CN117122571A - Oral medicinal preparation for resisting parasitic infection, and preparation method and application thereof - Google Patents

Oral medicinal preparation for resisting parasitic infection, and preparation method and application thereof Download PDF

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Publication number
CN117122571A
CN117122571A CN202210549794.1A CN202210549794A CN117122571A CN 117122571 A CN117122571 A CN 117122571A CN 202210549794 A CN202210549794 A CN 202210549794A CN 117122571 A CN117122571 A CN 117122571A
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China
Prior art keywords
oral pharmaceutical
reaction
total mass
preparation
adhesive
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CN202210549794.1A
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Chinese (zh)
Inventor
张亮
李守军
刘爱玲
郝小妹
李亚玲
张朋丽
王亚姣
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RINGPU (TIANJIN) BIO-PHARMACY CO LTD
Tianjin Ringpu Bio Technology Co Ltd
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RINGPU (TIANJIN) BIO-PHARMACY CO LTD
Tianjin Ringpu Bio Technology Co Ltd
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Application filed by RINGPU (TIANJIN) BIO-PHARMACY CO LTD, Tianjin Ringpu Bio Technology Co Ltd filed Critical RINGPU (TIANJIN) BIO-PHARMACY CO LTD
Priority to CN202210549794.1A priority Critical patent/CN117122571A/en
Priority to PCT/CN2023/093508 priority patent/WO2023221854A1/en
Publication of CN117122571A publication Critical patent/CN117122571A/en
Pending legal-status Critical Current

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    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61K31/42—Oxazoles
    • 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
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • 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

Abstract

The invention provides an oral pharmaceutical preparation for resisting parasitic infection, a preparation method and application thereof, wherein the oral pharmaceutical preparation comprises a filler, a flavoring agent, a phagostimulant, a forming agent, a preservative and an adhesive containing a first active component, and the first active component is an isoxazoline compound. The self-microemulsion solution of the active component is used as the adhesive in the oral pharmaceutical preparation for resisting the parasitic infection, so that the active component is uniformly distributed in the oral preparation, the drug release rate of the oral preparation can be obviously increased, and the bioavailability of the active component of the drug is improved.

Description

Oral medicinal preparation for resisting parasitic infection, and preparation method and application thereof
Technical Field
The invention belongs to the technical field of chemical pharmaceutical preparations, and particularly relates to an oral pharmaceutical preparation for resisting parasite infection, and a preparation method and application thereof.
Background
Controlling parasitic infections of animal groups has been an important global task. Pathogenic organisms can be classified as endoparasitic organisms of the nematoda, cestoda and trematoda or protozoan phylum, or ectoparasitic organisms of the arthropoda phylum. The former include infections of the stomach, intestinal tract, lymphatic system, tissues, liver, lung, heart and brain. The latter ectoparasites include ticks, mites, lice, flies and fleas. These organisms often act as vehicles and intermediate hosts for the transmission of endoparasites to animal hosts.
The isoxazolines are broad-spectrum pesticides, can inhibit the ligand-gated chloride ion channels of L-glutamic acid and gamma-aminobutyric acid at different positions, and have good insecticidal activity on pests such as tick order, flea order, louse order, hemiptera order, diptera order and the like. The four types of isoxazoline pesticides on the market at present all contain classical isoxazole rings and are mainly used for in-vitro disinsection of animals such as cats, dogs and the like. Due to the excellent insecticidal activity and high safety of isoxazolines, research on derivatives thereof has been increasing in recent years. Besides the four isoxazoline drugs that have been marketed, other isoxazoline drugs are only used in the agricultural field, such as fluxamide and Isocycloseram as broad-spectrum insecticides and acaricides for crops such as fruit trees and vegetables, cereals, rice, maize, soybean, sugar beet, cotton, etc. There is therefore a need to identify specific formulations that allow their veterinary use, i.e. safe administration, to effectively control parasites in animals.
The isoxazoline compound preparation which is marketed at present is mainly administered to target animals in an oral chewing tablet mode. Because of the low water solubility and in vivo bioavailability of isoxazoline compounds, increased amounts of active ingredients are often employed to enhance parasiticidal efficacy. The prior art oral preparation and the conventional oral ectoparasiticide preparation have the problems of low drug release rate, low bioavailability, poor insect repellent effect and the like.
Therefore, the self-microemulsion solution containing the medicine is used as the adhesive to prepare the soft chewing tablet, the active ingredients are dissolved, the prepared solution is used as the adhesive, the active ingredients are uniformly distributed in a tablet system, the problem of uneven mixing in the common chewing tablet is solved, meanwhile, the nanometer medicine carrying system with O/W (oil in water) and particle size smaller than 50nm can be rapidly emulsified and self-assembled under the actions of physiological temperature and gastrointestinal peristalsis after oral administration, the medicine is uniformly distributed and rapidly released in the gastrointestinal tract, and the bioavailability of the active ingredients is remarkably improved.
In summary, there is an urgent need in the art to develop an isoxazoline compound oral preparation with good solubility of active pharmaceutical ingredient, high insecticidal activity, good safety, fast release rate and high bioavailability.
Disclosure of Invention
In view of the above, the present invention aims to overcome the defects in the prior art, and provides an oral pharmaceutical preparation for resisting parasite infection, and a preparation method and application thereof.
In order to achieve the above purpose, the technical scheme of the invention is realized as follows:
as a first aspect of the present invention there is provided an oral pharmaceutical formulation for combating parasitic infections, comprising a filler, a flavouring agent, a phagostimulant, a shaping agent, a preservative and a binder comprising a first active ingredient, the first active ingredient being an isoxazoline compound.
Preferably, the binder includes an isoxazoline compound, a solvent, a surfactant, and a cosurfactant.
Preferably, the structural general formula of the isoxazoline compound is shown as formula (I):
wherein R is 1 Selected from H, OH, CN, NO 2 、OCH 3 、CF 3 、N(CH 3 ) 2 Br or F;
R 2 selected from the group consisting of More preferably, R 1 Selected from H or F, R 2 Selected from->
Preferably, the isoxazoline compound is selected from the following compounds 1 to 30:
preferably, the solvent is one or a combination of more of soybean oil, corn oil and medium chain triglyceride, and further preferably, the solvent is medium chain triglyceride.
Preferably, the surfactant is one or a combination of several of polyethylene glycol, stearate, stearoyl polyoxyethylene glyceride, diethylene glycol monoethyl ether, caprylic acid capric acid polyethylene glycol glyceride, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan tristearate, propylene glycol dicaprylate, propylene glycol dilaurate, propylene glycol ricinoleate and sodium laurate, and further preferably, the solvent is caprylic acid capric acid polyethylene glycol glyceride.
Preferably, the cosurfactant is one or a combination of a plurality of propylene glycol, n-propanol, isopropanol, n-butanol, isobutanol, n-amyl alcohol, isoamyl alcohol, 1-hexanol, 2-hexanol, 1-octanol, 2-octanol, fusel oil, p-nonylphenol, ethanol and glycerin. Further preferably, the solvent is glycerol.
Preferably, the oral pharmaceutical formulation further comprises a filler, a flavoring agent, a phagostimulant, a shaping agent, and a preservative.
More preferably, the filler is one or more of lactose, microcrystalline cellulose, mannitol, sorbitol, starch, sucrose, dextrin, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, and calcium sulfate dihydrate. Further preferably, the filler is starch.
