JPWO2012153870A1 - Glaucoma treatment material - Google Patents
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- JPWO2012153870A1 JPWO2012153870A1 JP2013514085A JP2013514085A JPWO2012153870A1 JP WO2012153870 A1 JPWO2012153870 A1 JP WO2012153870A1 JP 2013514085 A JP2013514085 A JP 2013514085A JP 2013514085 A JP2013514085 A JP 2013514085A JP WO2012153870 A1 JPWO2012153870 A1 JP WO2012153870A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
- A61K9/0051—Ocular inserts, ocular implants
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- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7084—Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
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- 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
- A61P27/06—Antiglaucoma agents or miotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
- A61F9/007—Methods or devices for eye surgery
- A61F9/00781—Apparatus for modifying intraocular pressure, e.g. for glaucoma treatment
Abstract
生体組織表面への接着層とバリア層とからなり、生分解性で薬剤を含まない積層体（Ａ）と、薬剤を含む生分解性マトリクス（Ｂ）より構成されるキットであるか、または生体組織表面への接着性を有する、薬剤を含有しない生分解性の接着層（Ｃ）と、薬剤を含有する生分解性の薬剤含有層（Ｄ）との積層体である緑内障治療材。これらの緑内障治療材を用いれば、強膜周辺の炎症瘢痕化がなく、濾過胞の形成維持に優れ、マイトマイシンＣの副作用の問題がなく、薬剤による結膜上皮細胞の脆弱化が起こらない。A kit comprising a laminate (A) comprising an adhesive layer and a barrier layer on the surface of a living tissue and biodegradable and not containing a drug, and a biodegradable matrix (B) containing the drug, or a living body A glaucoma treatment material, which is a laminate of a biodegradable adhesive layer (C) that does not contain a drug and has adhesiveness to the tissue surface and a biodegradable drug-containing layer (D) that contains the drug. When these glaucoma treatment materials are used, there is no inflammation scarring around the sclera, excellent filtration follicle formation maintenance, no side effect of mitomycin C, and no conjunctival epithelial cell weakening due to the drug.
Description
本発明は、薬物徐放性のある緑内障治療材に関する。さらに詳しくは、緑内障の手術（線維柱帯切除術；トラベクレクトミー）の際に用いられる、生分解性高分子からなり、組織表面への接着性を有する特定構造の薬物徐放性緑内障治療材に関する。
本発明の緑内障治療材を用いることで、副作用が懸念されるマイト マイシンＣ（ＭＭＣ）を用いる必要のない、新しい緑内障の治療方法が実現できる。The present invention relates to a glaucoma treatment material having sustained drug release. More specifically, the drug sustained-release glaucoma treatment with a specific structure that consists of biodegradable polymers and has adhesion to the tissue surface, used in glaucoma surgery (trabeculectomy; trabeculectomy) Regarding materials.
By using the material for treating glaucoma of the present invention, a new method for treating glaucoma that does not require the use of mitomycin C (MMC), which has a concern about side effects, can be realized.
