WO2017096530A1 - 癸氧喹酯固体分散体、其制备方法和用途 - Google Patents

癸氧喹酯固体分散体、其制备方法和用途 Download PDF

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WO2017096530A1
WO2017096530A1 PCT/CN2015/096689 CN2015096689W WO2017096530A1 WO 2017096530 A1 WO2017096530 A1 WO 2017096530A1 CN 2015096689 W CN2015096689 W CN 2015096689W WO 2017096530 A1 WO2017096530 A1 WO 2017096530A1
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hot melt
solid dispersion
polyethylene glycol
quinoxalate
composition
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PCT/CN2015/096689
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English (en)
French (fr)
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王洪星
范银洲
陈雪清
陈小平
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广州中科蓝华生物科技有限公司
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Priority to EP15910005.6A priority Critical patent/EP3388065B1/en
Priority to US15/531,244 priority patent/US10265270B2/en
Priority to JP2018529160A priority patent/JP6698161B2/ja
Priority to CN201580057788.2A priority patent/CN107427504B/zh
Priority to PCT/CN2015/096689 priority patent/WO2017096530A1/zh
Priority to GB1810964.5A priority patent/GB2561497B/en
Publication of WO2017096530A1 publication Critical patent/WO2017096530A1/zh

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    • 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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the field of medical technology, and in particular to a composition for hot melt extrusion, a method for preparing a hot melt extruded product using the hot melt extrusion composition, and the obtained quinoxaline solid dispersion And the pharmaceutical use of the composition and the solid dispersion of quinoxalate.
  • Malaria is an insect-borne disease caused by infection with Plasmodium by Anopheles bites or by inputting blood from patients with Plasmodium.
  • Plasmodium parasitic There are four types of Plasmodium parasitic in humans, namely Plasmodium vivax, Plasmodium falciparum, Plasmodium falciparum and Plasmodium ovale.
  • Plasmodium vivax Plasmodium falciparum
  • Plasmodium falciparum Plasmodium falciparum
  • Plasmodium ovale There is also a malaria that can be caused by both humans and monkeys caused by Plasmodium knowlesi. The main manifestations of this disease are periodic regular attacks, fever, excessive sweating, weakness, vomiting, and headache; after long-term multiple episodes, it can cause anemia and splenomegaly. Patients with falciparum malaria who are not treated promptly can cause cerebral malaria and death.
  • Plasmodium is divided into human infected Plasmodium and Plasmodium infected with other animals, depending on the host.
  • the life cycle of infected human Plasmodium is divided into two parts in the human body and in the Anopheles; in the human body, it is divided into the liver phase and the red blood cell phase.
  • Artemisinin an antimalarial drug invented by Chinese scientists, and most traditional antimalarial drugs such as chloroquine are drugs that act on the red blood cell phase, but not on the liver stage of the malaria parasite. Artemisinin is currently the most important antimalarial Disease medicine. Chinese manufacturers provide 90% of artemisinin APIs. The three WHO's finished drug suppliers are all foreign companies, because the artemisinin dosage forms with high foreign demand are not available in China.
  • Plasmodium In addition to extensive resistance to chloroquine and sulfonamides, Plasmodium also exhibits resistance to the first line of antimalarial drugs, the artemisinin component of the core drug based on artemisinin. (Ariey, F. et al. A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature 505, 50-55, 2014). Primaquine is a relatively new anti-malarial drug for the liver stage. However, these drugs have strong side effects.
  • Decoquinate (CAS No. 18507-89-6) is a coccidiosis inhibitor mainly used in poultry and cattle, horses, sheep and other animals, and is widely used worldwide including China. Its main site of action is the intestinal tract, which is used for anti-coccidial infections. In recent years, it has been found that quinoxalate has strong inhibition and killing of malaria parasites in both in vitro and in vivo experiments (Science 2011; 334: 1372-7). In terms of anti-malarial efficacy, it has obvious advantages over existing anti-malarial drugs (JID 2012: 205: 1278-86); its mechanism of action is to inhibit the cytochrome bcl complex of Plasmodium mitochondria.
  • the quinoxalate inhibited the development of Plasmodium in the liver stage and the growth of erythrocytes. Whether as a veterinary drug or in an animal toxicology experiment, no quinoxalate has been found to have significant side effects and toxic effects.
  • the experimental results of the inventors of the present invention and other researchers have shown that the chloroquine-resistant Plasmodium is not resistant to quinoxalate (see, a quinoxalate nano-formulation and its preparation method and application; JID 2012) :205:1278-86).
  • quinoxalate also has neurotoxicity against Sarcocystis (Intern J Appl Res Vet Med. Vol. 10, No. 1, 2012) and Toxoplasma gondii (Veterinary Record, 1996 [138] 434-436). Very good killing effect.
  • Oxaquine ester molecular weight 417.54, low water solubility, high lipophilicity (log Kow value 5.2-5.5), can be Learn to synthesize.
  • the oxime quinolate has a very low water solubility and a poor absorption rate in the intestine. When used as a veterinary drug against coccidiosis, it can be absorbed into the body without intestinal absorption. However, oral dosage forms are still the most convenient and feasible method of administration. Therefore, in order to develop anti-malarial drugs, it is necessary to solve the problem of effective absorption from the intestinal tract.
  • the intestinal absorption and bioavailability of the drug can be increased by making salts, enhancing solubility, and reducing particle size.
  • Various attempts to make quinoxalate a salt to enhance its water solubility have failed to work.
  • a preparation prepared by adding a surfactant or a method of reducing the particle size can improve the release of quinoxalate in the body and the anti-malarial effect.
  • this approach typically requires an organic solvent, requires multiple processes, and requires a longer manufacturing process.
  • the method for preparing a solid dispersion of quinoxalate by a hot melt method solves the problem that it is hardly soluble in water to some extent, but the process is relatively troublesome, the compound is easily decomposed by heat, and is not easily processed into a finished drug, but only applies to Veterinary medicine.
  • Solid dispersion is a commonly used preparation method. It refers to a poorly soluble or water-insoluble drug molecule containing colloids, microcrystals or amorphous materials. It is uniformly dispersed in a solid state in another water solution before adding water. In the substance.
  • Hot melt extrusion method is a new technology developed in the field of pharmacy in recent years to solve the problem of poorly soluble compounds. This technology combines the advantages of solid dispersion technology and mechanical preparation process, through the segmentation in the hot melt extruder.
  • Heating, twin-screw rotation and die assembly for material transport, mixing, shearing, melting and extrusion, the extrudate is a solid dispersion; this method does not require an organic solvent and can be continuously small scale or Large-scale preparation is therefore not only suitable for research and development, but also for commercial production.
  • thermally unstable drugs or polymer carriers are not suitable for hot melt or hot melt extrusion, degradation of drugs or excipients, and the production of related substances may reduce the efficacy and safety of the agents, and thus need to be avoided. The main reason for using hot melt extrusion.
  • the present invention provides a composition for hot melt extrusion, characterized in that, by weight percent, the composition comprises:
  • Polymer carrier material 60%-90%;
  • the polymeric carrier material is one or two of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, copolyvidone, povidone or polyethylene glycol. More than one combination.
  • the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer is Soluplus; the Soluplus acts in both a solid solution and solubilization.
  • the copovidone is Kollidon VA 64; the Kollidon VA 64 has a moisturizing effect to increase the drug loading and aid in reconstitution of the solid dispersion.
  • the povidone is povidone k17, povidone k25, povidone k30 or polyvinylpyrrolidone-10; the povidone has a moisturizing effect and contributes to solubilization Reconstituted with the solid dispersion.
  • the polyethylene glycol is polyethylene glycol 8000, polyethylene glycol 6000 or polyethylene glycol 4000; the polyethylene glycol mainly plays a suitable role in lowering the melting temperature during the melting process.
  • the circulation time in the blood in the body, prolonging the half-life, is conducive to improving the efficacy.
  • the surfactant is any one of sodium lauryl sulfate, lauric acid polyethylene glycol glyceride, stearic acid polyethylene glycol glyceride or polyoxyethylene hydrogenated castor oil. Or a combination of several; the surfactant is a formulation auxiliary for enhancing the water solubility of the poorly soluble compound, and the active ingredient quinoxalate is used as a molecule Or a very small particle state is dispersed therein, thereby contributing to enhancing the water solubility of the quinoxalate.
  • the lauric acid polyethylene glycol glyceride is Gelucire 44/14;
  • the stearic acid polyethylene glycol glyceride is Gelucire 50/13;
  • the polyoxyethylene hydrogenated castor oil is Kolliphor RH 40; the Kolliphor RH 40 may suitably adjust the melting temperature range, the respective components of the adhesive preparation, and lower the active ingredient during the melting of the composition.
  • the effect of the possibility of degradation of oxyquinol esters facilitates the formation of a solid dispersion of decylquinolate of uniform density.
  • the polymer material used in the present invention has a thermoplastic behavior, is deformable in a molten state, and has high thermal stability, is non-toxic, and can be solubilized; the surfactant selected in the present invention is also CFDA-compliant. And the FDA and other authorities approved hot melt excipients that can be used for clinical pharmacy without safety hazards.
  • the present invention provides a process for the preparation of a solid dispersion of quinoxalate, comprising: hot melt extruding the composition of the first aspect at a hot melt temperature.
  • the hot melt extrusion is carried out in a hot melt extruder; in particular, the composition as described in the first aspect is uniformly mixed and then added to a twin screw hot melt extruder through Different temperature treatment in different sections of the machine, pushing by twin-screw extrusion, processing of die forming, extrudate naturally cooling at room temperature, forming a strip-shaped solid mixture; the strip-shaped solid mixture is sheared, By pulverization, a powdery quinoxaline solid dispersion is obtained.
  • the hot melt extrusion temperature is from 50 to 200 ° C, preferably from 120 to 200 ° C; preferably, the hot melt extruder has a screw rotation speed of from 15 to 300 rpm, more preferably 20-150 rpm.
  • the melting temperature it is necessary to adjust the melting temperature according to the composition of the raw material composition, and the active ingredient quinoxaline is effectively mixed at a molecular level with the polymeric carrier material as an auxiliary material. It is also necessary to avoid thermal decomposition of the quinoxalate and the auxiliary materials.
  • Melting point is The temperature at which a solid transforms (melts) its state from a solid state to a liquid state, and is generally expressed by Tm.
  • Tm the temperature at which a solid transforms (melts) its state from a solid state to a liquid state
  • Tm the temperature at which a solid transforms (melts) its state from a solid state to a liquid state
  • Tm the temperature at which a solid transforms
  • the inventors of the present invention can design a composition of a specific composition comprising a nonoxyquine ester for hot melt extrusion so that the quinoxaline ester can be low when it is mixed with a polymer carrier material, a surfactant, or the like. It becomes a liquid at the temperature of its own melting point, which reduces the possibility of thermal decomposition and is beneficial for retaining its original structure and pharmacodynamic activity.
  • the present invention provides a solid dispersion of quinoxaline, which is produced by the preparation method as described in the second aspect.
  • the chemical structure of the active ingredient quinoxalate does not change, and therefore, the pharmacodynamic activity thereof is not lost;
  • the quinolate solid dispersion is easily suspended in the aqueous phase, in a uniform system in the aqueous phase, and does not precipitate in one week; in addition, the oxime sequence release rate and dissolution of the quinoxalate solid dispersion of the present invention Both are significantly improved, and the bioavailability and anti-malarial effects in animals are also significantly improved.
  • the present invention provides the pharmaceutical preparation according to the first aspect or the solid dispersion of quinoxalate as described in the third aspect for the preparation of a medicament for preventing and/or treating a disease caused by Plasmodium Use in
  • the disease is any one or more of vivax malaria, falciparum malaria, three-day malaria, oval malaria, and nova malaria.
  • the solid dispersion of the quinoxaline can be prepared into an oral dosage form such as a tablet, a granule or a filled capsule as needed.
