WO2024066765A1 - 一种抗病毒药物组合物及其制备工艺与应用 - Google Patents

一种抗病毒药物组合物及其制备工艺与应用 Download PDF

Info

Publication number
WO2024066765A1
WO2024066765A1 PCT/CN2023/112736 CN2023112736W WO2024066765A1 WO 2024066765 A1 WO2024066765 A1 WO 2024066765A1 CN 2023112736 W CN2023112736 W CN 2023112736W WO 2024066765 A1 WO2024066765 A1 WO 2024066765A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
compound
antiviral pharmaceutical
component
composition according
Prior art date
Application number
PCT/CN2023/112736
Other languages
English (en)
French (fr)
Inventor
郑阳
赖树挺
万小康
林日森
朱锦萍
曹付春
连远发
刘锋
Original Assignee
广州帝奇医药技术有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 广州帝奇医药技术有限公司 filed Critical 广州帝奇医药技术有限公司
Publication of WO2024066765A1 publication Critical patent/WO2024066765A1/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • 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.
  • 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.
  • 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.
  • compositions 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.
  • 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.
  • 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.
  • the present invention creatively discovered that the crystal form of compound I has a great influence on the release of the pharmaceutical composition.
  • 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.
  • the crystals in the pharmaceutical composition exist in a certain crystal habit, the pharmaceutical composition has a more ideal release behavior.
  • 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;
  • pharmaceutically acceptable salts of Compound I include but are not limited to the hydrochloride, bromate, sulfate, phosphate, methanesulfonate, pamoate and triphosphate of Compound I.
  • the pharmaceutically acceptable long-chain esters of Compound I include but are not limited to stearate, arachidate, behenate, dodecanoate, myristate, pentadecanoate, palmitate and heptadecanoate of Compound I.
  • 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.
  • component (i) in the form of plate-like crystals has the strongest XRD diffraction peak at 15.6 ⁇ 0.2°
  • component (i) in the form of columnar crystals has the strongest XRD diffraction peak at 17.4 ⁇ 0.2°.
  • 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.
  • the particle size of component (i) in the crystalline form, D90 is 15 ⁇ m or less.
  • 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.
  • PLGA poly(lactide-glycolide)
  • 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.
  • 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.
  • 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.
  • 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%.
  • the antiviral drug composition is in the form of granules or powders, with a particle size D50 of 50 ⁇ m to 100 ⁇ m, preferably 55 ⁇ m to 90 ⁇ m; further, a particle size D10 of 20 ⁇ m to 60 ⁇ m; further, a particle size D90 of 105 ⁇ m to 150 ⁇ m.
  • the antiviral drug composition is in the form of microspheres.
  • 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.
  • 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.
  • the antiviral pharmaceutical composition is clinically used for preventing and/or treating chronic hepatitis B patients.
  • the antiviral pharmaceutical composition is clinically used for preventing and/or treating patients with chronic hepatitis B complicated with decompensated liver cirrhosis.
  • the method for using the antiviral pharmaceutical composition is also within the protection scope of the present invention.
  • the dosage form of the antiviral pharmaceutical composition is an injection, including but not limited to an intramuscular injection and/or a subcutaneous injection.
  • the antiviral pharmaceutical composition is administered to patients after being dispersed and suspended in an aqueous excipient.
  • 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.
  • the aqueous excipient has a viscosity of 20 mPa.s to 100 mPa.s at 20°C.
  • the aqueous excipients include but are not limited to viscosity enhancers, wetting agents, osmotic pressure regulators, pH regulators,
  • the viscosity enhancer includes but is not limited to sodium carboxymethyl cellulose, sodium alginate and gelatin;
  • the wetting agent includes but is not limited to polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80;
  • the osmotic pressure regulator includes but is not limited to glucose, sodium chloride, phosphate and citrate;
  • the pH regulator includes but is not limited to hydrochloric acid, sulfuric acid, citric acid, sodium hydroxide, potassium hydroxide, sodium bicarbonate, disodium hydrogen phosphate and sodium dihydrogen phosphate.
  • 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.
  • the antiviral pharmaceutical composition is administered to a patient at a dose of 0.3 mg/day or more.
  • the antiviral drug composition is injected into the patient's body once every 1 to 3 months.
  • 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.
  • 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:
  • component (i) a biodegradable and biocompatible polymer into a solid dispersion, wherein component (i) exists in an amorphous state in the solid dispersion;
  • step b) adding the solid dispersion prepared in step a) and component (i) in crystalline form into an organic solvent to obtain a suspension;
  • step b) dispersing the suspension obtained in step b) in a hydrophilic polymer aqueous solution to form micron-sized emulsion droplets;
  • the amorphous form of component (i) in step a) accounts for 70% to 90% of the total mass of component (i).
  • 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.
  • the preparation method of the solid dispersion 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 solid dispersion;
  • 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 obtain the solution
  • the mixture was pre-frozen at a temperature below -25°C for 4 hours; then vacuumed and kept for 24 hours, and then heated to 25°C at a rate of 5°C/hour to obtain a solid dispersion.
  • 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.
  • the dispersion method in step c) is any one of ultrasound, vortex, homogenization, high-pressure homogenization and stirring.
  • the hydrophilic polymer in step c) is polyvinyl alcohol and/or polyvinyl pyrrolidone.
  • the encapsulation efficiency of the composition in step d) is 75% to 90%.
  • the drug loading rate of the composition in step d) is 15% to 35%.
  • 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.
  • the present invention has the following characteristics and advantages:
