WO2007013591A1 - Système non invasif d'administration de médicament qui vise le tissu postérieur de l'œil au moyen d’une composition sous forme de gel - Google Patents

Système non invasif d'administration de médicament qui vise le tissu postérieur de l'œil au moyen d’une composition sous forme de gel Download PDF

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Publication number
WO2007013591A1
WO2007013591A1 PCT/JP2006/314990 JP2006314990W WO2007013591A1 WO 2007013591 A1 WO2007013591 A1 WO 2007013591A1 JP 2006314990 W JP2006314990 W JP 2006314990W WO 2007013591 A1 WO2007013591 A1 WO 2007013591A1
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WIPO (PCT)
Prior art keywords
drug
tissue
agent
gel
delivery system
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Application number
PCT/JP2006/314990
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English (en)
Japanese (ja)
Inventor
Koumei Okabe
Fumitaka Tasaka
Original Assignee
Santen Pharmaceutical Co., Ltd.
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Filing date
Publication date
Application filed by Santen Pharmaceutical Co., Ltd. filed Critical Santen Pharmaceutical Co., Ltd.
Publication of WO2007013591A1 publication Critical patent/WO2007013591A1/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
    • A61K9/0012—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

Definitions

  • the present invention relates to a noninvasive drug delivery system for posterior ocular tissues such as the retina, choroid, sclera, optic nerve, optic nerve surrounding tissue, and vitreous body.
  • Typical diseases include age-related macular degeneration, diabetic retinopathy, diabetic macular edema, uveitis, retinitis pigmentosa, proliferative vitreoretinopathy, central retinal vein occlusion, retinal vein occlusion, central retina Examples include arterial occlusion, retinal artery branching occlusion, retinal detachment, cytomegalovirus retinitis, and optic neuropathy associated with glaucoma. These are all diseases that can cause a decrease in visual acuity and blindness, and development of an effective pharmacotherapy for such posterior ocular tissue diseases is desired.
  • Examples of effective drugs for posterior eye diseases include steroidal lj such as betamethasone and dexamethasone, anti-inflammatory agents such as bromofenac, antibacterial lj such as quinolone compounds and erythromycin, ganciclovir, and acyclovir.
  • Anti-cancer drugs such as lj, methotrexate, MMP inhibitors, etc., angiogenesis inhibitors such as endostatin, VEGF inhibitors, neuroprotective agents such as MK-801, timolol, antioxidants such as catechin, vitamin E, etc.
  • drugs such as bone resorption inhibitors such as bisphosphonates, drugs related to visual function maintenance such as retinoic acid and its derivatives, and the like.
  • the posterior segment of the posterior segment which is a disease site, is located in the back of the ocular tissue, and it is very difficult to transfer the drug to the segment. It was a challenge in developing drug treatments for the disease.
  • Non-Patent Document 1 describes a drug delivery system for posterior ocular tissue by intravitreal injection
  • Patent Documents 1 and 2 describe subconjunctival sustained-release microparticles containing a drug.
  • Drug delivery systems to the posterior ocular tissue by administration and drug delivery systems to the posterior ocular tissue by administering fine particles containing a drug under the Tenon capsule are described.
  • Patent Document 3 describes a biocompatible implant for transferring a drug to posterior eye tissue.
  • Patent Document 1 JP 2003-313119 A
  • Patent Document 2 Japanese Patent Laid-Open No. 2005-097275
  • Patent Document 3 Special Table 2004—No. 535886
  • Non-patent literature 1 Journal of ocular pharmacology ana therapeutics, (2001) 17/4 393-40 1
  • the drug delivery system of the present invention is a non-invasive drug delivery system, it is not tissue invasive by administration, unlike administration methods such as injection and implant that are widely used in the medical field. Patients do not suffer from the stress and pain associated with administration such as injections and implants.
  • the gel-like composition used in the drug delivery system of the present invention is administered to the ocular surface and can be administered by the patient himself. It is superior in terms of convenience compared to implants.
  • the present invention provides:
  • a noninvasive drug delivery system for posterior ocular tissue characterized by administering a gel-like composition comprising a drug and a mucoadhesive substance force to the ocular surface;
  • a gel-like composition containing a drug and a mucoadhesive substance that is administered to the ocular surface improves the transfer of the drug to the posterior ocular tissue.
  • the drug is an anti-inflammatory agent, immunosuppressive agent, antiviral agent, anticancer agent, antithrombotic agent, angiogenesis inhibitor, optic neuroprotective agent, antibacterial agent, antifungal agent or antioxidant agent.