  • the hot melt extrusion technique employed in the present invention is a technique for producing an amorphous solid dispersion in which a quinoxaline ester is dispersed or dispersed in a carrier material by melting or dissolving to produce and stabilize an amorphous form.
  • the form of quinoxalate compared with the simple hot melt method, the hot melt extrusion technology has the advantage of mechanical process, the mixing effect is excellent, and the active ingredient and all the components of the preparation are not thermally decomposed; and, the whole process does not need Organic solvent It reduces environmental pollution and simplifies the processing process.
  • the quinoxaline ester in the form of a solid dispersion can be considered as a solid solution or a solution.
  • Functional excipients such as surfactants, binders and the like are also added to the mixture to aid in the melt processing process and to improve the dissolution efficiency after administration of the formulation.
  • the improvement of dissolution efficiency enhances the intestinal absorption effect, and increases the bioavailability and biological activity in the body.
  • the melt is extruded through a shaped outlet and, after rapid cooling, remains a solid, single-phase, glassy amorphous matrix which is stable on the shelf.
  • post-extrusion processing equipment can be introduced to dominate the shape of the extrudate to meet the requirements for easy downstream processing into a dosage form.
  • these extruded materials are ground to reduce their granules so that they can be incorporated into conventional oral solid dosage forms, such as tablets or capsules, while maintaining the desired release profile for the drug.
  • the invention adopts a hot melt extrusion technique to prepare a solid dispersion of quinoxalate, and the inventors select a specific preparation auxiliary, a specific main drug and an auxiliary compound ratio, so that the oxime quinolate is in contact with the polymer carrier material and surface active.
  • the auxiliary agent When the auxiliary agent is mixed, it can be liquid at a temperature lower than its own melting point, which greatly reduces the possibility of thermal decomposition, and is beneficial for retaining its original structure and pharmacodynamic activity; further, the inventors passed Optimize the mechanical parameters, so that the active compound quinoxalate and the hot-melt auxiliary material are uniformly melted, and the extruded material is uniform, which is superior to the organic solvent method in enhancing the oral bioavailability and efficacy of the quinoxalate; and, and the organic solvent method Compared with the related products prepared by the hot melt method, the preparation method of the invention is more likely to improve the production efficiency, and thus it is easier to develop the laboratory results to the pilot level and the industrialization level, so as to be extended to the clinical application.
  • Fig. 1 is a comparison of the in vitro dissolution of the terpoxacin solid dispersion prepared in Example 1, Comparative Example 1, and the oxime quinolate.
  • Example 2 is a comparison of the in vitro dissolution rates of the terpoxacin solid dispersion prepared in Example 2, Comparative Example 2, and the oxime quinolate.
  • Example 3 is a solid dispersion of a nonoxyquinolate prepared in Example 3 and Comparative Example 3, and a body of a guanidinoquinone original drug. Comparison of external dissolution.
  • Example 4 is a comparison of the in vitro dissolution rates of the terpoxacin solid dispersion prepared in Example 4, Comparative Example 4, and the oxime quinolate.
  • Figure 5 is a comparison of the in vitro dissolution of the terpoxacin solid dispersion prepared in Example 5, Comparative Example 5, and the oxime quinolate.
  • Figure 6 is a comparison of the in vitro dissolution of the terpoxacin solid dispersion prepared in Example 6, Comparative Example 6, and the oxime quinolate.
  • Fig. 7 is a comparison of in vitro dissolution of the terpoxacin solid dispersion prepared in Example 7, Comparative Example 7, and the oxime quinolate.
  • Figure 8 is a comparison of the in vitro dissolution of the terpoxacin solid dispersion prepared in Example 8, Comparative Example 8, and the oxime quinolate.
  • FIG. 9A is a thermogravimetric (TG) analysis chart of a drug substance compound (standard) quinoxalate
  • FIG. 9B is a high pressure liquid chromatography of quinoxalate in a solid dispersion of oxime quinolate prepared in Example 1. Analysis chart.
  • Figure 10 is a hot-melt extrudate of the drug substance compound quinoxaline, the hydrazide-containing hot melt extrudate prepared in Example 1, the components other than the quinoxalate in Example 1, and Differential scanning calorimetry (DSC) of physical mixing of quinoxalate with excipients at ambient temperature.
  • DSC Differential scanning calorimetry
  • Figure 11 is a high pressure liquid chromatogram of a quinoxalate starting drug (i.e., a standard).
  • Figure 12 is a high pressure liquid chromatogram of a nonoxyquinol ester solid dispersion prepared by a hot melt method in Comparative Example 3; this figure shows that after preparation by a simple hot melt method, the oxime quinolate The peak shape in the high pressure liquid chromatogram has changed significantly.
  • Figure 13 is a high pressure liquid chromatogram of the oxime quinolate in a solid dispersion of quinoloquine prepared by hot melt extrusion (HME) technique of Example 3; the figure shows that after preparation by hot melt extrusion technique, There was no change in peak shape and residence time in the high pressure liquid chromatogram of quinoxaline.
  • HME hot melt extrusion
  • Figure 14 is a pharmacokinetics of Example 1 and Comparative Example 1; wherein the ordinate represents the concentration of quinoxalate in plasma and the abscissa represents the time of blood sampling of the animal.
  • Figure 15 is an animal efficacy test of the product prepared in Example 1.
  • DQ represents the solid dispersion of the oxime quinolate prepared in Example 1, the dose is calculated per gram of body weight of quinoxaline; the saline group is used as a negative control.
  • PQ represents the primary aminoquine group, which is used as a positive control at a dose of 30 mg/kg body weight of primary aminoquine; the ordinate indicates the infection rate of malaria parasites in the blood of animals, and the abscissa indicates the experimental grouping, as shown in the figure. The result of day 7 after Plasmodium infection.
  • Figure 16 is a graph showing the animal survival rate in subsequent experiments of the animal efficacy test of the product of Example 1 shown in Figure 15.
  • Decoquinate (Decoquinate, Zhejiang Jinbo Shi Pharmaceutical Co., Ltd., batch number: 130802, molecular weight: 417.53);
  • Loratadine standard (batch number: 100615-201404, content 99.7%, China Food and Drug Administration Institute);
  • New excipient polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer Soluplus (BASF, Germany);
  • Polyvinylpyrrolidone-10 polyvinylpyrrolidene 10, PVP10, molecular weight: 10000, Sigma-Aldrich, Sigma-Aldrich, USA;
  • Polyoxyethylene 40 hydrogenated castor oil Kolliphor RH 40 (BASF, Germany);
  • Polyethylene glycol is PEG 8000, PEG 6000 or PEG 2000 (Sigma-Aldrich Sigma Aldrich, USA);
  • This example consists of a composition for hot melt extrusion comprising a nonoxyquine ester as an active ingredient, Soludol, Kollidon VA 64 and PEG 6000, a solid dispersion of oxime quinolate prepared by hot melt extrusion;
  • a composition for hot melt extrusion decyloxyquine accounted for 10%, Soluplus accounted for 53%, Kollidon VA 64 accounted for 27%, and PEG 6000 accounted for 10% by weight of the total composition.
  • the specific preparation procedure is as follows:
  • the ruthenium quinolate solid dispersion prepared in this example has a uniform texture and a homogeneous phase in water; the particle size measurement shows that the average particle size of the particles is between 2 and 5 microns; the cumulative dissolution percentage is more than 75% within 90 minutes ( figure 1).
  • This embodiment prepares a solid dispersion of quinoxalate by a hot melt extrusion method from a composition for hot melt extrusion containing quinoxalate as an active ingredient, Soludol, Kollidon VA 64 and SDS; In the hot melt extruded composition, the mass fraction of the total composition, the oxime quinolate accounted for 10%, and the Souplus accounted for 65%. Kollidon VA 64 accounts for 15% and SDS accounts for 10%.
  • the specific preparation procedure is as follows:
  • the ruthenium quinolate solid dispersion prepared in this example has a uniform texture and a homogeneous phase in water; the particle size measurement shows that the average particle size of the particles is between 2 and 5 microns. The cumulative dissolution percentage was over 95% in 90 minutes ( Figure 2).
  • This example consists of a composition for hot melt extrusion comprising a nonoxyquine ester as an active ingredient, Kollidon VA 64 and Soluplus, a solid dispersion of oxime quinolate prepared by hot melt extrusion;
  • the melt-extruded composition based on the mass percentage of the total composition, was 20% of the oxime quinolate, 62.33% of the Souplus, and 17.66% of the Kollidon VA 64.
  • the specific preparation procedure is as follows:
  • the ruthenium quinolate solid dispersion prepared in this example has a uniform texture and a homogeneous phase in water; HPLC analysis shows that the residence time of the active component quinoxalate is lower than that of the quinoxaline standard (Fig. 11). There was no change with the content (Fig. 13); the particle size measurement showed that the average particle size of the particles was between 2 and 5 ⁇ m; the cumulative dissolution percentage was over 95% within 90 minutes (Fig. 3).
  • This example consists of a composition for hot melt extrusion comprising a nonoxyquine ester as an active ingredient, Soluplus and Kollidon VA 64, a solid dispersion of quinoxalate prepared by hot melt extrusion;
  • the melt-extruded composition based on the mass percentage of the total composition, was 20% of the oxime quinolate, 53% of the Souplus, and 27% of the Kollidon VA 64.
  • the specific preparation procedure is as follows:
  • the ruthenium quinolate solid dispersion prepared in this example has a uniform texture and a uniform phase in water; the particle size measurement shows that the average particle size of the particles is between 2 and 5 microns; the cumulative dissolution percentage is over 90% within 90 minutes ( Figure 4).
  • This embodiment prepares a solid dispersion of oxime quinolate by a hot melt extrusion method from a composition for hot melt extrusion containing quinoxalate and povidone PVP10 as active ingredients; In the extruded composition, the oxime quinolate accounted for 10% by weight of the total amount of the composition; PVP10 accounted for 90%.
  • the specific preparation procedure is as follows:
  • the particle size measurement showed that the average particle diameter of the particles was 2 to 5 ⁇ m; the cumulative dissolution percentage was over 95% in 90 minutes (Fig. 5).
  • This example consists of a composition for hot melt extrusion comprising a nonoxyquine ester as an active ingredient, Soludol, Kollidon VA 64 and PEG 6000, a solid dispersion of oxime quinolate prepared by hot melt extrusion;
  • a composition for hot melt extrusion 10% of the total mass percentage of the composition, 10% of the oxime quinolate, 15% of the Kollidon VA 64, and 10% of the PEG 6000.
  • the ruthenium quinolate solid dispersion prepared in this example has a uniform texture and a homogeneous phase in water; the particle size measurement shows that the average particle size of the particles is between 2 and 5 microns; the cumulative dissolution percentage is more than 75% within 90 minutes ( Figure 6).
  • This example consists of a composition for hot melt extrusion comprising a nonoxyquine ester as an active ingredient, Soluplus and Kollidon VA 64, a solid dispersion of quinoxalate prepared by hot melt extrusion; Melt extrusion combination In the total mass percentage of the total composition, the oxime quinolate accounted for 10%, the Solulus accounted for 60%, and the Kollidon VA 64 accounted for 30%.
  • the specific preparation procedure is as follows:
  • the ruthenium quinolate solid dispersion prepared in this example has a uniform texture and a homogeneous phase in water; the particle size measurement shows that the average particle size of the particles is 2 to 5 microns; the cumulative dissolution percentage is more than 75% within 60 minutes (Fig. 7). ).
  • This example consists of a composition for hot melt extrusion comprising a nonoxyquine ester as an active ingredient, Soluplus and Kollidon VA 64, a solid dispersion of quinoxalate prepared by hot melt extrusion;
  • the melt-extruded composition based on the mass percentage of the total composition, was 20% of the oxime quinolate, 71% of the Solulus, and 9% of the Kollidon VA 64.
  • the specific preparation procedure is as follows:
  • the ruthenium quinolate solid dispersion prepared in this example has a uniform texture and a uniform phase in water; the particle size measurement shows that the average particle size of the particles is between 2 and 5 microns; the cumulative dissolution percentage is over 80% within 90 minutes ( Figure 8).
  • HPLC high pressure liquid chromatography
  • DSC differential scanning calorimetry
  • the present comparative example consists of a composition for hot melt extrusion comprising a nonoxyquine ester as an active ingredient, Soluplus and Kollidon VA 64, a solid dispersion of quinoxalate prepared by a hot melt extrusion method; Melt extrusion combination In the total mass percentage of the total composition, the oxime quinolate accounted for 10%, the Solulus accounted for 60%, and the Kollidon VA 64 accounted for 30%.
  • the specific preparation procedure is as follows:
