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WO2018126522A1 - Médicament antiviral injectable intraoculaire à libération prolongée, son procédé de fabrication et son application - Google Patents

Médicament antiviral injectable intraoculaire à libération prolongée, son procédé de fabrication et son application Download PDF

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Publication number
WO2018126522A1
WO2018126522A1 PCT/CN2017/074975 CN2017074975W WO2018126522A1 WO 2018126522 A1 WO2018126522 A1 WO 2018126522A1 CN 2017074975 W CN2017074975 W CN 2017074975W WO 2018126522 A1 WO2018126522 A1 WO 2018126522A1
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WO
WIPO (PCT)
Prior art keywords
salt
foscarnet
microcrystal
phosphonic acid
phosphonoformate
Prior art date
Application number
PCT/CN2017/074975
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English (en)
Chinese (zh)
Inventor
陶勇
黄延宾
孙玉玲
曹庆辰
Original Assignee
首都医科大学附属北京朝阳医院
清华大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by 首都医科大学附属北京朝阳医院, 清华大学 filed Critical 首都医科大学附属北京朝阳医院
Publication of WO2018126522A1 publication Critical patent/WO2018126522A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • 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
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention belongs to the field of medicines, and particularly relates to an anti-virus sustained-release medicine which can be used for intraocular injection, a preparation method and application thereof.
  • Viral retinal disease is an ocular lesion with a high risk of visual impairment and blindness, and is diverse in many diseases, including cytomegalovirus retinitis, acute retinal necrosis, and progressive outer retinopathy.
  • the incidence of viral retinal diseases has increased in recent years due to the combination of an aging population, the spread of AIDS, the use of new immunosuppressants, unhealthy lifestyle habits, and increased stress.
  • Intravitreal injection of antiviral drugs is an important way to treat viral retinal diseases clinically.
  • Injectable drugs include sodium foscarnet and ganciclovir.
  • the half-life of sodium foscarnet in the eye is very short, and after 12 hours, the concentration of sodium foscarnet in the eye drops by more than half. After a single injection of sodium foscarnet, the effective drug concentration in the eye does not exceed 3 days. Therefore, clinically, patients with viral retinal diseases often require frequent intraocular drug injections, which greatly increases the economic burden on patients and families, and also makes the overall therapeutic effect of viral retinal diseases poor.
  • the FDA approved a sustained release device for ganciclovir but the device has the disadvantage of requiring re-surgery after the drug is released.
  • the upper limit of the injection volume is 0.1 mL, and considering that the solid content of the injection suspension cannot be too high, which requires that the sustained release system must have a high drug loading amount.
  • the dosage of sodium foscarnet is much higher than that of ganciclovir.
  • the long-term sustained release in the eye requires a specially designed system with a drug loading of nearly 100%, which is technically challenging.
  • intravitreal injection The needle model is 27G or finer, and its inner diameter is only 210 ⁇ m, which requires the particles of the sustained release system to have suitable size and is not easy to aggregate.
  • the intraocular environment requires strict sterile materials, and the materials used for injection must pass through. Strictly disinfected.
  • One of the objects of the present invention is to provide a phosphonic acid insoluble salt microcrystal.
  • the phosphoric acid insoluble salt is a polyvalent metal salt of foscarnet, and the polyvalent metal may be selected from at least one of calcium, magnesium, zinc and aluminum. .
  • the phosphonium insoluble salt microcrystals have a diameter ranging from 0.1 to 100 ⁇ m, preferably from 1 to 50 ⁇ m.
  • the foscarnet poorly soluble salt microcrystals may comprise bound water.
  • the foscarnet poorly soluble salt microcrystals provided by the present invention are prepared according to the method comprising the following steps:
  • the monovalent metal salt of the foscarnet and the soluble salt of the polyvalent metal are reacted in water to obtain a system containing the micron crystal of the phosphonium insoluble salt.
  • the monovalent metal salt of foscarnet may specifically be sodium foscarnet or potassium phosphonate.
  • the molar ratio of the monovalent metal salt of foscarnet to the soluble salt of the polyvalent metal is from 1:1 to 1:10.
  • the reaction time is from 0.1 to 24 hours, specifically 1 hour.
  • the reaction is carried out with stirring.
  • the monovalent metal salt of foscarnet is added as an aqueous solution; the soluble salt of the polyvalent metal is also added as an aqueous solution.
  • the aqueous solution of the monovalent metal salt of foscarnet has a concentration of 0.1 to 500 mg/mL, specifically 1 to 10 mg/mL.
  • the concentration of the aqueous solution of the soluble salt of the polyvalent metal is from 0.1 to 500 mg/mL, specifically from 1 to 10 mg/mL.
  • the method further includes the operation of isolating the phosphonic acid insoluble salt microcrystals from the obtained system containing the phosphonic acid insoluble salt microcrystals.
  • the operation is: the system containing the phosphonic acid insoluble salt microcrystals is allowed to stand, filtered, the solid is collected, washed, and the suspension is lyophilized to obtain a phosphonic acid insoluble salt microcrystal.