More preferably, the flavoring agent is one or more of sucrose, simple syrup, citric syrup, glycyrrhrizae radix syrup, glycerol, sorbitol, saccharin sodium, sodium alginate, stevioside, mannitol, and aspartame. Further preferably, the flavoring agent is aspartame.
More preferably, the phagostimulant is one or a combination of more than one of chicken liver powder, pork liver powder, beef powder, fish meal, chicken oil, chicken bone powder, lard, plant essence, animal essence and compound amino acid. Further preferably, the phagostimulant is pork liver powder.
More preferably, the forming agent is one or more of polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 3350, polyethylene glycol 4000, glycerin, propylene glycol, sorbitol, and polysorbate. Further preferably, the molding agent is polyethylene glycol 4000.
More preferably, the preservative is one or a combination of a plurality of benzyl alcohol, methyl benzoate, propyl benzoate and butyl toluene. Further preferably, the preservative is butylated hydroxytoluene.
Preferably, the oral pharmaceutical preparation comprises the following components in proportion:
the addition amount of the adhesive accounts for 5-15% of the total mass of the oral pharmaceutical preparation,
wherein, the addition of the isoxazoline compound accounts for 5-15% of the total mass of the adhesive, the addition of the solvent accounts for 20-50% of the total mass of the adhesive, the addition of the surfactant accounts for 10-40% of the total mass of the adhesive, and the addition of the cosurfactant accounts for 10-50% of the total mass of the adhesive;
the addition amount of the filler accounts for 70-80% of the total mass of the oral pharmaceutical preparation;
the addition amount of the flavoring agent is 0.1-2.0% of the total mass of the oral pharmaceutical preparation;
the addition amount of the phagostimulant is 0.1-2.0% of the total mass of the oral pharmaceutical preparation;
The addition amount of the forming agent accounts for 5-20% of the total mass of the oral pharmaceutical preparation;
the addition amount of the preservative accounts for 0.1-2.0% of the total mass of the oral pharmaceutical preparation;
as a second aspect of the present invention, there is provided a method for preparing the above oral pharmaceutical formulation for combating parasitic infection, comprising the steps of:
(1) Adding a surfactant, a cosurfactant and a solvent into an isoxazoline compound, and uniformly mixing to obtain an adhesive;
(2) Adding the adhesive in the step (1) into a filling agent, a flavoring agent, a phagostimulant, a forming agent and a preservative, and uniformly mixing;
(3) Sieving the mixture obtained in the step (2), and pressing to obtain the oral medicinal preparation for resisting parasite infection.
As a third aspect of the present invention, there is provided another pharmaceutical formulation for oral administration for combating parasitic infection, the adhesive of the pharmaceutical formulation for oral administration further comprising a second active ingredient, wherein the second active ingredient is one or more of the following compounds:
(a) Pyrethroids;
(b) A macrolide compound;
(c) Insect growth regulators;
(d) Carbamates;
(e) Formamidines;
(f) A nicotinoyl chloride;
(g) Imidazothiazoles;
(h) Benzimidazoles;
(i) Tetrahydroimidazoles;
(j) Isoquinolines;
(k) Salicylanilides.
Preferably, the pyrethroid compound is selected from one or more of permethrin, cypermethrin, deltamethrin, fenpropathrin, flumethrin, fenvalerate, phenothrin, tetramethrin and allethrin; the macrolide compound is one or more selected from ivermectin, siramectin, moxidectin, spinosad, milbemycin, avermectin and Ai Mode s; the insect growth regulator is selected from one or more of pyriproxyfen, lufenuron, desiccanil, s-methoprene, antifebrile, tebufenozide, diflubenzuron, chlorfluazuron, hexaflumuron, diafenthiuron, buprofezin and cyromazine; the carbamate compound is selected from one or more of indoxacarb, propoxur, isoprocarb, aldicarb, methomyl and carbofuran; the formamidine compound is selected from amitraz; the nicotinoyl chloride compound is one or more selected from dinotefuran, nitenpyram and thiamethoxam.
Preferably, the oral pharmaceutical preparation comprises the following components in proportion:
and (2) an adhesive: the addition amount of the adhesive accounts for 5-15% of the total mass of the oral pharmaceutical preparation,
wherein, the addition of the first active ingredient accounts for 5-15% of the total mass of the adhesive, the addition of the second active ingredient accounts for 5-15% of the total mass of the adhesive, the addition of the solvent accounts for 20-50% of the total mass of the adhesive, the addition of the surfactant accounts for 10-40% of the total mass of the adhesive, and the addition of the cosurfactant accounts for 10-50% of the total mass of the adhesive;
The addition amount of the filler accounts for 70-80% of the total mass of the oral pharmaceutical preparation;
the addition amount of the flavoring agent is 0.1-2.0% of the total mass of the oral pharmaceutical preparation;
the addition amount of the phagostimulant is 0.1-2.0% of the total mass of the oral pharmaceutical preparation;
the addition amount of the forming agent accounts for 5-20% of the total mass of the oral pharmaceutical preparation;
the addition amount of the preservative accounts for 0.1-2.0% of the total mass of the oral pharmaceutical preparation.
As a fourth aspect of the present invention, there is provided a method for preparing the above oral pharmaceutical formulation for combating parasitic infection, comprising the steps of:
(1) Adding a surfactant, a cosurfactant and a solvent into the first active component and the second active component, and mixing until the mixture is uniform to obtain an adhesive;
(2) Adding the adhesive in the step (1) into a filling agent, a flavoring agent, a phagostimulant, a forming agent and a preservative, and uniformly mixing;
(3) Sieving the mixture obtained in the step (2), and pressing to obtain the oral medicinal preparation for resisting parasite infection.
As a fourth aspect of the invention there is provided the use of an oral pharmaceutical formulation as described above in the manufacture of a medicament for the treatment or prophylaxis of parasites in non-human animals.
Compared with the prior art, the invention has the following advantages:
(1) The self-microemulsion solution of the active component is used as the adhesive in the oral pharmaceutical preparation for resisting the parasitic infection, so that the active component is uniformly distributed in the oral preparation, the drug release rate of the oral preparation can be obviously increased, and the bioavailability of the active component of the drug is improved.
(2) Compared with fluorine Lei Lana, the active ingredient in the oral medicinal preparation for resisting the parasitic infection can achieve effective insecticidal effect under the condition of lower dosage.
(3) The invention adopts isoxazoline compound to be used by being compounded with one or more of pyrethroid, macrolide compound, insect growth regulator, carbamate, formamidine, nicotinyl chloride, imidazothiazole, benzimidazole, tetrahydroimidazole, isoquinoline and salicylanilide, and can realize the simultaneous driving of internal and external parasites.
Detailed Description
Unless defined otherwise, technical terms used in the following examples have the same meaning as commonly understood by one of ordinary skill in the art to which the inventive concepts pertain. The test reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the experimental methods are conventional methods unless otherwise specified.
The invention will be described in detail with reference to examples.
EXAMPLE 1 an oral pharmaceutical formulation against parasite infections
Table 1 the oral pharmaceutical formulation of example 1
The preparation method comprises the following steps:
(1) And (3) placing the Fluximamide, medium-chain triglyceride, caprylic/capric acid polyethylene glycol glyceride and glycerol in a prescription amount into a liquid preparation device, setting the stirring rotation speed to be 150rpm, and mixing for 15min to uniformly mix the materials, thereby obtaining the self-microemulsion solution adhesive for standby.