  • Non-invasive drug delivery system or gel composition wherein the drug is an anti-inflammatory agent, immunosuppressive agent, antiviral agent, anticancer agent, antithrombotic agent, angiogenesis inhibitor, optic neuroprotective agent, antibacterial agent, antifungal agent or antioxidant agent.
  • mucoadhesive substance used in the present invention examples include polyacrylic acid derivatives such as carboxyvinyl polymer, polyacrylic acid, and sodium polyacrylate and salts thereof; polybulal alcohol, polybulurpyrrolidone; Hydroxyalkylcellulose derivatives such as tilcellulose and hydroxypropylcellulose, hydroxyethenorenorose derivatives such as hydroxyethenorenorerose, ethenoresenorelose, carboxymethylcellulose, carboxymethylcellulose Cellulose derivatives such as carboxyalkyl cellulose derivatives such as sodium and their salts; alginic acid and its salts; chitosan, agar, dextran, gelangam, xantha And polysaccharides such as gums and pectin and their derivatives, and combinations thereof.
  • polyacrylic acid derivatives such as carboxyvinyl polymer, polyacrylic acid, and sodium polyacrylate and salts thereof
  • polybulal alcohol polybulurpyrrolidone
  • Preferred materials include carboxybule polymer, hydroxypropyl cellulose, polyacryloleic acid, sodium alginate, and a combination of carboxyvinyl polymer and hydroxypropylcellulose (weight ratio of 100 ::! To 1: 100, preferably 10 :: ! ⁇ 1: 10, more preferably 3: g 1: 3).
  • the amount of the mucoadhesive substance is the same as that used for the gel composition. It depends on the type of quality, and is appropriately selected depending on the type of drug to be contained and the effective therapeutic concentration of the drug.
  • the drug delivery system of the present invention is excellent in the transferability of the drug directly to the posterior ocular tissue.
  • Direct drug transfer to posterior ocular tissue means that drug transfer to posterior ocular tissue is transferred to the posterior ocular tissue via the local ocular tissue, regardless of the systemic route.
  • the drug delivery system of the present invention is excellent in drug transferability to the posterior ocular tissue via the ocular local tissue.
  • the drug delivery system of the present invention is excellent in drug transferability to the posterior ocular tissue via the conjunctival and scleral tissues.
  • the drug delivery system of the present invention is used for treatment or prevention of diseases of the retina, choroid, sclera, optic nerve, perioptic nerve tissue, or vitreous.
  • diseases include inflammation caused by various causes, viral and bacterial infections, diseases caused by retinal choroidal neovascularization, diseases caused by retinal ischemia, and optic neuropathy caused by glaucoma. I can get lost.
  • uveitis cytomegalovirus retinitis
  • age-related macular degeneration diabetic retinopathy, diabetic macular edema
  • proliferative vitreoretinopathy retinal detachment
  • retinitis pigmentosa central retinal vein occlusion Retinal vein branch occlusion, central retinal artery occlusion, branch retinal artery occlusion, and the like.
  • the drug contained in the gel composition of the present invention is not particularly limited, and a drug suitable for the target disease can be selected.
  • steroid drugs such as betamethasone, dexamethasone, triamcinolone, prednisolone, fluorometholone, hyidocortisone, fluocinolone cetonide, or derivatives thereof; hormone drugs such as progesterone or testosterone; or derivatives thereof; Inflammatory agents; TNF- ⁇ inhibitors, anti-TNF-antibodies, PDE-IV inhibitors, ICE inhibitors, etc.
  • Cytokine-suppressed immunosuppressants such as cyclosporine, tacrolimus; ganciclovir, acyclovir, interferon j3, etc.
  • Antiviral agents antibacterial agents such as quinolone compounds, clarithromycin, erythromycin; ACE inhibitors such as captopril; HMG_CoA reductase inhibitors such as pravastatin, sympastatin; fluorouracil, methotrexate, MMP Anticancer such harm agent; endostatin, VEGF inhibitors, anti-VEGF antibody, Anchisensuo Rigo nucleotides, PKC inhibitors, adhesion factor inhibitors, angiostatic steroids such as the neovascularization Bioinhibitors; MK_801, neuroprotective agents such as timolol, creatine, taurine, BDNF ' Examples include antioxidants such as vitamin E, bone resorption inhibitors such as bisphosphonates, and drugs related to maintaining visual function such as retinoi
  • the drug contained in the gel composition of the present invention is preferably a fat-soluble compound.
  • the fat-soluble compound is a compound in which LogP representing an octanol / water partition coefficient is 1 or more, and preferably a compound in which LogP is 2 to 5.
  • LogP can be obtained using, for example, a widely used method or prediction software.
  • the present invention also provides a method for improving the transferability of a drug to the posterior ocular tissue with a mucoadhesive substance by applying a gel composition comprising a drug and a mucoadhesive substance force to the eye surface of a patient.
