WO2023221816A1 - 普拉克索长效缓释制剂及其制备方法 - Google Patents

普拉克索长效缓释制剂及其制备方法 Download PDF

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WO2023221816A1
WO2023221816A1 PCT/CN2023/092984 CN2023092984W WO2023221816A1 WO 2023221816 A1 WO2023221816 A1 WO 2023221816A1 CN 2023092984 W CN2023092984 W CN 2023092984W WO 2023221816 A1 WO2023221816 A1 WO 2023221816A1
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pramipexole
oil phase
release
long
microspheres
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WO2023221816A9 (zh
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苏正兴
丁多浩
陈志浩
赵栋
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四川科伦药物研究院有限公司
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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and specifically relates to a long-acting sustained-release preparation of pramipexole and a preparation method thereof.
  • Pramipexole is a second-generation, potent, selective non-ergoline dopamine D2 receptor agonist, used to treat primary Parkinson's disease and can cover the entire stage of disease treatment until the late stages. It can significantly improve the motor symptoms of patients with early and late Parkinson's disease, and can also improve the depressive symptoms associated with Parkinson's disease. Pramipexole is the drug of choice recommended by domestic and foreign Parkinson's disease treatment guidelines. The pramipexole hydrochloride tablets currently on the market require taking the medicine three times a day, and the dosing frequency is high. Parkinson's disease patients are often accompanied by clinical symptoms such as memory loss, trembling hands and feet, and difficulty swallowing.
  • sustained-release preparations can avoid the first-pass effect, improve bioavailability, extend the administration period, and reduce the frequency of administration, which greatly reduces the occurrence of the above-mentioned poor compliance and brings tangible clinical benefits to patients.
  • Degradable polymers polylactic acid-co-glycolic acid (PLGA) and polylactic acid (PLA) have excellent biocompatibility and have been certified by the U.S. Food and Drug Administration and included in the United States Pharmacopeia as pharmaceutical excipients.
  • Suitable sustained-release carriers for pramipexole Long-acting sustained-release preparations encapsulated in PLGA (or PLA), including microspheres, in-situ gels, etc., can be administered from 1 week to 6 months.
  • Pramipexole is a nucleophile with certain nucleophilic ability. It provides electrons during the preparation process of microspheres and acts as a Lewis base, causing the degradation of polymer materials. Because this type of degradation often occurs under unconscious and uncontrolled conditions, the degradation of PLGA is irregular and uncontrollable. When the molecular weight of PLGA (weight average molecular weight Mw, the same below) shows a regular overall decrease, it will cause the viscosity of the oil phase to decrease, thus affecting the particle size, drug loading and release cycle of the final product.
  • the molecular weight of PLGA decreases non-overall, which is manifested in the increase of molecular weight distribution (PDI), the production of oligomers and oligomers, and the increase of monomer residues, which will affect the batch-to-batch stability of the product ( Equivalent to the deterioration of process stability), the production of process impurities (produced by the reaction between API and monomers or oligomers), and at the same time, the increase in oligomers, oligomers and monomers affects the density and appearance of the microsphere structure. Porosity, thereby affecting the encapsulation rate and burst release of the product.
  • microsphere products do not control the degradation of polymer materials during the preparation process.
  • risperidone microspheres use higher molecular weight polymer materials during preparation, and then prepare microspheres when they degrade to the required molecular weight. .
  • This method cannot control the degradation of polymer materials, and can only prepare microspheres when they degrade to a suitable molecular weight. This is neither economical nor reliable, and is a last resort when the mechanism is not clear.
  • One purpose of the present invention is to develop pramipexole sustained-release drugs with stable drug release and long sustained-release period; another purpose is to control the compatibility of pramipexole and excipients to improve product quality.
  • a first aspect of the present invention provides a long-acting sustained-release preparation of pramipexole, which includes pramipexole pamoate or pramipexole palmitate, and polylactic acid-glycolic acid copolymer or polylactic acid, said
  • the drug loading amount of the preparation is 10% to 55%, preferably 10% to 50%, more preferably 15% to 45%; the molar ratio of lactic acid to glycolic acid of the polylactic acid-glycolic acid copolymer is 85:15-95: 5.
  • the molecular weight of the polylactic acid-glycolic acid copolymer is 10,000 Da to 100,000 Da; the molecular weight of the polylactic acid is 10,000 Da to 100,000 Da.
  • the molar ratio of pamoic acid to pramipexole in pramipexole pamoate is 1:2 or 1:1.
  • the molar ratio of palmitic acid to pramipexole in pramipexole palmitate is 1:1.
  • the dosage form of the long-acting sustained-release preparation of pramipexole is selected from microspheres, long-acting sustained-release microparticles or subcutaneous implants.
  • the dosage form of the long-acting sustained-release preparation of pramipexole is microspheres, and its drug loading capacity is 15-45%; preferably 30-45%, more preferably 35-40% .
  • the dosage form of the long-acting sustained-release preparation of pramipexole is long-acting sustained-release microparticles or subcutaneous implants, and its drug loading capacity is 15-55%, preferably 30-55% , more preferably 40-55%.
  • a second aspect of the present invention provides a method for preparing pramipexole microspheres, which includes the following steps:
  • Preparing the oil phase Dissolve pramipexole pamoate or pramipexole palmitate in the first solvent to obtain the first oil phase, and dissolve polylactic acid-glycolic acid copolymer or polylactic acid in the second solvent to obtain the second oil phase. oil phase, and then mixing the first oil phase and the second oil phase to obtain an oil phase;
  • the oil phase and the water phase are mixed and emulsified by high-speed shearing; the emulsified microspheres are solidified and the solvent is evaporated, washed with water, and freeze-dried.
  • the first solvent is selected from dimethyl sulfoxide, methanol, ethanol, Isopropyl alcohol, tert-butyl alcohol or N,N-dimethylformamide, preferably dimethyl sulfoxide or methanol;
  • the second solvent is selected from dichloromethane, chloroform or ethyl acetate, preferably dichloromethane.
