CN114762690A - Compound preparation - Google Patents

Abstract

A compound preparation comprises a first active ingredient and a second active ingredient, wherein the weight component of the antiparasitic compound preparation is 100, the weight component of the first active ingredient in the compound preparation is 5-95, and the weight component of the second active ingredient in the compound preparation is 5-95. The first active ingredient in the compound preparation is the antiparasitic drug praziquantel, and the second active ingredient is niclosamide or oxfendazole. The preparation method of the compound preparation is simple, has good stability and is easy to popularize.

Description

Translated fromChinese

复方制剂compound

技术领域technical field

本发明涉及一种抗寄生虫药物，具体涉及一种注射在动物体内用于防治成虫及/或幼虫的寄生虫的复方制剂。The invention relates to an antiparasitic drug, in particular to a compound preparation injected into an animal for preventing and treating adult and/or larval parasites.

背景技术Background technique

血吸虫病是一种危害严重的人畜共患寄生虫病，全球累计约2亿人感染血吸虫病，大部分集中在非洲，7.8亿人存在血吸虫病感染风险，每年就有 20万人死于该病。在我国流行的是日本血吸虫病，其中牛是主要传染源，对日本血吸虫感染的贡献率高达90％，为此阻断传染源-牛感染血吸虫病，则可有效防止血吸虫病。目前执行的“以机代牛”政策取得了很好的防控效果，但从成本-效益分析以及现场的实施来看，还存在可改进之处。Schistosomiasis is a serious zoonotic parasitic disease. About 200 million people worldwide are infected with schistosomiasis, most of which are concentrated in Africa. 780 million people are at risk of schistosomiasis infection, and 200,000 people die of the disease every year. . Schistosomiasis japonica is prevalent in my country, and cattle are the main source of infection, contributing up to 90% of the infection rate of schistosomiasis japonica. For this reason, blocking the source of infection - bovine infection with schistosomiasis can effectively prevent schistosomiasis. The currently implemented policy of "replacing cattle with machines" has achieved good prevention and control effects, but from the perspective of cost-benefit analysis and on-site implementation, there is still room for improvement.

目前现场用于防治血吸虫的一线药物只有吡喹酮，对成虫具有很好的治疗效果,但由于其代谢很快，无法应用于长期预防。氯硝柳胺对尾蚴具有很强的杀灭作用。本课题组应用新的缓释技术，制备氯硝柳胺长效注射剂，应用对象为牛等家畜，直接作用于传染源，只需一次给药，操作简便，节省药物使用量和人力物力；采用皮下注射，不见光，药物稳定不易分解；制备工艺简单，只需将处方中物质混匀即可，有利于现场防治工作的进行。现场试验表明，一次给药，可以预防牛感染血吸虫病4-6个月。但氯硝柳胺长效注射剂只能预防，但对血吸虫成虫效果很差。为此，本项目结合两种抗血吸虫药物的优势，制备复方缓释剂型，用于现场血吸虫病防控。Praziquantel is the only first-line drug used in the field to control schistosomiasis, which has a good therapeutic effect on adults. However, due to its rapid metabolism, it cannot be used for long-term prevention. Niclosamide has a strong killing effect on cercariae. This research group applied the new sustained-release technology to prepare niclosamide long-acting injection, which is applied to cattle and other livestock, directly acting on the source of infection, requiring only one administration, simple operation, saving the amount of drug usage and manpower and material resources; Subcutaneous injection, no light is visible, the drug is stable and not easy to decompose; the preparation process is simple, only need to mix the substances in the prescription, which is conducive to the on-site prevention and treatment work. Field trials have shown that a single administration can prevent schistosomiasis infection in cattle for 4-6 months. However, niclosamide long-acting injection can only prevent, but the effect on adult schistosomes is very poor. To this end, this project combines the advantages of two anti-schistosomiasis drugs to prepare compound sustained-release formulations for on-site schistosomiasis prevention and control.

包虫病(棘球蚴病)是一种严重危害人类健康和畜牧业发展的人兽共患病。囊型包虫病广泛分布于除南极洲以外的各大洲。据估计，包虫病的全球疾病负担(Global burdenof disease，GBD)为2×10⁷至5×10⁷伤残调整生命年(Disability-adjusted life year，DALY)，而囊型棘球蚴病相关的治疗费用及牲畜业损失每年约为20亿美元。所以，防治包虫病药物在国际市场的需求十分可观。据报道，抗绦虫、吸虫药物的需求超过1/3的市场，而开发新的犬用吡喹酮剂型以及包虫病诊断用试剂可达到每年8亿元的销售额，1.2亿元的利润，保障流行区0.66亿人的安全和5000万头以上的家畜，挽回经济损失约30亿元。Hydatid disease (echinococcosis) is a zoonotic disease that seriously endangers human health and the development of animal husbandry. Cystic hydatid disease is widespread on all continents except Antarctica. The estimated global burden of disease (GBD) for hydatid disease ranges from 2 × 10⁷ to 5 × 10⁷ disability-adjusted life years (DALYs), while cystic echinococcosis is associated with Treatment costs and losses to the livestock industry are approximately $2 billion per year. Therefore, the demand for hydatid control drugs in the international market is considerable. According to reports, the demand for anti-taenia and fluke drugs exceeds 1/3 of the market, and the development of new formulations of praziquantel for dogs and diagnostic reagents for hydatid disease can achieve an annual sales of 800 million yuan and a profit of 120 million yuan. The safety of 66 million people and more than 50 million livestock in endemic areas will be guaranteed, and economic losses of about 3 billion yuan will be recovered.

吡喹酮对控制包虫病具有里程碑意义，不但疗效理想，而且至今未在犬和猫中有抗药性报道。犬作为包虫病的传染源，降低其对棘球蚴原头节的感染可以有效地预防和控制棘球绦虫在疫区的传播。因此，目前采取“犬犬投药，月月驱虫”的方法，给犬每月喂食吡喹酮片剂是整个疫区控制包虫病的重要措施之一。但是，在实施过程中，由于当地人游牧的生活习性，无法做到对每只犬每个月都给药，野犬的给药就更难以实施，这样控制传染源降低疫区包虫病的传播水平难以实现。亟待发明新的缓释技术，起到给药1次可维持数月的防控效果，这样不需月月投药即可以对犬只达到数月的保护效果。Praziquantel is a milestone in the control of hydatid disease, not only the curative effect is ideal, but no drug resistance has been reported in dogs and cats so far. As the source of infection of hydatid disease in dogs, reducing the infection of Echinococcus Protocephalus can effectively prevent and control the spread of Echinococcus in endemic areas. Therefore, at present, the method of "dosing for dogs and dogs, deworming every month" and feeding praziquantel tablets to dogs every month is one of the important measures to control hydatid disease in the whole epidemic area. However, in the implementation process, due to the nomadic living habits of the local people, it is impossible to administer medicine to every dog every month, and it is even more difficult to implement the administration of wild dogs, so as to control the source of infection and reduce the spread of hydatid disease in the epidemic area level is difficult to achieve. There is an urgent need to invent a new sustained-release technology, which can achieve the prevention and control effect that can be maintained for several months after one administration, so that the protection effect for dogs can be achieved for several months without the need for monthly administration.

