24 hours, and then heated to 25°C at a rate of 5°C / hour, and then solid dispersion is obtained. Prescriptions 2-6 adopt this process.

[0106] There is no significant difference in the products prepared by the two processes.

[0107] Step B: Weigh the hot melt extrudate or solid dispersion of step A according to the weight in the prescription table, weigh the prescribed amount of compound I2, add 30.00 g of dichloromethane, and stir to obtain a suspension of compound I / PLGA / dichloromethane. Add the suspension to a 1.0% polyvinyl alcohol aqueous solution at 4°C, and mechanically stir at 2000 rpm for emulsification for 5-10 minutes. Then heat to 40°C to volatilize the organic solvent, filter and collect the microspheres, wash the microspheres with water for injection, and freeze-dry to obtain a sustained-release pharmaceutical composition of compound I.

[0108] Table 5 API hot melt extrusion prescriptions with different proportions

[0109]

[0110] Note: The weight of the hot melt extrudate or solid dispersion of Compound I1 / PLGA in the prescription table refers to the sample amount weighed in step B, and does not represent the yield of step A.

[0111] The test results are as follows:

[0112] Table 6

[0113]

[0114]

[0115] Table 7

[0116] Sample batch number D10(μm) D50(μm) D90(μm) 2-1 52.6 87.2 155.4 2-2 37.6 73.6 140.7 2-3 49.2 80.5 142.3 2-4 51.3 72.3 133.8 2-5 51.2 86.3 133.2

[0117] Table 8

[0118]

[0119] Table 9

[0120]

[0121] It can be seen from the microsphere crystal form detection data in Table 6 that the ratio of crystalline compound I and amorphous compound I in the prepared composition can be controlled by the preparation process of the pharmaceutical composition by adding compound I by hot melt extrusion (or dissolution-freeze drying) and without hot melt extrusion (or without dissolution-freeze drying).

[0122] From the data in Table 9, it can be seen that when the mass of amorphous compound I accounts for 70%-90% of the mass of total compound I, the in vitro release is most ideal. Figure 4 It can be seen from the PK drug-time curve that the drug composition shows no burst release phenomenon in the early stage in vivo, and can be continuously released in the later stage, with a stable blood drug concentration and a long drug release period to reach an effective blood drug concentration.

[0123] From the release data of Formulation 2-1 in Table 9, it can be seen that when the proportion of amorphous compound I in the pharmaceutical composition is less than 70%, the microspheres release rapidly in the early stage and the release rate becomes slower in the later stage. Figure 4 From the PK drug-time curve of Chinese prescription 2-1, it can be seen that the drug composition exhibits rapid release in the early stage of the body, with a higher blood drug concentration; and slower release in the later stage, with a lower blood drug concentration.

[0124] From the release data of formulations 2-5 in Table 9, it can be seen that when the proportion of amorphous compound I in the pharmaceutical composition is greater than 90%, the microspheres have a slow early release in vitro. Figure 4 The PK drug-time curve of Chinese prescription 2-5 shows that the drug composition in vivo exhibits a slow release in the early stage, with delayed release, low blood drug concentration, and cannot reach an effective concentration; the release becomes faster in the later stage, the blood drug concentration increases, and can reach an effective blood drug concentration. Samples of prescription 2-3 were taken for repeated administration in vivo release experiments, with administration once every four weeks and repeated administration 4 times. The blood drug concentration test results are shown in Figure 5 The experimental results show that the drug composition has a stable release in vivo and can be administered once every four weeks.

[0125] Example 3: Preparation of sustained release pharmaceutical composition (effect of crystal habit)

[0126] The process steps are the same as those in Example 2-1, and the prescription is shown in Table 10.

[0127] Table 10 Crystal habit investigation prescription table

[0128]

[0129] Note: The weight of the hot-melt extrudate of Compound I1 / PLGA in the prescription table refers to the sample amount weighed in step B, and does not represent the yield of step A.

[0130] The test results are as follows:

[0131] Table 11

[0132] Sample batch number D10(μm) D50(μm) D90(μm) 3-1 is 2-3 49.2 80.5 142.3 3-2 48.8 73.9 123.9

[0133] Table 12

[0134]

[0135]

[0136] Table 13

[0137]

[0138] From the release data of prescriptions 3-1 and 3-2 in Table 13, it can be seen that compared with the pharmaceutical composition prepared from the plate-like crystal habit compound I2, the release of the pharmaceutical composition prepared from the columnar crystal habit compound I2 is slower, and the release is slower in the early stage.