  • the weight ratio of pramipexole pamoate or pramipexole palmitate to polylactic acid-glycolic acid copolymer or polylactic acid is 1:1 to 1:5, preferably 1:1 to 1:3.
  • the weight-to-volume ratio (g/mL) of pramipexole pamoate or pramipexole palmitate to the first solvent is 1:1 to 1:10, preferably 1 :3 to 1:8.
  • the weight to volume ratio (g/mL) of polylactic acid-glycolic acid copolymer or polylactic acid to the second solvent is 1:1 to 1:10, preferably 1:2 to 1:8.
  • the first oil phase and the second oil phase are mixed and stirred at a temperature of ⁇ 25°C, preferably ⁇ 10°C, more preferably ⁇ 4°C, and the stirring time is ⁇ 10 h. , preferably ⁇ 2h, more preferably ⁇ 1h, more preferably ⁇ 0.5h.
  • a third aspect of the present invention provides a method for preparing pramipexole subcutaneous implants or long-acting sustained-release microparticles, which includes the following steps: combining pramipexole pamoate or pramipexole palmitate with polylactic acid-hydroxyl
  • the acetic acid copolymer or polylactic acid is crushed and mixed, and hot melt extrusion is used.
  • the extruded product is drawn and drawn into a short rod to obtain the pramipexole subcutaneous implant; the extruded product is drawn and drawn.
  • Use a granulator to granulate, and then crush it to the target particle size to obtain pramipexole long-acting sustained-release granules.
  • the weight ratio of pramipexole pamoate or pramipexole palmitate to polylactic acid-glycolic acid copolymer or polylactic acid is 5:1 to 1:1, preferably 3:1 to 1:1.
  • the extrusion temperature of hot melt extrusion is 30-200°C, preferably 40-160°C, and more preferably 80-120°C.
  • the present invention has the following beneficial effects:
  • the microspheres of the present invention have a round shape, smooth surface and no pores, which can effectively reduce the early burst release of drugs and solve the problem of high burst release of existing pramipexole pamoate microspheres; at the same time, they can effectively extend the sustained release cycle and solve the problem of high burst release of pramipexole pamoate microspheres.
  • the existing pramipexole pamoate microspheres have the problem of short release cycle, and the blood concentration fluctuation is smaller and the release is more stable.
  • the raw and auxiliary materials are prepared separately and then the obtained oil phase is mixed.
  • the auxiliary materials are controlled during the preparation process.
  • the degradation rate can control the production of oligomers and oligomers during the degradation process of excipients, thereby improving the batch-to-batch stability of the product and reducing the production of process impurities.
  • Figure 1 is an SEM image of pramipexole microspheres in Example 3.
  • Figures 2-1 and 2-2 are respectively the blood concentration curves of the early stage (within 24 hours) and the entire release cycle in rats after a single administration of pramipexole microspheres in Example 3.
  • Figures 3-1 and 3-2 are respectively the blood concentration curves of the early stage (within 24 hours) and the entire release cycle in rats after a single administration of pramipexole microspheres in Example 4.
  • Figures 4-1 and 4-2 respectively show the plasma concentration curves of the early stage (within 24 hours) and the entire release cycle in rats after a single administration of pramipexole microspheres in Comparative Example 1.
  • Figures 5-1 and 5-2 respectively show the plasma concentration curves of the pramipexole microspheres in Comparative Example 2 at the initial stage (within 24 hours) and throughout the release cycle in rats after a single administration.
  • Figure 6 is a blood drug concentration curve in rats after a single administration of the pramipexole subcutaneous implant of Example 5.
  • Figure 7 is a fitting curve of plasma concentration of pramipexole microspheres in Example 3 for multiple administrations using Phoenix WinNonlin software.
  • Figure 8 is a fitting curve of plasma concentration of pramipexole microspheres for multiple administrations using Phoenix WinNonlin software in Example 4.
  • Figure 9 shows the plasma concentration fitting curve of Comparative Example 1 pramipexole microspheres for multiple administrations using Phoenix WinNonlin software.
  • Figure 10 shows the plasma concentration fitting curve of Comparative Example 2 pramipexole microspheres for multiple administrations using Phoenix WinNonlin software.
  • the molar ratio of pamoic acid to pramipexole is 1:2; in the “pramipexole palmitate” mentioned in the examples ", the molar ratio of palmitic acid to pramipexole is 1:1.
  • Particle size detection Take an appropriate amount of microsphere powder, disperse it with pure water, and use a Master sizer 3000 laser particle size analyzer to measure the particle size of the microspheres.
  • Detection or calculation of drug loading First use acetonitrile or dimethyl sulfoxide to destroy the sustained-release preparation (such as microspheres, long-acting sustained-release particles or subcutaneous implants) to release pramipexole into the solution, and then dissolve the PLGA with water Precipitate, centrifuge and measure the content of pramipexole in the supernatant, and calculate the drug loading capacity based on the mass ratio of the active ingredient of pramipexole salt to the sustained-release preparation (such as microspheres, long-acting sustained-release particles or subcutaneous implants).
  • sustained-release preparation such as microspheres, long-acting sustained-release particles or subcutaneous implants
  • Encapsulation rate drug loading ⁇ theoretical drug loading ⁇ 100%.
  • solvent residual solvent mass ⁇ overall microsphere mass ⁇ 100%.
  • Viscosity measurement Use a rotational viscometer (Brookfield DV2T) to measure the dissolved oil phase, select a No. 40 rotor, accurately measure 500 ⁇ l, and measure the viscosity (cp) of the oil phase after standing for different times at 20°C and 4.0 rpm.
  • Brookfield DV2T Brookfield DV2T
  • Molecular weight determination Use gel chromatography (GPC) method, use dichloromethane as the mobile phase, connect three Aglient PLgel (5 ⁇ m, 300mm*7.5mm) chromatographic columns at a flow rate of 1mL/min, and the injection volume is 100 ⁇ l, detect PLGA or PLA The weight average molecular weight (Mw).