  • the antiviral pharmaceutical composition provided by the present invention contains both amorphous and crystalline forms of Compound I, and the preparation method used enables the ratio of different crystalline forms in the antiviral pharmaceutical composition to be controllable.
  • 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.
  • Figure 1 is the XRD detection diagram in Example 6, a is the XRD detection diagram of the compound I raw material medicine (API) with plate-like crystal habit, b is the XRD detection diagram of the compound I raw material medicine (API) with columnar crystal habit, and c is the XRD detection diagram of PLGA.
  • Figure 2 is a microscope image 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.
  • FIG3 is a microscopic image of some microspheres in Example 9; a is prescription 1-1, b is prescription 1-2, and c is prescription 2-3.
  • Figure 4 is an in vivo release diagram; 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.
  • FIG5 is a graph showing the in vivo blood drug concentration-time curve of repeated administration of Prescription 2-3.
  • 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.
  • 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.
  • 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.
  • the dispersion described in the following embodiments is high-speed homogenization.
  • Example 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.
  • Amorphous Compound I content measured total Compound I content - crystalline Compound I content.
  • the proportion of amorphous compound I in API amorphous compound I content/actually measured total compound I content*100%.
  • 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.
  • 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.
  • D10 means that the number of particles smaller than this size accounts for 10% of the total
  • D50 represents the intermediate particle size, that is, the number of particles smaller than this size accounts for 50% of the total
  • D90 means that the number of particles smaller than this size accounts for 90% of the total.
  • Encapsulation efficiency actual content/theoretical content*100%.
  • 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 filtered through a 0.22 ⁇ m microporous 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.
  • 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.
  • Example 1 Preparation of sustained-release pharmaceutical composition of Compound I (Compound I without hot-melt extrusion and Compound I fully hot-melt extrusion)
  • the compound I in this example has a plate-like crystal habit.
  • Prescription 1-1 Weigh 3.500g PLGA and 1.500g compound I2. Add PLGA and compound I2 to 30.00g 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 2000rpm for emulsification 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 compound I pharmaceutical composition.
  • 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% aqueous solution of polyvinyl alcohol at 4°C, and mechanically stir and emulsify at 2000rpm for 5-10min. The temperature is then raised to 40° C. to volatilize the organic solvent, the microspheres are collected by filtration, the microspheres are washed with water for injection, and freeze-dried to obtain a sustained-release pharmaceutical composition of Compound I.
  • 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.
  • Prescription 1-3 Weigh 3.000g of compound I1 and 7.000g of PLGA, mix well, and hot-melt extrude at 80°C ⁇ 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% 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 compound I pharmaceutical composition.
  • Prescription 1-4 is a repeated test of Prescription 1-3.
  • 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.
  • 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.
  • Example 1 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.
  • 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 by adding it without hot melt extrusion.
  • Compound I1 that has undergone the hot melt extrusion process step exists in an amorphous form
  • 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.
  • Example 2 Preparation of sustained-release pharmaceutical compositions (API in different proportions by hot-melt extrusion or dissolution-freeze drying)
  • the compound I in this example has a plate-like crystal habit, and the formula is shown in Table 5.
  • 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.
  • 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 obtained 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.
  • 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.
  • Table 5 API hot melt extrusion prescriptions with different ratios 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.
  • 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).
  • Example 4 Preparation of sustained release pharmaceutical composition (Effect of biodegradable and biocompatible polymer)
  • Example 2-1 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.
  • Table 14 Prescriptions of different types of polymers 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.
  • 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.
  • Example 2-1 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.
  • Example 6 API, microsphere crystal form detection (XRD)
  • Figure 1 shows the X-ray powder diffraction determination of 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 refers to the 2015 edition of the Chinese Pharmacopoeia Part IV 0451 X-ray diffraction method.
  • the 2 ⁇ angle range during the test 3-60°; step length: 0.02°; step time: 40s.
  • 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.
  • FIG2 shows the results of observation of the plate-like crystal compound I drug substance (a) and the columnar crystal compound I drug substance (b) under a microscope.
  • the API particle size distribution was determined using a laser particle size tester.
  • 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.
  • an appropriate amount of Compound I API was taken, an appropriate amount of purified water was added, and mixed.
  • the instrument was turned on, and the sample was added to the sample pool until the shading degree was 6-10%, and the measurement results were recorded. The measurement was repeated 3 times and the average value was taken.
  • D10 means that the number of particles smaller than this size accounts for 10% of the total
  • D50 means that the number of particles smaller than this size accounts for 10% of the total
  • D D90 means that the number of particles smaller than this size accounts for 90% of the total.
  • Microscope images of the microspheres prepared by Prescription 1-1(a), Prescription 1-2(b) and Prescription 2-3(c) are shown in FIG3 .
  • 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.
  • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Virology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