  • the ruthenium quinolate solid dispersion prepared in this comparative example has a uniform texture and a homogeneous phase in water; HPLC analysis shows that the residence time and content of the active component quinoxaline are not compared with the quinoxaline standard. Change; particle size measurement showed that the average particle size of the particles was between 2 and 5 microns; the cumulative dissolution percentage was over 80% in 60 minutes ( Figure 1).
  • the present comparative example consists of a composition for hot melt extrusion comprising a nonoxyquine ester as an active ingredient, Soluplus and Kollidon VA 64, a solid dispersion of quinoxalate prepared by a hot melt extrusion method; In the melt extruded composition, 10% of the total mass percentage of the composition, 10% of the oxime quinolate, 70% of the Solulus, and 20% of the Kollidon VA 64.
  • the specific preparation procedure is as follows:
  • the ruthenium quinolate solid dispersion prepared in this example has a uniform texture and a uniform phase in water; HPLC analysis shows that the residence time and content of the active component quinoxalate are not compared with the quinoxaline standard. Change; particle size measurement showed that the average particle size of the particles was between 2 and 5 microns; the cumulative dissolution percentage was less than 20% within 60 minutes ( Figure 2).
  • the present comparative example is prepared by a hot melt method for preparing a solid dispersion of quinoloquine by a composition comprising quinoxaline as an active ingredient, Kollidon VA 64 and Soluplus; in the composition, by mass% of the total amount of the composition Calculated, 20% of quinoxaline, Soltilus accounted for 62.33%, and Kollidon VA 64 accounted for 17.66%.
  • Specific preparation The order is as follows:
  • the present comparative example is prepared by a composition comprising a quinoxalate as an active ingredient, a composition of Sopullus and Kollidon VA64, and a hot dispersion method for preparing a solid dispersion of quinoxalate; wherein the composition is calculated as a percentage by mass of the total amount of the composition, Dioxyquine esters accounted for 20%, Soluplus accounted for 53%, and Kollidon VA 64 accounted for 27%.
  • the specific preparation procedure is as follows:
  • the cumulative dissolution percentage of the terpoxacin solid dispersion prepared in this comparative example was less than 20% in 60 minutes (Fig. 4).
  • the present comparative example prepares a solid dispersion of quinoxalate by hot melt extrusion from a composition for hot melt extrusion comprising quinoxalate as an active ingredient and Soluplus; said for hot melt extrusion In the composition, the oxime quinolate accounted for 10% and the Soluplus accounted for 90%, based on the mass percentage of the total amount of the composition.
  • the specific preparation procedure is as follows:
  • HPLC analysis showed that the retention time and content of the active component of the obtained product were not changed compared with the quinoxaline standard; the particle size measurement showed that the average particle size of the particles was 2 to 5 ⁇ m; the cumulative dissolution percentage Within 20% within 60 minutes ( Figure 5).
  • the present comparative example consists of a composition for hot melt extrusion comprising a nonoxyquine ester as an active ingredient, Soluplus and Kollidon VA 64, a solid dispersion of quinoxalate prepared by a hot melt extrusion method;
  • the melt-extruded composition based on the mass percentage of the total composition, is 10% of the oxime quinolate, 20% of the Solulus, and 70% of the Kollidon VA 64.
  • the specific preparation procedure is as follows:
  • the ruthenium quinolate solid dispersion prepared in this example has a uniform texture and a uniform phase in water; HPLC analysis shows that the residence time and content of the active component quinoxalate are not compared with the quinoxaline standard. Change; particle size measurement showed that the average particle size of the particles was between 2 and 5 microns. The cumulative dissolution percentage was less than 20% in 60 minutes ( Figure 6).
  • the present comparative example consists of a composition for hot melt extrusion comprising a nonoxyquine ester as an active ingredient, Soluplus and Kollidon VA 64, a solid dispersion of quinoxalate prepared by a hot melt extrusion method; In the melt extruded composition, 10% of the total mass percentage of the composition, 10% of the oxime quinolate, 60% of the Solulus, and 30% of the Kollidon VA 64.
  • the specific preparation procedure is as follows:
  • HPLC analysis showed that the retention time and content of the active ingredient quinoxaline did not change compared with the quinoxaline standard; the particle size measurement showed that the average particle size of the particles was 2 to 5 microns; the cumulative dissolution percentage was 60 minutes. Intrinsic below 20% (Figure 7).
  • This example consists of a composition for hot melt extrusion comprising a nonoxyquine ester as an active ingredient, Soluplus and Kollidon VA 64, a solid dispersion of quinoxalate prepared by hot melt extrusion;
  • the melt-extruded composition based on the mass percentage of the total composition, was 20% of the oxime quinolate, 71% of the Solulus, and 9% of the Kollidon VA 64.
  • the specific preparation procedure is as follows:
  • thermogravimetric analysis of the quinoxaline showed that the weight of the quinoxaline decreased to 99% at 250.5 ° C, indicating that the compound was very stable, no thermal decomposition occurred, and a small loss portion was judged to be a water molecule.
  • Thermogravimetric analysis of Soluplus, VA 64 and PEG 6000 also indicates that these polymeric carrier excipients for hot melt extrusion are thermally stable.
  • Fig. 9A is a thermogravimetric analysis diagram of the drug substance compound quinoxaline; as shown in Fig. 9A, the weight of the quinoxalate (DQ) is lowered to 99% at 250.5 ° C, indicating that the compound is still very stable at this temperature, without heat. Decomposition occurs, and a very small loss portion can be determined as a water molecule;
  • FIG. 9B is a high-pressure liquid chromatogram analysis of the quinoxaline ester in the solid dispersion of the oxime quinolate prepared in Example 1, which shows that the product is prepared. Peak type and residence time of quinoxalate There was no change, and it was consistent with the results of the high pressure liquid chromatography analysis of the product of Example 3 shown in Fig. 13, indicating that the active ingredient quinoxalate in the hot melt extruded product prepared by the present invention did not thermally decompose.
  • the hot melt extruded samples of the oxime quinolate prepared in each example were weighed and subjected to DSC measurement.
  • the reference substance was a quinoxalate raw material drug, only the hot melt extrudate of the preparation auxiliary, and the quinoxaline and the preparation auxiliary. Physical mixture at room temperature.
  • the instruments used were a ten thousandth balance (Sartorius, purchased from Sartorius Scientific Instruments Co., Ltd., model: BSA 124S) and a differential scanning calorimeter (NETZSCH DSC 204F1, Germany).
  • the method of use is N2: 20 mL/min, and the temperature rising procedure is: from room temperature to 265 ° C at a rate of 10 ° C / min, and the detection basis is: JY/T014-1996.
  • Example 1 A comparison chart of DSC analysis of the physical mixture of the oxime quinoxalate and the auxiliary material at room temperature in Example 1 (see FIG. 10); as seen from FIG.
  • the dissolution medium was a solution of 0.1 N hydrochloric acid (HCl) and 10 mmol (mM) sodium dodecyl sulfate (SDS).
  • the instrument used was an RC-6 dissolution tester (Tianjin).
  • the parameters of the dissolution apparatus were 37 ° C, 50 rpm, paddle method; 900 ml of dissolution medium was added to each dissolution cup to start the instrument. When the medium temperature in each cup reached 37 ° C, the corresponding samples were added, respectively, at 10, 20 1 ml was taken at 40, 60, 90, 120, 180, 240, 270 minutes, and 1 ml of dissolution medium was added.
  • the sample taken out was passed through a 0.45 ⁇ m microporous membrane, and the filtrate was taken for The amount of the deuterated quinoxalate was determined by high pressure liquid chromatography (HPLC, Agilent 1260).
  • HPLC high pressure liquid chromatography
  • the mobile phase of HPLC was 80% ethanol, 20% water, and the measurement wavelength was 260 nm.
  • Table 1 summarizes the percentage of each component in the examples and comparative examples, the melting temperature (TM) and the in vitro dissolution rate; wherein S represents Soluplus; VA 64 represents copolyvidone Kollidon VA 64; and PVP 10 represents polyvinylpyrrolidone - 10; SDS represents sodium dodecyl sulfate; PEG 6000 represents polyethylene glycol 6000.
  • 1 to 8 are comparison charts of in vitro dissolution results of the terpoxacin solid dispersion prepared in Examples 1-8 and Comparative Examples 1-8 and the oxime quinolate.
  • the standard curve for the quinoxalate used in the pharmacokinetic test was prepared by first dissolving the quinoxaline in ethanol at a concentration of 0.1 mg/ml and diluting it with ethanol to a series of concentrations (0.03 ⁇ g/ml to 30 ⁇ g/ml). , a total of 8 gradient concentrations. Each 45 ⁇ l of blank plasma was added with 5 ⁇ l of quinoxalate standard solution, 5 ⁇ l of 10 ⁇ g/ml internal standard loratadine, vortexed for 30 seconds, and 150 ⁇ l of protein precipitant ethanol was added.
  • the quality control sample was 10, 300, 2400 ng/ml of quinoxaline, and the treatment method was the same as above.
  • the chromatographic column was XTerra MS C18 5 ⁇ m, 4.6 mm X 50 mm; Part No.
  • the animals used in the pharmacokinetic experiments of the present invention were male rats (sprague-dawley male rats). Weigh the body before administration, usually between 180 and 200 grams. All rats were administered at a dose of 20 mg/Kg. The solid dispersion of quinoxaline solid was accurately weighed and sonicated with physiological saline to prepare a suspension having a drug concentration of 2 mg/ml. According to the animal's body weight, different volumes were administered by intragastric administration.
  • Table 2 shows the evaluation of the main pharmacokinetic parameters of the solid dispersion of the quinoxalate prepared in Example 1 and Comparative Example 1.
  • Figure 14 is a pharmacokinetic profile of Example 1 and Comparative Example 1; wherein the ordinate indicates the concentration of quinoxalate in plasma and the abscissa indicates the time of blood sampling of the animal.
  • Example 1 contains PEG 6000
  • Comparative Example 1 does not contain PEG 6000.
  • the addition of polyethylene glycol in an appropriate amount can not only prolong the circulation time of the active ingredient quinoxalate in the blood of the body, prolong the half-life, but also increase the oxyquinoline in the blood of the animal.
  • the concentration is beneficial to improve the efficacy.
  • mice used for the experiment were raised for at least 7 days after arrival. At the start of dosing, the mice were 7 weeks old. Only one mouse is raised in each cage. The room temperature is 18 ° C - 26 ° C, the relative humidity is 34% -68%, 12 hours of light and dark alternate turnover.
  • the food before and during the test was a standard feeding food (adlibitum). This experiment was conducted in strict accordance with the relevant animal test regulations (Guide for the Care and Use of Laboratory Animals, NRC publication, 2011 edition).
  • the quinoxaline suspension used in the animal experiments was the sample of Example 1, prepared with physiological saline, and sonicated for 5 minutes with an ultrasound machine.
  • the method of Plasmodium infection in NIH female mice is to inject 50,000 sporozoites of P. berghei ANKA into the tail vein of each mouse.
  • the gavage (oral) administration was divided into three times, that is, the day before, the day and the second day of the Plasmodium infection.
  • the positive control was used as the antimalarial drug primaquine for the liver stage Plasmodium.
  • the carrier blank refers to the component of the quinoxalate solid dispersion other than the quinoxalate. None of the components in the vector blank had anti-malarial activity, and the results were consistent with those obtained with physiological saline as a negative control.
  • the method of detecting the blood rate of the worm is to count the number of red blood cells per mm 3 blood according to the conventional red blood cell count, and make a thin blood film, staining with 3% Giemsa for 20 minutes, and counting the number of infected red blood cells per 1000 red blood cells under the oil microscope, and obtaining the red blood cell infection rate. (erythrocyte infected rate, EIR, ⁇ ). The survival rate was calculated on the 22nd day after infection.
  • Figure 15 Animal efficacy test of the product prepared in Example 1; the product dose of Example 1 was calculated per gram of body weight of quinoxaline, the negative control group was treated with physiological saline, and the positive control group was treated with primamine quinine 30 mg/kg body weight. The ordinate indicates the infection rate of the malaria parasite in the animal blood, and the abscissa indicates the experimental group, and the results are shown on the 7th day after the Plasmodium infection.
  • Figure 16 is a graph showing the animal survival rate in subsequent experiments of the animal efficacy test of the product of Example 1 shown in Figure 15.
  • Example 1 the preparation of Example 1 was administered to mice at a dose of 3 mg of quinoxaline per kg body weight, 10 mg of quinoxaline per kg body weight, and 30 mg of quinoxaline per kg body weight. Afterwards, no Plasmodium was detected in the plasma, indicating that all three doses were effective in preventing infection of the mouse Plasmodium sporozoites; in addition, the solid dispersion of the indoloquine ester of the present invention was observed at 21 days. Animals of the aminoquinine survived, while animals that did not control the antimalarial drug all died.