吡喹酮无论对成熟或未成熟的细粒棘球绦虫均作用显着，但研究发现吡喹酮对棘球绦虫的包囊期作用有限或完全没有作用，而且对其虫卵也无杀灭作用。奥芬达唑是一种新型的高效、广谱、低毒的苯并咪唑氨基甲酸酯类抗蠕虫药物。治疗小鼠实验性泡球蚴病有较好的治疗效果,尤其是轻、中度感染小鼠泡球蚴病效果更隹,可使囊泡缩小,症状减轻,治疗小鼠泡球蚴病效果明显优于阿苯达唑。Praziquantel has a significant effect on both mature and immature Echinococcus granulosus, but studies have found that praziquantel has limited or no effect on the cystic stage of Echinococcus granulosus, and does not kill its eggs. effect. Ofendazole is a novel high-efficiency, broad-spectrum, low-toxicity benzimidazole carbamate antihelminthic drug. It has a good therapeutic effect in the treatment of experimental alveolar disease in mice, especially in mice with mild and moderate infection, which can shrink the vesicles and relieve symptoms. Significantly better than albendazole.

发明内容SUMMARY OF THE INVENTION

根据现有技术的缺陷，本发明主要的目的在于提供一种复方制剂，该复方制剂为缓释剂型，可以对多种抗血吸虫的成虫及/或幼虫有良好的治疗效果。According to the defects of the prior art, the main purpose of the present invention is to provide a compound preparation, which is in a sustained-release dosage form and can have a good therapeutic effect on a variety of adults and/or larvae against schistosomiasis.

本发明的另一目的在于提供一种复方制剂，透过缓释剂型的复方制剂给药一次就能维持长期的防控及治疗效果，能够保护动物在感染季节甚至更长的时间不受病原侵染，进一步的可以控制寄生虫病传播，阻断动物传播寄生虫的传播链。Another object of the present invention is to provide a compound preparation, which can maintain long-term control and treatment effects through one administration of the compound preparation in a sustained-release dosage form, and can protect animals from pathogens during the infection season or even longer. It can further control the spread of parasitic diseases and block the transmission chain of animal-borne parasites.

根据上述目的，本发明披露一种复方制剂，包括有第一活性成分、第二活性成分，其中以抗寄生虫复方制剂的重量组分为100，第一活性成分占复方制剂的重量组分为5～95及第二活性成分占复方制剂的重量组分为5～95。According to the above purpose, the present invention discloses a compound preparation, comprising a first active ingredient and a second active ingredient, wherein the weight component of the antiparasitic compound preparation is 100, and the weight component of the first active ingredient in the compound preparation is 5-95 and the second active ingredient accounts for 5-95 of the weight component of the compound preparation.

在本发明较优选的实施例中，第一活性成分为吡喹酮。In a more preferred embodiment of the present invention, the first active ingredient is praziquantel.

在本发明较优选的实施例中，第二活性成分为氯硝柳胺或奥芬达唑。In a more preferred embodiment of the present invention, the second active ingredient is niclosamide or ofendazole.

在本发明较优选的实施例中，复方制剂进一步还包括生物可降解高分子材料、分散介质及增溶剂，且生物可降解高分子材料占复方制剂的重量组分为14.7～45.5、分散介质占复方制剂的重量组分为0～79.4及增溶剂占复方制剂的重量组分为0～45.5。In a more preferred embodiment of the present invention, the compound preparation further includes a biodegradable polymer material, a dispersion medium and a solubilizer, and the biodegradable polymer material accounts for 14.7-45.5% of the weight component of the compound preparation, and the dispersion medium accounts for 14.7-45.5%. The weight component of the compound preparation is 0-79.4 and the solubilizer accounts for 0-45.5 of the weight component of the compound preparation.

在本发明较优选的实施例中，生物可降解高分子材料为聚乳酸-羟基乙酸共聚物、聚己内酯或是泊洛沙姆407。In a more preferred embodiment of the present invention, the biodegradable polymer material is polylactic acid-glycolic acid copolymer, polycaprolactone or poloxamer 407.

在本发明较优选的实施例中,分散介质可以是N-甲基吡咯烷酮或聚乙二醇400。In a more preferred embodiment of the present invention, the dispersion medium can be N-methylpyrrolidone or polyethylene glycol 400.

在本发明较优选的实施例中,增溶剂可以是聚维酮(聚乙烯吡咯烷酮 (PVP))、吐温80或聚乙二醇6000。In a more preferred embodiment of the present invention, the solubilizer can be povidone (polyvinylpyrrolidone (PVP)), Tween 80 or polyethylene glycol 6000.

在本发明较优选的实施例中,复方制剂进一步还包含去离子水，且去离子水占复方制剂的重量组分为58.8～69.0。In a more preferred embodiment of the present invention, the compound preparation further comprises deionized water, and deionized water accounts for 58.8-69.0 of the weight component of the compound preparation.

本发明还披露复方制剂在制备用于抗寄生虫的药物中的用途；其中，所述寄生虫包括寄生虫的成虫和/或幼虫。The invention also discloses the use of the compound preparation in the preparation of a medicine for anti-parasitic; wherein, the parasite includes adult and/or larvae of the parasite.

因此本发明的复方制剂可充分发挥两种抗血吸虫药物的优势，只给药1 次，可维持数月的防控效果，本发明的复方制剂可制备长效注射剂，应用对象为牛等家畜，操作简便，节省药物使用量和人力物力。Therefore, the compound preparation of the present invention can give full play to the advantages of the two anti-schistosomiasis drugs, and it can be administered only once, and the control effect can be maintained for several months. The operation is simple and convenient, and the consumption of drugs and manpower and material resources are saved.

附图说明：Description of drawings:

图1为本发明复方制剂14的奥芬达唑及吡喹酮的体外累计溶出度图。Fig. 1 is a graph showing the cumulative in vitro dissolution rates of orfendazole and praziquantel of compound preparation 14 of the present invention.