本发明公开了一种抗病毒药物组合物及其制备工艺与应用，所述抗病毒药物组合物包含以下组分：(i)化合物I，或其一水合物，或其药物学可接受的盐，或其药学上可接受的长链酯，和，(ii)生物可降解生物相容性高分子；其中，组分(i)在组合物中以晶体和无定型两种形态同时存在。本发明所采取的制备方法能够得到药物晶体形态及含量可控的药物组合物，该组合物的药物含量高、包封率高，无延迟释放期，无突释，体内外释放平稳，能持续释放至少28天以上。

Description

一种抗病毒药物组合物及其制备工艺与应用 技术领域
本发明属于医药领域，具体涉及一种抗病毒药物的持久释放的药物组合物及其制备工艺与应用。
背景技术
化合物I是慢性乙肝治的治疗药物，在使用初期的1～2年，以1～3个月为单位开处方，待HBV稳定以后，以6个月为单位开处方，且需要服药终身。当慢性乙肝病人停止抗乙肝治疗后，发现有重度急性肝炎发作的报道，需要从临床和实验室检查等方面严密监察，并且至少随访数月。已上市的化合物I的制剂产品需要每天服用；另外，进餐会影响化合物I吸收，需要空腹服用，因此存在不便之处；停药后，疗效会出现反跳现象，导致疾病复发，预后不佳等严重的不良后果。
因此，亟需开发化合物I的持久释放制剂以延长药物释放时间，减少给药次数，提高患者的给药依从性，从而有效的降低因为漏服药物或停药而产生的复发或者产生耐药性；提高生物利用度，减少药品的不良反应。
发明内容
本发明提供一种持久缓慢释放的抗病毒药物组合物，提高患者的用药依从性，从而有效降低因为漏服药物或停药产生复发或产生耐药性的几率。
本发明提供一种具有高含量、高包封率、无延迟释放期、释放波动小以及残留溶剂容易控制等优势的抗病毒药物组合物。
本发明创造性的发现化合物I的晶体形态对药物组合物的释放有较大影响，当药 物组合物中的药物分别以晶体或非晶体形态存在时，药物组合物的释放度有明显区别。本发明通过控制无定型和晶体形态的化合物I的比例，可以得到理想释放度的药物组合物。进一步的，如果药物组合物中晶体以某一特定晶癖存在时，药物组合物具有更理想的释放行为。
本发明提供了一种抗病毒药物组合物，其包含以下组分：(i)化合物I，或其一水合物，或其药物学可接受的盐，或其药学上可接受的长链酯；和(ii)生物可降解生物相容性高分子；其中，所述组分(i)在组合物中以晶体和无定型两种形态同时存在；
其中，化合物I药学上可接受的盐包括但不限于化合物I的盐酸盐、溴酸盐、硫酸盐、磷酸盐、甲磺酸盐、双羟萘酸和三磷酸盐。
其中，化合物I药学上可接受的长链酯包括但不限于化合物I的硬脂酸酯、花生酸酯、山萮酸酯、十二酸酯、豆蔻酸酯、十五酸酯、棕榈酸酯和十七酸酯。
其中，组分(i)的晶型在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°、27.6±0.2°有XRD特征衍射峰；优选地，所述组分(i)的晶体在显微镜下显示晶癖为板状或柱状，或晶癖为板状和柱状的混合物；优选地，所述组分(i)的晶体在显微镜下显示的晶癖为板状。其中，板状晶体形态存在的组分(i)在15.6±0.2°有最强XRD衍射峰，柱状晶体形态存在的组分(i)在17.4±0.2°有最强XRD衍射峰。
在一些实施例中，组分(i)以无定型和晶体组分存在的比例以质量计为70～90:10～30，优选为75～85:15～25，更优选为80:20。
在一些实施例中，以晶体形态存在的组分(i)的粒径，D90为15μm以下。
在一些实施例中，所述的生物可降解生物相容性高分子为聚(丙交酯-乙交酯)(PLGA)、聚丙交酯和聚己内酯中的任意一种或几种组合物；所述的聚(丙交酯-乙交酯)中，丙交酯和乙交酯的摩尔比为50:50～95:5，优选为65:45～90:10，更优选为75:25～85:15。
在一些实施例中，所述的生物可降解生物相容性高分子的特性黏度为0.20dl/g～0.65dl/g，优选为0.30dl/g～0.45dl/g，更优选为0.30dl/g～0.40dl/g。
在一些实施例中，所述的生物可降解生物相容性高分子的重均分子量为20000Da～60000Da，优选为28000Da～45000Da，更优选为28000Da～35000Da。
在一些实施例中，所述的组分(i)的质量为抗病毒药物组合物总质量的15％～35％，优选为20％～35％，更优选为20％～30％，更优选为25％～30％。
在一些实施例中，所述的抗病毒药物组合物为颗粒或者粉末，粒径D50为50μm～100μm，优选为55μm～90μm；进一步的，粒径D10为20μm～60μm；进一步的，粒径D90为105μm～150μm。
在一些实施例中，所述的抗病毒药物组合物为微球形态。
本发明通过对抗病毒药物组合物为的体外释放和体内释放行为的对比研究，以及化合物I在体内的吸收、分布、代谢和排泄的研究，发现药物组合物在体外以特定的速率释放时，在体内也可以实现平稳的释放。
所述抗病毒药物组合物在制备用于预防和/或治疗慢性乙肝，或者用于预防和/或治疗慢性乙肝合并失代偿期肝硬化产品中的应用在本发明的保护范围之内。
所述抗病毒药物组合物在临床上的应用在本发明的保护范围之内。
所述抗病毒药物组合物在临床上用于预防和/或治疗慢性乙肝患者。
所述抗病毒药物组合物在临床上用于预防和/或治疗慢性乙肝合并失代偿期肝硬化患者。
所述抗病毒药物组合物的使用方法也在本发明的保护范围之内。
所述抗病毒药物组合物的剂型为注射剂，包括但不限于肌肉注射剂和/或皮下注射剂。
所述抗病毒药物组合物通过水性赋形剂分散混悬后施用患者。
所述抗病毒药物组合物以20mg/ml以上的(以API计)的浓度分散混悬于水性赋形剂中施用于患者，优选20-50mg/ml的浓度分散混悬于水性赋形剂中施用于患者。