緑内障は「目の成人病」といわれ、眼圧上昇などの原因から視神経が障害され、視野狭窄や視力低下を起こす病気である。抗緑内障薬によっても眼圧下降が不十分である場合、眼圧を低下させるために線維柱帯切除術（トラベクレクトミー；線維柱帯を切除し、房水を眼外に排出して眼圧を下降させる手術）を実施する（図１参照）。これにより、線維柱帯切除部から強膜弁下を通過して眼外に房水が排出され、結膜下に濾過胞が形成される。しかし、手術後に組織の炎症、癒着、瘢痕化などにより濾過胞が縮小・消失してしまうと眼圧が再び上昇し、緑内障が悪化する恐れがある。術後の炎症、癒着、瘢痕化を防ぐためにはＭＭＣが術中に塗布される。しかしＭＭＣの副作用により、結膜が菲薄化し、結膜から房水が漏出したり、濾過胞の感染症を引き起こすなどの問題点があった。
濾過胞を形成する手術に用いられる生体適合性の高い材料として、特開２００８−１３６７７０号公報にはハニカム構造を有するフィルム状の緑内障手術材料が記載されている。該フィルムを用いることで、ＭＭＣの投与量を減少あるいは不要となる可能性があることが記載されている。しかしながら、該フィルムだけでは結膜下の瘢痕化は抑えることができても強膜弁下の瘢痕化を十分におさえることができず、ＭＭＣ術中塗布を併用することが望ましいのが現状である。ＭＭＣを併用すると上述した副作用の課題を抱えることになり、薬物を用いない治療法としては満足できる方法ではない。
特開２００７−６１５５９号公報には、ハニカム構造を有する生分解性のフィルムにパクリタキセルを複合させたものが記載されている。すなわち、ドラッグデリバリー用のキャリアーとして非水溶性ポリマーからなるハニカム状多孔体が記載されており、ドラッグの例としてパクリタキセルが記載されている。しかしながら緑内障の治療に用いるための材料については何ら記載がない。
国際公開ＷＯ０６／０２２３５８号には、ハニカムフィルムを用いた積層体が記載されており、厚みがあり強度に優れるとしている。しかしながら緑内障の治療に用いるのに適した材料については記載されていない。Glaucoma is said to be an “adult disease of the eye” and is a disease in which the optic nerve is impaired due to causes such as increased intraocular pressure, resulting in narrowing of the visual field and decreased visual acuity. If the intraocular pressure drop is still insufficient even with anti-glaucoma drugs, trabeculectomy (trabectomy; excision of the trabecula and discharge of aqueous humor out of the eye to reduce intraocular pressure) (Surgery to lower the pressure) is performed (see FIG. 1). Thereby, the aqueous humor passes through the scleral flap from the trabeculectomy part and is discharged outside the eye, and a filtering bleb is formed under the conjunctiva. However, if the filtering bleb shrinks or disappears due to tissue inflammation, adhesion, or scarring after surgery, the intraocular pressure may rise again and glaucoma may worsen. MMC is applied intraoperatively to prevent post-operative inflammation, adhesions, and scarring. However, the side effects of MMC have caused problems such as thinning of the conjunctiva, leakage of aqueous humor from the conjunctiva, and infection of the filtering bleb.
JP-A-2008-136770 discloses a film-like glaucoma surgical material having a honeycomb structure as a highly biocompatible material used for surgery for forming a filtering bleb. It is described that the use of the film may reduce or eliminate the dose of MMC. However, even if the film alone can suppress scarring under the conjunctiva, scarring under the sclera can not be sufficiently suppressed, and it is desirable to use MMC intraoperative application together. When MMC is used in combination, the above-mentioned problem of side effects is caused, and it is not a satisfactory method as a treatment method without using a drug.
Japanese Patent Application Laid-Open No. 2007-61559 describes a composite of paclitaxel and a biodegradable film having a honeycomb structure. That is, a honeycomb-like porous body made of a water-insoluble polymer is described as a carrier for drug delivery, and paclitaxel is described as an example of a drug. However, there is no description of materials for use in the treatment of glaucoma.
International Publication WO06 / 022358 describes a laminate using a honeycomb film, which is thick and excellent in strength. However, no materials suitable for use in the treatment of glaucoma are described.