具体实施方式Detailed ways

为了使本发明的目的、技术特征及优点，能更为相关技术领域人员所了解，并得以实施本发明，具体阐明本发明的技术特征与实施方式，并列举较佳实施例进一步说明。而关于本案实施方式的说明中涉及本领域技术人员所熟知的技术内容，亦不再加以陈述。In order to make the purpose, technical features and advantages of the present invention more understandable to those in the relevant technical field and to implement the present invention, the technical features and embodiments of the present invention are specifically explained, and preferred embodiments are given for further explanation. The description about the embodiments of the present application involves technical contents well known to those skilled in the art, and will not be described again.

本发明披露了一种复方制剂，特别是一种具有缓释剂型的复方制剂，此复方制剂可以同时预防寄生虫的成虫及幼虫，且由于缓释的功能，此复方制剂可以只给药一次，但就可在体外缓释1天或数月，具有长时间的治疗且可以不受病原侵染的潜力。其中复方制剂包括有第一活性成分、第二活性成分，其中以复方制剂的重量组分为100，第一活性成分占复方制剂的重量组分为 5～95及第二活性成分占复方制剂的重量组分为5～95。在本发明的一实施例中，第一活性成份为吡喹酮、第二活性成分可以是氯硝柳胺或奥芬达唑。另外，在复方制剂中还包含有生物可降解高分子材料、分散介质及增溶剂，其中生物可降解高分子材料占复方制剂的重量组分为14.7～45.5、分散介质占复方制剂的重量组分为0～79.4及增溶剂占复方制剂的重量组分为0-45.5，其中生物可降解高分子材料可以是聚乳酸-羟基乙酸共聚物、聚己内酯、泊洛沙姆407、壳聚糖、聚三亚甲基碳酸酯、聚羟基乙酸、聚乳酸、聚羟基丁酸羟基戊酸共聚物、聚羟基丁酸酯、聚原酸酯和聚酸酐类化合物中的一种或多种及其衍生物，生物可降解高分子材料的重量平均分子量较佳地为10,000～150,000。生物可降解高分子材料的重量平均分子量可以根据不同的缓释时间进行选择，当需要药物缓释时间较长时，倾向于选择分子量较高的生物可降解高分子材料，如重量平均分子量为100,000～150,000；当药物缓释时间无需很长时，倾向于选择分子量较低的生物可降解高分子材料，如重量平均分子量为16,000。The invention discloses a compound preparation, especially a compound preparation with a sustained-release dosage form. The compound preparation can simultaneously prevent the adults and larvae of parasites, and due to the function of sustained release, the compound preparation can be administered only once, However, it can be released in vitro for one day or several months, and it has the potential for long-term treatment and no pathogenic infection. Wherein the compound preparation includes a first active ingredient and a second active ingredient, wherein the weight component of the compound preparation is 100, the first active ingredient accounts for 5-95% of the weight of the compound preparation, and the second active ingredient accounts for 100% of the compound preparation. The weight component is 5-95. In an embodiment of the present invention, the first active ingredient is praziquantel, and the second active ingredient may be niclosamide or ofendazole. In addition, the compound preparation also includes a biodegradable polymer material, a dispersion medium and a solubilizer, wherein the biodegradable polymer material accounts for 14.7-45.5% of the weight component of the compound preparation, and the dispersion medium accounts for 14.7-45.5% of the weight component of the compound preparation. It is 0-79.4 and the solubilizer accounts for 0-45.5 of the weight component of the compound preparation, wherein the biodegradable polymer material can be polylactic acid-glycolic acid copolymer, polycaprolactone, poloxamer 407, chitosan , one or more of polytrimethylene carbonate, polyglycolic acid, polylactic acid, polyhydroxybutyric acid-hydroxyvaleric acid copolymer, polyhydroxybutyrate, polyorthoester and polyanhydride compounds and their derivatives The weight average molecular weight of the biodegradable polymer material is preferably 10,000-150,000. The weight-average molecular weight of the biodegradable polymer material can be selected according to different sustained release times. When the sustained release time of the drug is required to be longer, the biodegradable polymer material with a higher molecular weight tends to be selected. For example, the weight average molecular weight is 100,000. ~150,000; when the sustained release time of the drug does not need to be very long, the biodegradable polymer material with lower molecular weight tends to be selected, such as the weight average molecular weight of 16,000.

分散介质可以是N-甲基吡咯烷酮或聚乙二醇400，当采用聚乙二醇作为分散剂时，通常选择分子量较低的聚乙二醇，如聚乙二醇200或聚乙二醇400。The dispersion medium can be N-methylpyrrolidone or polyethylene glycol 400. When polyethylene glycol is used as a dispersant, a polyethylene glycol with a lower molecular weight is usually selected, such aspolyethylene glycol 200 or polyethylene glycol 400. .

增溶剂可以是聚维酮(聚乙烯吡咯烷酮(PVP))、吐温80或聚乙二醇6000。另外，本发明的复方制剂还包含有去离子水，其中去离子水占复方制剂的重量组分为58.8～69.0。The solubilizer can be povidone (polyvinylpyrrolidone (PVP)),Tween 80 or polyethylene glycol 6000. In addition, the compound preparation of the present invention also contains deionized water, wherein the weight component of the compound preparation is 58.8-69.0 of the deionized water.

以下是本发明针对具有缓释剂型的复方制剂的制备实施例的具体说明。The following is a specific description of the preparation examples of the present invention for the compound preparation with sustained-release dosage form.

制备例一(复方制剂1)：Preparation example 1 (compound preparation 1):

将0.1g吡喹酮、0.1g氯硝柳胺、0.5g聚乳酸-羟基乙酸共聚物、0.2g 吐温80，溶于2mL N-甲基吡咯烷酮中，即得复方制剂1。Compound preparation 1 is obtained by dissolving 0.1 g of praziquantel, 0.1 g of niclosamide, 0.5 g of polylactic acid-glycolic acid copolymer, and 0.2 g ofTween 80 in 2 mL of N-methylpyrrolidone.

制备例二(复方制剂2)：Preparation example two (compound preparation 2):

将0.1g吡喹酮、0.1g氯硝柳胺、0.5g聚乳酸-羟基乙酸共聚物、0.2g 聚乙二醇400，溶于2mL N-甲基吡咯烷酮中，即得复方制剂2。Compound preparation 2 was obtained by dissolving 0.1 g of praziquantel, 0.1 g of niclosamide, 0.5 g of polylactic acid-glycolic acid copolymer, and 0.2 g of polyethylene glycol 400 in 2 mL of N-methylpyrrolidone.