在一些实施例中，所述水性赋形剂在20℃条件下具有20mPa.s～100mPa.s的粘度。
所述水性赋形剂包括但不限于含有粘度增强剂、润湿剂、渗透压调节剂、pH值调 节剂。所述的粘度增强剂包括但不限于羧甲基纤维素钠、海藻酸钠和明胶；所述的润湿剂包括但不限于聚山梨酯20、聚山梨酯40、聚山梨酯60和聚山梨酯80；所述的渗透压调节剂包括但不限于葡萄糖、氯化钠、磷酸盐和枸橼酸盐；所述的pH值调节剂包括但不限于盐酸、硫酸、枸橼酸、氢氧化钠、氢氧化钾、碳酸氢钠、磷酸氢二钠和磷酸二氢钠。
所述抗病毒药物组合物通过水性赋形剂分散混悬后，使用0.6#～1.0#针头施用于患者。
所述抗病毒药物组合物以0.3mg/天以上的剂量施用于患者。
所述抗病毒药物组合物以1个月至3个月一次的频率注射至患者体内。
所述抗病毒药物组合物在至少28天持续提供化合物I，如28天、30天、56天、60天、84天，化合物I的血药浓度在0.1ng/mL以上，优选在0.2ng/mL以上，更优选在0.3ng/mL以上。
所述抗病毒药物组合物的制备工艺也在本发明的保护范围之内，在一些实施例中，包括以下步骤：
a)将组分(i)与生物可降解生物相容性高分子制备成固体分散体，固体分散体中组分(i)以无定型形态存在；
b)将步骤a)制得的固体分散体与以晶体形态存在的组分(i)加入有机溶剂中，得到混悬液；
c)将步骤b)制得的混悬液分散于亲水性高分子水溶液中，形成微米级乳滴；
d)除去乳滴中的有机溶剂，过滤，洗涤，干燥，即得持久释放组合物。
在一些实施例中，步骤a)中所述无定型形态存在的组分(i)为组分(i)总质量的70％～90％。
在一些实施例中，步骤a)中所述的固体分散体的制备方法为热熔挤出；其中，热熔挤出的温度为80℃～110℃，优选为90℃～100℃。
在一些实施例中，步骤a)中所述的固体分散体的制备方法为溶解-冷冻干燥法，具体为将组分(i)与生物可降解生物相容性高分子溶于共溶剂中，然后冷冻干燥得到；所述共溶剂包括二甲基亚砜、二甲基甲酰胺、二甲基乙酰胺、二氯甲烷、氯仿、丙酮、乙醇、乙腈、乙酸乙酯的任意一种或几种组合；所述冷冻干燥的工艺为将得到的溶液 在-25℃以下预冻4小时；然后抽真空，保持24个小时后，以5℃/小时的速度升温到25℃，然后得到固体分散体。
在一些实施例中，步骤b)中所述的有机溶剂为组分(i)的非良溶剂，组分(i)在其中微溶、极微溶解、几乎不溶或不溶；具体的，所述的有机溶剂包括二氯甲烷、乙酸乙酯、甲醇、乙醇、异丙醇、丙酮、乙醚和正庚烷中的任意一种或几种组合，优选为二氯甲烷。
在一些实施例中，步骤c)中所述的分散的方式为超声、涡旋、均质、高压均质和搅拌中的任意一种。
在一些实施例中，步骤c)中所述的亲水性高分子为聚乙烯醇和/或聚乙烯吡咯酮。
在一些实施例中，步骤d)中所述的组合物的包封率为75％～90％。
在一些实施例中，步骤d)中所述的组合物的载药率为15％～35％。
不同于目前已公开的技术方法，通过本发明公开的技术，可以制备得到特定晶型且不同晶体形态的比例可控的化合物I的持久释放制剂。
有益效果：与现有技术相比，本发明具有如下特点和优势：
(1)本发明所提供的抗病毒药物组合物中同时存在无定型和晶体形态的化合物I，所采用的制备方法使该抗病毒药物组合物中不同晶体形态的比例可控。
(2)本发明所提供的抗病毒药物组合物的药物含量高、包封率高，无延迟释放期，无突释，体内外释放平稳，能持续释放化合物I至少28天以上。
附图说明
图1为实施例6中XRD检测图，a为板状晶癖的化合物I原料药(API)XRD检测图，b为柱状晶癖的化合物I原料药(API)XRD检测图，c为PLGA的XRD检测图。
图2为实施例7中API显微镜图；a为板状晶癖的化合物I原料药的显微镜图，b为柱状晶癖的化合物I原料药的显微镜图。
图3为实施例9中部分微球显微镜图；a为处方1-1，b为处方1-2，c为处方2-3。
图4为体内释放图；a为处方2-1的体内释放图，b为处方2-3的体内释放图，c为处方2-5的体内释放图。
图5为处方2-3的重复给药体内血药浓度-时间曲线图。
具体实施方式
根据下述实施例，可以更好地理解本发明。然而，本领域的技术人员容易理解，实施例所描述的内容仅用于说明本发明，而不应当也不会限制权利要求书中所详细描述的本发明。
下述实施例中，化合物I1和化合物I2为同一物质，均为化合物I，但加入工艺不同。其中，化合物I1是指热熔挤出步骤加入的化合物I；化合物I2是指非热熔挤出步骤加入的化合物I。
下述实施例中，所述理论含量为投料时，化合物I的总量占整个处方的含量值；所述实测含量为产品实际测得化合物I的含量。
若无特殊说明，下述实施例中所述PLGA均为：PLGA型号为75/25，标示粘度为0.30dl/g，分子量为28000Da。
若无特殊说明，下述实施例中所述分散均为高速均质。
下述实施例中，所涉及的检测方法如下：
(1)实施例1和实施例2各组合物中晶体形态化合物I的含量和占比的检测方法为：以ZnO为内标物，使用XRD定量测定。
无定型化合物I含量＝实测化合物I总含量-晶体化合物I含量。
无定型化合物I占API比例＝无定型化合物I含量/实测化合物I总含量*100％。
(2)微球粒度分布
采用激光粒度测试仪测定释微球粒径分布。泵速度40％，测定时间90s，等待时间30s，PIDS设置为“开”，测定次数为1。测定时，取缓释微球适量，加入适量表面活性剂溶液，然后再加入1mL水，混匀。打开仪器，向样品池中加样，直至遮光度为8-12％，记录测定结果，平行测定3次，取平均值。其中D10表示小于该粒径的数量占总量的10％，D50表示中间粒径，即小于该粒径的占总量的50％，D90表示小于该粒径的数量占总量的90％。
(3)含量测定、微球包封率测定