本発明が解決しようとする課題は、強膜弁周囲の癒着・瘢痕化がなく、濾過胞の形成維持に優れた緑内障治療材を提供することである。
本発明の発明者らは、強膜周辺の炎症、癒着、瘢痕化がなく、濾過胞の形成維持に優れた緑内障治療用の生分解性治療材料について鋭意研究した結果、本来薬効を発現すべき炎症部位には薬を含まない接着性のあるフィルムとバリア層からなる積層材料を用い、バリア層によって患部とは隔離された場所に薬剤を含有した生分解性のマトリクス材料を用いることで、特異的に患部の瘢痕化を抑制し、かつ緑内障の治療に有効な濾過胞を維持できることを見出した。
さらに、本発明の発明者らは、強膜弁直上の濾過胞壁の保護膜として、薬剤を含まない接着性のあるフィルムと薬剤を含む層からなる積層材料を用いることでも、強膜弁周囲の癒着・瘢痕化を抑制できることを見出した。
すなわち第一の本発明は、生体組織表面への接着層とバリア層とからなり、生分解性で薬剤を含まない積層体（Ａ）と、薬剤を含む生分解性マトリクスである薬剤含有マトリクス（Ｂ）より構成されるキットである、緑内障治療材である。
また、第二の本発明は、生体組織表面への接着性を有する、薬剤を含有しない生分解性の接着層（Ｃ）と、薬剤を含有する生分解性の薬剤含有層（Ｄ）との積層体からなる緑内障治療材である。
本発明には、緑内障の繊維中退切除術における切除面に、生体組織表面への接着層とバリア層とからなり、生分解性で薬剤を含まない積層体（Ａ）を固定する工程と、薬剤含有マトリクス（Ｂ）を切除面とは異なる部位に固定する工程とを含む、緑内障の治療方法が含まれる。
本発明にはさらに、緑内障の繊維柱帯切除術における切除面に、前記第二の本発明の緑内障治療材を固定する工程を含む、緑内障の治療方法が包含される。
発明の効果
緑内障の手術であるトラベクレクトミーに本発明の緑内障治療材を用いることにより、強膜弁周囲の炎症、癒着、瘢痕化を抑制し、健常な濾過胞の形成維持が可能となることで、長期にわたって緑内障の再発や進行を抑え、濾過胞感染症などの副作用の心配が少ない治療方法が提供される。The problem to be solved by the present invention is to provide a glaucoma therapeutic material that is free from adhesion and scarring around the scleral flap and is excellent in maintaining the formation of filtration follicles.
As a result of earnest research on the biodegradable therapeutic material for the treatment of glaucoma, the inventors of the present invention have no inflammation, adhesion, or scarring around the sclera and are excellent in maintaining the formation of filter bleb. By using a laminated material consisting of an adhesive film that does not contain drugs and a barrier layer for the inflamed area, and using a biodegradable matrix material that contains the drug in a location that is isolated from the affected area by the barrier layer, In particular, the present inventors have found that it is possible to maintain a filtering follicle effective in suppressing scarring of the affected area and effective in treating glaucoma.
Furthermore, the inventors of the present invention can also use a laminated material composed of an adhesive film not containing a drug and a layer containing a drug as a protective film for the filtration cell wall directly above the scleral valve. It was found that the adhesion and scarring can be suppressed.
That is, the first aspect of the present invention comprises a laminate (A) comprising an adhesive layer to the surface of a biological tissue and a barrier layer, biodegradable and not containing a drug, and a drug-containing matrix (a biodegradable matrix containing a drug ( It is a glaucoma treatment material which is a kit composed of B).
In addition, the second aspect of the present invention provides a biodegradable adhesive layer (C) containing no drug and having adhesiveness to the surface of a living tissue, and a biodegradable drug-containing layer (D) containing a drug. It is a glaucoma treatment material consisting of a laminate.
The present invention includes a step of fixing a biodegradable and drug-free laminate (A) comprising an adhesive layer and a barrier layer to the surface of a biological tissue on a resection surface in a fiber withdrawal operation for glaucoma, A method for treating glaucoma, comprising a step of fixing the containing matrix (B) to a site different from the excision surface.
The present invention further includes a method for treating glaucoma, comprising the step of fixing the glaucoma therapeutic material of the second present invention to a resection surface in trabeculectomy for glaucoma.
Effects of the Invention By using the glaucoma treatment material of the present invention for trabeculectomy, which is an operation for glaucoma, it is possible to suppress inflammation, adhesion, and scarring around the scleral flap, and to maintain the formation of a healthy filtering bleb. Thus, a treatment method can be provided that suppresses the recurrence and progression of glaucoma over a long period of time and is less worried about side effects such as follicular infection.
図１は、線維柱帯切除術（トラベクレクトミー）の説明図である。
図２は、実施例５の緑内障濾過手術の説明図である。
図３は、実施例９の緑内障濾過手術の説明図である。FIG. 1 is an explanatory diagram of trabeculectomy (travelectomy).
FIG. 2 is an explanatory diagram of glaucoma filtration surgery of Example 5.
FIG. 3 is an explanatory diagram of glaucoma filtration surgery of Example 9.