(2) Weighing starch, aspartame, pork liver powder, polyethylene glycol 4000 and butylated hydroxytoluene with the prescribed amount, sequentially putting the materials into a wet mixing granulator, setting the rotating speed to 300rpm, mixing for 30min, adding the self-microemulsion solution adhesive, cutting for 10min, and discharging for later use.
(3) And (3) granulating the mixed material prepared in the step (2) through a 24-mesh screen, and tabletting through a tabletting machine.
The preparation method of the compound 1 comprises the following steps:
adding the initial material 1 and oxalyl chloride (1.5 eq) into a reaction bottle, reacting for 12 hours at 20-30 ℃ in a solvent dichloromethane, detecting the reaction progress by using Thin Layer Chromatography (TLC) in the reaction process, concentrating until no fraction is obtained after the reaction is completed, adding the intermediate state of the acyl chloride into ammonia water, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, extracting the water phase by using dichloromethane, concentrating and recrystallizing the organic phase to obtain the intermediate 1.
Intermediate 1, triethyl orthoformate (15.0 eq) and methoxyamine hydrochloride (1.5 eq) are added into a reaction bottle to react at 50-60 ℃, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, and after the reaction is completed, an organic phase is filtered, concentrated and recrystallized to obtain the compound 1.
Example 2
The active ingredient is compound 2, and the other components and the amounts of the components in the preparation are the same as those in example 1.
The preparation method of the compound 2 comprises the following steps:
adding the initial material 1 and oxalyl chloride (1.5 eq) into a reaction bottle, reacting for 12 hours at 20-30 ℃ in a solvent dichloromethane, detecting the reaction progress by using Thin Layer Chromatography (TLC) in the reaction process, concentrating until no fraction is obtained after the reaction is completed, adding the intermediate state of the acyl chloride into ammonia water, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, extracting the water phase by using dichloromethane, concentrating and recrystallizing the organic phase to obtain the intermediate 1.
Intermediate 1, triethyl orthoformate (15.0 eq) and methylamine hydrochloride (1.5 eq) are added into a reaction bottle to react at 50-60 ℃, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, and after the reaction is completed, an organic phase is filtered, concentrated and recrystallized to obtain a compound 2.
Example 3
The active ingredient is compound 3, and the other components and the amounts of the components in the preparation are the same as those in example 1.
The preparation method of the compound 3 comprises the following steps:
adding the initial material 1 and oxalyl chloride (1.5 eq) into a reaction bottle, reacting for 12 hours at 20-30 ℃ in dichloromethane, detecting the reaction progress by Thin Layer Chromatography (TLC) in the reaction process, concentrating until no fraction is obtained after the reaction is completed, adding the intermediate state of the acyl chloride into ammonia water, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, extracting the water phase by using dichloromethane, concentrating and recrystallizing the organic phase to obtain the intermediate 1.
Intermediate 1, trimethyl orthoformate (15.0 eq) and S-methyl thiohydroxylamine hydrochloride (1.2 eq) are added into a reaction bottle to react at 30-40 ℃, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, and after the reaction is completed, an organic phase is filtered, concentrated and recrystallized to obtain a compound 3.
Example 4
The active ingredient is compound 4, and the other components and the amounts of the components in the preparation are the same as in example 1.
The preparation method of the compound 4 comprises the following steps:
adding the initial material 1 and oxalyl chloride (1.5 eq) into a reaction bottle, reacting for 12 hours at 20-30 ℃ in a solvent dichloromethane, detecting the reaction progress by using Thin Layer Chromatography (TLC) in the reaction process, concentrating until no fraction is obtained after the reaction is completed, adding the intermediate state of the acyl chloride into ammonia water, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, extracting the water phase by using dichloromethane, concentrating and recrystallizing the organic phase to obtain the intermediate 1.
Intermediate 1, triethyl orthoformate (13.0 eq) and O-cyclopropyl hydroxylamine hydrochloride (1.5 eq) are added into a reaction bottle to react at 50-60 ℃, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, and after the reaction is completed, an organic phase is filtered, concentrated and recrystallized to obtain the compound 4.
Example 5
The active ingredient is compound 5, and the other components and the amounts of the components in the preparation are the same as in example 1.
The preparation method of the compound 5 comprises the following steps:
adding the initial material 5 and thionyl chloride (1.5 eq) into a reaction bottle, reacting for 8 hours at 60-70 ℃ in toluene, detecting the reaction progress by Thin Layer Chromatography (TLC) in the reaction process, concentrating until no fraction is obtained after the reaction is completed, adding the intermediate to ammonia water, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, extracting the water phase by ethyl acetate, concentrating and recrystallizing the organic phase to obtain the intermediate 5.
Intermediate 5, trimethyl orthoformate (13.0 eq) and methoxyamine hydrochloride (1.3 eq) are added into a reaction bottle to react at 30-40 ℃, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, and after the reaction is completed, an organic phase is filtered, concentrated and recrystallized to obtain the compound 5.
Example 6
The active ingredient is compound 6, and the other components and the amounts of the components in the preparation are the same as in example 1.
The preparation method of the compound 6 comprises the following steps:
adding the initial material 6 and thionyl chloride (1.5 eq) into a reaction bottle, reacting for 8 hours at 60-70 ℃ in toluene, detecting the reaction progress by Thin Layer Chromatography (TLC) in the reaction process, concentrating until no fraction is obtained after the reaction is completed, adding the intermediate to ammonia water, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, extracting the water phase by ethyl acetate, concentrating and recrystallizing the organic phase to obtain the intermediate 6.
Intermediate 6, triethyl orthoformate (14.0 eq) and methoxyamine hydrochloride (1.3 eq) are added into a reaction bottle to react at 50-60 ℃, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, and after the reaction is completed, an organic phase is filtered, concentrated and recrystallized to obtain the compound 6.
Example 7
The active ingredient is compound 7, and the other components and the amounts of the components in the preparation are the same as in example 1.
The preparation method of the compound 7 comprises the following steps:
adding the initiator 7 and oxalyl chloride (1.3 eq) into a reaction bottle, reacting for 8 hours at 20-30 ℃ in tetrahydrofuran, detecting the reaction progress by Thin Layer Chromatography (TLC) in the reaction process, concentrating until no fraction is obtained after the reaction is completed, adding the intermediate to ammonia water, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, extracting the water phase by tetrahydrofuran, concentrating and recrystallizing the organic phase to obtain the intermediate 7.
Intermediate 7, trimethyl orthoformate (10.0 eq) and methoxyamine hydrochloride (1.1 eq) are added into a reaction bottle to react at 30-40 ℃, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, and after the reaction is completed, an organic phase is filtered, concentrated and recrystallized to obtain the compound 7.
Example 8
The active ingredient is compound 8, and the other components and the amounts of the components in the preparation are the same as in example 1.
The preparation method of the compound 8 comprises the following steps:
adding an initiator 8 and thionyl chloride (1.5 eq) into a reaction bottle, reacting for 8 hours at 60-70 ℃ in toluene, detecting the reaction progress by Thin Layer Chromatography (TLC) in the reaction process, concentrating until no fraction is obtained after the reaction is completed, adding the intermediate to ammonia water, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, extracting the water phase by ethyl acetate, concentrating the organic phase, and recrystallizing to obtain an intermediate 8.