取精密称定药物组合物20mg，加入乙腈7mL超声溶解，再加入适量甲醇超声溶解，用甲醇定容至25mL。精密量取1mL，置20mL容量瓶中，用流动相A(乙腈- 水-三氟乙酸(1：99：0.1))稀释至刻度，摇匀。倒取适量至离心管中，离心(10000rpm，10min)，取上清液即得。平行配制两份。
同法操作，配制化合物I标准品溶液。参照美国药中典化合物I片含量测定方法，使用HPLC测定。
包封率＝实际含量/理论含量*100％。
(4)体外释放度
测试方法：精密称定微球30mg，加入200mL的pH值为7.4的PBS作为释放介质，于37℃水浴摇床中进行释放实验。摇床转速50rpm，在固定的时间，取出样品静置，然后取上清液并过0.22μm微孔滤膜，同时补充新鲜的释放介质，样品使用含量测定的方法，测定样品含量，并计算释放度。每批次微球平行3份进行。
(5)实施例2中各药物组合物体内释放
化合物I按成人每日服用剂量1.0mg、成人以60kg体重计，即成人服用剂量为0.01667mg/kg/天。比格犬与人给药剂量换算系数为1.72，则比格犬给药剂量为0.02867mg/kg/天。注射用化合物I微球目标产品为四周给药一次，则一次给药剂量为0.8028mg/kg。以上剂量换算均以活性成分计算。每只比格犬在给药前，给药后1h、24h、4d，以后每隔4天取血一次，然后进行检测。
实施例1：化合物I持久释放药物组合物的制备(化合物I不经热熔挤出和化合物I全部热熔挤出)
本实施例中的化合物I为板状晶癖。
处方1-1：称取3.500g PLGA，称取1.500g的化合物I2。将PLGA和化合物I2加入30.00g的二氯甲烷中，搅拌得到化合物I/PLGA/二氯甲烷的混悬液。将混悬液加入4℃的1.0％的聚乙烯醇水溶液中，在2000rpm下机械搅拌乳化5-10min。然后升温至40℃挥发有机溶剂，过滤收集微球，以注射用水清洗微球，冷冻干燥得持久释放的化合物I药物组合物。
处方1-2：称取3.000g化合物I1和7.000g PLGA，混匀，以热熔挤出机90℃～110℃热熔挤出，得化合物I1/PLGA的热熔挤出物。称取5.000g化合物I1/PLGA的热熔挤出物，加入至30.00g的二氯甲烷中，搅拌得到化合物I/PLGA/二氯甲烷的混悬液。将混悬液加入4℃的1.0％的聚乙烯醇水溶液中，在2000rpm下机械搅拌乳化5-10min。 然后升温至40℃挥发有机溶剂，过滤收集微球，以注射用水清洗微球，冷冻干燥得持久释放的化合物I药物组合物。
处方1-2-1：取处方1-2中的化合物I1/PLGA的热熔挤出物，粉碎，过筛收集500目至100目之间的颗粒，注射用水洗涤，冷冻干燥冻干得化合物I药物组合物。
处方1-3：称取3.000g化合物I1和7.000g PLGA，混匀，以热熔挤出机80℃～89℃热熔挤出，得化合物I1/PLGA的热熔挤出物。称取5.000g化合物I1/PLGA的热熔挤出物，加入至30.00g的二氯甲烷中，搅拌得到化合物I/PLGA/二氯甲烷的混悬液。将混悬液加入4℃的1.0％的聚乙烯醇水溶液中，在2000rpm下机械搅拌乳化5-10min。然后升温至40℃挥发有机溶剂，过滤收集微球，以注射用水清洗微球，冷冻干燥得持久释放的化合物I药物组合物。
处方1-4，为处方1-3的重复试验。
各检测结果如下所示：
表1
表2
表3
表4
对比要点：
通过实施例1中处方1-1、1-2、1-3、1-4的含量、释放度和XRD数据分析可知：
API不经过热熔挤出直接制备微球，微球包封率低(见表3中处方1-1)，且有突释现象(见表4中处方1-1)，通过XRD检测，药物组合物中化合物I几乎全部为晶体。
API完全经过热熔挤出，包封率高，但是有延迟释放(见表4中处方1-2释放度数据)，通过XRD检测，药物组合物中化合物I全部为无定型。
通过XRD检测可以发现，降低热熔挤出工艺步骤的挤出温度(80℃～89℃)(处方1-3)，药物组合物中化合物I部分以晶体形态存在，部分以无定型形态存在，包封率高，无延迟释放。但在，该工艺步骤难以重复(处方1-4)，晶体形态和无定型形态存在的化合物I的比例存在批间差异，无法准确控制，不利于质量控制。
通过实施例1中处方1-2、1-2-1的释放度数据分析可知，热熔挤出物粉碎制备得到的组合物有较大的突释。
进一步的，本发明意外发现，通过分别将化合物I经热熔挤出和不经热熔挤出两种加入制备微球步骤可以更好的进行质量控制，经过热熔挤出工艺步骤的化合物I1均以无定型形态存在，不经过热熔挤出工艺步骤的化合物I2以晶体形态存在，批间差异非常小。
实施例2：持久释放药物组合物的制备(不同比例API经热熔挤出或溶解-冷冻干燥)
本实施例中的化合物I为板状晶癖，处方见表5。
步骤A：按照表5的重量称取处方量的化合物I1与处方量的PLGA，混匀，以热熔挤出机95℃±5℃热熔挤出，得化合物I1/PLGA的热熔挤出物，待用。处方2-1～2-5采用此工艺。
或者按照处方表的重量称取处方量的化合物I1与处方量的PLGA，加入化合物I1和PLGA总质量9倍重量的二甲基亚砜和1倍重量的二氯甲烷使其溶解，将得到的溶液在-25℃以下预冻4小时；然后抽真空，保持24个小时后，以5℃/小时的速度升温到25℃，然后到固体分散体。处方2-6采用此工艺。
两种工艺制备的到的产品无明显差异。
步骤B：按照处方表的重量称取步骤A的热熔挤出物或固体分散体，称取处方量的化合物I2，加入30.00g二氯甲烷，搅拌得到化合物I/PLGA/二氯甲烷的混悬液。将混悬液加入4℃的1.0％的聚乙烯醇水溶液中，2000rpm机械搅拌乳化5-10min。然后升温至40℃挥发有机溶剂，过滤收集微球，以注射用水清洗微球，冷冻干燥得到持久释放的化合物I药物组合物。
表5 不同比例API热熔挤出处方表