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Abstract

一种热熔挤出固体分散体组合物及其制备方法和该组合物在制备用于预防和/或治疗由疟原虫引起的疾病的药剂中的用途。按重量百分比计，该组合物包括癸氧喹酯5%-30%、高分子载体材料60%-90%和表面活性剂0%-10%。组合物的制备方法包括在热熔温度下热挤出该组合物的步骤。

Description

癸氧喹酯固体分散体、其制备方法和用途 技术领域
本发明涉及医药技术领域，具体地，涉及一种用于热熔挤出的组合物，使用该热熔挤出组合物制备热熔挤出产品的方法，所制得的癸氧喹酯固体分散体，以及所述组合物及癸氧喹酯固体分散体的制药用途。
背景技术
疟疾(malaria)是经按蚊叮咬或输入带疟原虫患者的血液而感染疟原虫所致的虫媒传染病。寄生于人体的疟原虫共有四种，即间日疟原虫，三日疟原虫，恶性疟原虫和卵形疟原虫。还有一种人和猴均可患的疟疾由诺氏疟原虫引起。本病主要表现为周期性规律发作，发烧，多汗，虚弱，呕吐，头痛；长期多次发作后，可引起贫血和脾肿大。恶性疟患者如不及时诊治可引致脑型疟和死亡。经过医务工作者多年的努力，我国的疟疾发病率已降到很低的水平，据1992年的统计，全国发病人数已降至7万。在我国主要是间日疟原虫和恶性疟原虫，其它三种少见；近年也有一些病例是从国外输入或由出国旅游观光者带入的。但是从全球的发病情况看，疟疾仍然在许多个国家和地区流行，特别是在非洲、东南亚和中、南美洲的一些国家，恶性疟死亡率极高。据世界卫生组织(WHO)近年统计的数字估计，世界上还有近34亿人口处于罹患疟疾的危险，其中12亿处在高风险中。每年大约有62万人死于疟疾，其中70％以上是5岁以下的儿童。
按宿主不同，疟原虫分为感染人的疟原虫和感染其它动物的疟原虫。感染人的疟原虫的生活周期分为在人体内和按蚊体内二个部分；在人体内又分为肝期和红细胞内期。中国科学家发明的抗疟疾药青蒿素以及大多数传统的抗疟疾药物如氯喹是作用于红细胞内期的药物，而对于肝期的疟原虫则无抑制作用。青蒿素是当前最主要的抗疟 疾药。中国厂家提供90％的青蒿素原料药。世界卫生组织的三家成品药供货商都是外国企业，原因是国外需求很大的青蒿素剂型国内都没有。全球范围内已出现疟原虫对现有抗疟药的耐药性。疟原虫除了广泛对氯喹和磺胺类耐药外，也呈现出对抗疟第一线药物，即基于青蒿素的联合治疗中的核心药物青蒿素组份的耐药性。(Ariey，F.et al.A molecular marker of artemisinin-resistant Plasmodium falciparum malaria.Nature 505，50-55，2014)。伯氨喹类是较新的用于肝期的抗疟疾药物。但是这类药有很强的副作用，它不仅可引起部分疟疾病人的急性溶血性贫血，而且对红细胞内期的恶性疟原虫完全无效，不能作为控制症状的药物应用。还有些作用于肝期的药如阿托伐醌/氯胍组成的复方马拉隆，价格比较贵，一般病人难以负担。由此推论，国际市场需要有新型的，高效的，低毒的，廉价的，无耐药性的抗疟疾药来保护易感人群。
癸氧喹酯(Decoquinate，CAS号为18507-89-6)是一种球虫抑制药物，主要用于家禽和牛，马，羊等牲口，在包括中国在内的全球范围内广泛使用。其主要的作用部位为肠道，用于抗球虫感染。近年来发现，癸氧喹酯在体外和体内的实验中均有很强的抑制和杀灭疟原虫的作用(Science 2011；334：1372-7)。在抗疟疾药效方面，较现有的抗疟疾药有明显的优势(JID 2012：205：1278-86)；其作用机理是抑制疟原虫线粒体的细胞色素bcl复合物。癸氧喹酯对疟原虫在肝期的发育和红细胞内期生长均有抑制作用。无论是作为兽药，还是在动物毒理实验中，均没有发现癸氧喹酯有明显的副作用和毒性作用。本专利发明人和其他研究者的实验研究结果证明，对氯喹耐药的疟原虫对癸氧喹酯没有耐药性(参见，一种癸氧喹酯纳米制剂及其制备方法与应用；JID 2012：205：1278-86)。此外，有研究证实，癸氧喹酯对神经毒性肉孢子虫(Intern J Appl Res Vet Med.Vol.10，No.1，2012)和弓形虫(Veterinary Record，1996[138]434-436)也有很好的杀灭作用。
癸氧喹酯，分子量417.54，低水溶性，高亲脂性(log Kow值为5.2-5.5)，可由化 学合成制得。癸氧喹酯的水溶性极低，在肠道吸收率很差。当作为抗球虫病的兽药使用时，它可以不经肠道吸收入体内而发挥药效。然而，口服剂型仍然是最方便可行的用药方式，因此，癸氧喹酯要想发展为抗疟疾药使用，就必须解决其从肠道有效吸收的问题。
对于在体外有高度生物活性的难溶化合物，可以通过制成盐，增强溶解度，减小粒径等方法以增加药物的肠道吸收和生物利用度。致力于将癸氧喹酯制成盐而增强其水溶性的多种尝试均未能凑效。通过添加表面活性剂或减小粒径的方法制备的制剂可以提高癸氧喹酯在体内的释放以及抗疟疾药效。但是，这种方法通常需要有机溶剂，需要多个流程，以及需要较长时间的后续制作过程。通过热熔法制备癸氧喹酯固体分散体的方法在一定程度上解决了其难溶于水的问题，但是流程比较烦锁，化合物容易受到热分解，不易加工成成品药，而只适用于兽药。
固体分散是一种常用的制剂方法，该方法是指难溶性或不溶于水的药物分子，含胶体，微晶体或无定形材料，在加入水之前，是以固体状态均匀分散在另外的水溶性物质中。热熔挤出法是近年来药剂学领域为解决难溶化合物问题而发展起来的一种新技术，该技术结合了固体分散技术和机械制备工艺的优势，通过热熔挤出机中的分段加热，双螺杆转动和口模装置，进行物料的输送，混合，剪切，熔融和挤出，挤出物即为固体分散体；这一方法不需要有机溶剂，可连续性地进行小规模或大规模的制备，因此不仅适用于研发，也适合商品化生产。但是，热不稳定的药物或高分子载体却不适合用热熔法或热熔挤出法，药物或辅料的降解，有关物质的产生会使药剂的药效和安全性降低，因而也是需要避免使用热熔挤出法的主要原因。
发明内容
本发明的目的在于提供一种用于热熔挤出的组合物，使用该热熔挤出组合物制备热熔挤出产品的方法，所制得的癸氧喹酯固体分散体，以及所述组合物及癸氧喹酯固 体分散体的制药用途。
本发明通过以下技术方案实现上述目的：
第一方面，本发明提供了一种用于热熔挤出的组合物，其特征在于，按重量百分比计，所述组合物包括：
癸氧喹酯          5％-30％；
高分子载体材料    60％-90％；和
表面活性剂             0％-10％。
在优选的实施方案中，所述高分子载体材料为聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物、共聚维酮、聚维酮或聚乙二醇中的一种或两种以上的组合。
在进一步优选的实施方案中，所述聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物为Soluplus；所述Soluplus起到固态溶液和增溶的双重作用。
在进一步优选的实施方案中，所述共聚维酮为Kollidon VA 64；所述Kollidon VA 64具湿化作用，能提高载药量，有助于固体分散体复溶。
在进一步优选的实施方案中，所述聚维酮为聚维酮k17、聚维酮k25、聚维酮k30或聚乙烯吡咯烷酮-10；所述聚维酮具湿化作用，有助于增溶和固体分散体复溶。
在进一步优选的实施方案中，所述聚乙二醇为聚乙二醇8000，聚乙二醇6000或聚乙二醇4000；所述聚乙二醇在熔融过程中主要起到适当降低熔融温度的作用，从而降低活性成分癸氧喹酯发生降解的可能性，有利于增加配方的易处理性，但是使配方的物理稳定性下降；此外，聚乙二醇还可以延长活性成分癸氧喹酯在体内血液中的循环时间，延长半衰期，有利于提高药效。
在优选的实施方案中，所述表面活性剂为十二烷基硫酸钠、月桂酸聚乙二醇甘油酯、硬脂酸聚乙二醇甘油酯或聚氧乙烯氢化蓖麻油中的任意一种或几种的组合；所述表面活性剂是增强难溶性化合物水溶性的制剂辅料，可使得活性成分癸氧喹酯以分子 或极小颗粒状态分散于其中，从而有利于增强癸氧喹酯的水溶性。
进一步优选地，所述月桂酸聚乙二醇甘油酯为Gelucire 44/14；
进一步优选地，所述硬脂酸聚乙二醇甘油酯为Gelucire 50/13；
进一步优选地，所述聚氧乙烯氢化蓖麻油为Kolliphor RH 40；所述Kolliphor RH 40在组合物的熔融过程中可能起到适当调节熔融温度范围、粘合制剂的各个组分并降低活性成分癸氧喹酯发生降解的可能性的作用，有利于形成密度均匀的癸氧喹酯固体分散体。
此外，本发明中所采用的高分子材料具有热塑性行为，在熔融状态下可变形，并且具有高度热稳定性，无毒，可增溶等特点；本发明中所选用的表面活性剂也是经CFDA和FDA等权威机构批准可用于临床制药的、无安全隐患的热熔辅料。
第二方面，本发明提供了一种癸氧喹酯固体分散体的制备方法，其包括：在热熔温度下，热熔挤出如第一方面所述的组合物。
在具体实施方案中，所述热熔挤出在热熔挤出机中进行；具体地，将如第一方面所述的组合物混合均匀后，加入到双螺杆热熔挤出机中，经过机器内不同区段不同温度的处理，双螺杆挤压的推动，口模成型的加工，挤出物在室温自然冷却后，成为条状固态混合体；所述条状固态混合体经剪切、粉碎加工，即得粉末状癸氧喹酯固体分散体。
在优选的实施方案中，所述热熔挤出温度为50～200℃，优选120～200℃；优选地，所述热熔挤出机的螺杆旋转速度为15-300转/分钟，更优选20-150转/分钟。
在制备癸氧喹酯固体分散体的过程中，需要根据原料组合物的组成调节熔融的温度，既要使活性成分癸氧喹酯与作为辅料的高分子载体材料在分子水平上有效地混合，又要避免癸氧喹酯与辅料的热分解。