Adding the intermediate 8, triisopropyl orthoformate (13.0 eq) and methoxyamine hydrochloride (1.2 eq) into a reaction bottle to react at 60-70 ℃, detecting the reaction progress by Thin Layer Chromatography (TLC) in the reaction process, and filtering, concentrating and recrystallizing an organic phase after the reaction is completed to obtain the compound 8.
Example 9
The active ingredient is compound 9, and the other components and the amounts of the components in the preparation are the same as in example 1.
The preparation method of the compound 9 comprises the following steps:
adding the initiator 9 and oxalyl chloride (1.5 eq) into a reaction bottle, reacting for 8 hours at 20-30 ℃ in tetrahydrofuran, detecting the reaction progress by Thin Layer Chromatography (TLC) in the reaction process, concentrating until no fraction is obtained after the reaction is completed, adding the intermediate to ammonia water, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, extracting the water phase by tetrahydrofuran, concentrating and recrystallizing the organic phase to obtain the intermediate 9.
Intermediate 9, triethyl orthoformate (15.0 eq) and methoxyamine hydrochloride (1.5 eq) are added into a reaction bottle to react at 50-60 ℃, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, and after the reaction is completed, an organic phase is filtered, concentrated and recrystallized to obtain the compound 9.
Example 10
The active ingredient is compound 10, and the amounts of other components and components in the preparation are the same as in example 1.
The preparation method of the compound 10 comprises the following steps:
adding the initial material 10 and oxalyl chloride (1.3 eq) into a reaction bottle, reacting for 12 hours at 20-30 ℃ in dichloromethane, detecting the reaction progress by Thin Layer Chromatography (TLC) in the reaction process, concentrating until no fraction is obtained after the reaction is completed, adding the intermediate state of the acyl chloride into ammonia water, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, extracting the water phase by using dichloromethane, concentrating and recrystallizing the organic phase to obtain the intermediate 10.
Intermediate 10, triethyl orthoformate (12.0 eq) and methoxyamine hydrochloride (1.1 eq) are added into a reaction bottle to react at 50-60 ℃, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, and after the reaction is completed, an organic phase is filtered, concentrated and recrystallized to obtain the compound 10.
Example 11
The active ingredient is compound 11, and the other components and the amounts of the components in the preparation are the same as in example 1.
The preparation method of the compound 11 comprises the following steps:
adding the initial material 11 and oxalyl chloride (1.1 eq) into a reaction bottle, reacting at 0-10 ℃ in dichloromethane, detecting the reaction progress by Thin Layer Chromatography (TLC) during the reaction, adding the reaction liquid of the intermediate state of the acyl chloride into ammonia water after the reaction is completed, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, extracting the water phase by using dichloromethane, concentrating and recrystallizing the organic phase to obtain the intermediate 11.
Intermediate 11, triisopropyl orthoformate (15.0 eq) and methoxyamine hydrochloride (1.5 eq) are added into a reaction bottle to react at 60-70 ℃, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, and after the reaction is completed, an organic phase is filtered, concentrated and recrystallized to obtain the compound 11.
Example 12
The active ingredient is compound 12, and the other components and the amounts of the components in the preparation are the same as in example 1.
The preparation method of the compound 12 comprises the following steps:
intermediate 1, N-dimethylformamide (10.0V), N-bromosuccinimide (1.5 eq) and purified water (2.0V) are added into a reaction bottle for reaction at 60-70 ℃, the progress of the reaction is detected by Thin Layer Chromatography (TLC) in the reaction process, water is added for dilution after the reaction is completed, ethyl acetate is used for extracting an aqueous phase, liquid separation and water washing are carried out, and an organic phase is concentrated and recrystallized to obtain the compound 12.
Example 13
The active ingredient is compound 5, and the other components and the amounts of the components in the preparation are the same as in example 1.
The preparation method of the compound 13 comprises the following steps:
intermediate 11, N-dimethylformamide (8.0V), N-bromosuccinimide (1.3 eq) and purified water (1.0V) are added into a reaction bottle for reaction at 60-70 ℃, the progress of the reaction is detected by Thin Layer Chromatography (TLC) in the reaction process, water is added for dilution after the reaction is completed, ethyl acetate is used for extracting an aqueous phase, the aqueous phase is separated, water is used for washing, and an organic phase is concentrated and recrystallized to obtain the compound 13.
Example 14
The active ingredient is compound 14, and the other components and the amounts of the components in the preparation are the same as in example 1.
The preparation method of the compound 14 comprises the following steps:
the reaction of the initial material 11 and oxalyl chloride (1.1 eq) in dichloromethane at 0-10 deg.c is completed, the progress of the reaction is detected by Thin Layer Chromatography (TLC), the intermediate acid chloride reaction solution is added into ammonia water after the reaction is completed, 1M hydrochloric acid is added to terminate the reaction, dichloromethane is used to extract water phase, and the organic phase is concentrated and recrystallized to obtain compound 14 (intermediate 11).
Example 15
The active ingredient is compound 15, and the other components and the amounts of the components in the preparation are the same as in example 1.
The preparation method of the compound 15 comprises the following steps:
adding the initial material 1 and oxalyl chloride (1.5 eq) into a reaction bottle, reacting for 12 hours at 20-30 ℃ in dichloromethane, detecting the reaction progress by Thin Layer Chromatography (TLC) in the reaction process, concentrating until no fraction is obtained after the reaction is completed, adding the intermediate acid chloride into methoxyamine, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, extracting the water phase by using dichloromethane, concentrating and recrystallizing the organic phase to obtain the compound 15.
Example 16
The active ingredient is compound 16, and the other components and the amounts of the components in the preparation are the same as in example 1.
The preparation method of the compound 16 comprises the following steps:
adding the initial material 1 and oxalyl chloride (1.5 eq) into a reaction bottle, reacting for 12 hours at 20-30 ℃ in dichloromethane, detecting the reaction progress by Thin Layer Chromatography (TLC) in the reaction process, concentrating until no fraction is obtained after the reaction is completed, adding the intermediate acid chloride into methanol, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, extracting the water phase by using dichloromethane, concentrating and recrystallizing the organic phase to obtain the compound 16.
Example 17
The active ingredient is compound 17, and the other components and the amounts of the components in the preparation are the same as in example 1.
The preparation method of the compound 17 comprises the following steps:
Intermediate 1, triethyl orthoformate (15.0 eq) and hydroxylamine hydrochloride (1.5 eq) are added into a reaction bottle to react at 50-60 ℃, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, and after the reaction is completed, an organic phase is filtered, concentrated and recrystallized to obtain a compound 17.
Examples 18 to 19
The active ingredients are compounds 18-19, and the amounts of other components and components in the preparation are the same as in example 1.
The preparation method of the compounds 18 and 19 comprises the following steps:
compound 18 is according to literature: the method is characterized in that the method is prepared by the method in 'Sun Hongyang, yang Xu, zhang Jing, etc. fluorine Lei Lana synthesis and insecticidal activity determination [ J ]. Fine chemical engineering, 2020,37 (5): 6'; compound 19 was prepared from compound 18 as an intermediate for the preparation of Fluxametamide.