第一の本発明は、生体組織表面への接着層とバリア層とからなり、生分解性で薬剤を含まない積層体（Ａ）と、薬剤を含む生分解性マトリクスである薬剤含有マトリクス（Ｂ）より構成されるキットである、緑内障治療材である。かかる積層体（Ａ）は接着層とバリア層との積層体であり、いずれの層も生分解性であり、かつ薬剤を含まないフィルム状の部材である。接着層のうち組織表面と接触する面（接着面）の反対側にバリア層が位置することになる。かかる積層体（Ａ）は、接着層にしてもバリア層にしても、生分解性高分子を成形加工することで得られる。
第二の本発明は、生体組織表面への接着性を有する、薬剤を含有しない生分解性の接着層（Ｃ）と、薬剤を含む生分解性の薬剤含有層（Ｄ）との積層体からなる緑内障治療材である。かかる積層体を構成するの接着層（Ｃ）と薬剤含有層（Ｄ）は、それぞれ生分解性高分子を成形加工することで得られる。
こうした生分解性高分子としては、具体的にはポリ乳酸、ポリグリコール酸、ポリ乳酸−ポリグリコール酸共重合体、ポリカプロラクトン、ポリグリセロールセバシン酸、ポリヒドロキシアルカン酸、ポリブチレンサクシネートなどの脂肪族ポリエステル類、ポリトリメチレンカーボネートなどの脂肪族ポリカーボネート類、セルロースジアセテート、セルローストリアセテート、メチルセルロース、プロピルセルロース、ベンジルセルロースなどの多糖類誘導体、フィブロイン、ゼラチン、コラーゲンなどの蛋白質やこれらの誘導体が例示できる。
これらのなかでもポリ乳酸、ポリグリコール酸、ポリ乳酸−ポリグリコール酸共重合体、ポリカプロラクトン、ポリ乳酸−ポリカプロラクトン共重合体が好ましく、ポリ乳酸、ポリ乳酸−ポリカプロラクトン共重合体がさらに好ましい。
かかる生分解性高分子の分子量は１×１０３〜５×１０６であり、好ましくは１×１０４〜１×１０６、より好ましくは５×１０４〜５×１０５である。ここで、生分解性高分子の末端構造やポリマーを重合する触媒は任意に選択できる。
第一の本発明における積層体（Ａ）や、第二の本発明における接着層（Ｃ）が組織表面と接触する面（接着面）には、材料の生分解性高分子に立体的な凹凸加工が施されていることが好ましい。ここで、組織表面と接着するとは、具体的には積層体等を組織表面に置いたとき、重力による落下や体液の漏洩によって積層体がずれたりすることなく、上から指で軽く押してみても積層体が動くことなく組織表面にはりついている状態をいう。ピンセットなどの器具で積層膜を挟み持ち上げることによって積層膜を剥がし取ることができる程度に弱い接着である場合も含まれる。術後の成績を高める目的で、積層膜を組織表面に縫合糸で部分的に固定してもよい。
ここで、組織表面とは、外科的手術の必要性が生じた眼の組織表面をいう。具体的には強膜や結膜、角膜などが挙げられる。表面の状態は特に限定されないが、好ましくは連続的な出血のない状態である。また、かかる凹凸構造は、好ましくは１００ｎｍ〜１０μｍ程度の大きさに加工されているもので、好ましい一例としてハニカム状のパターン構造を挙げることができる。生体組織への接着面の一部または全部にハニカム構造が形成されていることが好ましい。
ここでいうハニカム状のパターン構造とは、生分解性高分子の有機溶媒のドープをガラス板上にキャストしてフィルムを形成する際、結露によって表面に水滴を形成させることで、水滴が鋳型となって形成される構造である。このハニカム状のパターン構造は、フィルム内部に形成された均一な大きさの孔が互いに連結した構造を有し、横方向に連結しているため、患部の血液や体液の移動が早く、フィルムが患部に張り付きやすい特徴を有する。
フィルムの片面にハニカム状の構造を形成させる方法としては、特開２００８−１３６７７０号公報に記載されているようなリン脂質を界面活性剤として用いることで、ハニカム状で相互に連結した孔を形成する方法がある。
かかるリン脂質としては、動物組織から抽出したものでも、人工的に合成して製造したものでも使用できる。具体的にはホスファチジルエタノールアミン、ホスファチジルコリン、ホスファチジルセリン、ホスファチジルグリセロール、およびそれらの誘導体からなる群から選択される。好ましくはホスファチジルエタノールアミンであり、さらに好ましくはＬ−α−ホスファチジルエタノールアミン ジオレオイルである。リン脂質の量としては、ポリマー１００重量部に対し、０．０１〜１００重量部を含有することができるが、好ましくは０．２〜１０重量部である。
ハニカムの孔径や膜厚は特に制限はないが、好ましくは孔径が１〜１０μｍ、膜厚が５〜２０μｍである。
第一の本発明においては、積層体（Ａ）の組織表面に接着する面とは反対側に、少なくとも１層のバリア層が設けられる。バリア層とは、水や空気が実質的に通らない生分解性高分子膜でできた層であり、生分解性高分子を平膜状に加工したフィルムや単分子膜などが挙げられる。かかるフィルムとしては、溶媒キャスト膜、溶融押し出し成型膜、スピンコート膜、凝固浴を用いて成型された湿式製膜などから任意に選択できるが、好ましくは溶液キャスト膜である。
バリア層と接着層との接着加工の方法は、熱圧着やプレス加工などから任意に選択でき、特に限定はないが、好ましくは熱圧着法である。接着する条件については特に制限はなく、所望により接着剤も使用できる。
