WO2002015888A1 - Systeme de controle de liberation de medicament - Google Patents

Systeme de controle de liberation de medicament Download PDF

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Publication number
WO2002015888A1
WO2002015888A1 PCT/JP2001/007290 JP0107290W WO0215888A1 WO 2002015888 A1 WO2002015888 A1 WO 2002015888A1 JP 0107290 W JP0107290 W JP 0107290W WO 0215888 A1 WO0215888 A1 WO 0215888A1
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WO
WIPO (PCT)
Prior art keywords
drug
nanospheres
retina
vitreous
release
Prior art date
Application number
PCT/JP2001/007290
Other languages
English (en)
Japanese (ja)
Inventor
Yuichiro Ogura
Noriyuki Kunou
Original Assignee
Santen Pharmaceutical Co., Ltd.
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.)
Filing date
Publication date
Application filed by Santen Pharmaceutical Co., Ltd. filed Critical Santen Pharmaceutical Co., Ltd.
Priority to AU2001280165A priority Critical patent/AU2001280165A1/en
Publication of WO2002015888A1 publication Critical patent/WO2002015888A1/fr

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Classifications

    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
    • 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
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P31/04—Antibacterial 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
    • A61P31/10—Antimycotics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • the present invention relates to a system for controlling the release of drugs into the retina or the vitreous.
  • Description Background Art There are many intractable diseases in diseases of the inner eye such as the retina and the vitreous, and development of an effective treatment method thereof is needed. Is desired.
  • the most common treatment for ocular diseases is to administer the drug by eye drops, but the drug hardly migrates to the inner eye such as the retina and the vitreous. This makes treatment of diseases in the inner eye more difficult. Since the intraocular delivery of systemically administered drugs is limited by the blood-eye barrier, it is difficult to transfer drugs to effective concentrations.
  • a method of directly administering a drug to the inner ocular region has been attempted.
  • a technique has been reported in which ribosomes or microspheres containing a drug are administered to the inner ocular region such as the vitreous body.
  • ribosomes have difficulty in controlling the release of drugs, and microspheres have a large particle size, so there is a problem in maintaining uniform dispersibility and transparency in the vitreous body.
  • Studies have been conducted to include the drug in the capsule and administer the vitreous.
  • a pharmaceutical carrier system containing spherical particles with a diameter of less than or equal to the diameter Japanese Patent Application Laid-Open No.
  • Japanese Patent Application Laid-Open No. 6-5088369 describes a bioadhesive polymer as a carrier, and a drug is adsorbed to the polymer, and the release rate and duration of the drug are appropriately controlled.
  • the effect is unsatisfactory, and the one described in Japanese Patent Application Laid-Open No. 221213/22 relates to a nanocapsule containing a central core having lipid properties, which is applicable only to fat-soluble drugs, and Release rate The appropriate control effect between them is not satisfactory.
  • a drug release control system that can control the release rate and duration of the drug appropriately and that can be applied to the retina or vitreous body without restriction on the type of drug. Disclosure of the invention
  • the present inventors have focused on using nanospheres as the drug release control system.
  • the use of synthetic biodegradable macromolecules results in the carrier being rapidly decomposed and absorbed together with the release of the drug or after the release of the drug, resulting in nanospheres suitable for actual medical treatment.
  • the drug can be contained as a matrix type, enabling uniform dispersion of the drug in the fine particles, and further, the release rate of the drug based on the decomposition of the carrier. We have found that the duration can be controlled appropriately.
  • nano-sized fine particles can ensure uniform dispersibility of the fine particles in the retina or the vitreous body. Furthermore, the nanospheres administered into the vitreous are taken into the retina in a state in which the nanospheres contain the drug, and the smaller the particle size, the longer they remain in the retina or the vitreous for a long period of time. It has been found that, when a nanosphere having a diameter of 20 O nm or less is selected, the persistence of the drug concentration in the retina can be more suitably improved by remaining in the retina for a long period of time.
  • the present invention relates to a drug release control system characterized in that a nanosphere in which a drug is uniformly contained in fine particles formed of a nanosized synthetic biodegradable polymer is administered to the retina or the vitreous body.
  • a nanosphere in which a drug is uniformly contained in fine particles formed of a nanosized synthetic biodegradable polymer is administered to the retina or the vitreous body.
  • the use of nano-sized fine particles ensures uniform dispersion of the fine particles in the vitreous body.
  • the carrier is designed to be decomposed and absorbed together with the release of the drug or immediately after the release of the drug.3)
  • the drug is incorporated into the fine particles in a matrix form.
  • the drug release control system of the present invention comprises a nanosphere in which a drug is uniformly contained in microparticles formed of nanosized synthetic biodegradable polymer, and this is a retina or a target site.