EXAMPLE 20 an oral pharmaceutical formulation against parasite infections
Table 2 the oral pharmaceutical formulation of example 20
The preparation method comprises the following steps:
(1) And (3) placing the Isocycloseram, medium-chain triglyceride, caprylic/capric acid polyethylene glycol glyceride and glycerol in a prescription amount into a liquid preparation device, setting the stirring rotation speed to be 150rpm, and mixing for 15min to uniformly mix the components, thereby obtaining the self-microemulsion solution adhesive for standby.
(2) Weighing starch, aspartame, pork liver powder, polyethylene glycol 4000 and butylated hydroxytoluene with the prescribed amount, sequentially putting the materials into a wet mixing granulator, setting the rotating speed to 300rpm, mixing for 30min, adding the self-microemulsion solution adhesive, and slicing for 10min for later use.
(3) And (3) granulating the mixed material prepared in the step (2) through a 24-mesh screen, and tabletting through a tabletting machine.
The preparation method of the compound 20 comprises the following steps:
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the starting material 20-1 and oxalyl chloride (2.0 eq) are added into a reaction bottle, the reaction is carried out for 12 hours at 20-30 ℃ in methylene dichloride, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, and the reaction is concentrated until no fraction is obtained after the reaction is completed.
Adding the initial material 20-2 (1.5 eq), triethylamine (5.0 eq) and ethyl acetate into a reaction bottle, stirring and mixing uniformly, adding the intermediate state of acyl chloride into the reaction bottle, detecting the reaction progress by Thin Layer Chromatography (TLC) in the reaction process, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, concentrating an organic phase, and recrystallizing to obtain the compound 20.
Example 21
The active ingredient is compound 21, and the amounts of other components and components in the preparation are the same as in example 20.
The preparation method of the compound 21 comprises the following steps:
the starting material 20-1 and oxalyl chloride (2.0 eq) are added into a reaction bottle, the reaction is carried out for 12 hours at 20-30 ℃ in methylene dichloride, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, and the reaction is concentrated until no fraction is obtained after the reaction is completed.
Adding the starting material 21-2 (1.3 eq), triethylamine (4.0 eq) and ethyl acetate into a reaction bottle, stirring and mixing uniformly, adding the intermediate acid chloride into the reaction bottle, detecting the reaction progress by Thin Layer Chromatography (TLC) in the reaction process, adding 1M hydrochloric acid to terminate the reaction after the reaction is completed, concentrating an organic phase, and recrystallizing to obtain the compound 21.
Example 22
The active ingredient was compound 22, and the amounts of other components and each component in the formulation were the same as in example 20.
The preparation method of the compound 22 comprises the following steps:
the starting material 20-1 and oxalyl chloride (2.0 eq) are added into a reaction bottle, the reaction is carried out for 12 hours at 20-30 ℃ in methylene dichloride, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, and the reaction is concentrated until no fraction is obtained after the reaction is completed.
The starting material 16-2 (1.3 eq), triethylamine (5.0 eq) and tetrahydrofuran are added into a reaction bottle, stirred and mixed uniformly, the intermediate state of acyl chloride is added into the reaction bottle, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, 1M hydrochloric acid is added after the reaction is completed to terminate the reaction, and the organic phase is concentrated and recrystallized to obtain the compound 22.
Example 23
The active ingredient was compound 23, and the amounts of other components and each component in the formulation were the same as in example 20.
The preparation method of the compound 23 comprises the following steps:
the starting material 20-1 and oxalyl chloride (2.0 eq) are added into a reaction bottle, the reaction is carried out for 12 hours at 20-30 ℃ in methylene dichloride, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, and the reaction is concentrated until no fraction is obtained after the reaction is completed.
The starting material 23-2 (1.3 eq), triethylamine (3.0 eq) and tetrahydrofuran are added into a reaction bottle, stirred and mixed uniformly, the intermediate state of acyl chloride is added into the reaction bottle, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, 1M hydrochloric acid is added after the reaction is completed to terminate the reaction, and the organic phase is concentrated and recrystallized to obtain the compound 23.
Example 24
The active ingredient is compound 24, and the other components and the amounts of the components in the preparation are the same as in example 20.
The preparation method of the compound 24 comprises the following steps:
the starting material 20-1 and oxalyl chloride (2.0 eq) are added into a reaction bottle, the reaction is carried out for 12 hours at 20-30 ℃ in methylene dichloride, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, and the reaction is concentrated until no fraction is obtained after the reaction is completed.
The initiator 24-2 (1.5 eq), triethylamine (5.0 eq) and tetrahydrofuran are added into a reaction bottle, stirred and mixed uniformly, the intermediate state of acyl chloride is added into the reaction bottle, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, 1M hydrochloric acid is added after the reaction is completed to terminate the reaction, and the organic phase is concentrated and recrystallized to obtain the compound 24.
Example 25
The active ingredient was compound 25, and the amounts of other components and each component in the formulation were the same as in example 20.
The preparation method of the compound 25 comprises the following steps:
the starting material 20-1 and oxalyl chloride (2.0 eq) are added into a reaction bottle, the reaction is carried out for 12 hours at 20-30 ℃ in methylene dichloride, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, and the reaction is concentrated until no fraction is obtained after the reaction is completed.
The starting material 25-2 (1.2 eq), triethylamine (5.0 eq) and tetrahydrofuran are added into a reaction bottle, stirred and mixed uniformly, the intermediate state of acyl chloride is added into the reaction bottle, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, 1M hydrochloric acid is added after the reaction is completed to terminate the reaction, and the organic phase is concentrated and recrystallized to obtain the compound 25.
Example 26
The active ingredient was compound 26, and the amounts of other components and each component in the formulation were the same as in example 20.
The preparation method of the compound 26 comprises the following steps:
the initiator 26-1 and thionyl chloride (1.5 eq) are added into a reaction bottle, the reaction is carried out for 8 hours at 60-70 ℃ in toluene, the reaction progress is detected by Thin Layer Chromatography (TLC) during the reaction, and the reaction is concentrated until no fraction is obtained after the reaction is completed.
The starting materials 20-2 (1.2 eq), triethylamine (5.0 eq) and methylene dichloride are added into a reaction bottle, stirred and mixed uniformly, the intermediate state of the acyl chloride is added into the reaction bottle, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, 1M hydrochloric acid is added after the reaction is completed to terminate the reaction, and the organic phase is concentrated and recrystallized to obtain the compound 26.
Example 27
The active ingredient was compound 27, and the amounts of other components and each component in the formulation were the same as in example 20.
The preparation method of the compound 27 comprises the following steps:
the initiator 8 and thionyl chloride (1.5 eq) are added into a reaction bottle, the reaction is carried out for 8 hours at 60-70 ℃ in toluene, the reaction progress is detected by Thin Layer Chromatography (TLC) during the reaction, and the reaction is concentrated until no fraction is obtained after the reaction is completed.
The starting materials 20-2 (1.2 eq), triethylamine (4.0 eq) and tetrahydrofuran are added into a reaction bottle, stirred and mixed uniformly, the intermediate state of acyl chloride is added into the reaction bottle, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, 1M hydrochloric acid is added after the reaction is completed to terminate the reaction, and the organic phase is concentrated and recrystallized to obtain the compound 27.
Example 28
The active ingredient was compound 28, and the amounts of the other components and the respective components in the preparation were the same as in example 20.