  • GPC gel chromatography
  • PLGA 7525 3A is abbreviated as 7525 3A, where "7525” indicates that the LA:GA block ratio is 75:25, and “3” indicates that the intrinsic viscosity (IV) of the product is 0.3dL/g. Left and right, "A” indicates carboxyl end capping.
  • PLA 2A means PLA, IV is about 0.2dL/g, carboxyl-terminated.
  • the mixing temperature is preferably ⁇ 25°C, more preferably ⁇ 10°C, and more preferably ⁇ 4°C. Dissolving pramipexole and PLGA separately and then mixing them can reduce the mixing time of pramipexole and PLGA, and can also achieve the purpose of inhibiting the degradation of PLGA during the preparation process of the oil phase.
  • 5g PLGA 5050 4.5A was dissolved in a mixed solvent of methanol and dichloromethane (15mL, 25mL) as the oil phase.
  • a mixed solvent of methanol and dichloromethane 15mL, 25mL
  • the speed of the high-speed shear 1000 rpm
  • use a syringe to inject the oil phase into the water phase (1L) at 5 mL/min for shear emulsification.
  • the microsphere suspension is mechanically stirred and solidified at a rate of 300 rpm for 4 hours.
  • the microspheres are collected and rinsed with 1 L of deionized water. After freeze-drying, powdered microspheres are obtained (recorded as microsphere sample 1).
  • microspheres prepared by mixing pramipexole and PLGA and then dissolving in a solvent to obtain an oil phase have severe degradation of the polymer material, resulting in a smaller viscosity of the oil phase and a smaller particle size of the microspheres, including The closure rate is very low.
  • Microspheres are prepared by dissolving pramipexole and PLGA in solvents and then mixing them to obtain an oil phase. The molecular weight of the polymer material decreases very little, and the microspheres have high drug loading capacity and encapsulation rate.
  • pramipexole pamoate (the molar ratio of pamoate and pramipexole is 1:2) was dissolved in 17.5mL DMSO as the first oil phase; 6g PLGA (8515, 5A) was dissolved in 17.5mL DMSO. Methyl chloride, as the second oil phase. The first oil phase and the second oil phase were stirred and mixed at a temperature of 4°C for 0.5 h to form the oil phase.
  • Freeze-drying Dry the microspheres with a freeze-dryer or three-in-one drying to get the finished product.
  • pramipexole pamoate (the molar ratio of pamoate and pramipexole is 1:2) is dissolved in 17.5mL DMSO as the first oil phase; 6g PLA 2A is dissolved in 17.5mL methylene chloride , as the second oil phase.
  • the first oil phase and the second oil phase were stirred and mixed at a temperature of 4°C for 0.5 h to form the oil phase.
  • Freeze-drying Dry the microspheres with a freeze-dryer or three-in-one drying to get the finished product.
  • pramipexole pamoate the molar ratio of pamoate and pramipexole is 1:2
  • PLA 5A the molar ratio of pamoate and pramipexole is 1:2
  • the extruded material is drawn and drawn into A short rod of 3 ⁇ 30mm is then irradiated and sterilized at 8kGy to obtain a pramipexole subcutaneous implant.
  • Hot melt extrusion parameters Use Thermo Fisher Pharma 11 and parallel counter-rotating twin screws, turn on the hot melt extruder, set the feed temperature: room temperature, push temperature: 35 ⁇ 40°C, mixing temperature: 80 ⁇ 100°C, degassing Temperature: 100°C, extrusion temperature: 80°C, die temperature: 60°C. Pressure: 60bar, extrusion speed: 100rpm, torque: 7 ⁇ 8N.cm.
  • Example 5 The extrudate of Example 5 is pulled and drawn, granulated with a pelletizer, and then pulverized to particles with a particle size of 60-100 ⁇ m, and then irradiated and sterilized under 8 kGy conditions to obtain pramipexole long-acting sustained-release granules. .
  • pramipexole pamoate (the molar ratio of pamoate and pramipexole is 1:2) is dissolved in 17.5mL DMSO as the first oil phase; 6g PLGA (5050, 4.5A) is dissolved in 17.5mL Dichloromethane, as the second oil phase.
  • the first oil phase and the second oil phase were stirred and mixed at a temperature of 4°C for 0.5 h to form the oil phase.
  • Freeze-drying Dry the microspheres with a freeze-dryer or three-in-one drying to get the finished product.
  • pramipexole pamoate (the molar ratio of pamoate and pramipexole is 1:2) was dissolved in 17.5mL DMSO as the first oil phase; 6g PLGA (7525, 5A) was dissolved in 17.5mL DMSO. Methyl chloride, as the second oil phase. Put the first oil The first phase and the second oil phase were stirred and mixed at a temperature of 4°C for 0.5 h to form the oil phase.
  • Freeze-drying Dry the microspheres with a freeze-dryer or three-in-one drying to get the finished product.
  • burst release AUC 0-24 ⁇ AUC 0-last * 100%; According to the method described in Test Example 2, the samples of Examples 3-6 and Comparative Examples 1-2 were tested.
  • Samples of Examples 3-5 and Comparative Examples 1-2 and solid oral formulations were selected for animal experiments. Screen 25 male rats with a body weight of about 250g and randomly group them into groups of 5. Mix the sample with the solvent (0.5% CMC-Na, 0.1% Tween-20, 0.9% NaCl) evenly, and give 4mg via intramuscular injection. /kg drug, administered only once. Venous blood was collected before and after administration, and the concentration of pramipexole in plasma after administration was measured.
  • Example 3-4 is significantly lower than that of Comparative Example 1-2.
  • the present invention improves the ratio of LA in PLGA (LA:GA ⁇ 85:15) can effectively reduce the early burst release of drugs and solve the problem of high burst release of existing pramipexole pamoate microspheres.