注明：处方表中化合物I1/PLGA的热熔挤出物或固体分散体的重量是指步骤B中所称取的样
品量，不代表步骤A的收率。
各检测结果如下所示：
表6
表7
表8
表9
由表6微球晶型检测数据可知，采用分别将化合物I经热熔挤出(或者溶解-冷冻干燥)和不经热熔挤出(或者不经过溶解-冷冻干燥)两种加入的方式制备药物组合物的制备工艺，制备得到的组合物中晶体形态化合物I和无定型化合物I比例可控。
由表9数据可知，无定型化合物I的质量占总化合物I的质量70％-90％时，体外释放度最为理想。由图4的PK药时曲线图可知，药物组合物在体内表现为前期无突释现象，后期可以持续释放，血药浓度平稳，达到有效血药浓度的释药周期长。
由表9中处方2-1释放度数据可知，当药物组合物中无定型化合物I的比例小于 70％时，微球体外前期释放快，后期释放速度变慢。由图4中处方2-1的PK药时曲线图可知，药物组合物在体内表现为前期快速释放，血药浓度较高；后期释放变慢，血药浓度较低。
由表9中处方2-5释放度数据可知，当药物组合物中无定型化合物I的比例大于90％时，微球体外前期释放慢。由图4中处方2-5的PK药时曲线图可知，药物组合物在体内表现为前期缓慢释放，存在延迟释放，血药浓度较低，无法达到有效浓度；后期释放变快，血药浓度升高，可以至有效血药浓度。取处方2-3样品进行重复给药体内释放度实验，四周给药一次，重复给药4次，血药浓度检测结果见图5。实验结果表明，该药物组合物体内释放平稳，可以每四周给药1次。
实施例3：持久释放药物组合物的制备(晶癖的影响)
工艺步骤同实施例2-1，处方见表10。
表10 晶癖考察处方表