制备例三(复方制剂3)：Preparation example three (compound preparation 3):

将0.5g泊洛沙姆407和0.2g吐温80低温(冰水浴)溶于2mL去离子水中以形成混合溶液，再将0.1g吡喹酮及0.1g氯硝柳胺加入上述混合溶液中并均匀混合，即得复方制剂3。Dissolve 0.5g poloxamer 407 and 0.2g Tween 80 low temperature (ice water bath) in 2mL deionized water to form a mixed solution, then add 0.1g praziquantel and 0.1g niclosamide to the above mixed solution and Mix uniformly to obtain compound preparation 3.

制备例四(复方制剂4)：Preparation example four (compound preparation 4):

将0.5g泊洛沙姆407和0.2g聚乙二醇400低温(冰水浴)溶于2mL去离子水中以形成混合溶液，再将0.1g吡喹酮及0.1g氯硝柳胺加入上述混合溶液中并均匀混合，即得复方制剂4。Dissolve 0.5g poloxamer 407 and 0.2g polyethylene glycol 400 in 2mL deionized water at low temperature (ice water bath) to form a mixed solution, then add 0.1g praziquantel and 0.1g niclosamide to the above mixed solution and uniformly mixed to obtain compound preparation 4.

制备例五(复方制剂5)：Preparation example five (compound preparation 5):

将1g泊洛沙姆407溶于4mL去离子水中，低温(冰水浴)搅拌溶解，再加入重量百分比14.2％的氯硝柳胺热溶液1.4mL(溶剂为N-甲基吡咯烷酮)，继续加入0.2g吡喹酮均匀混合，即得复方制剂5。Dissolve 1 g of poloxamer 407 in 4 mL of deionized water, stir and dissolve at low temperature (ice-water bath), add 1.4 mL of a 14.2% niclosamide hot solution by weight (solvent is N-methylpyrrolidone), and continue to add 0.2 Mix g praziquantel evenly to obtain compound preparation 5.

制备例六(复方制剂6)：Preparation example six (compound preparation 6):

将0.1g吡喹酮、0.1g奥芬达唑、0.5g聚乳酸-羟基乙酸共聚物、0.2g 聚乙二醇400溶于2mL N-甲基吡咯烷酮中，即得复方制剂6。Compound preparation 6 was obtained by dissolving 0.1 g of praziquantel, 0.1 g of orendazole, 0.5 g of polylactic acid-glycolic acid copolymer, and 0.2 g of polyethylene glycol 400 in 2 mL of N-methylpyrrolidone.

制备例七(复方制剂7)：Preparation example seven (compound preparation 7):

将1g泊洛沙姆407溶于4mL去离子水中，搅拌中加入重量百分比16.6％的奥芬达唑溶液1.2mL(溶剂为N-甲基吡咯烷酮，于N-甲基吡咯烷酮溶剂内含有0.1g聚维酮)，继续加入0.2g吡喹酮均匀混合，即得复方制剂7。Dissolve 1 g of poloxamer 407 in 4 mL of deionized water, add 1.2 mL of a 16.6% by weight solution of orfendazole (solvent is N-methylpyrrolidone, and contain 0.1 g of polyamide in the N-methylpyrrolidone solvent) while stirring. Vidone), continue to add 0.2 g of praziquantel and evenly mix to obtain compound preparation 7.

制备例八(复方制剂8)：Preparation example eight (compound preparation 8):

将1g泊洛沙姆407溶于4mL去离子水中，搅拌中加入重量百分比16.6％的奥芬达唑溶液1.2mL(溶剂为N-甲基吡咯烷酮，于N-甲基吡咯烷酮溶剂内含有0.05g聚维酮)，继续加入0.2g吡喹酮均匀混合，即得复方制剂8。Dissolve 1 g of poloxamer 407 in 4 mL of deionized water, add 1.2 mL of a 16.6% by weight solution of orfendazole (the solvent is N-methylpyrrolidone, and the N-methylpyrrolidone solvent contains 0.05 g of poly) Vidone), continue to add 0.2 g of praziquantel and evenly mix to obtain compound preparation 8.

制备例九(复方制剂9)：Preparation example nine (compound preparation 9):

将1g泊洛沙姆407溶于4mL去离子水中，搅拌中加入重量百分比16.6％的奥芬达唑溶液1.2mL(溶剂为N-甲基吡咯烷酮)，继续加入0.2g吡喹酮均匀混合，即得复方制剂9。Dissolve 1 g of poloxamer 407 in 4 mL of deionized water, add 1.2 mL of 16.6% by weight of orfendazole solution (solvent is N-methylpyrrolidone) during stirring, and continue to add 0.2 g of praziquantel to mix evenly, namely Compound preparation 9 was obtained.

制备例十(复方制剂10)：Preparation example ten (compound preparation 10):

将0.1g吡喹酮与1g聚己内酯加热熔融混匀，置于-80度冰箱冷却30分钟后，再置于干燥器中干燥至少24小时以得到第一中间物。将此第一中间物，颗粒较大的固体分散体经过研钵研磨，过60目筛，将过筛后通过筛子的粉末收集以得到第一粉末。另外，将0.1g氯硝柳胺与1g聚乙二醇6000加热熔融混匀，置于-80℃冰箱冷却30分钟后，再置于干燥器中干燥至少24小时以得到第二中间物，将此第二中间物经由研钵研磨，并且过60目筛将过筛后通过筛子的粉末收集以得到第二粉末。将第一粉末与第二粉末以重量比1：1的比例混合均匀，即得复方制剂10。0.1 g of praziquantel and 1 g of polycaprolactone are heated, melted and mixed, placed in a -80 degree refrigerator to cool for 30 minutes, and then placed in a desiccator to dry for at least 24 hours to obtain the first intermediate. The first intermediate, the solid dispersion with larger particles, was ground in a mortar, passed through a 60-mesh sieve, and the powder passed through the sieve after being sieved was collected to obtain a first powder. In addition, 0.1 g of niclosamide and 1 g of polyethylene glycol 6000 were heated, melted and mixed, placed in a -80°C refrigerator to cool for 30 minutes, and then placed in a desiccator to dry for at least 24 hours to obtain the second intermediate. This second intermediate was ground through a mortar, and the sieved powder was collected through a 60 mesh sieve to obtain a second powder. The first powder and the second powder are uniformly mixed at a weight ratio of 1:1 to obtain the compound preparation 10 .