一方、薬剤含有マトリクス（Ｂ）は、積層体（Ａ）と接した状態で用いても離れた状態で用いてもよいが、好ましくは離れた状態で用いられる。かかる薬剤含有マトリクスの材質としては、積層体（Ａ）に用いられる生分解性高分子の中から選択できる。好ましくは、ポリ乳酸、ポリ乳酸−ポリグリコール酸共重合体が用いられる。
薬剤含有マトリクス（Ｂ）の形状としてはシートやフィルムであることが好ましいが、多孔体や繊維構造体などの多孔質材料も用いることができる。また、水分によって変形しない材質を用いても、水分を含むことで膨潤する材質を用いてもよい。生分解性を有することで徐々に分解や溶解が進み、最終的には消失する。消失していく過程でマトリクス中に含まれる薬剤を放出する。薬剤含有マトリクス（Ｂ）の表面の一部または全部にハニカム構造が形成されていることが好ましい。
第二の本発明の緑内障治療材においては、接着層（Ｃ）の組織表面に接着する面（接着面）とは反対側に、少なくとも１層の薬剤含有層（Ｄ）が積層されている。薬剤含有層（Ｄ）は、水や空気が実質的に通らない生分解性高分子膜よりできた層をいい、生分解性高分子を平膜状に加工したフィルムや単分子膜などが挙げられる。かかるフィルムとしては、溶媒キャスト膜、溶融押し出し成型膜、スピンコート膜、凝固浴を用いて成型された湿式製膜などから任意に選択できるが、好ましくは溶液キャスト膜である。
第二の本発明における接着層（Ｃ）と薬剤含有層（Ｄ）の接着加工法は、熱圧着やプレス加工などから任意に選択でき、特に限定はないが、好ましくは熱圧着法である。接着する条件については特に制限はなく、所望により接着剤も使用できる。
なお、第一の本発明における薬剤含有マトリクス（Ｂ）の表面や、第二の本発明における薬剤含有層の表面の一部または全部に、前記したハニカム構造が形成されていてもよい。
第一の本発明における薬剤含有マトリクス（Ｂ）や、第二の本発明における薬剤含有層（Ｄ）には、薬剤が含まれる。かかる薬剤は、線維芽細胞やがん細胞の増殖を抑える効果をもつものが好ましく、パクリタキセルやドキセタキセル、ＤＨＡ−パクリタキセル、アブラキサン、ポリグルタメート化パクリタキセルなどのタキサン類、５−フルオロウラシル、ミトザントロン、ダウノルビシン、ドキソルビシン、シスプラチン、カルボプラチン、メトトレキサート、ベバシズマブなどの抗がん剤、タクロリムスもしくはその類縁体、スタチン類などがあげられるが、パクリタキセルやドキセタキセルが好ましく用いられる。また、揮発性溶媒中において活性を維持することが可能であれば蛋白質製剤、核酸医薬であってもよい。薬剤の含有量は特に制限はないが、生分解性高分子に対して０．０１〜１０％の範囲が好ましい。生分解性高分子と薬剤の混合方法についても特に制限はなく、双方ともに溶解しうる溶媒を用いて均一な混合溶液を作成し、これを成型加工してもよく、生分解性高分子溶液に薬剤を分散させてフィルム状に成型してもよく、粉体を混合して圧縮して成型してもよい。なお、薬剤以外のもの、例えば金属、多糖、脂肪酸、リン脂質、界面活性剤をさらに含んでいてもよい。
第一の本発明における積層体（Ａ）や薬剤含有マトリクス（Ｂ）、第二の本発明における接着層（Ｃ）や薬剤含有層（Ｄ）は、所望により縫合や固定具を用いて組織表面に固定化してもよい。縫合には縫合糸を用いることができ、固定具としてはステイプラやピンなどが挙げられる。
本発明の緑内障治療材は、患者に適用すると徐々に分解され、吸収される。その分解期間については特に制限はないが、３ヶ月〜１年程度で完全に吸収されるのものがよい。薬剤の放出速度についても特に制限はないが、術後１ヶ月程度の期間、薬剤が放出されることが好ましい。The first aspect of the present invention comprises a laminate (A) comprising an adhesive layer to the surface of a biological tissue and a barrier layer, biodegradable and containing no drug, and a drug-containing matrix (B) which is a biodegradable matrix containing the drug ) Is a kit composed of glaucoma treatment material. Such a laminate (A) is a laminate of an adhesive layer and a barrier layer, and each layer is a biodegradable film-like member that does not contain a drug. A barrier layer will be located in the other side of the surface which contacts a tissue surface (adhesion surface) among contact bonding layers. Such a laminate (A) can be obtained by molding a biodegradable polymer, whether it is an adhesive layer or a barrier layer.