  • the drug can be efficiently delivered to the retina or the vitreous.
  • the present invention also provides a method for administering to a retina or vitreous a nanosphere in which a drug is uniformly contained in fine particles formed of a nanosized synthetic biodegradable polymer, and administering an effective amount of the drug to the retina or vitreous.
  • a method for treating retinal or vitreous disease is also provided.
  • the type of synthetic biodegradable polymer that forms nanospheres is not particularly limited, but specific examples include polylactic acid, lactic acid-glycolic acid copolymer, and polyanhydride (Polyanhydride). ), Polyorthoesters (Poly, or orthoester)), poly (epsilon) -caprolactone (Poly ⁇ -caprolactone), polyalkyl cyanoacryl at e, polyhydroxyalkanoate (Polyhydroxyalkanoate) And a biodegradable polymer such as polyphosphoester, etc.
  • a preferred example is polylactic acid or a lactic acid-glycolic acid copolymer.
  • the body, D body or DL body can be used.
  • the molecular weight of these synthetic biodegradable polymers is not particularly limited, and can be appropriately selected depending on the type of drug contained in the nanosphere, the required effective concentration of the drug, the release period of the drug, and the like.
  • the particle size of the fine particles forming the nanospheres is nano-sized, but when it is required to remain in the retina for a long time, the average particle size is more preferably set to 200 nm or less. preferable. There is no particular lower limit, but if it is too small, it should be set to 50 nm or more due to manufacturing restrictions. preferable. Incidentally, the average particle diameter in the present invention was measured by a light scattering method.
  • the drug release control system of the present invention is used for treating or preventing various diseases of the retina and the vitreous body.
  • Specific diseases include intraocular inflammation due to various causes, viral and bacterial infections, proliferative vitreoretinopathy accompanied by changes in the growth of new blood vessels and retinal cells, retinal hemorrhage due to various causes, Retinal detachment, retinoblastoma and the like.
  • the drug contained in the nanosphere is not particularly limited, and a drug suitable for the target disease can be selected.
  • an anti-inflammatory drug such as methasone is used.
  • an immunosuppressant such as cyclosporine is used.
  • an immunosuppressant such as cyclosporine is used.
  • viral infection are antiviral agents such as ganciclovir, antibacterial agents such as ofloxacin for postoperative infections, doxorubicin and carmustine for proliferative vitreoretinopathy.
  • antiviral agents such as ganciclovir
  • antibacterial agents such as ofloxacin for postoperative infections, doxorubicin and carmustine for proliferative vitreoretinopathy.
  • these drugs may be in the form of salts such as hydrochlorides and esters such as phosphate esters.
  • the amount of drug contained in nanospheres depends on the type of drug and the required effective concentration of drug.
  • the dose may be appropriately increased or decreased according to the drug release period, symptoms, and the like.
  • the drug is 0.01 to 10% by weight of the nanosphere, preferably 0.1 to 5% by weight, but the content of the drug is a balance between the sustained release effect and the amount required for treatment. Can be determined in consideration of
  • the nanosphere used in the present invention can be manufactured by using a known interface deposition method or interface reaction method.
  • the in-liquid drying method which is an interfacial deposition method (J. Control. Release, 2, 343-352 (1985), J. Control led. Release, .36, 1095-1103 (198 8)), etc. , Interfacial polymerization methods (Int. J. Pherm., 28, 125-132 (1986)), and self-emulsifying solvent diffusion method (J. Control. Release, 25, 89-98 (1993)). It is possible to appropriately select an appropriate production method from these production methods in consideration of the particle size of the nanosphere ⁇ the type, properties and content of the drug contained.
  • nanospheres As a specific example of the production of nanospheres, an example of the production of nanospheres containing betamethasone, which is an anti-inflammatory agent, as a drug and using a lactic acid-glycolic acid copolymer as a carrier is shown in Examples below.
  • the carrier is decomposed and absorbed together with the release of the drug or immediately after the release of the drug, and the degradation rate is determined by the molecular weight of the synthetic biodegradable polymer. Therefore, the release rate of the drug can be controlled according to the purpose.
  • a nanobiosphere is produced by dissolving a synthetic biodegradable polymer that is a carrier and a drug in an appropriate solvent, so that the drug is contained in the fine particles in a matrix form.
  • a synthetic biodegradable polymer that is a carrier and a drug
  • an appropriate solvent so that the drug is contained in the fine particles in a matrix form.
  • a drug can be efficiently delivered to the retina or vitreous as a target site, so that the compounding amount of the drug can be reduced and the effect of reducing side effects can be expected.
  • the nanosphere used in the drug release control system of the present invention is administered by various methods such as injection and infusion, which can be introduced into the vitreous body.
  • This preparation can be prepared using commonly used preparation techniques.
  • an injection can be prepared by dispersing a drug-containing nanosphere in a BSS (Balanced Salt Solution) solution.
  • BSS Breast Salt Solution