制备例十一(复方制剂11)：Preparation example eleven (compound preparation 11):

将0.1g吡喹酮与1g泊洛沙姆407加热熔融混匀，置于-80度冰箱冷却 30分钟后，再置于干燥器中干燥至少24小时以得到第一中间物。将此第一中间物，颗粒较大的固体分散体经过研钵研磨，过60目筛，将过筛后通过筛子的粉末收集以得到第一粉末。另外，将0.1g氯硝柳胺与1g聚乙二醇6000 加热熔融混匀，置于-80℃冰箱冷却30分钟后，再置于干燥器中干燥至少24 小时以得到第二中间物，将此第二中间物经由研钵研磨，并且过60目筛，将过筛后通过筛子的粉末收集以得到第二粉末。将第一粉末与第二粉末以重量比1：1混合均匀，即得复方制剂11。0.1 g of praziquantel and 1 g of poloxamer 407 were heated, melted and mixed, placed in a -80 degree refrigerator to cool for 30 minutes, and then placed in a desiccator to dry for at least 24 hours to obtain the first intermediate. The first intermediate, the solid dispersion with larger particles, was ground in a mortar, passed through a 60-mesh sieve, and the powder passed through the sieve after being sieved was collected to obtain a first powder. In addition, 0.1 g of niclosamide and 1 g of polyethylene glycol 6000 were heated, melted and mixed, placed in a -80°C refrigerator to cool for 30 minutes, and then placed in a desiccator to dry for at least 24 hours to obtain the second intermediate. This second intermediate was ground through a mortar and passed through a 60 mesh screen, and the powder passed through the screen was collected to obtain a second powder. The first powder and the second powder are uniformly mixed at a weight ratio of 1:1 to obtain compound preparation 11.

制备例十二(复方制剂12)：Preparation Example Twelve (Compound Preparation 12):

将0.1g吡喹酮与1g聚己内酯加热熔融混匀，置于-80度冰箱冷却30分钟后，置于干燥器中干燥至少24小时以得到第一中间物，将此第一中间物，颗粒较大的固体分散体经过研钵研磨，过60目筛，将过筛后通过筛子的粉末收集以得到第一粉末。另外，将0.1g奥芬达唑与1g聚乙二醇6000加热熔融混匀，置于-80℃冰箱冷却30分钟后，再置于干燥器中干燥至少24小时以得到第二中间物，将此第二中间物经由研钵研磨，过60目筛，将过筛后通过筛子的粉末收集以得到第二粉末。将第一粉末与第二粉末以重量比1：1比例混合均匀，即得复方制剂12。0.1g of praziquantel and 1g of polycaprolactone were heated, melted and mixed, placed in a -80 degree refrigerator to cool for 30 minutes, and dried in a desiccator for at least 24 hours to obtain the first intermediate. , the solid dispersion with larger particles is ground in a mortar and passed through a 60-mesh sieve, and the powder passing through the sieve after being sieved is collected to obtain the first powder. In addition, 0.1 g of ovendazole and 1 g of polyethylene glycol 6000 were heated, melted and mixed, placed in a -80°C refrigerator to cool for 30 minutes, and then placed in a desiccator to dry for at least 24 hours to obtain the second intermediate. This second intermediate was ground through a mortar and passed through a 60 mesh sieve, and the powder passed through the sieve was collected to obtain a second powder. The first powder and the second powder are uniformly mixed in a weight ratio of 1:1 to obtain the compound preparation 12 .

制备例十三(复方制剂13)：Preparation Example Thirteen (Compound Preparation 13):

将0.1g吡喹酮与1g泊洛沙姆407加热熔融混匀，置于-80度冰箱冷却 30分钟后，置于干燥器中干燥至少24小时以得到第一中间物，将此第一中间物，颗粒较大的固体分散体经过研钵研磨，过60目筛，将过筛后通过筛子的粉末收集以得到第一粉末。另外，将0.1g奥芬达唑与1g聚乙二醇6000 加热熔融混匀，置于-80℃冰箱冷却30分钟后，置于干燥器中干燥至少24 小时以得到第二中间物，将此第二中间物经由研钵研磨，过60目筛，将过筛后通过筛子的粉末收集以得到第二粉末。将第一粉末及第二粉末1：1比例混合均匀，即得复方制剂13。0.1 g of praziquantel and 1 g of poloxamer 407 were heated and melted and mixed, placed in a -80 degree refrigerator to cool for 30 minutes, and then placed in a desiccator to dry for at least 24 hours to obtain the first intermediate. The solid dispersion with larger particles is ground in a mortar and passed through a 60-mesh sieve, and the powder passing through the sieve after being sieved is collected to obtain the first powder. In addition, 0.1 g of offendazole and 1 g of polyethylene glycol 6000 were heated, melted and mixed, placed in a -80°C refrigerator to cool for 30 minutes, and then dried in a desiccator for at least 24 hours to obtain the second intermediate. The second intermediate was ground through a mortar and passed through a 60 mesh sieve, and the sieved powder passed through the sieve was collected to obtain a second powder. Mix the first powder and the second powder uniformly in a ratio of 1:1 to obtain compound preparation 13 .

制备例十四(复方制剂14)：Preparation Example Fourteen (Compound Preparation 14):

将1.0g的吡喹酮、1.0g的奥芬达唑、0.5g的聚乳酸-羟基乙酸共聚物(济南岱罡生物工程有限公司，分子量1.6万，PLGA 75：25)，分散于2mL的 N-甲基吡咯烷酮中，即得复方制剂14。Disperse 1.0 g of praziquantel, 1.0 g of orfendazole, and 0.5 g of polylactic acid-glycolic acid copolymer (Jinan Daigang Bioengineering Co., Ltd., molecular weight 16,000, PLGA 75:25) in 2 mL of N -Methylpyrrolidone, compound preparation 14 is obtained.

以上复方制剂1-14配比整理后列于表1。The above compound preparations 1-14 are listed in Table 1 after sorting.

表1Table 1

用上述复方制剂进行体外释放度研究。首先需制备体外释放度研究所需两种缓冲液，分别为0.5％吐温磷酸盐缓冲液(pH7.4)及0.5％SDS磷酸盐缓冲液(pH7.4)，其制备方法步骤如下：In vitro release studies were performed with the above compound formulations. Firstly, two kinds of buffers need to be prepared for in vitro release studies, namely 0.5% Tween phosphate buffer (pH7.4) and 0.5% SDS phosphate buffer (pH7.4). The preparation method steps are as follows:

取磷酸二氢钾1.36g，加入0.1mol/L氢氧化钠溶液79mL，用水稀释至 200mL，加入1g吐温80混匀，即得0.5％吐温磷酸盐缓冲液(pH7.4)。Take 1.36 g of potassium dihydrogen phosphate, add 79 mL of 0.1 mol/L sodium hydroxide solution, dilute to 200 mL with water, add 1 g ofTween 80 and mix to obtain 0.5% Tween phosphate buffer (pH 7.4).