  • Example 3-4 can effectively prolong the sustained release of the preparation compared with Comparative Example 1-2. cycle, indicating that the present invention can effectively extend the sustained release cycle by increasing the LA ratio in PLGA (LA:GA ⁇ 85:15) and solve the problem of short release cycle of existing pramipexole pamoate microspheres.
  • the pramipexole pamoate subcutaneous implant prepared in Example 5 can be administered every 3 months, with low burst release and stable drug release.
  • microspheres of the present invention have a longer administration period, smaller fluctuations in blood concentration, and more stable release.

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Abstract

一种普拉克索长效缓释制剂及其制备方法，所述的普拉克索长效缓释制剂，包括双羟萘酸普拉克索或棕榈酸普拉克索，和聚乳酸-羟基乙酸共聚物或聚乳酸，所述的制剂载药量为10％～50％，所述的聚乳酸-羟基乙酸共聚物的乳酸与羟基乙酸的摩尔比为85：15～95：5。该微球形态圆整，表面光滑，无孔隙，可有效降低药物早期突释，解决现有双羟萘酸普拉克索微球突释高的问题；同时可有效延长缓释周期，解决现有双羟萘酸普拉克索微球释放周期短的问题，并且血药浓度波动更小，释放更平稳。

Description

普拉克索长效缓释制剂及其制备方法 发明领域
本发明属于药物制剂领域，具体涉及一种普拉克索长效缓释制剂及其制备方法。
发明背景
相关研究表明，帕金森类疾病(简称PD)在60岁以上人群的患病率为1.37％，而随着中国人口老龄化程度增加，庞大PD患者群体的护理与治疗将是社会民生不可忽略的问题。
普拉克索是第二代强效、选择性非麦角碱多巴胺D2受体激动剂，用于治疗原发性帕金森病，并且可以覆盖疾病治疗的整个阶段直至晚期。其可以显著改善早期及晚期帕金森病患者的运动症状，还可改善帕金森病患者伴发的抑郁症状。普拉克索是国内外帕金森病治疗指南推荐的首选药物。而目前市场上的盐酸普拉克索片剂，一日需要三次服药，给药频率高，而帕金森病患者常常伴随记忆力减退、手脚颤抖、吞咽困难等临床症状。因此患者漏服现象普遍发生，这导致病情恶化，甚至发生呛咳、窒息，危及生命。采用长效缓释制剂可以避免首过效应，提升生物利用度，并且延长给药周期、降低给药频率，极大的减少了上述依从性差的情况发生，为患者带来切实的临床获益。
可降解高分子聚乳酸-羟基乙酸共聚物(PLGA)和聚乳酸(PLA)因为具有优良的生物相容性，已通过美国食品药品监督管理局的认证，作为药用辅料收录进美国药典，是合适的普拉克索缓释载体。由PLGA(或PLA)包载的长效缓释制剂，包括微球、原位凝胶等，可实现1周～6个月给药。然而，现有的PLGA缓释制剂往往面临突释高、释药不稳定(血药浓度波动大)的挑战，其血药浓度波动度(PTF)甚至超过口服制剂，不符合我国对于制剂创新减毒增效的基本要求。因此，开发释药平稳且缓释周期长(一周及以上)的普拉克索/PLGA或PLA缓释药物对于PD的治疗具有重要意义，其在临床中也有巨大的应用前景。
普拉克索是具有一定亲核能力的亲核试剂，其在微球制备过程中提供电子，呈路易斯碱，造成高分子材料的降解。因为这类降解往往是在无意识的不受控的条件下发生，所以PLGA的降解不规律且不可控。当PLGA分子量(重均分子量Mw，下同)呈现规律性的整体下降会造成油相粘度的下降，从而影响终产品的粒径、载药量和释放周期。而更多的情况是PLGA分子量非整体下降，具体表现为分子量分布(PDI)增大，低聚物和寡聚体的产生，单体残留的增加，这会影响到产品的批间稳定性(相当于工艺稳定性变差)、工艺杂质的产生(API与单体或寡聚体反应产生)，同时由于低聚物、寡聚体和单体的增加影响微球结构的致密性和表观孔隙率，从而影响产品的包封率和突释情况。
现有的微球产品在制备过程中都没有控制高分子材料的降解，例如：利培酮微球，在制备时选用较高分子量的聚合物材料，降解到需要的分子量时再制备成微球。运用此方法不能控制高分子材料降解，只能在降解到合适分子量时制备微球，这样既不经济又不可靠，是在未明确机理情况下的不得已手段。
发明概述
本发明的一个目的是开发释药平稳且缓释周期长的普拉克索缓释药物；另一个目的是控制普拉克索与辅料相容性，提高产品质量。
本发明的第一方面，提供一种普拉克索长效缓释制剂，其包括双羟萘酸普拉克索或棕榈酸普拉克索，和聚乳酸-羟基乙酸共聚物或聚乳酸，所述的制剂载药量为10％～55％，优选为10％～50％，更优选为15％～45％；聚乳酸-羟基乙酸共聚物的乳酸与羟基乙酸的摩尔比为85：15～95：5。