  • FIG. 1 is a graph showing a temporal change in the concentration of nanospheres containing betamethasonezone in the vitreous body.
  • FIG. 2 is a fluorescence micrograph showing that 200 nm nanospheres are incorporated into the retina.
  • This method is a production method based on the self-emulsifying solvent diffusion method (J. Control. Release, 25, 89-98 (1993)).
  • Betamethasone-containing lactic acid-glycolic acid copolymer nanospheres Betamethasone (1 Omg) and a lactic acid-glycolic acid copolymer (lOOmg) having a weight average molecular weight of 70,000 and a copolymerization ratio of 50/50 were converted to dichloromethane (0 Dissolve in 5 mL). Add acetone (10 mL) to this and mix well. This solution is added dropwise to an aqueous polyvinyl alcohol solution (2 wZv ⁇ , 5 OmL) with stirring. Stir for 2 hours under reduced pressure, and filter using a membrane filter (pore size: 1 m).
  • the filtrate is ultracentrifuged (156000 Xg) for 1 hour to precipitate the nanospheres.
  • An appropriate amount of purified water is added to the obtained nanospheres, redispersed, and ultracentrifuged again to wash the nanospheres. This washing operation is repeated twice.
  • the precipitate finally obtained is redispersed in purified water (1 OmL) and freeze-dried to obtain methacrylate-containing lactic acid-glycolic acid copolymer nanospheres (103 mg).
  • the average particle size of the obtained nanospheres is 100 nm (measured by light scattering method).
  • nanospheres obtained in the above production examples are abbreviated as "betamethasone-containing nanospheres".
  • Nanospheres using drugs such as cyclosporine, ganciclovir, doxorubicin hydrochloride, and carmustine can be produced in the same manner as described above.
  • the following shows an example of preparing an injection solution.
  • the nanosphere powder containing betamethasone (50 mg) was re-dispersed in BSS (1 mL) to prepare an injection solution.
  • Betamethasone-containing nanospheres manufactured in the above manufacturing example particle size: 100 nm
  • a nanosphere containing betamethasone having a particle diameter of 1 _im and 10 ⁇ (when the particle diameter is 1 iLim or more, it is usually referred to as a microsphere, but here it is referred to as a nanosphere for convenience. Unless otherwise specified, the same applies hereinafter.) )
  • the intravitreal concentration of betamethasone was measured according to the following method.
  • a nanosphere containing betamethasone having particle diameters of 1 / m and 10 ⁇ was prepared according to the following method. ⁇
  • Betamethasone (1 Omg) and a lactic acid-glycolic acid copolymer (lOOmg) having a weight average molecular weight of 700,000 and a copolymerization ratio of 50/50 were added to dichloromethane (0.5m Dissolve in L).
  • acetone 7.5 mL
  • This solution is added dropwise to an aqueous solution of polypinyl alcohol (2 w / v%, 50 mL) with stirring. Stir under reduced pressure for 2 hours, and filter the solution using a membrane filter (pore size: 1 im).
  • the finally obtained precipitate is redispersed in purified water (10 mL) and freeze-dried to obtain a microsphere containing betamethasone with an average particle diameter of 1 m.
  • the amount of acetone is changed by 6 mL, and the pore size of the filter is changed to obtain microspheres containing betamethasone with an average particle diameter of 10 / im.
  • Fig. 1 shows the results of the time course of the concentration of the drug.
  • a suspension of polystyrene nanospheres (particle diameter 50 nm) containing 5% fluorescent dye (maximum excitation wavelength: 458 nm, maximum fluorescence wavelength: 540 nm) was diluted 200-fold with sterile purified water to obtain fluorescein.
  • the fluorescence intensity was the same as that of a sodium aqueous solution (10 Og / niL).
  • the particle size of nanospheres is 50 nm, 100 nm, 200 nm, 2 urn And 20 m suspensions were similarly prepared.
  • An aqueous solution of fluorescein sodium (10. Oig / mL) was used as a control solution.
  • Intravitreal Intravitreal fluorescence intensity was measured with time using a vitreous fluorometer after 1, 3, 7, 14, 21, and 28 days, and the half-life was calculated.
  • nebul injection solution (5 mL) was intravenously administered to the ear vein, and anesthesia was killed.
  • Table 1 shows the half-life of the nanospheres of each particle size in the vitreous body.
  • FIG. 2 shows a fluorescence micrograph showing that 200 nm of nanospheres were taken into the retina. Particle size of nanosphere (nm) Half-life (days)
  • Table 1 shows that the smaller the particle size of the nanospheres, the longer the drug remains in the eye for an extended period of time. From FIG. 1, it was confirmed that nanospheres having a particle diameter of 200 nm were taken into the retina. In addition, almost no uptake was observed with nanospheres having a particle size larger than the nanosize.
  • the persistence of the drug effect in the retina or the vitreous can be significantly improved.
  • the particle size of nanospheres to 200 nm or less, it is expected that drug release can be controlled over a long period of time from the inside of the retina by incorporating the nanospheres into the retina. Therefore, according to the present invention, it is possible to provide a treatment method in which the persistence of drug efficacy in the retina or vitreous body is improved.
  • the present invention provides a drug release control system capable of appropriately controlling the release rate and duration of a drug and being applicable to the retina or the vitreous body without any restriction on the type of drug.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Virology (AREA)
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Abstract