取磷酸二氢钠二水合物1.56g，加入0.1mol/L氢氧化钠溶液79mL，用水稀释至200mL，加入1g SDS混匀，即得0.5％SDS磷酸盐缓冲液(pH7.4)。Take 1.56 g of sodium dihydrogen phosphate dihydrate, add 79 mL of 0.1 mol/L sodium hydroxide solution, dilute to 200 mL with water, add 1 g of SDS and mix to obtain 0.5% SDS phosphate buffer (pH 7.4).

在完成体外释放度研究所需缓冲液的制备后，以制备例进行体外释放度研究的步骤方法如下：After completing the preparation of the buffers required for the in vitro release study, the steps and methods for the in vitro release study with the preparation example are as follows:

复方制剂1至复方制剂5，每份取制剂0.2mL，加入50mL带塞EP管中，加入30mL0.5％吐温磷酸盐缓冲液(复方制剂3至复方制剂5置37℃放置5min 后再加入)。于37±1℃的恒温振荡仪中以150r/min的转速震荡，定时取样，取释放介质经0.22μm微孔滤膜过滤，取续滤液，分别于270nm和340nm 处测定OD值；按标准曲线计算计算释放介质中药物浓度，根据式(1)计算累积释放度。Compound preparation 1 to compound preparation 5, take 0.2 mL of each preparation, add it to a 50 mL EP tube with a stopper, add 30 mL of 0.5% Tween phosphate buffer (compound preparation 3 to compound preparation 5, and place it at 37°C for 5 minutes before adding ). Shake at 150r/min in a constant temperature oscillator at 37±1℃, take samples regularly, take the release medium and filter it through a 0.22μm microporous membrane, take the continuous filtrate, and measure the OD value at 270nm and 340nm respectively; according to the standard curve Calculate the drug concentration in the release medium, and calculate the cumulative release rate according to formula (1).

式(1)如下所示，其中，Rn表示第n天的累积释放度，R_n-1表示第n-1 天的累积释放度，C_n表示第n天的释放介质浓度。Formula (1) is shown below, wherein Rn represents the cumulative release degree on the nth day, Rn_-1 represents the cumulative release degree on the n-1th day, and_Cn represents the release medium concentration on the nth day.

复方制剂6至复方制剂9及复方制剂14，每份取制剂0.2mL，加入50mL 带塞EP管中，加入30mL0.5％SDS磷酸盐缓冲液(复方制剂7至复方制剂9 置37℃放置5分钟后再加入)。在37±1℃的恒温振荡仪中以150r/min的转速震荡，定时取样，取释放介质经0.22μm微孔滤膜过滤，取续滤液，分别于270nm和296nm处测定OD值；按标准曲线计算计算释放介质中药物浓度，根据式(1)计算累积释放度。复方制剂14的奥芬达唑及吡喹酮的体外累计溶出度参见图1所示。Compound preparation 6 to compound preparation 9 and compound preparation 14, take 0.2 mL of each preparation, add it to a 50 mL EP tube with a stopper, add 30 mL of 0.5% SDS phosphate buffer (compound preparation 7 to compound preparation 9, place it at 37°C for 5 after a few minutes). Shake at 150r/min in a constant temperature oscillator at 37±1℃, take samples regularly, take the release medium and filter it through a 0.22μm microporous membrane, take the continuous filtrate, and measure the OD value at 270nm and 296nm respectively; according to the standard curve Calculate the drug concentration in the release medium, and calculate the cumulative release rate according to formula (1). Figure 1 shows the cumulative in vitro dissolution rates of orfendazole and praziquantel in compound formulation 14.

复方制剂10及复方制剂11，每份取制剂0.1g，加入50mL带塞EP管中，加入30mL0.5％吐温磷酸盐缓冲液。于37±1℃的恒温振荡仪中以150 r/min的转速震荡，定时取样，取释放介质经0.22μm微孔滤膜过滤，取续滤液，分别于270nm和340nm处测定OD值；按标准曲线计算计算释放介质中药物浓度，根据式(1)计算累积释放度。For compound preparation 10 and compound preparation 11, 0.1 g of the preparation was taken from each portion, added to a 50 mL EP tube with a stopper, and 30 mL of 0.5% Tween phosphate buffer was added. Shake at 150 r/min in a constant temperature oscillator at 37±1℃, take samples regularly, filter the release medium through a 0.22 μm microporous membrane, take the continuous filtrate, and measure the OD value at 270 nm and 340 nm respectively; according to the standard The curve calculation calculates the drug concentration in the release medium, and calculates the cumulative release rate according to formula (1).

复方制剂12及复方制剂13，每份取制剂0.1g，加入50mL带塞EP管中，加入30mL0.5％SDS磷酸盐缓冲液。于37±1℃的恒温振荡仪中以150r/min 的转速震荡，定时取样，取释放介质经0.22μm微孔滤膜过滤，取续滤液，分别于270nm和296nm处测定OD值；按标准曲线计算计算释放介质中药物浓度，根据式(1)计算累积释放度。For compound preparation 12 and compound preparation 13, 0.1 g of the preparation was taken from each portion, added to a 50 mL EP tube with a stopper, and 30 mL of 0.5% SDS phosphate buffer was added. Shake at 150r/min in a constant temperature oscillator at 37±1℃, take samples regularly, take the release medium and filter it through a 0.22μm microporous membrane, take the continuous filtrate, and measure the OD value at 270nm and 296nm respectively; according to the standard curve Calculate the drug concentration in the release medium, and calculate the cumulative release rate according to formula (1).

氯硝柳胺进行体外释放度研究的结果如表2所示，复方制剂10，氯硝柳胺4小时累积释放度为64.8％，吡喹酮4小时仅释放17.6％；复方制剂11，氯硝柳胺4小时累积释放度为75.3％，吡喹酮4小时仅释放45.6％。复方制剂 10和复方制剂11，氯硝柳胺释放速度比吡喹酮快。复方制剂5中，药物释放三周左右，氯硝柳胺释放速度与吡喹酮无显着差异。复方制剂3及复方制剂 4中，药物释放2个月左右。复方制剂1及复方制剂2，药物释放两个月以上，其中复方制剂1中氯硝柳胺78天仅释放47.4％，吡喹酮78天释放了100.0％，吡喹酮释放速度比氯硝柳胺快。The results of in vitro release studies of niclosamide are shown in Table 2. Compound preparation 10, the cumulative release of niclosamide in 4 hours is 64.8%, and praziquantel is only released 17.6% in 4 hours; compound preparation 11, niclosamide The 4-hour cumulative release of sulfamide was 75.3%, and the 4-hour release of praziquantel was only 45.6%. For Compound 10 and Compound 11, the release rate of niclosamide was faster than that of praziquantel. In compound preparation 5, the drug was released for about three weeks, and the release rate of niclosamide was not significantly different from that of praziquantel. In compound preparation 3 and compound preparation 4, the drug was released for about 2 months. Compound preparation 1 and compound preparation 2 have drug release for more than two months. Among them, niclosamide in compound preparation 1 only releases 47.4% in 78 days, and praziquantel releases 100.0% in 78 days. The release rate of praziquantel is higher than that of niclosamide. Amine is fast.