在本发明第一方面的一些实施方案中，聚乳酸-羟基乙酸共聚物的分子量为10000Da～100000Da；聚乳酸的分子量为10000Da～100000Da。
在本发明第一方面的一些实施方案中，双羟萘酸普拉克索中双羟萘酸与普拉克索的摩尔比为1:2或1:1。
在本发明第一方面的一些实施方案中，棕榈酸普拉克索中棕榈酸与普拉克索的摩尔比为1:1。
在本发明第一方面的一些实施方案中，普拉克索长效缓释制剂的剂型选自微球、长效缓释微粒或皮下植入剂。
在本发明第一方面的一些实施方案中，普拉克索长效缓释制剂的剂型为微球，其载药量为15-45％；优选为30-45％，更优选为35-40％。
在本发明第一方面的一些实施方案中，普拉克索长效缓释制剂的剂型为长效缓释微粒或皮下植入剂，其载药量为15-55％，优选为30-55％，更优选为40-55％。
本发明的第二方面，提供一种普拉克索微球的制备方法，其包括以下步骤：
制备油相：将双羟萘酸普拉克索或棕榈酸普拉克索溶于第一溶剂中得到第一油相，将聚乳酸-羟基乙酸共聚物或聚乳酸溶于第二溶剂中得到第二油相，然后将第一油相和第二油相混合得到油相；
制备聚乙烯醇水溶液作为水相；
将油相与水相混合，高速剪切乳化；将乳化后的微球固化和挥发溶剂，水洗，冻干。
在本发明第二方面的一些实施方案中，所述的第一溶剂选自二甲基亚砜、甲醇、乙醇、 异丙醇、叔丁醇或N,N-二甲基甲酰胺，优选为二甲基亚砜或甲醇；第二溶剂选自二氯甲烷、氯仿或乙酸乙酯，优选为二氯甲烷。
在本发明第二方面的一些实施方案中，双羟萘酸普拉克索或棕榈酸普拉克索与聚乳酸-羟基乙酸共聚物或聚乳酸的重量比为1:1至1:5，优选为1:1至1:3。
在本发明第二方面的一些实施方案中，双羟萘酸普拉克索或棕榈酸普拉克索与第一溶剂的重量体积比(g/mL)为1:1至1:10，优选为1:3至1:8。
在本发明第二方面的一些实施方案中，聚乳酸-羟基乙酸共聚物或聚乳酸与第二溶剂的重量体积比(g/mL)为1:1至1:10，优选为1:2至1:8。
在本发明第二方面的一些实施方案中，第一油相与第二油相混合是在温度≤25℃、优选≤10℃、更优选≤4℃的条件下混合搅拌，搅拌的时间≤10h、优选≤2h、更优选≤1h、更优选≤0.5h。
本发明的第三方面，提供一种普拉克索皮下植入剂或长效缓释微粒的制备方法，包括以下步骤：将双羟萘酸普拉克索或棕榈酸普拉克索与聚乳酸-羟基乙酸共聚物或聚乳酸粉碎后混合，采用热熔挤出，挤出后的挤出物牵引拉丝成短棒即得普拉克索皮下植入剂；将上述挤出后的挤出物牵引拉丝、用切粒机造粒，然后粉碎至目标粒径即得普拉克索长效缓释颗粒。
在本发明第三方面的一些实施方案中，双羟萘酸普拉克索或棕榈酸普拉克索与聚乳酸-羟基乙酸共聚物或聚乳酸的重量比为5:1至1:1，优选为3:1至1:1。
在本发明第三方面的一些实施方案中，热熔挤出的挤出温度为30～200℃，优选为40～160℃，更优选为80-120℃。
与现有技术相比，本发明具有以下的有益效果：
本发明的微球形态圆整，表面光滑，无孔隙，可有效降低药物早期突释，解决现有双羟萘酸普拉克索微球突释高的问题；同时可有效延长缓释周期，解决现有双羟萘酸普拉克索微球释放周期短的问题，并且血药浓度波动更小，释放更平稳。
本发明的微球制备方法中，将原辅料单独配制而后混合所获得的油相，通过控制原辅料的混合时间；控制油相的混合的温度以及选择辅料型号等手段，控制辅料在配制过程中的降解率，控制辅料降解过程中低聚物和寡聚体的产生，从而提高产品的批间稳定性、降低工艺杂质的产生。
附图简要说明
图1为实施例3的普拉克索微球的SEM图。
图2-1和图2-2分别为实施例3的普拉克索微球单次给药后大鼠体内初期(24h内)和整个释放周期的血药浓度曲线。
图3-1和图3-2分别为实施例4的普拉克索微球单次给药后大鼠体内初期(24h内)和整个释放周期的血药浓度曲线。
图4-1和图4-2分别为对比例1的普拉克索微球单次给药后大鼠体内初期(24h内)和整个释放周期的血药浓度曲线。
图5-1和图5-2分别为对比例2的普拉克索微球单次给药后大鼠体内初期(24h内)和整个释放周期的血药浓度曲线。
图6为实施例5的普拉克索皮下植入剂单次给药后大鼠体内的血药浓度曲线。
图7为实施例3普拉克索微球使用Phoenix WinNonlin软件进行多次给药的血药浓度拟合曲线。
图8为实施例4普拉克索微球使用Phoenix WinNonlin软件进行多次给药的血药浓度拟合曲线。
图9为对比例1普拉克索微球使用Phoenix WinNonlin软件进行多次给药的血药浓度拟合曲线。
图10为对比例2普拉克索微球使用Phoenix WinNonlin软件进行多次给药的血药浓度拟合曲线。
发明详述
以下通过具体实施方式，对本发明的上述内容做进一步的详细说明。但不应该将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术方案均属于本发明的范围。除非另外具体说明，否则以下实施例中的检测可依照《中华人民共和国药典》(2020年版)中描述的方法进行。
除非另外明确说明，实施例中提到的“双羟萘酸普拉克索”中，双羟萘酸与普拉克索的摩尔比为1:2；实施例中提到的“棕榈酸普拉克索”中，棕榈酸与普拉克索的摩尔比为1:1。
粒径检测：取适量微球粉末，用纯水分散，采用Master sizer 3000激光粒度仪测得微球粒径。
载药量检测或计算：先用乙腈或二甲基亚砜破坏缓释制剂(例如微球、长效缓释微粒或皮下植入剂)，使普拉克索释放至溶液中，再用水将PLGA析出，离心测定上清液中普拉克索的含量，以普拉克索盐活性成分与缓释制剂(例如微球、长效缓释微粒或皮下植入剂)质量比例计算载药量。