The second aspect of the present invention is a laminate comprising a biodegradable adhesive layer (C) that does not contain a drug and has adhesiveness to the surface of a living tissue, and a biodegradable drug-containing layer (D) that contains the drug. It is a glaucoma treatment material. The adhesive layer (C) and the drug-containing layer (D) constituting such a laminate can be obtained by molding a biodegradable polymer.
Specific examples of such biodegradable polymers include polylactic acid, polyglycolic acid, polylactic acid-polyglycolic acid copolymer, polycaprolactone, polyglycerol sebacic acid, polyhydroxyalkanoic acid, and polybutylene succinate. Examples include aliphatic polyesters such as aromatic polyesters, polytrimethylene carbonate, polysaccharide derivatives such as cellulose diacetate, cellulose triacetate, methylcellulose, propylcellulose, and benzylcellulose, proteins such as fibroin, gelatin, and collagen, and derivatives thereof. .
Among these, polylactic acid, polyglycolic acid, polylactic acid-polyglycolic acid copolymer, polycaprolactone, and polylactic acid-polycaprolactone copolymer are preferable, and polylactic acid and polylactic acid-polycaprolactone copolymer are more preferable.
The molecular weight of the biodegradable polymer is 1 × 10 3 to 5 × 10 6 , preferably 1 × 10 4 to 1 × 10 6 , more preferably 5 × 10 4 to 5 × 10 5 . Here, the terminal structure of the biodegradable polymer and the catalyst for polymerizing the polymer can be arbitrarily selected.
On the surface (adhesive surface) where the laminate (A) in the first invention and the adhesive layer (C) in the second invention are in contact with the tissue surface (three-dimensional unevenness) on the biodegradable polymer of the material It is preferable that processing has been performed. Here, adhesion to the tissue surface means that when the laminate is placed on the tissue surface, the laminate may not be displaced due to gravity drop or body fluid leakage, and lightly pressed with a finger from above. A state in which the laminate is stuck to the tissue surface without moving. The case where the adhesion is weak enough that the laminated film can be peeled off by sandwiching and lifting the laminated film with an instrument such as tweezers is also included. In order to improve the postoperative results, the laminated film may be partially fixed to the tissue surface with a suture.