  • a therapeutically effective amount of a gel composition composed of a drug and a mucoadhesive substance is administered to the eye surface of the patient, and the transfer of the drug to the posterior ocular tissue is improved by the mucoadhesive substance.
  • the present invention relates to a method for treating eye diseases.
  • the dose of the gel composition of the present invention may be appropriately increased or decreased depending on the type of drug, effective therapeutic concentration, drug release period, symptoms, etc.
  • the drug content is 0.01. ⁇ 95% by weight, preferably 0 ⁇ :! ⁇ 30% by weight, may be instilled once to several times a day.
  • the gel composition of the present invention is prepared, for example, by dissolving or dispersing a drug in a base containing a mucoadhesive substance.
  • the base of the gel composition is preferably water, particularly purified water.
  • Gel-like compositions include isotonic agents such as glycerin, propylene glycol, sodium chloride and potassium chloride, buffering agents such as phosphoric acid, boric acid and trometamol, hydrochloric acid, citrate, sodium hydroxide, sodium carbonate, carbonate Requires pH adjusters such as sodium hydrogen, stabilizers such as edetic acid, preservatives such as salt benzalkonium and methyl paraoxybenzoate, solubilizers such as polysorbate 80 and polyoxyethylene castor oil It can be blended according to.
  • the gel composition prepared in the examples is a method that is widely used as a method for easily and highly sensitively assessing the ability to migrate to the posterior ocular tissue.
  • the fluorescent dyes fluorescein and sodium fluorescein were used instead of the product.
  • the gel-like composition used in the drug delivery system of the present invention can be administered to the ocular surface by itself without requiring any special technique when administered to the ocular surface.
  • S can.
  • the number of administrations of the gel composition of the present invention can be appropriately selected according to symptoms, age, base, etc. It may be administered 1 to several times a day (for example, 1 to 6 times).
  • a gel-like composition containing a combination of a fluorescent dye and a mucoadhesive substance, polyacrylic acid or carboxyvinyl polymer, and hydroxypropylcellulose is administered to the ocular surface.
  • a clear difference is observed in the concentration of the fluorescent dye present in the retina choroid between the administered eye and the non-administered eye. That is, by administering a gel-like composition containing a drug and a mucoadhesive substance to the ocular surface, the transfer of the drug directly to the posterior ocular tissue via the ocular local tissue can be improved.
  • the fluorescent dye contained in the gel composition is a fat-soluble fluorescent dye
  • the concentration of the fluorescent dye in the retina choroid between the administered eye and the non-administered eye even after a certain period of time.
  • the drug contained in the gel composition is more lipophilic and can further improve the transfer of the drug to the posterior ocular tissue.
  • this preparation is referred to as Test preparation 1.
  • HPC Wako Pure Chemical (Hydroxypropyl Cellulose) was used, and for CVP, BSF (Carboxybule Polymer 974P) was used.
  • Test formulation 1 prepared in Example 1 was instilled into one eye (right eye) of a rat (dosage of fluorescein: 40 ⁇ g per eye) and sacrificed 30 minutes later. Both eyes were removed and the retina choroid was recovered. The collected retina choroid is taken as 1 sample for 2 eyes, added with methanol Z water (1/1) mixture (250 ⁇ ), homogenized and centrifuged (13000 rpm, 10 minutes), insoluble. After removing the substances, the fluorescence intensity was measured (Em: 485 nm, Ex: 530 nm), and the concentration of fluorescein in the choroid was calculated. The fluorescein concentration was calculated using a calibration curve. A calibration curve was prepared by using a methanol Z water (lZl) mixed solution in which fluorescein was dissolved as a standard solution and adding it to the retina choroid of a normal eye, followed by the same recovery operation as described above.
  • FIG. 1 shows the concentration of fluorescein in the retina choroid 30 minutes after administration of test preparation 1 and comparative preparation 1 in the administered and non-administered eyes (6 eyes, 3 cases).
  • FIG. 2 shows the fluorescein concentration in plasma 30 minutes after administration of test preparation 1 and comparative preparation 1 (6 eyes, 3 cases).
  • the eye administered with Test preparation 1 showed a significantly higher value in the concentration of fluorescein in the retina choroid compared to the non-administered eye, whereas the eye administered with Comparative preparation 1 The value was slightly higher than that of the non-administered eye.