The preparation method of the compound 28 comprises the following steps:
the initiator 6 and thionyl chloride (1.5 eq) are added into a reaction bottle, the reaction is carried out for 8 hours at 60-70 ℃ in toluene, the reaction progress is detected by Thin Layer Chromatography (TLC) during the reaction, and the reaction is concentrated until no fraction is obtained after the reaction is completed.
The starting materials 20-2 (1.3 eq), triethylamine (5.0 eq) and tetrahydrofuran are added into a reaction bottle, stirred and mixed uniformly, the intermediate state of acyl chloride is added into the reaction bottle, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, 1M hydrochloric acid is added after the reaction is completed to terminate the reaction, and the organic phase is concentrated and recrystallized to obtain the compound 28.
Example 29
The active ingredient was compound 29, and the amounts of the other components and the respective components in the preparation were the same as in example 20.
The preparation method of the compound 29 comprises the following steps:
adding the initial material 9 and oxalyl chloride (1.5 eq) into a reaction bottle, reacting for 8 hours at 20-30 ℃ in tetrahydrofuran, detecting the reaction progress by Thin Layer Chromatography (TLC) during the reaction process, concentrating until no fraction is obtained after the reaction is completed, obtaining the intermediate state of the acyl chloride
The starting materials 20-2 (1.2 eq), triethylamine (3.0 eq) and tetrahydrofuran are added into a reaction bottle, stirred and mixed uniformly, the intermediate state of acyl chloride is added into the reaction bottle, the reaction progress is detected by Thin Layer Chromatography (TLC) in the reaction process, 1M hydrochloric acid is added after the reaction is completed to terminate the reaction, and the organic phase is concentrated and recrystallized to obtain the compound 29.
Example 30
Compound 30 is according to literature: the "Sun Hongyang, yang Xu, zhang Jing, etc. fluorine Lei Lana synthesis and insecticidal activity assay [ J ]. Fine chemical engineering, 2020,37 (5): 6.
EXAMPLE 31 an oral pharmaceutical formulation against parasite infections
Table 3 oral pharmaceutical formulation of example 31
The preparation method comprises the following steps:
(1) And (3) placing the Fluximamide, medium-chain triglyceride, caprylic/capric acid polyethylene glycol glyceride and glycerol in a prescription amount into a liquid preparation device, setting the stirring rotation speed to be 150rpm, and mixing for 15min to uniformly mix the materials, thereby obtaining the self-microemulsion solution adhesive for standby.
(2) Weighing starch, aspartame, pork liver powder, polyethylene glycol 4000 and butylated hydroxytoluene with the prescribed amount, sequentially putting the materials into a wet mixing granulator, setting the rotating speed to 300rpm, mixing for 30min, adding the self-microemulsion solution adhesive, and slicing for 10min for later use.
(3) And (3) granulating the mixed material prepared in the step (2) through a 24-mesh screen, and tabletting through a tabletting machine.
EXAMPLE 32 an oral pharmaceutical formulation against parasite infections
Table 4 the oral pharmaceutical formulation of example 32
The preparation method comprises the following steps:
(1) Taking prescribed amounts of Fluximamide, milbexime, medium-chain triglyceride, caprylic/capric polyethylene glycol glyceride and glycerol, placing into a liquid preparation device, setting stirring rotation speed to 150rpm, mixing for 15min, and uniformly mixing to obtain the self-microemulsion solution adhesive for later use.
(2) Weighing starch, aspartame, pork liver powder, polyethylene glycol 4000 and butylated hydroxytoluene with the prescribed amount, sequentially putting the materials into a wet mixing granulator, setting the rotating speed to 300rpm, mixing for 30min, adding the self-microemulsion solution adhesive, and slicing for 10min for later use.
(3) And (3) granulating the mixed material prepared in the step (2) through a 24-mesh screen, and tabletting through a tabletting machine.
EXAMPLE 33 an oral pharmaceutical formulation against parasite infections
Table 5 the oral pharmaceutical formulation of example 33
The preparation method comprises the following steps:
(1) And (3) placing the Isocycloseram, milbexime, medium-chain triglyceride, caprylic-capric acid polyethylene glycol glyceride and glycerol with the prescribed amounts in a liquid preparation device, setting the stirring rotation speed to be 150rpm, and mixing for 15min to uniformly mix the components, thereby obtaining the self-microemulsion solution adhesive for standby.
(2) Weighing starch, aspartame, pork liver powder, polyethylene glycol 4000 and butylated hydroxytoluene with the prescribed amount, sequentially putting the materials into a wet mixing granulator, setting the rotating speed to 300rpm, mixing for 30min, adding the self-microemulsion solution adhesive, and slicing for 10min for later use.
(3) And (3) granulating the mixed material prepared in the step (2) through a 24-mesh screen, and tabletting through a tabletting machine.
EXAMPLE 34 an oral pharmaceutical formulation against parasite infections
Table 6 the oral pharmaceutical formulation of example 34
The preparation method comprises the following steps:
(1) And (3) placing the Isocycloseram, medium-chain triglyceride, caprylic/capric acid polyethylene glycol glyceride and glycerol in a prescription amount into a liquid preparation device, setting the stirring rotation speed to be 150rpm, and mixing for 15min to uniformly mix the components, thereby obtaining the self-microemulsion solution adhesive for standby.
(2) Weighing starch, aspartame, pork liver powder, polyethylene glycol 4000 and butylated hydroxytoluene with the prescribed amount, sequentially putting the materials into a wet mixing granulator, setting the rotating speed to 300rpm, mixing for 30min, adding the self-microemulsion solution adhesive, and slicing for 10min for later use.
(3) And (3) granulating the mixed material prepared in the step (2) through a 24-mesh screen, and tabletting through a tabletting machine.
The nuclear magnetic hydrogen spectrum data and mass spectrum data for compounds 1-30 are shown in the following table:
table 7 Nuclear magnetic Hydrogen Spectrometry and Mass Spectrometry data for Compounds 1-30
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Comparative example 1 an oral pharmaceutical formulation against parasitic infection
Table 8 oral pharmaceutical formulation recipe for comparative example 1
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The preparation method comprises the following steps:
(1) Sequentially adding starch, aspartame, pork liver powder, polyethylene glycol 4000, butylhydroxytoluene and Fluxamide with a prescription amount into a wet mixing granulator, setting the rotating speed to 300rpm, mixing for 30min, adding medium chain triglyceride, cutting for 10min, and discharging for later use.
(2) And (3) granulating the mixture prepared in the step (1) through a 24-mesh screen, and tabletting through a tabletting machine.
Comparative example 2 an oral pharmaceutical formulation against parasitic infection
Table 9 oral pharmaceutical formulation of comparative example 2
The preparation method comprises the following steps:
(1) Sequentially adding starch, aspartame, pork liver powder, polyethylene glycol 4000, butylhydroxytoluene and Isocycloseram with a prescription amount into a wet mixing granulator, setting the rotating speed to 300rpm, mixing for 30min, adding medium chain triglyceride, cutting for 10min, and discharging for later use.
(2) And (3) granulating the mixture prepared in the step (1) through a 24-mesh screen, and tabletting through a tabletting machine.