众所周知，物质有晶体和非晶体之分，晶体开始融化时的温度叫做熔点。熔点是 固体将其物态由固态转变(熔化)为液态的温度，一般可用Tm表示。对于有机化合物而言，一般都有固定熔点；即，在一定压力下，固-液两相之间的变化都是非常敏锐的，初熔至全熔的温度，即熔点范围或称熔距、熔程，一般较窄；但是，如果混有其它物质则其熔点下降，且熔距也较长。癸氧喹酯的熔点为242～246℃。本发明的发明人通过设计特定组成的包含癸氧喹酯的用于热熔挤出的组合物，使得癸氧喹酯在与高分子载体材料、表面活性剂等辅料混熔时，可在低于其本身熔点的温度下成为液态，这也就降低了其热分解的可能性，有利于保留其原有的结构与药效活性。
第三方面，本发明提供了一种癸氧喹酯固体分散体，其由如第二方面所述的制备方法制成。
如上所述，在本发明癸氧喹酯固体分散体的制备过程中，其活性成分癸氧喹酯的化学结构未发生任何改变，因此，其药效活性未有任何损失；所制备的癸氧喹酯固体分散体易混悬于水相，在水相中呈均一体系，并且在一周内不发生任何沉淀；此外，本发明癸氧喹酯固体分散体的癸氧喹酯释放速率和溶出度均明显提高，生物利用度和动物体内抗疟疾药效也明显提高。
第四方面，本发明提供了如第一方面所述的组合物或如第三方面所述的癸氧喹酯固体分散体在制备用于预防和/或治疗由疟原虫引起的疾病的药物制剂中的用途；
优选地，所述疾病为间日疟、恶性疟、三日疟、卵形疟和诺氏疟中的任意一种或几种。
所述癸氧喹酯固体分散体可以根据需要制成片剂、颗粒、充填胶囊等口服剂型。
本发明所采用的热熔挤出技术是用于制造无定形固体分散体的一种技术，其中癸氧喹酯经熔化或溶解而分散于载体物质内，并且与其混合，以产生和稳定无定形形式的癸氧喹酯；与单纯的热熔法相比，热熔挤出技术具有机械工艺的优势，混匀效果极佳，且活性成份和所有制剂成份无热分解现象；并且，整个过程中无需有机溶剂，因 而减少了环境污染并简化了加工程序。
以固体分散体形式存在的癸氧喹酯，可被认为是一种固态溶液或溶解体。功能性赋形剂，如表面活性剂，粘合剂等也被加入到混合物中，辅助熔融加工流程，并且增进在服用制剂后的溶出效率。溶出效率的提高，增强了肠道吸收的效果，加大了生物利用度和体内的生物活性。熔融物通过一个成形的出口挤出，并且在快速冷却后，仍保持一种固体的，单相的，玻璃状无定形基质，而且这种基质在物品架上存放保持稳定。同时，还可引入挤出后加工设备，用来主导挤出物的形状，使其满足易于进行下游加工成剂型的要求。在一般情况下，这些挤出材料被研磨，以减小其颗粒，使之可掺入到传统的口服固体剂型，例如片剂或胶囊，同时维持了对药物所期望的释放曲线。
本发明采用热熔挤出技术来制备癸氧喹酯固体分散体，发明人通过选择特定的制剂辅料，特定的主药与辅料配比，使得癸氧喹酯在与高分子载体材料、表面活性剂等辅料混熔时，可在低于其本身熔点的温度下成为液态，这大大降低了其热分解的可能性，有利于保留其原有的结构与药效活性；进一步地，发明人通过优化机械参数，使得活性化合物癸氧喹酯与热熔辅料熔融均匀，挤出物质地均一，在增强癸氧喹酯口服生物利用度和药效方面优于有机溶剂法；并且，与有机溶剂法和热熔法制备的相关产品相比，本发明的制备方法更加易于提高生产效率，因而更加易于将实验室成果发展到中试水平以及产业化水平，以致于推广到临床应用中。
附图说明
图1为实施例1、对比例1所制备的癸氧喹酯固体分散体以及癸氧喹酯原药的体外溶出度的比较。
图2为实施例2、对比例2所制备的癸氧喹酯固体分散体以及癸氧喹酯原药的体外溶出度的比较。
图3为实施例3、对比例3所制备的癸氧喹酯固体分散体以及癸氧喹酯原药的体 外溶出度的比较。
图4为实施例4、对比例4所制备的癸氧喹酯固体分散体以及癸氧喹酯原药的体外溶出度的比较。
图5为实施例5、对比例5所制备的癸氧喹酯固体分散体以及癸氧喹酯原药的体外溶出度的比较。
图6为实施例6、对比例6所制备的癸氧喹酯固体分散体以及癸氧喹酯原药的体外溶出度的比较。
图7为实施例7、对比例7所制备的癸氧喹酯固体分散体以及癸氧喹酯原药的体外溶出度的比较。
图8为实施例8、对比例8所制备的癸氧喹酯固体分散体以及癸氧喹酯原药的体外溶出度的比较。
图9A为原料药化合物(标准品)癸氧喹酯的热重(TG)分析图；图9B为实施例1所制备的癸氧喹酯固体分散体中，癸氧喹酯的高压液相色谱分析图。
图10为原料药化合物癸氧喹酯、实施例1中制备的含癸氧喹酯的热熔挤出物、实施例1中除癸氧喹酯以外的其它组分的热熔挤出物以及癸氧喹酯与辅料在常温下的物理混合的差示扫描量热分析图(DSC)。
图11为癸氧喹酯原料药(即标准品)的高压液相色谱图。
图12为对比例3通过热熔法制备的癸氧喹酯固体分散体中，癸氧喹酯的高压液相色谱图；该图表明，经单纯的热熔法制备后，癸氧喹酯的高压液相色谱图中的峰型已经发生明显的改变。
图13为实施例3通过热熔挤出(HME)技术制备的癸氧喹酯固体分散体中，癸氧喹酯的高压液相色谱图；该图表明，经热熔挤出技术制备后，癸氧喹酯的高压液相色谱图中的峰型与滞留时间均未发生改变。
图14实施例1和对比例1的药物代谢动力学；其中，纵坐标表示血浆中癸氧喹酯浓度，横坐标表示动物血液取样时间。
图15实施例1所制备产品的动物药效实验；其中，DQ表示实施例1所制备癸氧喹酯固体分散体组，其剂量按癸氧喹酯每公斤体重计算；生理盐水组作为阴性对照使用；PQ表示伯氨奎宁组，其作为阳性对照使用，其剂量为伯氨奎宁30毫克每公斤体重；纵坐标表示动物血中疟原虫感染率，横坐标表示实验分组，图中所示为疟原虫感染后第7天的结果。
图16为图15中所示实施例1产品的动物药效实验的后续实验中动物存活率的统计。
具体实施方式
为便于理解本发明，本发明列举实施例如下。本领域技术人员应该明了，所述实施例仅仅是帮助理解本发明，不应视为对本发明的具体限制。
以下实施例所用原料及其来源
癸氧喹酯(Decoquinate，浙江金伯士药业有限公司，批号：130802，分子量：417.53)；
氯雷他定标准品(批号：100615-201404，含量99.7％，中国食品药品检定研究院)；
新型辅料聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物Soluplus(德国巴斯夫公司)；
月桂酸聚乙二醇甘油酯Gelucire 44/14(法国嘉法狮公司)；
硬脂酸聚乙二醇甘油酯Gelucire 50/13(法国嘉法狮公司)；
聚乙烯吡咯烷酮-10(polyvinylpyrrolidene 10，PVP10，分子量：10000，美国Sigma-Aldrich西格玛奥德里奇)；
共聚维酮Kollidon VA 64，聚维酮k17，聚维酮k25，或聚维酮k30(德国巴斯夫公 司)；
聚氧乙烯40氢化蓖麻油Kolliphor RH 40(德国巴斯夫公司)；
聚乙二醇为PEG 8000，PEG 6000或PEG 2000(美国Sigma-Aldrich西格玛奥德里奇)；
十二烷基磺酸钠(SDS，sodium lauryl sulfate，美国Sigma-Aldrich西格玛奥德里奇)。
实施例1
本实施例由包含作为活性成分的癸氧喹酯，Soluplus，Kollidon VA 64和PEG 6000的用于热熔挤出的组合物、通过热熔挤出法制备癸氧喹酯固体分散体；所述用于热熔挤出的组合物中，以占组合物总量的质量百分比计，癸氧喹酯占10％，Soluplus占53％，Kollidon VA 64占27％，PEG 6000占10％。具体制备程序如下：
称取癸氧喹酯3克，Soluplus 16克，Kollidon VA 64共聚维酮8克，PEG 6000 3克，并将其混合均匀；设置双螺杆热熔挤出机的熔融温度为120-160℃，当所有实际温度达到设置温度时，开始添加混合物料，并且缓慢启动螺杆，开始转速为20转/分钟，观察机器显示屏上压力和扭矩，如果数字显示在正常范围内，将螺杆转速加快到150转/分钟，经分段加热，混合，熔融，推挤的过程，熔融物由口模处呈条状物出来，在室温下瞬即冷却成固体，粉碎处理后得癸氧喹酯固体分散体粉末。
本实施例制备的癸氧喹酯固体分散体基质质地均匀，在水中呈均一相；粒径测定显示，颗粒平均粒径在2～5微米之间；累积溶出百分率90分钟内达75％以上(图1)。
实施例2
本实施例由包含作为活性成分的癸氧喹酯，Soluplus，Kollidon VA 64和SDS的用于热熔挤出的组合物、通过热熔挤出法制备癸氧喹酯固体分散体；所述用于热熔挤出的组合物中，以组合物总量的质量百分比计算，癸氧喹酯占10％，Soluplus占65％， Kollidon VA 64占15％，SDS占10％。具体制备程序如下：
称取癸氧喹酯2克，Soluplus 13克，Kollidon VA 64共聚维酮3克，SDS 2克，混合均匀。热熔挤出机参数的设置及加料后的操作步骤与实施例1相同。
本实施例制备的癸氧喹酯固体分散体基质质地均匀，在水中呈均一相；粒径测定显示，颗粒平均粒径在2～5微米之间。累积溶出百分率90分钟内达95％以上(图2)。
实施例3
本实施例由包含作为活性成分的癸氧喹酯，Kollidon VA 64和Soluplus的用于热熔挤出的组合物、通过热熔挤出法制备癸氧喹酯固体分散体；所述用于热熔挤出的组合物中，以组合物总量的质量百分比计算，癸氧喹酯占20％，Soluplus占62.33％，Kollidon VA 64占17.66％。具体制备程序如下：
称取癸氧喹酯6克，Soluplus 18.7克，Kollidon VA 64共聚维酮5.3克混合均匀。热熔挤出机参数的设置及加料后的操作步骤与实施例1相同。
本实施例制备的癸氧喹酯固体分散体基质质地均匀，在水中呈均一相；HPLC分析显示，与癸氧喹酯标准品(图11)相比，其活性成份癸氧喹酯的滞留时间与含量均无改变(图13)；粒径测定显示，颗粒平均粒径在2～5微米之间；累积溶出百分率90分钟内达95％以上(图3)。