  • the test preparation 1 showed a clearly lower value than the comparative preparation 1 in the plasma fluorescein concentration. Therefore, it was found that the use of the gel composition of the present invention can promote the transfer of the fluorescent dye to the retina choroid tissue through the local eye tissue. That is, it was suggested that administration of the gel composition of the present invention to the ocular surface can promote the transfer of the drug to the posterior ocular tissue via the local ocular tissue.
  • this preparation is referred to as Comparative preparation 2.
  • PEG500000 was manufactured by Wako Pure Chemical Industries (PEG 500000).
  • Test preparation 1 and Comparative preparation 2 perform the same operation as in ⁇ 1 2.
  • concentration of fluorescein in the retina choroid 0.5 and 1.5 hours after application was calculated.
  • Fig. 3 shows the concentration of fluorescein in the retina choroid in the treated and non-administered eyes after a certain period of time (0.5, 1.5 hours) administration of test preparation 1 and comparative preparation 2 (number of cases: 6 eyes, 3 Example).
  • the gel composition in order to efficiently transfer the drug to the posterior ocular tissue such as the retina choroid tissue, or to improve the drug transfer directly to the posterior ocular tissue via the local ocular tissue, the gel composition It was shown that the mucoadhesive substance contained in the product is an important factor.
  • test preparation 2 For test preparation 2, the same operation as in “1 2. Test method” was performed, and the concentration of fluorescein in the retina choroid 0.5 and 1.5 hours after administration was calculated.
  • Test results and discussion Fig. 4 shows the concentration of fluorescein in the retina choroid in the administered and non-administered eyes after the lapse of a fixed time (0.5, 1.5 hours) of the test preparation 2 (number of cases 4-6 eyes, 2 ⁇ 3 cases).
  • the eye administered with the test preparation 2 clearly showed a higher value in the concentration of fluorescein in the retina choroid than the non-administered eye.
  • gel compositions containing mucoadhesive substances such as polyacrylic acid other than HPC and CVP can efficiently transfer drugs to the posterior ocular tissue such as the choroidal tissue, and after passing through the ocular local tissue It has been shown that drug transfer directly to ocular tissue can be improved.
  • HPC (0. 05 g), CVP (0. lg) and polysorbate 80 (0. 005 g) were dissolved in purified water.
  • a preparation (gel composition) was obtained.
  • this preparation is referred to as Test preparation 3.
  • the same HP C and CVP as in Example 1 were used.
  • test preparations 1 and 3 perform the same procedure as “1 _ 2.
  • Test method (dosage of fluorescein or fluorescein sodium: 40 xg per eye), after administration The concentration of fluorescein in the retina choroid after 5 and 1.5 hours was calculated.
  • Fig. 5 shows the concentration of fluorescein in the retina choroid in treated and non-administered eyes after a certain period (0.5, 1.5 hours) of administration of test preparations 1 and 3 (6 eyes, 3 cases) ).
  • test preparation 3 which is a gel composition containing fluorescein sodium, which is a water-soluble fluorescent dye
  • the test preparation 3 which is a gel composition containing fluorescein sodium, which is a water-soluble fluorescent dye
  • Test Formulation 1 which is a gel composition containing fluorescein, a fat-soluble fluorescent dye
  • Test Formulation 1 was administered at both 0.5 hours and 1.5 hours after administration at the concentration of fluorescein in the choroid. was clearly higher than that in the non-administered eye. That is, it was shown that the drug contained in the gel composition of the present invention is more lipophilic and can further improve the migration to the posterior segment tissue, which is the effect of the present invention.
  • Polysorbate 80 appropriate amount
  • Fig. 1 is a graph showing the concentration of fluorescein in the retina choroid in the administration eye and non-administration eye 30 minutes after administration of test preparation 1 and comparative preparation 1.
  • FIG. 2 is a graph showing plasma fluorescein concentrations 30 minutes after administration of test preparation 1 and comparative preparation 1.
  • FIG. 3 is a graph showing the concentration of fluorescein in the retina choroid in the administered eye and the non-administered eye after the lapse of a fixed time after administration of test preparation 1 and comparative preparation 2.
  • Fig. 4 is a graph showing the concentration of fluorescein in the retina choroid in the administered eye and the non-administered eye after the lapse of a certain time after administration of Test preparation 2.
  • FIG. 5 is a graph showing the concentration of fluorescein in the retina choroid in the administered eye and the non-administered eye after a lapse of a certain time after administration of test preparations 1 and 3.