[0139] Example 4: Preparation of sustained release pharmaceutical composition (Effect of biodegradable and biocompatible polymer)

[0140] The process steps are the same as those of Example 2-1, and the prescription is shown in Table 14. Compound I in this example is a plate-like crystal.

[0141] Table 14 Prescriptions for different types of polymers

[0142]

[0143] Note: The weight of the hot-melt extrudate of Compound I1 / PLGA in the prescription table refers to the sample amount weighed in step B, and does not represent the yield of step A.

[0144] The test results are as follows:

[0145] Table 15

[0146] Sample batch number D10(μm) D50(μm) D90(μm) 4-1 29 62.1 109 4-2 31.8 65.9 108.8 4-3 is 2-3 49.2 80.5 142.3 4-4 29.6 59.7 105.6 4-5 38.6 63.7 108.6 4-6 34.7 61.9 105.7 4-7 44.5 73.3 118.0 4-8 36.5 67.0 114.0 4-9 43.0 69.4 109.5 4-10 39.0 66.6 109.9

[0147] Table 16

[0148] Prescription form Theoretical content / % Measured content / % Encapsulation rate / % 4-1 30 24.6 82.0 4-2 30 23.7 79.0 4-3 is 2-3 30 24.1 80.3 4-4 30 24.8 82.7 4-5 30 24.7 82.3 4-6 30 25.0 83.3 4-7 30 23.8 79.3 4-8 30 24.8 82.7 4-9 30 24.9 83.0 4-10 30 24.5 81.7

[0149] Table 17

[0150]

[0151]

[0152] Table 18

[0153]

[0154]

[0155] It can be seen from the data in Tables 17 and 18 that the antiviral drug composition prepared by the preparation method of the present invention using different types of biodegradable and biocompatible polymers can be released for about 1-3 months, which can meet the dosing cycle of once every 1 to 3 months.

[0156] Example 5: Preparation of pharmaceutical compositions with different theoretical contents

[0157] The process steps are the same as those of Example 2-1, and the prescription is shown in Table 19. Compound I in this example is a plate-like crystal.

[0158] Table 19

[0159]

[0160] The test results are as follows:

[0161] Table 20

[0162] Sample batch number D10(μm) D50(μm) D90(μm) 5-1 24.9 57.9 107.3 5-2 35.7 63.8 114.9 5-3 36 68.1 121.6 5-4 is 2-3 49.2 80.5 142.3 5-5 54.6 82.7 132.3 5-6 59.5 89.6 134.5

[0163] Table 21

[0164]

[0165] Table 22

[0166]

[0167]

[0168] From the data in Table 21 and Table 22, it can be seen that when the theoretical content of the drug composition is 15% to 35%, the microsphere encapsulation efficiency is 76.9% to 88.4%, and the microspheres have no delayed release and no burst release. When the theoretical content is not less than 40%, the microsphere encapsulation efficiency drops to 46.8%, and there is an in vitro delayed release phenomenon.

[0169] Example 6: API, microsphere crystal form detection (XRD)

[0170] Figure 1 X-powder diffraction was performed for plate-like crystal habit compound I API (a), columnar crystal habit compound I API (b), and PLGA (PLGA model 75 / 25, nominal viscosity 0.30 dl / g, molecular weight 28000 Da) (c), and the detection method was referenced to the 2015 edition of the Chinese Pharmacopoeia, Part IV 0451 X-ray diffraction method. During the test, the 2θ angle range was: 3-60°; the step length was: 0.02°; and the step time was: 40s.

[0171] Among them, a and b are XRD diagrams of API. The characteristic peaks of the two are the same, but the strongest peaks are different, that is, the crystal habits are different.

[0172] Example 7: API Microscope Image

[0173] Figure 2 The results of observation under a microscope are those of the plate-like crystal compound I drug substance (a) and the columnar crystal compound I drug substance (b).

[0174] Example 8: API Particle Size Distribution

[0175] Weigh 1.0 g of Compound I API (plate-like crystal form), add 10 mL of purified water, and vortex the sample into a uniform suspension. Use a laser particle size analyzer to measure. Set the stirring speed and measure the time. Gradually add the Compound I-water suspension to the sample cell until the desired shading ratio (6% to 12%) is reached and then measure.

[0176] The API particle size distribution is determined using a laser particle size tester. The pump speed is 40%, the measurement time is 90s, the waiting time is 30s, the PIDS is set to "on", and the number of measurements is 1. During the measurement, take an appropriate amount of compound I raw material, add an appropriate amount of purified water, and mix well. Turn on the instrument, add the sample to the sample pool until the shading degree is 6-10%, record the measurement results, measure 3 times in parallel, and take the average value. Among them, D10 means that the number of particles smaller than this particle size accounts for 10% of the total, D50 represents the intermediate particle size, that is, the number of particles smaller than this particle size accounts for 50% of the total, and D90 means that the number of particles smaller than this particle size accounts for 90% of the total.