实施例4
本实施例由包含作为活性成分的癸氧喹酯，Soluplus和Kollidon VA 64的用于热熔挤出的组合物、通过热熔挤出法制备癸氧喹酯固体分散体；所述用于热熔挤出的组合物中，以组合物总量的质量百分比计算，癸氧喹酯占20％，Soluplus占53％，Kollidon VA 64占27％。具体制备程序如下：
称取癸氧喹酯6克，Soluplus 16克，Kollidon VA 64共聚维酮8克，混合均匀。热熔挤出机参数的设置及加料后的操作步骤与实施例1相同。
本实施例制备的癸氧喹酯固体分散体基质质地均匀，在水中呈均一相；粒径测定显示，颗粒平均粒径在2～5微米之间；累积溶出百分率90分钟内达90％以上(图4)。
实施例5
本实施例由包含作为活性成分的癸氧喹酯和聚维酮PVP10的用于热熔挤出的组合物、通过热熔挤出法制备癸氧喹酯固体分散体；所述用于热熔挤出的组合物中，以组合物总量的质量百分比计算，癸氧喹酯占10％；PVP10占90％。具体制备程序如下：
称取癸氧喹酯2克，聚维酮PVP10 18克，混合均匀。热熔挤出机参数的设置及加料后的操作步骤与实施例1相同。
粒径测定显示，颗粒平均粒径在2～5微米；累积溶出百分率90分钟内达95％以上(图5)。
实施例6
本实施例由包含作为活性成分的癸氧喹酯，Soluplus，Kollidon VA 64和PEG 6000的用于热熔挤出的组合物、通过热熔挤出法制备癸氧喹酯固体分散体；所述用于热熔挤出的组合物中，以组合物总量的质量百分比计算，癸氧喹酯占10％，Soluplus占15％，Kollidon VA 64占65％，PEG 6000占10％。具体制备程序如下：
称取癸氧喹酯2克，Soluplus 3克，Kollidon VA 64共聚维酮13克，PEG 6000 2克，混合均匀。热熔挤出机参数的设置及加料后的操作步骤与实施例1相同。
本实施例制备的癸氧喹酯固体分散体基质质地均匀，在水中呈均一相；粒径测定显示，颗粒平均粒径在2～5微米之间；累积溶出百分率90分钟内达75％以上(图6)。
实施例7
本实施例由包含作为活性成分的癸氧喹酯，Soluplus和Kollidon VA 64的用于热熔挤出的组合物、通过热熔挤出法制备癸氧喹酯固体分散体；所述用于热熔挤出的组合 物中，以组合物总量的质量百分比计算，癸氧喹酯占10％，Soluplus占60％；Kollidon VA 64占30％。具体制备程序如下：
称取癸氧喹酯3克，Soluplus 18克，Kollidon VA 64共聚维酮9克，混合均匀。设置双螺杆热熔挤出机的熔融温度为120-200℃，其余步骤与实施例1相同。
本实施例制备的癸氧喹酯固体分散体基质质地均匀，在水中呈均一相；粒径测定显示，颗粒平均粒径在2～5微米；累积溶出百分率60分钟内达75％以上(图7)。
实施例8
本实施例由包含作为活性成分的癸氧喹酯，Soluplus和Kollidon VA 64的用于热熔挤出的组合物、通过热熔挤出法制备癸氧喹酯固体分散体；所述用于热熔挤出的组合物中，以组合物总量的质量百分比计算，癸氧喹酯占20％，Soluplus占71％，Kollidon VA 64占9％。具体制备程序如下：
称取癸氧喹酯6克，Soluplus 21.3克，Kollidon VA 64共聚维酮2.7克，混合均匀。热熔挤出机参数的设置及加料后的操作步骤与实施例1相同。
本实施例制备的癸氧喹酯固体分散体基质质地均匀，在水中呈均一相；粒径测定显示，颗粒平均粒径在2～5微米之间；累积溶出百分率90分钟内达80％以上(图8)。
发明人对上述实施例的产品进行了高压液相色谱(HPLC)分析和差示扫描量热(DSC)分析(具体分析方法见下文所述)。HPLC分析结果显示，与癸氧喹酯标准品(图11)相比，所有实施例的产品中的活性成份癸氧喹酯的滞留时间与含量均无改变，与实施例1的HPLC分析一致(图9B)。DSC分析结果显示，与癸氧喹酯标准品相比，所有实施例中的产品的活性成份癸氧喹酯已经与制剂辅料溶融。
对比例1
本对比例由包含作为活性成分的癸氧喹酯，Soluplus和Kollidon VA 64的用于热熔挤出的组合物、通过热熔挤出法制备癸氧喹酯固体分散体；所述用于热熔挤出的组合 物中，以组合物总量的质量百分比计算，癸氧喹酯占10％，Soluplus占60％，Kollidon VA 64占30％。具体制备程序如下：
称取癸氧喹酯3克，Soluplus 18克，Kollidon VA 64共聚维酮9克，混合均匀。热熔挤出机参数的设置及加料后的操作步骤与实施例1相同。
本对比例制备的癸氧喹酯固体分散体基质质地均匀，在水中呈均一相；HPLC分析显示，与癸氧喹酯标准品相比，其活性成份癸氧喹酯的滞留时间与含量均无改变；粒径测定显示，颗粒平均粒径在2～5微米之间；累积溶出百分率60分钟内达80％以上(图1)。
对比例2
本对比例由包含作为活性成分的癸氧喹酯，Soluplus和Kollidon VA 64的用于热熔挤出的组合物、通过热熔挤出法制备癸氧喹酯固体分散体；所述用于热熔挤出的组合物中，以组合物总量的质量百分比计算，癸氧喹酯占10％，Soluplus占70％，Kollidon VA 64占20％。具体制备程序如下：
称取癸氧喹酯2克，Soluplus 14克，Kollidon VA 64共聚维酮4克，混合均匀。热熔挤出机参数的设置及加料后的操作步骤与实施例1相同。
本实施例制备的癸氧喹酯固体分散体基质质地均匀，在水中呈均一相；HPLC分析显示，与癸氧喹酯标准品相比，其活性成份癸氧喹酯的滞留时间与含量均无改变；粒径测定显示，颗粒平均粒径在2～5微米之间；累积溶出百分率60分钟内小于20％(图2)。
对比例3
本对比例由包含作为活性成分的癸氧喹酯，Kollidon VA 64和Soluplus的组合物、通过热熔法制备癸氧喹酯固体分散体；所述组合物中，以组合物总量的质量百分比计算，癸氧喹酯占20％，Soluplus占62.33％，Kollidon VA 64占17.66％。具体制备程 序如下：
称取癸氧喹酯0.6克，Soluplus 1.87克，Kollidon VA 64共聚维酮0.53克混合均匀。加热至160℃，熔融3min，边熔融边搅拌，室温冷却。
HPLC分析显示，与癸氧喹酯标准品相比，本对比例制备的癸氧喹酯固体分散体的癸氧喹酯的峰型有所改变(图12)，表明：此制备方法可引起作为活性成分的癸氧喹酯一定程度的热分解；癸氧喹酯固体分散体的累积溶出百分率60分钟内小于20％(图3)。
对比例4
本对比例由包含作为活性成分的癸氧喹酯，Soluplus和KollidonVA64的组合物通过、热熔法制备癸氧喹酯固体分散体；所述组合物中，以组合物总量的质量百分比计算，癸氧喹酯占20％，Soluplus占53％，Kollidon VA 64占27％。具体制备程序如下：
称取癸氧喹酯0.6克，Soluplus 1.6克，Kollidon VA 64共聚维酮0.8克混合均匀。加热至160℃，熔融3min，边熔融边搅拌，室温冷却。
本对比例制备的癸氧喹酯固体分散体的累积溶出百分率60分钟内小于20％(图4)。
对比例5
本对比例由包含作为活性成分的癸氧喹酯和Soluplus的用于热熔挤出的组合物、通过热熔挤出法制备癸氧喹酯固体分散体；所述用于热熔挤出的组合物中，以组合物总量的质量百分比计算，癸氧喹酯占10％，Soluplus占90％。具体制备程序如下：
称取癸氧喹酯2克，Soluplus 18克，混合均匀。热熔挤出机参数的设置及加料后的操作步骤与实施例1相同。
HPLC分析显示，与癸氧喹酯标准品相比，所得产物的活性成份癸氧喹酯的滞留时间与含量均无改变；粒径测定显示，颗粒平均粒径在2～5微米；累积溶出百分率 60分钟内在20％以下(图5)。
对比例6
本对比例由包含作为活性成分的癸氧喹酯，Soluplus和Kollidon VA 64的用于热熔挤出的组合物、通过热熔挤出法制备癸氧喹酯固体分散体；所述用于热熔挤出的组合物中，以组合物总量的质量百分比计算，癸氧喹酯占10％，Soluplus占20％，Kollidon VA 64占70％。具体制备程序如下：
称取癸氧喹酯2克，Soluplus 4克，Kollidon VA 64共聚维酮14克，混合均匀。热熔挤出机参数的设置及加料后的操作步骤与实施例1相同。
本实施例制备的癸氧喹酯固体分散体基质质地均匀，在水中呈均一相；HPLC分析显示，与癸氧喹酯标准品相比，其活性成份癸氧喹酯的滞留时间与含量均无改变；粒径测定显示，颗粒平均粒径在2～5微米之间。累积溶出百分率60分钟内小于20％(图6)。
对比例7
本对比例由包含作为活性成分的癸氧喹酯，Soluplus和Kollidon VA 64的用于热熔挤出的组合物、通过热熔挤出法制备癸氧喹酯固体分散体；所述用于热熔挤出的组合物中，以组合物总量的质量百分比计算，癸氧喹酯占10％，Soluplus占60％，Kollidon VA 64占30％。具体制备程序如下：
称取癸氧喹酯3克，Soluplus 18克，Kollidon VA 64共聚维酮9克，混合均匀。设置双螺杆热熔挤出机的熔融温度为120-240℃，其余步骤与实施例1相同。
HPLC分析显示，与癸氧喹酯标准品相比，其活性成份癸氧喹酯的滞留时间与含量均无改变；粒径测定显示，颗粒平均粒径在2～5微米；累积溶出百分率60分钟内在20％以下(图7)。
对比例8
本实施例由包含作为活性成分的癸氧喹酯，Soluplus和Kollidon VA 64的用于热熔挤出的组合物、通过热熔挤出法制备癸氧喹酯固体分散体；所述用于热熔挤出的组合物中，以组合物总量的质量百分比计算，癸氧喹酯占20％，Soluplus占71％，Kollidon VA 64占9％。具体制备程序如下：