以上复方制剂吡喹酮、氯硝柳胺体外释放溶出度整理后列于表2。The above compound preparations praziquantel and niclosamide in vitro release and dissolution rate are listed in Table 2 after sorting.

表2Table 2

奥芬达唑进行体外释放度研究的结果如表3所示，复方制剂7、复方制剂8及复方制剂9和复方制剂13，1-6天即释放完全。复方制剂6释放时间最长，其中奥芬达唑23天仅释放了77.5％，吡喹酮9天释放99.7％，吡喹酮释放速度比奥芬达唑快。复方制剂12中，奥芬达唑1天释放了97.2％，吡喹酮11天仅释放61.8％，奥芬达唑释放速度比吡喹酮快。Table 3 shows the results of in vitro release studies of ovendazole. Compound preparation 7, compound preparation 8, compound preparation 9 and compound preparation 13 were completely released within 1-6 days. Compound preparation 6 had the longest release time, in which only 77.5% of orfendazole was released in 23 days, 99.7% of praziquantel was released in 9 days, and the release rate of praziquantel was faster than that of orendazole. In compound preparation 12, 97.2% of orfendazole was released in 1 day, and only 61.8% of praziquantel was released in 11 days, and the release rate of orendazole was faster than that of praziquantel.

以上复方制剂吡喹酮、奥芬达唑体外释放溶出度整理后列于表3。The in vitro release and dissolution rates of the above compound preparations praziquantel and ofendazole are listed in Table 3.

表3table 3

综上，本发明制备了不同的复方制剂，达到了1天-数个月的缓释效果。同时采用不同的处方工艺，可以调节复方中药物释放速度的快慢，为后期的现场应用提供了更多的用药方案，具有广阔的应用前景。In conclusion, the present invention prepares different compound preparations, and achieves a sustained release effect of 1 day to several months. At the same time, different prescription processes can be used to adjust the speed of drug release in the compound, which provides more drug regimens for later field applications, and has broad application prospects.

应用例：泡型包虫病药效试验Application example: efficacy test of alveolar hydatid disease

采用本发明上述复方制剂14对预防小鼠感染多房棘球蚴进行药效实验，实验过程具体如下：The above-mentioned compound preparation 14 of the present invention is used to carry out a drug effect experiment on preventing the infection of Echinococcus multilocularis in mice, and the experimental process is as follows:

1、实验材料：空白制剂(区别在于不含有复方制剂14的第一活性成分和第二活性成分，用量等同复方制剂14)及本发明复方制剂14。1. Experimental materials: blank preparation (the difference is that it does not contain the first active ingredient and the second active ingredient of compound preparation 14, and the dosage is equivalent to compound preparation 14) and compound preparation 14 of the present invention.

2、动物：2. Animals:

来源和种属品系：昆明系小鼠；Source and species strain: Kunming mouse;

提供单位：上海中国科学院实验动物中心；Provided by: Laboratory Animal Center, Chinese Academy of Sciences, Shanghai;

小鼠性别：雌性。Mouse gender: female.

3、分组与动物数：3. Grouping and number of animals:

随机分组，每组观察鼠为10只。Randomly divided into 10 mice in each group.

4、实验方法步骤：4. Experimental method steps:

(1)虫源(1) Insect source

多房棘球蚴原头节及组织：由多房棘球蚴保种的实验室提供保种动物(小鼠、大鼠或长爪沙鼠等)。用碘酒和75％乙醇对种鼠的皮肤进行消毒，剖开腹腔后，用无菌法剥离多房棘球蚴囊。若有干酪样团块或呈无菌性囊肿者应剔除。将采集的多房棘球蚴囊称重，并放置在培养皿内，用眼科弯头剪刀将囊组织尽量剪得细碎，然后用抗生素(含青霉素、链霉素50万U/L和两性霉素B 0.25mg/L)的HBSS洗涤囊组织，每次10min、共5～8次，然后再用含抗生素的HBSS稀释至含囊组织80～100mg/ml备用。Multilocular Echinococcus protocephalus and tissues: The preservation animals (mice, rats or gerbils, etc.) are provided by the multilocular hydatid conservation laboratory. The skin of the breeding mice was sterilized with iodine and 75% ethanol, the peritoneal cavity was opened, and the multilocular hydatid cyst was aseptically removed. If there is a caseous mass or a sterile cyst, it should be removed. The collected multilocular hydatid cysts were weighed and placed in a petri dish. The sac tissue was cut as finely as possible with ophthalmic elbow scissors. Cyst tissue was washed with HBSS containing B 0.25mg/L) for 10 min each time, 5-8 times in total, and then diluted with HBSS containing antibiotics to 80-100mg/ml containing cyst tissue for later use.

(2)接种(2) Inoculation

在盛有多房棘球蚴囊组织悬液的烧杯内加入磁搅拌子，置于磁力搅拌器上，调节转速以保持原头节和囊组织混悬。用1ml注射器吸取多房棘球蚴囊组织0.3ml(约40～50mg囊组织)，再用75％酒精擦涂小鼠皮肤，然后将囊组织注入小鼠腹腔内。A magnetic stirrer was added to the beaker containing the multilocular hydatid cyst tissue suspension, placed on the magnetic stirrer, and the rotational speed was adjusted to keep the protosegment and capsule tissue suspended. Take 0.3 ml of Echinococcus multilocularis cyst tissue (about 40-50 mg of cyst tissue) with a 1 ml syringe, wipe the mouse skin with 75% alcohol, and then inject the cyst tissue into the abdominal cavity of the mouse.