  • Another object of the present invention is to provide an antiviral drug having a sustained release effect which can be injected intraocularly.
  • the antiviral drug having a sustained release effect which can be administered intraocularly according to the present invention is the above-mentioned phosphonic acid insoluble salt microcrystal or a suspension containing the above-mentioned phosphonium insoluble salt microcrystal.
  • the invention aims at the special requirement of intraocular injection and controlled release, and designs and develops a phosphonium insoluble salt microcrystalline sustained release system, which can be loaded with a nominal amount of more than 100% relative to the sodium foscarnet.
  • the sustained release of the drug in the vitreous cavity is achieved by preparing an injectable phosphofuric acid insoluble salt microcrystal using its dissolution equilibrium.
  • the foscarnet insoluble salt microcrystalline sustained-release drug prepared by the invention can well solve the problem that the sodium foscarnet needs frequent injections, and the insoluble salt of the foscarnet should be used as a glass. Injectable slow release techniques for antiviral drugs in body cavity are used.
  • FIG. 1 is a flow chart showing the preparation of a phosphonium insoluble salt microcrystalline sustained-release drug prepared by the present invention.
  • FIG. 2 is a scanning electron micrograph of a phosphonium insoluble salt microcrystalline sustained-release drug prepared according to the present invention.
  • Figure 3 is an X-ray diffraction pattern of the foscarnet insoluble salt microcrystalline sustained release drug and the raw material sodium foscarnet prepared according to the present invention.
  • Fig. 4 is a view showing the presence of a phosphonium insoluble salt microcrystalline sustained-release drug prepared by the present invention in rabbit eyes and the health condition of a rabbit eye in an animal experiment.
  • Figure 5 is a scanning electron micrograph of a foscarnet insoluble salt microcrystalline sustained release drug taken from rabbit eyes in an animal experiment.
  • Figure 6 is a graph showing changes in the concentration of foscarnet in the vitreous and aqueous humor of rabbit eyes in an animal experiment.
  • a phosphonic acid insoluble salt microcrystal was prepared.
  • a 6 mg/mL sodium phosphonate sodium aqueous solution and a 6 mg/mL calcium chloride solution were prepared, and the two solutions were mixed and reacted in a volume ratio of 1:1 to obtain a product b.
  • Fig. 2 (a), (b) and (c) are scanning electron micrographs of the prepared micronized crystals of foscarnet insoluble salts, a, b and c, respectively, and the average sizes thereof are estimated to be 10 ⁇ m, 60 ⁇ m and 100 ⁇ m, respectively.
  • the crystals are grown in the radial direction from the center to form a micron-sized spherical crystal.
  • X-ray diffraction characterization phosphonic acid insoluble salt microcrystal freeze-dried powder and sodium foscarnet standard They were respectively ground with a mortar, sieved with a 100 mesh sieve, and characterized by an X-ray diffractometer. The test conditions were: 2 ° 2 ⁇ / min, step size 0.02 ° 2 ⁇ , using Cu K ⁇ ray. The experimental results are shown in Figure 3.
  • the size of the phosphonium insoluble salt microcrystalline sustained release drug can be controlled by adjusting the initial concentration of the sodium foscarnet solution and the calcium chloride solution and the mixing volume ratio.
  • the crystallinity of the sample is close to 100%, and its crystal structure is different from that of the raw material sodium foscarnet.
  • Determination of the content of Ca, Na and P elements foscarnet insoluble salts extended release pharmaceutical micron crystals utilizing plasma mass spectrometry (ICP-MS), whereby molecular structure was confirmed foscarnet insoluble salts of Ca 3 (CO 5 P) 2 or write Ca 3 (pfa) 2 .
  • Table 1 is the equilibrium solubility value of the foscarnet insoluble salt microcrystals (product a) prepared in Example 1 under different conditions.
  • micron crystal of the foscarnet insoluble salt microcrystal can be prepared by directly mixing the sodium phosphonate solution with the calcium chloride solution, and the insoluble intravitate microcrystal can satisfy the intraocular injection (the particle size is below 100 microns). And have the basic requirements of anti-viral drugs with sustained release effect.
  • Example 3 Intraocular sustained release experiment of micron crystals of foscarnet insoluble salt microcrystals
  • the animal experiment steps are as follows:
  • Fig. 4 is a view showing the presence of a phosphonium insoluble salt microcrystalline sustained-release drug prepared by the present invention in rabbit eyes and the health condition of a rabbit eye in an animal experiment.
  • the foscarnet insoluble salt microcrystalline sustained-release drug prepared by the invention can be stably and sustainedly released in the vitreous cavity of the rabbit eye, and the concentration of the phosphonate root in the vitreous cavity is maintained above the effective therapeutic concentration of the sodium foscarnet, and the sustained release period is long. After 12 weeks, the rabbit eyes were in good health after 12 weeks. Therefore, it has been proved by animal experiments that the foscarnet insoluble salt microcrystalline sustained-release drug prepared by the invention can well solve the problem that the sodium foscarnet needs frequent injections, and the insoluble salt of the foscarnet should be used as a glass. Injectable slow release techniques for antiviral drugs in body cavity are used.