Example 33 in vitro dissolution measurement
The oral preparations of example 1, example 20 and comparative examples 1 and 2 were subjected to dissolution measurement using 3% CTAB-pH 6.8 phosphate as a dissolution medium at a rotation speed of 100r/min, operated according to the method, sampled at different times by the method at 37.+ -. 0.5 ℃ respectively, filtered, and the subsequent filtrate was subjected to sample content measurement by HPLC method, and the dissolution amount was calculated. The whole tablets were measured and the simulated pet chewed, and the tablets were broken to dissolve. The detection results are shown in the following table:
Table 10 dissolution test results of oral formulations (n=12)
As can be seen from Table 10, the dissolution rate of the oral preparation of the invention is obviously increased, more than 80% of active ingredient is released within 15min, and the RSD value is smaller, which proves that the release stability of the oral preparation is obviously higher than that of the conventional oral tablet.
EXAMPLE 34 blood concentration test
The oral preparations of example 1, example 20 and comparative examples 1 and 2 were orally administered to dogs (6 animals/group, 3 animals/female) at a dose of 5mg/kg body weight. Plasma samples were collected from all dogs on day 0, day 1, day 3, day 5, day 7 and weekly thereafter until day 35, 2 hours, 4 hours, 8 hours before and after dosing. Plasma was analyzed for Fluxamethamide and Isocycloseram concentrations. The detection results are shown in the following table:
table 11 pharmacokinetic results of oral formulations (n=6)
As can be seen from Table 11, the oral preparation of the present invention has a rapid drug release rate, achieves Cmax within 4 hours, and has a Cmax much higher than that of conventional oral tablets, and improves the bioavailability of the active ingredient in vivo.
EXAMPLE 35 test for evaluating efficacy of insect repellent
(1) In vitro insect repellent (tick)
In this evaluation, beagle dogs of mixed gender were used and assigned to the blank control group, the commercially available positive group, and the inventive example group (examples 1, 3, 4, 6, 7, 9, 10, 11, 16, 18, 20, 23, 24, 27, 28, 29, 31, 32, 33, 34), and the experimental dogs were challenged with 50 adult ticks that were not fed (rhizus).
Dogs were treated on day 0 with oral formulations at a dose of 25mg/kg of fluorine Lei Lana, 5mg/kg of isoxazolines and 2.5mg/kg of milbexime in the example group of the invention. Average rates of detection of ticks in dogs at day 0, day 5, day 10, day 20 and day 30 after dosing were counted for each group of drugs, and any immediate response of dogs to treatment was observed at day 1, day 2 and day 7 after dosing, as well as adverse effects, skin irritation and the characteristics of the test formulations after treatment.
Table 12 average detection rate of drug against in vitro ticks
(2) External insect repellent (flea)
In this evaluation, beagle dogs of mixed gender were used and assigned to the blank control group, the commercially available positive group, and the inventive example group (examples 1, 2, 5, 8, 12, 13, 14, 15, 17, 19, 20, 21, 22, 25, 26, 30, 31, 32, 33, 34), the experimental dogs were challenged with 50 non-fed adult fleas (Chlamydia felis).
Oral formulations were administered at a dose of 25mg/kg of fluorine Lei Lana, 5mg/kg of the isoxazoline derivative and 2.5mg/kg of milbexime in the example group of the present invention, at day 0 the dogs received treatment. The dose is administered in the form of a line at the back neck of the skull base.
Average rates of detection of ticks in dogs at day 0, day 5, day 10, day 20 and day 30 after dosing were counted for each group of drugs, and any immediate response of dogs to treatment was observed at day 1, day 2 and day 7 after dosing, as well as adverse effects, skin irritation and the characteristics of the test formulations after treatment.
Table 13 mean detection rate of drugs against fleas in vitro
(3) In vitro insect repellent (mite)
In this evaluation, beagle dogs of mixed sex were used and assigned to a blank control group, a commercially available positive group and an experimental group of the present invention (examples 32 to 34), and the experimental dogs were infested with 50 non-feeding adult mites (ear mites).
Dogs received treatment on day 0 at a dose of 5mg/kg Fluximamide, 5mg/kg Isoxycloseram and 2.5mg/kg milbexime. The formulation was administered using a pipette. The dose is administered in the form of a line at the back neck of the skull base.
Average rates of detection of ticks in dogs at day 0, day 5, day 10, day 20 and day 30 after dosing were counted for each group of drugs, and any immediate response of dogs to treatment was observed at day 1, day 2 and day 7 after dosing, as well as adverse effects, skin irritation and the characteristics of the test formulations after treatment.
Table 14 average detection rate of drug against in vitro mites
(4) Insect repellent in vivo
In this evaluation, beagle dogs of mixed sex were used and assigned to a blank control group, a commercially available positive group and a test group (examples 32 to 34), and the test dogs were found to be infected with a large number of intestinal parasites including hookworm, whipworm, roundworm, tapeworm, and the like by a laboratory fecal floatation method and a direct smear method.
Dogs received treatment on day 0 at a dose of 5mg/kg Fluximamide, 5mg/kg Isoxycloseram and 2.5mg/kg milbexime. The formulation was administered using a pipette. The dose is administered in the form of a line at the back neck of the skull base.
Average detection rates of nematodes and tapeworms in dogs were counted for each group of drugs on days 0, 5, 10, 20 and 30 after administration, and any immediate response of dogs to treatment was observed on days 1, 2 and 7 after administration, and adverse reactions, skin irritation and properties of the test preparations after treatment were observed.
Table 15 average rate of detection of nematodes in vivo with drugs
As can be seen from tables 12-15, the invention has obvious insecticidal effect on the internal and external parasites of dogs, the detection rate is lower than that of a blank control group and a commercial positive group, the action time is long, and the invention has good in-vitro and in-vivo insecticidal effect at 30 days. The test result shows that the long-acting compound vermifuge liquid preparation prepared by the embodiment of the invention has good vermifuge effect on internal and external parasites of dogs within 30 days.
The above embodiments are merely preferred embodiments of the present invention and are not intended to limit the present invention, and any modifications, equivalent substitutions, improvements, etc. within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. An oral pharmaceutical formulation for combating parasitic infections, characterized in that: the oral pharmaceutical preparation comprises a filler, a flavoring agent, a phagostimulant, a forming agent, a preservative and a binder containing a first active component, wherein the first active component is an isoxazoline compound.
2. An oral pharmaceutical formulation against parasitic infection according to claim 1, wherein: the adhesive comprises isoxazoline compounds, solvents, surfactants and cosurfactants; preferably, the structural general formula of the isoxazoline compound is shown as formula (I):
wherein R is 1 Selected from H, OH, CN, NO 2 、OCH 3 、CF 3 、N(CH 3 ) 2 Br or F;
R 2 selected from the group consisting of NH 2 、/>OH、/> More preferably, R 1 Selected from H or F, R 2 Selected from->
3. An oral pharmaceutical formulation against parasitic infection according to claim 1, wherein: the isoxazoline compound is selected from the following compounds 1-30:
4. an oral pharmaceutical formulation against parasitic infection according to claim 2, wherein: the solvent is one or a combination of more of soybean oil, corn oil and medium chain triglyceride, and more preferably, the solvent is medium chain triglyceride;
Preferably, the surfactant is one or more of polyethylene glycol, stearate, stearoyl polyoxyethylene glyceride, diethylene glycol monoethyl ether, caprylic capric acid polyethylene glycol glyceride, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20) sorbitan tristearate, propylene glycol dicaprylate, propylene glycol dilaurate, propylene glycol ricinoleate, and sodium laurate, and more preferably, the solvent is caprylic capric acid polyethylene glycol glyceride;
preferably, the cosurfactant is one or a combination of a plurality of propylene glycol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol, isoamyl alcohol, 1-hexanol, 2-hexanol, 1-octanol, 2-octanol, fusel oil, p-nonylphenol, ethanol and glycerin, and more preferably, the solvent is glycerin.