包封率的计算：包封率＝载药量÷理论载药量×100％。
溶剂残留的计算：溶剂残留＝溶剂质量÷整体微球质量×100％。
粘度测定：将溶解好的油相用旋转粘度计(Brookfield DV2T)，选用40号转子，精密量取500μl，在20℃、4.0rpm下检测静置不同时间后油相粘度(cp)。
分子量测定：使用凝胶色谱(GPC)法，以二氯甲烷为流动相，1mL/min的流速连接三根Aglient PLgel(5μm，300mm*7.5mm)色谱柱，进样量为100μl，检测PLGA或PLA的重均分子量(Mw)。
如本发明中所涉及高分子材料，例如PLGA 7525 3A简写为7525 3A，其中“7525”表示LA:GA嵌段比例为75:25，“3”表示产品特性粘度(IV)为0.3dL/g左右，“A”表示羧基封端。PLA 2A表示PLA，IV为0.2dL/g左右，羧基封端。
实施例1
2g双羟萘酸普拉克索和5g PLGA(7525 3A)混合均匀。在25℃下，溶于甲醇和二氯甲烷(15mL，25mL)的混合溶剂中，继续搅拌0.5h混合均匀(记作油相样品①)。
2.2g棕榈酸普拉克索和5g PLGA(7525 3A)混合均匀。在25℃下，溶于甲醇和二氯甲烷(15mL，25mL)的混合溶剂中，继续搅拌0.5h混合均匀(记作油相样品②)。
2.2g棕榈酸普拉克索和5g PLGA(7525 3A)混合均匀。在10℃下，溶于甲醇和二氯甲烷(15mL，25mL)的混合溶剂中，继续搅拌0.5h混合均匀(记作油相样品③)。
2.2g棕榈酸普拉克索和5g PLGA(7525 3A)混合均匀。在4℃下，溶于甲醇和二氯甲烷(15mL，25mL)的混合溶剂中，继续搅拌0.5h混合均匀(记作油相样品④)。
2.2g棕榈酸普拉克索溶于15mL甲醇中，作为第一油相；5g PLGA(7525 3A)溶于25mL二氯甲烷中，作为第二油相。在25℃下，将第一油相和第二油相搅拌0.5h，混合均匀(记作油相样品⑤)。
2.2g棕榈酸普拉克索溶于15mL甲醇中，作为第一油相；5g PLGA(7525 3A)溶于25mL二氯甲烷中，作为第二油相。在25℃下，将第一油相和第二油相搅拌1h，混合均匀(记作油相样品⑥)。
2.2g棕榈酸普拉克索溶于15mL甲醇中，作为第一油相；5g PLGA(7525 3A)溶于25mL二氯甲烷中，作为第二油相。在25℃下，将第一油相和第二油相搅拌2h，混合均匀(记作油相样品⑦)。
2.2g棕榈酸普拉克索溶于15mL甲醇中，作为第一油相；5g PLGA(5050，4.5A)溶于25mL二氯甲烷中，作为第二油相。在25℃下，将第一油相和第二油相搅拌0.5h，混合均匀(记作油相样品⑧)。
2.2g棕榈酸普拉克索溶于15mL甲醇中，作为第一油相；5g PLGA(8515，4A)溶于25mL二氯甲烷中，作为第二油相。在25℃下，将第一油相和第二油相搅拌0.5h，混合均匀(记作油相样品⑨)。
2.2g棕榈酸普拉克索溶于15mL甲醇中，作为第一油相；5g PLA(2A)溶于25mL二氯甲烷中，作为第二油相。在25℃下，将第一油相和第二油相搅拌0.5h，混合均匀(记作油相样品⑩)。
检测上述油相样品①-⑩静置不同时间后的PLGA或PLA的重均分子量(Mw)，结果见下表。
从上表可知，减少PLGA中GA比例，降低普拉克索与PLGA的混合温度和减少混合时间都可改善油相中PLGA分子量的下降。优选混合温度≤25℃，更优选≤10℃，更优选≤4℃。将普拉克索与PLGA分别溶解后再混合，可减少普拉克索与PLGA的混合时间，也可以达到在油相制备过程中抑制PLGA降解的目的。
实施例2
将30g聚乙烯醇溶解于3L纯化水中制备成水相，备用。
5g PLGA(5050 4.5A)溶于甲醇和二氯甲烷混合溶剂(15mL，25mL)中，作为油相。25℃下，调节高速剪切机转速至1000rpm，用注射器将油相以5mL/min注入水相(1L)中剪切乳化。乳化结束后，将微球混悬液以300rpm的速率机械搅拌固化4h，收集微球并用1L去离子水冲洗，冷冻干燥后得到粉末状微球(记作微球样品①)。
2.2g棕榈酸普拉克索和5g PLGA(5050 4.5A)混合后溶于甲醇和二氯甲烷混合溶剂(15mL，25mL)中，作为油相。25℃时，调节高速剪切机转速至1000rpm，用注射器将油相以5mL/min注入水相(1L)中剪切乳化。乳化结束后，将微球混悬液以300rpm的速率机械搅拌固化4h，收集微球并用1L去离子水冲洗，冷冻干燥后得到粉末状微球(记作微球样品②)。
2.2g棕榈酸普拉克索溶于15mL甲醇中，作为第一油相；5g PLGA(5050 4.5A)溶于25mL二氯甲烷中，作为第二油相，在4℃下将第一油相和第二油相搅拌0.5h，混合均匀作为油相。低温4℃条件下，调节高速剪切机转速至1000rpm，注射器将油相以5mL/min注入水相(1L) 中剪切乳化。乳化结束后，将微球混悬液以300rpm的速率机械搅拌挥发溶剂并固化4h，收集微球并用1L去离子水冲洗，冷冻干燥后得到粉末状微球(记作微球样品③)。
上述微球样品①-③的粒径、载药量、包封率和PLGA分子量的检测结果见下表：
从上表可知，采用普拉克索与PLGA混合后溶于溶剂得到油相的方法制备的微球，高分子材料的降解严重，从而导致油相粘度变小，微球的粒径减小，包封率很低。采用普拉克索与PLGA分别溶于溶剂后混合得到油相的方法制备的微球，高分子材料分子量降低很少，微球载药量和包封率高。
实施例3