L'invention concerne un système de contrôle approprié de libération de médicament (vitesse et libération prolongée), pour application à la rétine ou au corps vitreux, sans limitation de type de médicament. Le système comprend des nanosphères de fines particules en polymère synthétique biodégradable de nano-taille qui contiennent uniformément un médicament, avec possibilité de libération efficace à la rétine ou au corps vitreux (site cible). De préférence, ce polymère est un copolymère d'acide polylactique ou d'acide lactique/glycolique. De préférence, le médicament se présente sous la forme de matrice dans les particules. La taille moyenne des particules dans les nanosphères est comprise entre 50 et 200 mm.
PCT/JP2001/007290 2000-08-24 2001-08-24 Systeme de controle de liberation de medicament WO2002015888A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001280165A AU2001280165A1 (en) 2000-08-24 2001-08-24 Drug-release controlling system

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JP2000-301241 2000-08-24
JP2000301241 2000-08-24

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0330180A1 (fr) * 1988-02-24 1989-08-30 Biomaterials Universe, Inc. Microsphères du type acide polylactique contenant des substances physiologiquement actives et leur procédé de préparation
JPH04208217A (ja) * 1990-11-30 1992-07-29 Earth Chem Corp Ltd 徐放性製剤およびその製造方法
JPH0558882A (ja) * 1991-09-04 1993-03-09 Yoshiaki Kawashima ナノカプセルの製造法
US5308624A (en) * 1990-04-03 1994-05-03 Laboratorios Cusi, S.A. Ophthalmic product

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0330180A1 (fr) * 1988-02-24 1989-08-30 Biomaterials Universe, Inc. Microsphères du type acide polylactique contenant des substances physiologiquement actives et leur procédé de préparation
US5308624A (en) * 1990-04-03 1994-05-03 Laboratorios Cusi, S.A. Ophthalmic product
JPH04208217A (ja) * 1990-11-30 1992-07-29 Earth Chem Corp Ltd 徐放性製剤およびその製造方法
JPH0558882A (ja) * 1991-09-04 1993-03-09 Yoshiaki Kawashima ナノカプセルの製造法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
T. NIWA ET AL.: "Preparations of biodegradable nanospheres of water-soluble and insoluble drugs with D,L-lactide/glycolode copolymer by a novel spontaneous emulsification solvent duffusion method and the drug release behavior", JOURNAL OF CONTROLLED RELEASE, vol. 25, 1993, pages 89 - 98, XP002949590 *

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