(3)药物筛选和实验治疗(3) Drug screening and experimental treatment

治疗开始时间：20只小鼠，随机分组，每组10只。阴性对照组接种空白制剂0.1mL/只，给药组接种复方制剂0.1mL/只。接种后1小时，20只小鼠再接种多房棘球蚴。Treatment start time: 20 mice were randomly divided into groups of 10 mice. The negative control group was inoculated with blank preparation 0.1mL/a, and the administration group was inoculated with compound preparation 0.1mL/a. One hour after inoculation, 20 mice were re-inoculated with E. multilocularis.

小鼠接种5个月后剖检。用断颈法处死，剖开腹腔，仔细剥离和摘取多房棘球蚴组织，并称取每只小鼠的囊重。Mice were necropsied 5 months after inoculation. The mice were sacrificed by cervical dislocation, the abdominal cavity was opened, and the Echinococcus multilocularis tissue was carefully stripped and excised, and the sacs of each mouse were weighed.

疗效计算：计算药物组与对照组的平均囊重，按下式计算囊重抑制率。Efficacy calculation: Calculate the average cyst weight of the drug group and the control group, and calculate the cyst weight inhibition rate according to the following formula.

囊重抑制率＝(阴性对照组囊重-给药组囊重)/对照组囊重*100Sac weight inhibition rate=(Sac weight of negative control group-Sac weight of administration group)/Sac weight of control group*100

实验结果参见下述表4所示。The experimental results are shown in Table 4 below.

表4、感染多房棘球蚴小鼠用阿苯达唑大豆油-司盘混悬液治疗的效果 (重量单位：克)Table 4. The effect of treatment with albendazole soybean oil-Span suspension in mice infected with Echinococcus multilocularis (weight unit: g)

由表4的结果可见，早期感染多房棘球蚴的小鼠用本发明的复方制剂具有显著的囊重抑制效果，囊重抑制率为67.4％。复方制剂达到了较好的抑制囊重发展的效果，复方制剂组10例小鼠的平均“囊重：体重”为0.07943，且有6例的“囊重：体重”数值低于平均。说明本发明提供的复方制剂由于其具有的缓释效应，从而具备良好的预防血吸虫病发展的效果，可以延缓动物感染血吸虫之后的症状发展趋势，并且为后续的治疗争取时间。It can be seen from the results in Table 4 that the compound preparation of the present invention has a significant cyst weight inhibition effect on mice infected with E. multilocularis at an early stage, and the cyst weight inhibition rate is 67.4%. The compound preparation achieved a good effect of inhibiting the development of cyst weight. The average "sac weight: body weight" of 10 mice in the compound preparation group was 0.07943, and the "sac weight: body weight" value of 6 cases was lower than the average. It is explained that the compound preparation provided by the present invention has a good effect of preventing the development of schistosomiasis due to its slow-release effect, can delay the development trend of symptoms after animals are infected with schistosomiasis, and buy time for subsequent treatment.

以上仅为本发明之较佳实施例，并非用以限定本发明之权利范围；同时以上的描述，对于相关技术领域之专门人士应可明了及实施，因此其他未脱离本发明所揭示之精神下所完成的等效改变或修饰，均应包含在申请专利范围中。The above are only preferred embodiments of the present invention, and are not intended to limit the scope of the rights of the present invention; at the same time, the above description should be understood and implemented by those skilled in the relevant technical fields, so others do not depart from the spirit disclosed in the present invention. The completed equivalent changes or modifications should be included in the scope of the patent application.

Claims (9)

Translated fromChinese

1.一种复方制剂，其特征在于，包括有第一活性成分、第二活性成份，其中以所述抗寄生虫复方制剂的重量组分为100，所述第一活性成分占所述复方制剂的重量组分为5～95及所述第二活性成分占所述复方制剂的重量组分为5～95。1. a compound preparation, is characterized in that, comprises the first active ingredient, the second active ingredient, wherein with the weight component of described antiparasitic compound preparation is 100, and described first active ingredient accounts for described compound preparation. The weight component of the compound preparation is 5-95 and the second active ingredient accounts for 5-95 of the weight component of the compound preparation.2.如权利要求1所述的复方制剂，其特征在于，所述第一活性成分是吡喹酮。2. The compound preparation of claim 1, wherein the first active ingredient is praziquantel.3.如权利要求1所述的复方制剂，其特征在于，所述第二活性成分是氯硝柳胺或奥芬达唑。3. The compound preparation of claim 1, wherein the second active ingredient is niclosamide or ofendazole.4.如权利要求1所述的复方制剂，其特征在于，所述复方制剂进一步包括生物可降解高分子材料、分散介质及增溶剂，且所述生物可降解高分子材料占所述复方制剂的重量组分为14.7～45.5、所述分散介质占所述复方制剂的重量组分为0～79.4及所述增溶剂占复方制剂的重量组分为0～45.5。4. compound preparation as claimed in claim 1 is characterized in that, described compound preparation further comprises biodegradable macromolecular material, dispersion medium and solubilizer, and described biodegradable macromolecule material accounts for described compound preparation The weight component is 14.7-45.5, the weight component of the dispersion medium is 0-79.4 of the compound preparation, and the solubilizer is 0-45.5 of the weight component of the compound preparation.5.如权利要求4所述的复方制剂，其特征在于，所述生物可降解高分子材料可以是聚乳酸-羟基乙酸共聚物、聚己内酯或是泊洛沙姆407。5 . The compound preparation according to claim 4 , wherein the biodegradable polymer material can be polylactic acid-glycolic acid copolymer, polycaprolactone or poloxamer 407. 6 .6.如权利要求4所述的复方制剂，其特征在于，所述分散介质可以是N-甲基吡咯烷酮或聚乙二醇400。6 . The compound preparation according to claim 4 , wherein the dispersion medium can be N-methylpyrrolidone or polyethylene glycol 400. 7 .7.如权利要求4所述的复方制剂，其特征在于，所述增溶剂为聚维酮(聚乙烯吡咯烷酮(PVP))、吐温80或聚乙二醇6000。7 . The compound preparation according to claim 4 , wherein the solubilizer is povidone (polyvinylpyrrolidone (PVP)), Tween 80 or polyethylene glycol 6000. 8 .8.如权利要求1所述的复方制剂，其特征在于，进一步包含去离子水，且所述去离子水占所述复方制剂的重量组分为58.8～69.0。8 . The compound preparation according to claim 1 , further comprising deionized water, and the deionized water accounts for 58.8-69.0 of the weight component of the compound preparation. 9 .9.权利要求1-8任一项所述的复方制剂在制备用于抗寄生虫的药物中的用途；其中，所述寄生虫包括寄生虫的成虫和/或幼虫。9. Use of the compound preparation according to any one of claims 1-8 in the preparation of a medicament for anti-parasites; wherein the parasites include adults and/or larvae of parasites.

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