称取癸氧喹酯6克，Soluplus 21.3克，Kollidon VA 64共聚维酮2.7克，混合均匀。设置双螺杆热熔挤出机的熔融温度为120-240℃，其余步骤与实施例1相同。
HPLC分析显示，与癸氧喹酯标准品相比，其活性成份癸氧喹酯的滞留时间与含量均无改变；粒径测定显示，颗粒平均粒径在2～5微米；累积溶出百分率60分钟内在20％以下(图8)。
以上实施例及对比例所制备产品的性能及效果实验及其结果分析如下：
热重分析
称取原料药癸氧喹酯进行热重分析。所用仪器为万分之一天平(Sartorius，购自赛多利科学仪器有限公司，型号：BSA124S)和热重分析仪(德国NETZSCH公司，型号：TG209F1)
检测条件，氮气：20mL/min，扫描程序：室温升至350℃，升温速率：10℃/min；检测依据为热分析法通则JY/T 014-1996。通过热重分析癸氧喹酯显示，癸氧喹酯于250.5℃时重量下降到99％，说明化合物非常稳定，无热分解发生，而极小损失部分可判定为水分子。而对Soluplus，VA 64和PEG 6000的热重分析，也表明于这些用于热熔挤出的高分子载体辅料具有热稳定性。
图9A为原料药化合物癸氧喹酯的热重分析图；由图9A可知，癸氧喹酯(DQ)在250.5℃时重量下降到99％，说明化合物在该温度时仍非常稳定，无热分解发生，而极小损失部分可判定为水分子；图9B为实施例1所制备的癸氧喹酯固体分散体中，癸氧喹酯的高压液相色谱图分析，其显示：所制备产品的癸氧喹酯的峰型与滞留时间 均未发生改变，并与图13所示实施例3产品的高压液相色谱分析结果一致，说明本发明所制备热熔挤出产品中的活性成分癸氧喹酯未发生热分解。
差示扫描量热(DSC)分析
称取各实施例所制备的癸氧喹酯热熔挤出样品分别进行DSC测定，参照物为癸氧喹酯原料药，仅制剂辅料的热熔挤出物，以及癸氧喹酯与制剂辅料在室温下的物理混合物。所用仪器为万分之一天平(Sartorius，购自赛多利科学仪器有限公司，型号：BSA 124S)和差示扫描量热仪(德国NETZSCH公司DSC 204F1)。
使用方法为N2：20mL/min，升温程序：从室温以10℃/min的速率升到265℃，检测依据：JY/T014-1996。
此处仅示出了原料药化合物癸氧喹酯、实施例1中制备的含癸氧喹酯的热熔挤出物、实施例1中除癸氧喹酯以外的其它组分的热熔挤出物以及实施例1中癸氧喹酯与辅料在常温下的物理混合的DSC分析比较图(见图10)；由图10可见，实施例1所制备的癸氧喹酯固体分散体中，癸氧喹酯与其它高分子载体辅料已经融为一体；不含癸氧喹酯的辅料的热熔挤出物没有典型的癸氧喹酯峰型；此外，对癸氧喹酯与辅料在常温下的物理混合物进行DSC分析时，在低于90oC的温度下，该混合物与原料药化合物癸氧喹酯有一个重叠的峰，而在240oC以上时就基本上没有重叠了，这可能是由于在进行DSC分析时，温度升高后，癸氧喹酯与辅料也出现了相当程度的融合。
体外溶出试验
溶出介质是浓度为0.1N的盐酸(HCl)和10毫摩尔(mM)的十二烷基磺酸钠(SDS)的溶液。所用仪器为RC-6溶出度测定仪(天津)。溶出仪参数为37℃，50rpm，桨法；将每个溶出杯中均加入900ml的溶出介质，启动仪器，当每个杯中的介质温度达到37℃后加入相应的样品，分别于10、20、40、60、90、120、180、240、270分钟时取样1ml，补充1ml溶出介质。将取出的样品过0.45μm微孔滤膜，取滤液用于 高压液相色谱(HPLC，Agilent 1260)测定溶出癸氧喹酯的量。HPLC的流动相为乙醇80％，水20％，测定波长为260nm。
表1概括了实施例和对比例中各组分所占百分比，熔融温度(TM)以及体外溶出率；其中，S表示Soluplus；VA 64表示共聚维酮Kollidon VA 64；PVP 10表示聚乙烯吡咯烷酮-10；SDS表示十二烷基磺酸钠；PEG 6000表示聚乙二醇6000。
表1
Figure PCTCN2015096689-appb-000001
图1-图8为实施例1-8、对比例1-8所制备的癸氧喹酯固体分散体以及癸氧喹酯原药的体外溶出结果对比图。
由图1-图8、表1结果可知，与对比例(除对比例1外)制备的癸氧喹酯固体分散体以及癸氧喹酯原药相比，本发明实施例所制备的癸氧喹酯固体分散体具有明显更好的体外溶出度；尽管对比例1的体外溶出效果较好，然而其体内的药物代谢动力学明显不如实施例1的癸氧喹酯固体分散体(参见下文描述的药物代谢动力学实验及其实验结果，附图14)。
药物代谢动力学实验
用于药代试验的癸氧喹酯标准曲线的制定是先将癸氧喹酯按0.1毫克/毫升的浓度溶于乙醇中，再用乙醇稀释成一系列浓度(0.03μg/ml～30μg/ml)，共8个梯度浓度。每45微升空白血浆加5微升癸氧喹酯标准液，5微升浓度为10μg/ml内标氯雷他定，涡旋30秒钟混匀，分别加入150μl的蛋白沉淀剂乙醇。涡旋2分钟后，于4℃高速离心15000转/分钟，离心5分钟，取100μl上清液入自动进样器小管，进行HPLC-MS/MS分析，进样量为5μl。质量控制的样品为癸氧喹酯10、300、2400ng/ml，处理方法同上。色谱分析柱为XTerra MS C18 5μm，4.6mm X 50mm；Part No.186000482；S/N：03083432513203；流动相为含0.1％甲酸的甲醇：含0.1％甲酸的水(90：10：，v/v)；流速为600μl/min；柱温为30℃，进样器温度为15℃。
本发明药物代谢动力学实验中所用动物为雄性大鼠(sprague-dawley male rats)。给药前先称体重，一般为180～200克之间。所有大鼠的给药剂量为20mg/Kg。精密称取癸氧喹酯固体分散体粉末，用生理盐水超声溶解，制备成含药浓度为2mg/ml的混悬液。按动物体重取不同体积灌胃给药。给药后分别于15分钟、30分钟、1小时、2小时、4小时、6小时、8小时、24小时、48小时、72小时从尾静脉采全血250μl，于4℃离心机3500转/分钟，离心10分钟，取上清血浆于负80℃冰箱保存待分析。采用蛋白沉淀方法对血浆样本进行处理。选用乙醇作为蛋白沉淀试剂。样本分析前的处理是取50μl含药血浆，加5μl浓度为10μg/ml内标氯雷他定标准溶液(乙醇溶解)，涡旋30秒钟混匀，分别加入150μl的蛋白沉淀剂乙醇。余下的步骤同上述标准曲线的制备。
表2为实施例1和对比例1所制备的癸氧喹酯固体分散体的各项主要药物代谢动力学参数的评价。
表2
Figure PCTCN2015096689-appb-000002
图14为实施例1和对比例1的药物代谢动力学曲线；其中，纵坐标表示血浆中癸氧喹酯浓度，横坐标表示动物血液取样时间。
由表2及图14可知：尽管实施例1的体外溶出率不比对比例1的更有效，但是在动物体内的相同时间点的血浆浓度却是对比例1的近2倍，半衰期也比对比例1的长2倍多。对比这2种制剂组分，可看出其差别在于，实施例1中含有PEG 6000，而对比例1不含有PEG 6000。在本发明人的设计中，适量加入了聚乙二醇后，不仅可以延长活性成分癸氧喹酯在体内血液中的循环时间，延长半衰期，还可以提高动物体内癸氧喹酯在血中的浓度，有利于提高药效。
体内药效实验
用于实验的雌性(NIH)小鼠，在到达后，至少要养7天。开始给药时，小鼠的年龄为7周。每个笼子只养一只小鼠。室温为18℃-26℃，相对湿度为34％-68％，12小时的灯光和黑暗交替周转。试验前和试验中的食物为标准的喂养食品(adlibitum)。此实验是严格按照有关动物实验法规所进行的(Guide for the Care and Use of Laboratory Animals，NRC publication，2011 edition)。动物实验中所用的癸氧喹酯混悬液是实施例1的样品，用生理盐水配制，再用超声仪超声5分钟。每次动物实验至少重复三次，每次每组5只小鼠，因此每组至少测试15只小鼠。NIH雌性小鼠的疟原虫感染的方法是每只小鼠尾静脉注射5万个伯氏疟原虫(P.berghei ANKA)的子孢子。灌胃(口服)给药共分为三次，即疟原虫感染的前一天，当天和第二天。阳性对照是用作用于肝期疟原虫的抗疟药伯氨奎宁。载体空白是指除癸氧喹酯以外的癸氧喹酯固 体分散体中的成份。载体空白中的任何成份均无抗疟疾活性，其结果与用生理盐水作为阴性对照所得到的结果一致。虫血率的检测的方法是按常规红细胞计数每mm3血液的红细胞数，并制薄血膜，3％Giemsa染色20分钟，油镜下计数每1000个红细胞中感染红细胞数，得红细胞感染率(erythrocyte infected rate，EIR，‰)。生存率的计算是在感染后第22天进行统计。
图15实施例1所制备产品的动物药效实验；实施例1的产品剂量按癸氧喹酯每公斤体重计算，阴性对照组用生理盐水，阳性对照组用伯氨奎宁30毫克每公斤体重；纵坐标表示动物血中疟原虫感染率，横坐标表示实验分组，图中所示为疟原虫感染后第7天的结果。图16为图15中所示实施例1产品的动物药效实验的后续实验中动物存活率的统计。
由图15、图16可知，实施例1制剂在以3毫克癸氧喹酯每公斤体重，10毫克癸氧喹酯每公斤体重，以及30毫克癸氧喹酯每公斤体重的剂量施用给小鼠后，在血浆中均检测不到疟原虫，说明这三种剂量均能有效地阻止小鼠疟原虫子孢子的感染；此外，观察到21天时，施用本发明癸氧喹酯固体分散体或伯氨奎宁的动物均存活，而没有用抗疟疾药的对照组的动物则全部死亡。
申请人声明，本发明通过上述实施例来说明本发明的产品、用途及其使用方式，但本发明并不局限于上述详细用途和使用方式，即不意味着本发明必须依赖上述详细用途和使用方式才能实施。所属技术领域的技术人员应该明了，对本发明的任何改进，对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等，均落在本发明的保护范围和公开范围之内。