注明：处方表中化合物I1/PLGA的热熔挤出物的重量是指步骤B中所称取的样品量，不代表
步骤A的收率。
各检测结果如下所示：
表11
表12
表13
由表13中处方3-1和3-2释放度数据，由该数据可知，相对于板状晶癖化合物I2制备得到的药物组合物，柱状晶癖化合物I2制备得到的药物组合物释放度变慢，前期 释放较慢。
实施例4：持久释放药物组合物的制备(生物可降解生物相容性高分子的影响)
工艺步骤同实施例2-1，处方见表14。本实施例中的化合物I为板状晶型。
表14 不同型号高分子聚合物考察处方表

注明：处方表中化合物I1/PLGA的热熔挤出物的重量是指步骤B中所称取的样品量，不代表
步骤A的收率。
各检测结果如下所示：
表15
表16
表17
表18

由表17和表18数据可知，通过本发明的制备方法，不同型号生物可降解生物相容性高分子所制备的抗病毒药物组合物可以释放约1-3个月，可以满足1个月至3个月一次的给药周期。
实施例5：不同理论含量药物组合物的制备
工艺步骤同实施例2-1，处方见表19。本实施例中的化合物I为板状晶型。
表19
各检测结果如下所示：
表20
表21
表22

由表21和表22数据可知，药物组合物理论含量为15％～35％时，微球包封率为76.9％～88.4％，微球无延迟释放，无突释。当理论含量不低于40％时，微球包封率下降至46.8％，并且具有体外延迟释放现象。
实施例6：原料药、微球晶型检测(XRD)
图1为板状晶癖化合物I原料药(API)(a)、柱状晶癖化合物I原料药(API)(b)、PLGA(PLGA型号为75/25，标示粘度为0.30dl/g，分子量为28000Da)(c)进行X-粉末衍射测定，检测方法参考2015版《中国药典》四部0451X射线衍射法。测试时2θ角范围：3-60°；步长：0.02°；步长时间：40s。
其中，a、b均为API的XRD图，两者特征峰一样，但是最强峰不一样，即晶癖不同。
实施例7：API显微镜图
图2为板状晶型的化合物I原料药(a)和柱状晶型的化合物I原料药(b)于显微镜下观察的结果。
实施例8：API粒度分布
称取1.0g化合物I原料药(板状晶型)，加入10mL纯化水，将样品涡旋成均匀的混悬液。使用激光粒度仪测定。设置搅拌速度，测量时间。将化合物I-水混悬液逐渐滴加到样品池中，至所需遮光(6％～12％)比然后测定。
采用激光粒度测试仪测定API粒径分布。泵速度40％，测定时间90s，等待时间30s，PIDS设置为“开”，测定次数为1。测定时，取化合物I原料药适量，加入适量纯化水，混匀。打开仪器，向样品池中加样，直至遮光度为6-10％，记录测定结果，平行测定3次，取平均值。其中D10表示小于该粒径的数量占总量的10％，D50表示中 间粒径，即小于该粒径的占总量的50％，D90表示小于该粒径的数量占总量的90％。
表23
实施例9：部分微球显微镜图
处方1-1(a)，处方1-2(b)和处方2-3(c)制备得到微球的显微镜图见图3。
可以看出处方1-1微球含量较低，其显微镜观察图中微球呈现透明部分较多，而处方1-2和处方2-3制备得到的微球含量较高，微球呈现均一的黑色。
本发明提供了一种抗病毒药物组合物及其制备工艺与应用的思路及方法，具体实现该技术方案的方法和途径很多，以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。本实施例中未明确的各组成部分均可用现有技术加以实现。

Claims (15)

  1. 一种抗病毒药物组合物，其特征在于，包含以下组分：
    (i)化合物I，或其一水合物，或其药物学可接受的盐，或其药学上可接受的长链酯，和，
    (ii)生物可降解生物相容性高分子；
    其中，组分(i)在组合物中以晶体和无定型两种形态同时存在；
  2. 根据权利要求1所述的抗病毒药物组合物，其特征在于，组分(i)在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°、27.6±0.2°有XRD特征衍射峰，且在15.6±0.2°或17.4±0.2°有最强衍射峰。
  3. 根据权利要求1所述的抗病毒药物组合物，其特征在于，无定型组分(i)和晶体组分(i)的比例以质量计为70～90:10～30。
  4. 根据权利要求1所述的抗病毒药物组合物，其特征在于，以晶体形态存在的组分(i)的粒径的D90为15μm以下。
  5. 根据权利要求1所述的抗病毒药物组合物，其特征在于，所述的生物可降解生物相容性高分子为聚(丙交酯-乙交酯)、聚丙交酯和聚己内酯中的任意一种或几种组合物。
  6. 根据权利要求5所述的抗病毒药物组合物，其特征在于，所述的聚(丙交酯-乙交酯)中，丙交酯和乙交酯的摩尔比为50:50～95:5。
  7. 根据权利要求1所述的抗病毒药物组合物，其特征在于，所述的生物可降解生物相容性高分子的粘度为0.20dl/g～0.65dl/g。
  8. 根据权利要求1所述的抗病毒药物组合物，其特征在于，所述的生物可降解生物相容性高分子的重均分子量为20000Da～60000Da。
  9. 根据权利要求1所述的抗病毒药物组合物，其特征在于，所述的组分(i)的质量为抗病毒药物组合物总质量的15％～35％。
  10. 根据权利要求1所述的抗病毒药物组合物，其特征在于，所述的抗病毒药物组合物 的粒径D50为50μm～100μm。
  11. 权利要求1～10中任意一项所述抗病毒药物组合物的制备工艺，其特征在于，包括以下步骤：
    a)将组分(i)与生物可降解生物相容性高分子制备成固体分散体，固体分散体中组分(i)以无定型形态存在；
    b)将步骤a)制得的固体分散体与以晶体形态存在的组分(i)加入有机溶剂中，得到混悬液；
    c)将步骤b)制得的混悬液分散于亲水性高分子水溶液中，形成微米级乳滴；
    d)除去乳滴中的有机溶剂，过滤，洗涤，干燥，即得组合物。
  12. 根据权利要求11所述的制备工艺，其特征在于，步骤a)中，所述的固体分散体的制备方法为热熔挤出法或溶解-冷冻干燥法。
  13. 权利要求1～10中任意一项所述的抗病毒药物组合物在制备用于预防和/或治疗慢性乙肝，或者用于预防和/或治疗慢性乙肝合并失代偿期肝硬化产品中的应用。
  14. 根据权利要求13所述的应用，其特征在于，所述抗病毒药物组合物以0.3mg/天以上的剂量施用于患者。
  15. 根据权利要求13所述的应用，其特征在于，化合物I的血药浓度在0.1ng/mL以上。
PCT/CN2023/112736 2022-09-30 2023-08-11 一种抗病毒药物组合物及其制备工艺与应用 WO2024066765A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202211206081.1 2022-09-30
CN202211206081.1A CN116650497A (zh) 2022-09-30 2022-09-30 一种抗病毒药物组合物及其制备工艺与应用

Publications (1)

Publication Number Publication Date
WO2024066765A1 true WO2024066765A1 (zh) 2024-04-04

Family

ID=87710550

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/112736 WO2024066765A1 (zh) 2022-09-30 2023-08-11 一种抗病毒药物组合物及其制备工艺与应用

Country Status (2)