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  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Ophthalmology & Optometry (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

L’invention propose un système non invasif d'administration de médicament ayant une excellente capacité de transfert du médicament dans un tissu postérieur de l'œil à travers un tissu local de l'œil. Une composition sous forme de gel qui comprend un médicament à administrer et une substance adhérente à la muqueuse peut être administrée à la surface de l'œil. Ainsi, un système d'administration de médicament ayant une excellente capacité de transfert du médicament dans un tissu postérieur de l'œil à travers un tissu local de l'œil peut être obtenu.
PCT/JP2006/314990 2005-07-29 2006-07-28 Système non invasif d'administration de médicament qui vise le tissu postérieur de l'œil au moyen d’une composition sous forme de gel WO2007013591A1 (fr)

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JP2005221404 2005-07-29
JP2005-221404 2005-07-29

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63174924A (ja) * 1987-01-14 1988-07-19 Toko Yakuhin Kogyo Kk 軟膏基剤および軟膏剤
JPS63253023A (ja) * 1987-03-02 1988-10-20 アメリカン・サイアナミド・カンパニー アセトアゾラミドを含有する安定な眼科用製剤
JPH0725750A (ja) * 1993-05-20 1995-01-27 Medproject Pharma Entwickl & Vertriebs Gmbh 眼科用ゲル
JPH09508907A (ja) * 1994-02-17 1997-09-09 ドクトル ゲルハルト マン ケム−ファルム． ファブリック ゲゼルシャフト ミット ベシュレンクテル ハフツンク 滅菌プレドニソロンゲルの製造方法
JPH1071822A (ja) * 1996-08-30 1998-03-17 Matsushita Electric Ind Co Ltd 自動車用空調装置
JP2004196787A (ja) * 2002-12-04 2004-07-15 Santen Pharmaceut Co Ltd 結膜下デポによるドラッグデリバリーシステム
WO2004058289A1 (fr) * 2002-12-20 2004-07-15 Chakshu Research, Inc. Formulation ophtalmique pour la prevention et le traitement de pathologies oculaires

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63174924A (ja) * 1987-01-14 1988-07-19 Toko Yakuhin Kogyo Kk 軟膏基剤および軟膏剤
JPS63253023A (ja) * 1987-03-02 1988-10-20 アメリカン・サイアナミド・カンパニー アセトアゾラミドを含有する安定な眼科用製剤
JPH0725750A (ja) * 1993-05-20 1995-01-27 Medproject Pharma Entwickl & Vertriebs Gmbh 眼科用ゲル
JPH09508907A (ja) * 1994-02-17 1997-09-09 ドクトル ゲルハルト マン ケム−ファルム． ファブリック ゲゼルシャフト ミット ベシュレンクテル ハフツンク 滅菌プレドニソロンゲルの製造方法
JPH1071822A (ja) * 1996-08-30 1998-03-17 Matsushita Electric Ind Co Ltd 自動車用空調装置
JP2004196787A (ja) * 2002-12-04 2004-07-15 Santen Pharmaceut Co Ltd 結膜下デポによるドラッグデリバリーシステム
WO2004058289A1 (fr) * 2002-12-20 2004-07-15 Chakshu Research, Inc. Formulation ophtalmique pour la prevention et le traitement de pathologies oculaires

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