5. An oral pharmaceutical formulation against parasitic infection according to claim 1, wherein: the filler is one or more of lactose, microcrystalline cellulose, mannitol, sorbitol, starch, sucrose, dextrin, calcium sulfate, calcium hydrogen phosphate, calcium carbonate and calcium sulfate dihydrate, and more preferably the filler is starch;
Preferably, the flavoring agent is one or more of sucrose, simple syrup, citric syrup, licorice syrup, glycerin, sorbitol, saccharin sodium, sodium alginate, stevioside, mannitol and aspartame, and more preferably, the flavoring agent is aspartame;
preferably, the phagostimulant is one or a combination of more than one of chicken liver powder, pork liver powder, beef powder, fish meal, chicken oil, chicken bone powder, lard, plant essence, animal essence and compound amino acid, more preferably, the phagostimulant is pork liver powder;
preferably, the forming agent is one or a combination of several of polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 3350, polyethylene glycol 4000, glycerin, propylene glycol, sorbitol and polysorbate, more preferably, the forming agent is polyethylene glycol 4000;
preferably, the preservative is one or a combination of a plurality of benzyl alcohol, methyl benzoate, propyl benzoate and butyltoluene, and more preferably, the preservative is butylhydroxytoluene.
6. An oral pharmaceutical formulation against parasitic infection according to claim 1, wherein: the oral pharmaceutical preparation comprises the following components in proportion:
The addition amount of the adhesive accounts for 5-15% of the total mass of the oral pharmaceutical preparation,
wherein, the addition of the isoxazoline compound accounts for 5-15% of the total mass of the adhesive, the addition of the solvent accounts for 20-50% of the total mass of the adhesive, the addition of the surfactant accounts for 10-40% of the total mass of the adhesive, and the addition of the cosurfactant accounts for 10-50% of the total mass of the adhesive;
the addition amount of the filler accounts for 70-80% of the total mass of the oral pharmaceutical preparation;
the addition amount of the flavoring agent is 0.1-2.0% of the total mass of the oral pharmaceutical preparation;
the addition amount of the phagostimulant is 0.1-2.0% of the total mass of the oral pharmaceutical preparation;
the addition amount of the forming agent accounts for 5-20% of the total mass of the oral pharmaceutical preparation;
the addition amount of the preservative accounts for 0.1-2.0% of the total mass of the oral pharmaceutical preparation.
7. A process for the preparation of an oral pharmaceutical formulation against parasitic infections according to any one of claims 1 to 6, characterized in that: the method comprises the following steps:
(1) Adding a surfactant, a cosurfactant and a solvent into an isoxazoline compound, and uniformly mixing to obtain an adhesive;
(2) Adding the adhesive in the step (1) into a filling agent, a flavoring agent, a phagostimulant, a forming agent and a preservative, and uniformly mixing;
(3) Sieving the mixture obtained in the step (2), and pressing to obtain the oral medicinal preparation for resisting parasite infection.
8. An oral pharmaceutical formulation against parasitic infection according to claim 1, wherein: the adhesive also comprises a second active component, wherein the second active component is one or more of the following compounds:
(a) Pyrethroids;
(b) A macrolide compound;
(c) Insect growth regulators;
(d) Carbamates;
(e) Formamidines;
(f) A nicotinoyl chloride;
(g) Imidazothiazoles;
(h) Benzimidazoles;
(i) Tetrahydroimidazoles;
(j) Isoquinolines;
(k) Salicylanilides;
preferably, the pyrethroid compound is selected from one or more of permethrin, cypermethrin, deltamethrin, fenpropathrin, flumethrin, fenvalerate, phenothrin, tetramethrin and allethrin; the macrolide compound is one or more selected from ivermectin, siramectin, moxidectin, spinosad, milbemycin, avermectin and Ai Mode s; the insect growth regulator is selected from one or more of pyriproxyfen, lufenuron, desiccanil, s-methoprene, antifebrile, tebufenozide, diflubenzuron, chlorfluazuron, hexaflumuron, diafenthiuron, buprofezin and cyromazine; the carbamate compound is selected from one or more of indoxacarb, propoxur, isoprocarb, aldicarb, methomyl and carbofuran; the formamidine compound is selected from amitraz; the nicotinoyl chloride compound is one or more selected from dinotefuran, nitenpyram and thiamethoxam;
Preferably, the oral pharmaceutical preparation comprises the following components in proportion:
and (2) an adhesive: the addition amount of the adhesive accounts for 5-15% of the total mass of the oral pharmaceutical preparation,
wherein, the addition of the first active ingredient accounts for 5-15% of the total mass of the adhesive, the addition of the second active ingredient accounts for 5-15% of the total mass of the adhesive, the addition of the solvent accounts for 20-50% of the total mass of the adhesive, the addition of the surfactant accounts for 10-40% of the total mass of the adhesive, and the addition of the cosurfactant accounts for 10-50% of the total mass of the adhesive;
the addition amount of the filler accounts for 70-80% of the total mass of the oral pharmaceutical preparation;
the addition amount of the flavoring agent is 0.1-2.0% of the total mass of the oral pharmaceutical preparation;
the addition amount of the phagostimulant is 0.1-2.0% of the total mass of the oral pharmaceutical preparation;
the addition amount of the forming agent accounts for 5-20% of the total mass of the oral pharmaceutical preparation;
the addition amount of the preservative accounts for 0.1-2.0% of the total mass of the oral pharmaceutical preparation.
9. A method of preparing an oral pharmaceutical formulation for combating parasitic infections according to claim 8, wherein: the method comprises the following steps:
(1) Adding a surfactant, a cosurfactant and a solvent into the first active component and the second active component, and mixing until the mixture is uniform to obtain an adhesive;
(2) Adding the adhesive in the step (1) into a filling agent, a flavoring agent, a phagostimulant, a forming agent and a preservative, and uniformly mixing;
(3) Sieving the mixture obtained in the step (2), and pressing to obtain the oral medicinal preparation for resisting parasite infection.
10. Use of an oral pharmaceutical formulation according to any one of claims 1-6, 8 for the preparation of a medicament for the treatment or prophylaxis of parasitic infections in non-human animals.
CN202210549794.1A 2022-05-20 2022-05-20 Oral medicinal preparation for resisting parasitic infection, and preparation method and application thereof Pending CN117122571A (en)

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TWI556741B (en) * 2007-08-17 2016-11-11 英特威特國際股份有限公司 Isoxazoline compositions and their use as antiparasitics
EP2833867B2 (en) * 2012-04-04 2023-05-10 Intervet International B.V. Solid oral pharmaceutical compositions for isoxazoline compounds
AU2015343387A1 (en) * 2014-11-03 2017-05-18 Zoetis Services Llc Palatable chewable veterinary composition
CA3146043A1 (en) * 2019-07-22 2021-01-28 Intervet International B.V. Soft chewable veterinary dosage form
US20230372249A1 (en) * 2020-09-04 2023-11-23 Elanco Us Inc. Palatable formulations

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