4.0g双羟萘酸普拉克索(双羟萘酸根与普拉克索的摩尔比为1:2)溶解于17.5mL DMSO，作为第一油相；6g PLGA(8515，5A)溶解于17.5mL二氯甲烷，作为第二油相。将第一油相和第二油相在温度为4℃下搅拌混合0.5h时间，作为油相。
30g PVA加入到3L水中溶解，作为水相。
在剪切机转速为8000rpm的条件下将油相和水相加入混合剪切乳化。然后将乳化后的微球溶液在温度4℃的条件下搅拌固化1小时，恒速升温至25℃，再固化2小时，挥发溶液中的溶剂。
收集：将固化好的微球经筛网筛分，筛选出所需微球，并用纯化水洗涤2～3遍。
冻干：将微球用冻干机干燥或三合一干燥，即可得到成品。
对所制备得到的微球进行扫描电子显微镜检测，所得图片如图1所示。
实施例4
4.0g双羟萘酸普拉克索(双羟萘酸根与普拉克索的摩尔比为1:2)溶解于17.5mL DMSO中，作为第一油相；6g PLA 2A溶解于17.5mL二氯甲烷中，作为第二油相。将第一油相和第二油相在温度为4℃下搅拌混合0.5h时间，作为油相。
30g PVA加入到3L水中溶解，作为水相。
在剪切机转速为8000rpm的条件下将油相和水相加入混合剪切乳化。然后将乳化后的微球溶液在温度4℃的条件下搅拌固化1小时，恒速升温至25℃，再固化2小时，挥发溶液中的溶剂。
收集：将固化好的微球经筛网筛分，筛选出所需微球，并用纯化水洗涤2～3遍。
冻干：将微球用冻干机干燥或三合一干燥，即可得到成品。
实施例5
40g双羟萘酸普拉克索(双羟萘酸根与普拉克索的摩尔比为1:2)和25g PLA 5A粉碎，混匀后采用热熔挤出，挤出后的挤出物牵引拉丝成3×30mm的短棒，然后在8kGy的条件下辐照灭菌，即得普拉克索皮下植入剂。
热熔挤出参数：选用Thermo Fisher Pharma 11和平行逆向双螺杆，开启热熔挤出机，设置进料温度：室温，推进温度：35～40℃，混炼温度：80～100℃，脱气温度：100℃，挤出温度：80℃，模口温度：60℃。压力：60bar，挤出速度：100rpm，扭矩：7～8N.cm。
实施例6
将实施例5的挤出物牵引拉丝，用切粒机造粒，然后粉碎至60-100μm粒径的颗粒，然后在8kGy的条件下辐照灭菌，即得普拉克索长效缓释颗粒。
对比例1
4.0g双羟萘酸普拉克索(双羟萘酸根与普拉克索的摩尔比为1:2)溶解于17.5mL DMSO，作为第一油相；6g PLGA(5050，4.5A)溶解于17.5mL二氯甲烷，作为第二油相。将第一油相和第二油相在温度为4℃下搅拌混合0.5h时间，作为油相。
30g PVA加入到3L水中溶解，作为水相。
在剪切机转速为8000rpm的条件下将油相和水相加入混合剪切乳化。然后将乳化后的微球溶液在温度4℃的条件下搅拌固化1小时，恒速升温至25℃，再固化2小时，挥发溶液中的溶剂。
收集：将固化好的微球经筛网筛分，筛选出所需微球，并用纯化水洗涤2～3遍。
冻干：将微球用冻干机干燥或三合一干燥，即可得到成品。
对比例2
4.0g双羟萘酸普拉克索(双羟萘酸根与普拉克索的摩尔比为1:2)溶解于17.5mL DMSO，作为第一油相；6g PLGA(7525，5A)溶解于17.5mL二氯甲烷，作为第二油相。将第一油 相和第二油相在温度为4℃下搅拌混合0.5h时间，作为油相。
30g PVA加入到3L水中溶解，作为水相。
在剪切机转速为8000rpm的条件下将油相和水相加入混合剪切乳化。然后将乳化后的微球溶液在温度4℃的条件下搅拌固化1小时，恒速升温至25℃，再固化2小时，挥发溶液中的溶剂。
收集：将固化好的微球经筛网筛分，筛选出所需微球。
冻干：将微球用冻干机干燥或三合一干燥，即可得到成品。
试验例1
对实施例3-4和对比例1-2的普拉克索微球、实施例5的普拉克索皮下植入剂和实施例6的普拉克索长效缓释颗粒的载药量、包封率、粒径、突释、溶剂残留和分子量等进行检测，其结果见下表。
注1：将给药后动物体内24h内的释放率定义为突释，即24h的暴露量占全周期暴露量的比例，其计算公式为：突释＝AUC0-24÷AUC0-last*100％；依据试验例2中描述的方法，对实施例3-6和对比例1-2的样品进行测试。
试验例2
选择实施例3-5和对比例1-2以及固体口服制剂(盐酸普拉克索片剂)的样品进行动物实验。筛选体重在250g左右雄性大鼠25只，随机分组，每组5只，将样品与溶媒(0.5％CMC-Na，0.1％吐温-20，0.9％NaCl)混合均匀，分别经肌肉注射给予4mg/kg药物，仅给药一次。分别于给药前和给药后静脉采血，测定给药后血浆中普拉克索浓度。
结合附图2-1、3-1、4-1和5-1可知，实施例3-4的突释较对比例1-2有明显降低，本发明通过提高PLGA中LA比例(LA:GA≥85:15)可有效降低药物早期突释，解决现有双羟萘酸普拉克索微球突释高的问题。
同时结合附图2-2、3-2、4-2和5-2可知，实施例3-4较对比例1-2可有效延长制剂缓释 周期，表明本发明通过提高PLGA中LA比例(LA:GA≥85:15)可有效延长缓释周期，解决现有双羟萘酸普拉克索微球释放周期短的问题。
从图6可知，实施例5制备得双羟萘酸普拉克索皮下植入剂可以实现每隔3个月给药，突释较低且释药平稳。
根据单周期给药血药浓度曲线，使用Phoenix WinNonlin[2]软件进行多次给药的拟合，用于评价上述实施例3-4和对比例1-2在体内达到稳态后血药浓度的波动，结果见下表和图7-10。
注[2]：Phoenix WinNonlin是分析药代动力学和药效动力学数据的行业标准，适用于非临床和临床PK/PD研究的分析平台从早期非临床研究到大型临床试验。