[0177] Table 23

[0178] Sample batch number Actual shading ratio% D10(μm) D50(μm) D90(μm) 1 7.8 1.407 7.469 14.543

[0179] Example 9: Microscope image of some microspheres

[0180] Microscopic images of microspheres prepared by Prescription 1-1 (a), Prescription 1-2 (b) and Prescription 2-3 (c) are shown in Figure 3 .

[0181] It can be seen that the microsphere content of prescription 1-1 is lower, and the microspheres in the microscope observation image show more transparent parts, while the microspheres prepared by prescriptions 1-2 and 2-3 have higher content and the microspheres are uniformly black.

[0182] The present invention provides an antiviral drug composition and its preparation process and application ideas and methods. There are many methods and ways to implement the technical solution. The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention. All components not specified in this embodiment can be implemented by existing technologies.

Claims

1. An antiviral pharmaceutical composition, characterized in that: Contains the following ingredients: (i) Compound I, or a monohydrate thereof, or a pharmaceutically acceptable salt thereof, and, (ii) a biodegradable biocompatible polymer; the biodegradable biocompatible polymer is any one or a combination of poly(lactide-glycolide), polylactide and polycaprolactone; Wherein, component (i) exists in the composition in both crystalline and amorphous forms; the ratio of amorphous component (i) to crystalline component (i) is 70-90:10-30 by mass; The mass of component (i) is 15% to 35% of the total mass of the antiviral pharmaceutical composition; 2. The antiviral pharmaceutical composition according to claim 1, characterized in that: Component (i) has XRD characteristic diffraction peaks at 5.3±0.2°, 15.6±0.2°, 17.4±0.2°, 19.7±0.2°, 25.0±0.2°, 25.5±0.2°, 26.3±0.2°, and 27.6±0.2°, and has the strongest diffraction peak at 15.6±0.2° or 17.4±0.2°.

3. The antiviral pharmaceutical composition according to claim 1, characterized in that: The particle size D90 of the component (i) in the form of crystals is 15 μm or less.

4. The antiviral pharmaceutical composition according to claim 1, characterized in that: In the poly(lactide-glycolide), the molar ratio of lactide to glycolide is 50:50 to 95:

5.

5. The antiviral pharmaceutical composition according to claim 1, characterized in that: The viscosity of the biodegradable and biocompatible polymer is 0.20 dl / g to 0.65 dl / g.

6. The antiviral pharmaceutical composition according to claim 1, characterized in that: The weight average molecular weight of the biodegradable and biocompatible polymer is 20000Da to 60000Da.

7. The antiviral pharmaceutical composition according to claim 1, characterized in that: The crystals of the component (i) have a columnar and / or plate-like crystal habit under a microscope.

8. The antiviral pharmaceutical composition according to claim 1, characterized in that: The particle size D50 of the antiviral drug composition is 50 μm to 100 μm.

9. The process for preparing the antiviral pharmaceutical composition according to any one of claims 1 to 8, characterized in that: The following steps are involved: a) preparing component (i) and a biodegradable biocompatible polymer into a solid dispersion, wherein component (i) exists in an amorphous state in the solid dispersion; the biodegradable biocompatible polymer is any one or a combination of poly(lactide-glycolide), polylactide and polycaprolactone; b) adding the solid dispersion prepared in step a) and component (i) in crystalline form into an organic solvent to obtain a suspension; c) dispersing the suspension obtained in step b) in a hydrophilic polymer aqueous solution to form micron-sized emulsion droplets; d) removing the organic solvent from the emulsion droplets, filtering, washing and drying to obtain a composition; Wherein, component (i) exists in the composition in both crystalline and amorphous forms; the ratio of amorphous component (i) to crystalline component (i) is 70-90:10-30 by mass; The mass of the component (i) is 15% to 35% of the total mass of the antiviral pharmaceutical composition.

10. The preparation process according to claim 9, characterized in that: In step a), the solid dispersion is prepared by hot melt extrusion or dissolution-freeze drying.

11. Use of the antiviral pharmaceutical composition according to any one of claims 1 to 8 in the preparation of a product for preventing and / or treating chronic hepatitis B, or for preventing and / or treating chronic hepatitis B combined with decompensated cirrhosis.

12. The use according to claim 11, characterized in that: The antiviral pharmaceutical composition is administered to a patient at a dose of 0.3 mg / day or more.

13. The use according to claim 11, characterized in that: The blood concentration of compound I is above 0.1 ng / mL.

Images