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

Abstract

L'invention concerne un médicament antiviral injectable intraoculaire à libération prolongée, son procédé de fabrication et son application. Le médicament antiviral est un microcristal de sel de phosphonoformate insoluble. Le sel de phosphonoformate insoluble est un sel métallique multivalent d'acide phosphonoformique. Le procédé de fabrication selon l'invention comprend : la mise en réaction d'un sel métallique monovalent d'acide phosphonoformique avec un sel métallique multivalent soluble dans l'eau ; et l'obtention d'un système contenant le microcristal de sel de phosphonoformate insoluble. Un système de libération prolongée de microcristaux du sel de phosphonoformate insoluble est conçu et développé pour répondre aux besoins spéciaux d'une injection intraoculaire à libération prolongée et contrôlée. La charge nominale du médicament du système est supérieure à 100 %. Le médicament antiviral à libération prolongée du sel de phosphonoformate insoluble peut être libéré de manière durable et stable dans la cavité vitréenne d'un œil de lapin. La concentration vitreuse du phosphonoformate reste en continu supérieure à une concentration thérapeutique efficace du phosphonoformate de sodium. Le médicament antiviral a une période de libération prolongée allant jusqu'à 12 semaines et n'induit pas de réactions toxiques ou inflammatoires significatives. Le sel de phosphonoformate insoluble peut être utilisé en tant que médicament antiviral approprié pour une technologie d'injection intravitréenne à libération prolongée.
PCT/CN2017/074975 2017-01-05 2017-02-27 Médicament antiviral injectable intraoculaire à libération prolongée, son procédé de fabrication et son application WO2018126522A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710006803.1 2017-01-05
CN201710006803.1A CN108276440B (zh) 2017-01-05 2017-01-05 一种可眼内注射使用的抗病毒缓释药物及其制备方法与应用

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CN111467355B (zh) * 2020-04-07 2021-04-23 中国科学院深圳先进技术研究院 膦甲酸钠在制备预防和治疗冠状病毒的药物中的应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1433764A (zh) * 2003-02-28 2003-08-06 蔡惠明 膦甲酸钠凝胶制剂及其制备方法
CN101564374A (zh) * 2008-04-25 2009-10-28 北京和润创新医药科技发展有限公司 一种药物眼用即型凝胶
CN103126981A (zh) * 2013-03-05 2013-06-05 宁夏康亚药业有限公司 膦甲酸钠滴眼液及其制备方法
DE102012103717A1 (de) * 2012-04-27 2013-11-14 Westfälische Wilhelms-Universität Münster Arzneimittel zur Behandlung von Tumorerkrankungen
CN104906587A (zh) * 2015-05-15 2015-09-16 青岛大学 一种膦甲酸钠眼玻璃体腔内缓释药物

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1433764A (zh) * 2003-02-28 2003-08-06 蔡惠明 膦甲酸钠凝胶制剂及其制备方法
CN101564374A (zh) * 2008-04-25 2009-10-28 北京和润创新医药科技发展有限公司 一种药物眼用即型凝胶
DE102012103717A1 (de) * 2012-04-27 2013-11-14 Westfälische Wilhelms-Universität Münster Arzneimittel zur Behandlung von Tumorerkrankungen
CN103126981A (zh) * 2013-03-05 2013-06-05 宁夏康亚药业有限公司 膦甲酸钠滴眼液及其制备方法
CN104906587A (zh) * 2015-05-15 2015-09-16 青岛大学 一种膦甲酸钠眼玻璃体腔内缓释药物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SUN, YULING ET AL.: "Foscarnet Calcium Microcrystals as the Intravitreal Drug Depot", CHEM. COMMUN., vol. 53, 13 April 2017 (2017-04-13), pages 5139 - 5142, XP055511401 *

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