Country Link
CN (1) CN116650497A (zh)
WO (1) WO2024066765A1 (zh)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101245068A (zh) * 2007-02-14 2008-08-20 浙江医药股份有限公司新昌制药厂 结晶型态的恩替卡韦及其制备方法和其药物组合物及用途
CN105001223A (zh) * 2015-06-30 2015-10-28 湖南三清药业有限公司 一种恩替卡韦晶体化合物及其胶囊制剂
CN105722503A (zh) * 2013-08-06 2016-06-29 东国制药株式会社 恩替卡韦微球及包含其的非口服给药用药学组合物
WO2022042641A1 (zh) * 2020-08-26 2022-03-03 上海博志研新药物技术有限公司 恩替卡韦药用盐及其制备方法、药物组合物和应用

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1694657A1 (en) * 2003-12-09 2006-08-30 Pfizer Inc. Compositions comprising an hiv protease inhibitor
CN1698623A (zh) * 2005-03-30 2005-11-23 美德（江西）生物科技有限公司 无结晶型态的抗乙肝病毒药物分散组合物及其药物制剂
US9408849B2 (en) * 2007-02-14 2016-08-09 Zhejiang Medicine Co., Ltd. Xinchang Pharmaceutical Factory Crystal entecavir, crystal entecavir formulation and methods for the preparation thereof
CN101787026A (zh) * 2010-01-08 2010-07-28 福建广生堂药业有限公司 无定型的恩替卡韦甲苯磺酸盐,及其制备方法和药物应用
CN106749250A (zh) * 2017-01-13 2017-05-31 信泰制药（苏州）有限公司 一种恩替卡韦中间体的晶型
CN107213136B (zh) * 2017-06-07 2021-06-01 广州帝奇医药技术有限公司 一种长效缓释药物制剂及其制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101245068A (zh) * 2007-02-14 2008-08-20 浙江医药股份有限公司新昌制药厂 结晶型态的恩替卡韦及其制备方法和其药物组合物及用途
CN105722503A (zh) * 2013-08-06 2016-06-29 东国制药株式会社 恩替卡韦微球及包含其的非口服给药用药学组合物
CN105001223A (zh) * 2015-06-30 2015-10-28 湖南三清药业有限公司 一种恩替卡韦晶体化合物及其胶囊制剂
WO2022042641A1 (zh) * 2020-08-26 2022-03-03 上海博志研新药物技术有限公司 恩替卡韦药用盐及其制备方法、药物组合物和应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ZHANG CHUNYAN; WANG AIPING; WANG HUIYUN; YAN MAOCAI; LIANG RONGCAI; HE XIUTING; FU FENGHUA; MU HONGJIE; SUN KAOXIANG: "Entecavir-loaded poly (lactic-co-glycolic acid) microspheres for long-term therapy of chronic hepatitis-B: Preparation andin vitroandin vivoevaluation", INTERNATIONAL JOURNAL OF PHARMACEUTICS, ELSEVIER, NL, vol. 560, 1 January 1900 (1900-01-01), NL , pages 27 - 34, XP085630454, ISSN: 0378-5173, DOI: 10.1016/j.ijpharm.2019.01.052 *

Also Published As

Publication number Publication date
CN116650497A (zh) 2023-08-29

Similar Documents

Publication Publication Date Title
US20220087943A1 (en) Injectable sustained release composition and method of using the same for treating inflammation in joints and pain associated therewith
ES2968917T3 (es) Composición de risperidona de microesferas de liberación controlada
CN105232471A (zh) 含有无定形cddo-me的延迟释放口服组合物
EA011584B1 (ru) Микрокапсулы с замедленным высвобождением, основанные на сополимере лактида и гликолида, включающие полипептид и сахар
NO333301B1 (no) Farmasoytisk sammensetning som inneholder fenofibrat og fremgangsmate til fremstilling derav
MXPA04009385A (es) Microparticulas de drogas.
WO2019218409A1 (zh) 一种阿立哌唑缓释微球及其制备方法
WO2010118639A1 (zh) 氨氯地平微球制剂、其制备方法及应用
WO2017036389A1 (zh) 卡格列净与药用辅料的组合物及其制备方法
WO2017107906A1 (zh) 一种艾塞那肽微球制剂及其制备方法
CN113413372A (zh) 一种基于阿立哌唑微晶凝聚体的长效可注射微球及其制备方法
WO2020119698A1 (zh) 一种维拉佐酮固体分散体及其制备方法
WO2024083026A1 (zh) 一种卢美哌隆药物组合物、长效微球缓释制剂及其制备方法
WO2024066765A1 (zh) 一种抗病毒药物组合物及其制备工艺与应用
CN110787130B (zh) 一种18β-甘草次酸固体分散体及其制备方法
CN116459220A (zh) 昔萘酸普拉克索缓释微球及其制备方法与应用
Lu et al. Novel Colon-Specific Microspheres With Highly Dispersed Hydroxycamptothecin Cores: Their Preparation, ReleaseBehavior, and Therapeutic Efficiency Against Colonic Cancer
Zhu et al. A biodegradable long-term contraceptive implant with steady levonorgestrel release based on PLGA microspheres embedded in PCL-coated implant
CN114681406B (zh) 一种卡利拉嗪长效缓释微球及其制备方法
CN115124532B (zh) 大黄酸与苦参碱共晶物及制备方法和其组合物与用途
CN1861054A (zh) 一种含舒铂等铂类化合物的复方抗癌缓释剂
Liu et al. Preparation of Polylactic Acid/Glycolic Acid Copolymer Nanoparticles and Its Effect in the Treatment of Diabetes
CN117530933B (zh) 一种吡仑帕奈长效缓释微球、制备方法及缓释注射剂
WO2024187537A1 (zh) 昔萘酸普拉克索缓释微球及其制备方法与应用
CN113402463B (zh) 一种塞来昔布微晶、负载塞来昔布微晶的温敏性凝胶及其制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23870011

Country of ref document: EP

Kind code of ref document: A1