结合上表及图7-10可知，本发明的微球给药周期更长，血药浓度波动更小，释放更平稳。
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式，便于具体和详细地理解本发明的技术方案，但并不能因此而理解为对发明专利保护范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。应当理解，本领域技术人员在本发明提供的技术方案的基础上，通过合乎逻辑的分析、推理或者有限的试验得到的技术方案，均在本发明所附权利要求的保护范围内。因此，本发明专利的保护范围应以所附权利要求的内容为准，说明书可以用于解释权利要求的内容。

Claims (9)

  1. 一种普拉克索长效缓释制剂，其特征在于，包括双羟萘酸普拉克索或棕榈酸普拉克索，和聚乳酸-羟基乙酸共聚物或聚乳酸，所述的制剂载药量为10％～55％，优选为10％～50％，更优选为15％～45％；聚乳酸-羟基乙酸共聚物的乳酸与羟基乙酸的摩尔比为85：15～95：5。
  2. 权利要求1所述的普拉克索长效缓释制剂，其特征在于，聚乳酸-羟基乙酸共聚物的分子量为10000Da～100000Da；聚乳酸的分子量为10000Da～100000Da。
  3. 权利要求1或2所述的普拉克索长效缓释制剂，其特征在于，双羟萘酸普拉克索中双羟萘酸与普拉克索的摩尔比为1:2或1:1。
  4. 权利要求1至3任一项所述的普拉克索长效缓释制剂，其特征在于，普拉克索长效缓释制剂的剂型选自微球、长效缓释微粒或皮下植入剂。
  5. 一种普拉克索微球的制备方法，其特征在于，包括以下步骤：
    制备油相：将双羟萘酸普拉克索或棕榈酸普拉克索溶于第一溶剂中得到第一油相，将聚乳酸-羟基乙酸共聚物或聚乳酸溶于第二溶剂中得到第二油相，然后将第一油相和第二油相混合得到油相；
    制备聚乙烯醇水溶液作为水相；
    将油相与水相混合，高速剪切乳化；将乳化后的微球固化和挥发溶剂，水洗，冻干。
  6. 权利要求5所述的普拉克索微球的制备方法，其特征在于，所述的第一溶剂选自二甲基亚砜、甲醇、乙醇、异丙醇、叔丁醇或N,N-二甲基甲酰胺，优选为二甲基亚砜或甲醇；第二溶剂选自二氯甲烷、氯仿或乙酸乙酯，优选为二氯甲烷。
  7. 权利要求5或6所述的普拉克索微球的制备方法，其特征在于，第一油相与第二油相混合是在温度≤25℃、优选≤10℃、更优选≤4℃的条件下混合搅拌，搅拌的时间≤10h、优选≤2h、更优选≤1h、更优选≤0.5h。
  8. 一种普拉克索皮下植入剂或长效缓释微粒的制备方法，其特征在于，包括以下步骤：将双羟萘酸普拉克索或棕榈酸普拉克索与聚乳酸-羟基乙酸共聚物或聚乳酸粉碎后混合，采用热熔挤出，挤出后的挤出物牵引拉丝成短棒即得普拉克索皮下植入剂；将上述挤出后的挤出物牵引拉丝、用切粒机造粒，然后粉碎至目标粒径即得普拉克索长效缓释颗粒。
  9. 权利要求8所述普拉克索皮下植入剂或长效缓释微粒的制备方法，其特征在于，热熔挤出的挤出温度为30～200℃，优选为40～160℃，更优选为80-120℃。
PCT/CN2023/092984 2022-05-16 2023-05-09 普拉克索长效缓释制剂及其制备方法 WO2023221816A1 (zh)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103271890A (zh) * 2013-06-26 2013-09-04 北京华睿鼎信科技有限公司 盐酸普拉克索胶囊及其制备方法
CN108685858A (zh) * 2017-04-08 2018-10-23 沈阳药科大学 一种注射用普拉克索缓释制剂及其制备方法
CN108992408A (zh) * 2017-11-11 2018-12-14 刘丽 一种盐酸普拉克索缓释制剂的制备方法
CN110090203A (zh) * 2019-04-29 2019-08-06 南京锐利施生物技术有限公司 一种近红外响应型的载普拉克索的可降解微球制剂
CN111728956A (zh) * 2020-07-06 2020-10-02 济南大学 一种普拉克索缓释微球及其制备方法
CN115260119A (zh) * 2022-07-26 2022-11-01 山东京卫制药有限公司 一种普拉克索昔萘酸盐及其药物缓释制剂

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103271890A (zh) * 2013-06-26 2013-09-04 北京华睿鼎信科技有限公司 盐酸普拉克索胶囊及其制备方法
CN108685858A (zh) * 2017-04-08 2018-10-23 沈阳药科大学 一种注射用普拉克索缓释制剂及其制备方法
CN108992408A (zh) * 2017-11-11 2018-12-14 刘丽 一种盐酸普拉克索缓释制剂的制备方法
CN110090203A (zh) * 2019-04-29 2019-08-06 南京锐利施生物技术有限公司 一种近红外响应型的载普拉克索的可降解微球制剂
CN111728956A (zh) * 2020-07-06 2020-10-02 济南大学 一种普拉克索缓释微球及其制备方法
CN115260119A (zh) * 2022-07-26 2022-11-01 山东京卫制药有限公司 一种普拉克索昔萘酸盐及其药物缓释制剂

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