Claims (10)

  1. 一种用于热熔挤出的组合物，其特征在于，按重量百分比计，所述组合物包括：
    癸氧喹酯           5％-30％；
    高分子载体材料     60％-90％；和
    表面活性剂         0％-10％。
  2. 根据权利要求1所述的组合物，其特征在于，所述高分子载体材料为聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物、共聚维酮、聚维酮或聚乙二醇中的一种或两种以上的组合。
  3. 根据权利要求2所述的组合物，其特征在于，所述聚乙烯己内酰胺-聚醋酸乙烯酯-聚乙二醇接枝共聚物为Soluplus；
    优选地，所述共聚维酮为Kollidon VA 64；
    优选地，所述聚维酮为聚维酮k17、聚维酮k25、聚维酮k30或聚乙烯吡咯烷酮-10；
    优选地，所述聚乙二醇为聚乙二醇8000，聚乙二醇6000或聚乙二醇4000。
  4. 根据权利要求1所述的组合物，其特征在于，所述表面活性剂为十二烷基硫酸钠、月桂酸聚乙二醇甘油酯、硬脂酸聚乙二醇甘油酯或聚氧乙烯氢化蓖麻油中的任意一种或几种的组合。
  5. 根据权利要求4所述的组合物，其特征在于，所述月桂酸聚乙二醇甘油酯为Gelucire 44/14；
    优选地，所述硬脂酸聚乙二醇甘油酯为Gelucire 50/13；
    优选地，所述聚氧乙烯氢化蓖麻油为Kolliphor RH 40。
  6. 一种癸氧喹酯固体分散体的制备方法，其包括：在热熔温度下，热熔挤出如权利要求1-5任一项所述的组合物。
  7. 根据权利要求6所述的制备方法，其特征在于，所述热熔温度为50～200℃，优选120～200℃。
  8. 根据权利要求6或7所述的制备方法，其特征在于，所述热熔挤出在热熔挤出机中进行；
    优选地，所述热熔挤出机的螺杆旋转速度为15-300转/分钟，更优选20-150转/分钟。
  9. 一种癸氧喹酯固体分散体，其由如权利要求6-8任一项所述的制备方法制成。
  10. 如权利要求1-5任一项所述的组合物或如权利要求9所述的癸氧喹酯固体分散体在制备用于预防和/或治疗由疟原虫引起的疾病的药物制剂中的用途；
    优选地，所述疾病为间日疟、恶性疟、三日疟、卵形疟和诺氏疟中的任意一种或几种。
PCT/CN2015/096689 2015-12-08 2015-12-08 癸氧喹酯固体分散体、其制备方法和用途 WO2017096530A1 (zh)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110075065A (zh) * 2019-06-04 2019-08-02 河南健恒动物药业有限公司 一种抗球虫药物癸氧喹酯溶液及其制备方法
RU2785565C2 (ru) * 2017-11-30 2022-12-08 Бит Фарма Гмбх Способ и устройство для получения твердой дисперсии

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110354080A (zh) * 2018-04-10 2019-10-22 孟斯琴 一种抗关节炎药物固体分散体组合物及其制备方法
US11246836B2 (en) * 2018-05-17 2022-02-15 Bluelight Pharmatech Co., Ltd. Intramuscular depot of decoquinate compositions and method of prophylaxis and treatment thereof
CN111698990A (zh) * 2019-01-02 2020-09-22 广州蓝亮医药科技有限公司 固态溶液形式的癸氧喹酯纳米粒子制剂
CN113101270B (zh) * 2020-01-10 2024-07-09 广东东阳光药业股份有限公司 一种巴洛沙韦酯药物组合物及其制备方法
US20220030913A1 (en) * 2020-08-03 2022-02-03 Hoxie Feedyard, LLC Supplement for livestock
CN113952300B (zh) * 2021-10-19 2024-04-19 吉林医药学院 尼群地平自胶束化非晶态固体分散体的制备及效果分析
CN114469947B (zh) * 2022-03-22 2023-03-17 平顶山市妇幼保健院 一种新型抗组胺药物制剂在喉炎中的应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101564376A (zh) * 2009-04-10 2009-10-28 烟台绿叶动物保健品有限公司 癸氧喹酯固体分散体及其制备

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101590055B (zh) * 2009-07-07 2011-07-06 河南亚卫动物药业有限公司 一种水溶性癸氧喹酯及其制备方法
CN101606908B (zh) * 2009-07-10 2013-11-20 广州华农大实验兽药有限公司 癸氧喹酯可溶性粉及其制备方法
CN102274189A (zh) * 2011-07-21 2011-12-14 瑞普（天津）生物药业有限公司 一种含有癸氧喹酯的干混悬剂组方及其制备方法
CN104906044B (zh) * 2015-05-22 2019-05-07 广州蓝亮医药科技有限公司 一种癸氧喹酯纳米制剂及其制备方法与应用

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101564376A (zh) * 2009-04-10 2009-10-28 烟台绿叶动物保健品有限公司 癸氧喹酯固体分散体及其制备

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
ARIEL, F. ET AL.: "A molecular marker of artemisinin-resistant Plasmodium falciparum malaria", NATURE, vol. 505, 2014, pages 50 - 55
CHEMICAL ABSTRACTS, Columbus, Ohio, US; abstract no. 18507-89-6
INTERN J APPL RES VET MED., vol. 10, no. 1, 2012
JID, vol. 205, 2012, pages 1278 - 86
SCIENCE, vol. 334, 2011, pages 1372 - 7
See also references of EP3388065A4
VETERINARY RECORD, vol. 138, 1996, pages 434 - 436

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2785565C2 (ru) * 2017-11-30 2022-12-08 Бит Фарма Гмбх Способ и устройство для получения твердой дисперсии
CN110075065A (zh) * 2019-06-04 2019-08-02 河南健恒动物药业有限公司 一种抗球虫药物癸氧喹酯溶液及其制备方法

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