Here, the tissue surface refers to the tissue surface of the eye where the necessity of surgical operation has occurred. Specifically, sclera, conjunctiva, cornea and the like can be mentioned. The state of the surface is not particularly limited, but is preferably a state without continuous bleeding. Further, such a concavo-convex structure is preferably processed to a size of about 100 nm to 10 μm, and a preferable example is a honeycomb pattern structure. It is preferable that a honeycomb structure is formed on a part or all of the adhesion surface to the living tissue.
As used herein, the honeycomb-shaped pattern structure means that when forming a film by casting a dope of an organic solvent of a biodegradable polymer onto a glass plate, water droplets are formed on the surface by condensation, so that the water droplets and the mold are formed. This is the structure formed. This honeycomb pattern structure has a structure in which holes of uniform size formed inside the film are connected to each other and are connected in the horizontal direction, so that the blood and body fluid in the affected area move quickly, and the film It has the characteristic that it sticks easily to the affected part.
As a method for forming a honeycomb-like structure on one side of the film, a phospholipid as described in JP-A-2008-136770 is used as a surfactant to form a honeycomb-like interconnected hole. There is a way to do it.
Such phospholipids can be extracted from animal tissues or artificially synthesized. Specifically, it is selected from the group consisting of phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, phosphatidylglycerol, and derivatives thereof. Preferred is phosphatidylethanolamine, and more preferred is L-α-phosphatidylethanolamine dioleoyl. The amount of the phospholipid can be 0.01 to 100 parts by weight, preferably 0.2 to 10 parts by weight, based on 100 parts by weight of the polymer.
The pore diameter and film thickness of the honeycomb are not particularly limited, but preferably the pore diameter is 1 to 10 μm and the film thickness is 5 to 20 μm.
In the first aspect of the present invention, at least one barrier layer is provided on the side opposite to the surface that adheres to the tissue surface of the laminate (A). The barrier layer is a layer made of a biodegradable polymer film that is substantially impermeable to water and air, and examples thereof include a film or a monomolecular film obtained by processing a biodegradable polymer into a flat film. Such a film can be arbitrarily selected from a solvent cast film, a melt-extruded film, a spin coat film, a wet film formed using a coagulation bath, and is preferably a solution cast film.
The method for bonding the barrier layer and the adhesive layer can be arbitrarily selected from thermocompression bonding, pressing, and the like, and is not particularly limited, but is preferably a thermocompression bonding method. There is no restriction | limiting in particular about the conditions to adhere | attach, An adhesive agent can also be used if desired.
On the other hand, the drug-containing matrix (B) may be used in a state where it is in contact with the laminate (A) or in a separated state, but is preferably used in a separated state. The material of the drug-containing matrix can be selected from biodegradable polymers used for the laminate (A). Preferably, polylactic acid or polylactic acid-polyglycolic acid copolymer is used.
The shape of the drug-containing matrix (B) is preferably a sheet or a film, but a porous material such as a porous body or a fiber structure can also be used. In addition, a material that is not deformed by moisture may be used, or a material that swells by containing moisture may be used. By having biodegradability, decomposition and dissolution gradually progress and eventually disappear. In the process of disappearing, the drug contained in the matrix is released. A honeycomb structure is preferably formed on part or all of the surface of the drug-containing matrix (B).
In the glaucoma treatment material of the second aspect of the present invention, at least one drug-containing layer (D) is laminated on the side opposite to the surface (adhesive surface) that adheres to the tissue surface of the adhesive layer (C). The drug-containing layer (D) is a layer made of a biodegradable polymer film that is substantially impermeable to water and air, and includes a film or a monomolecular film obtained by processing a biodegradable polymer into a flat film. It is done. Such a film can be arbitrarily selected from a solvent cast film, a melt-extruded film, a spin coat film, a wet film formed using a coagulation bath, and is preferably a solution cast film.
The adhesion processing method of the adhesive layer (C) and the drug-containing layer (D) in the second aspect of the present invention can be arbitrarily selected from thermocompression bonding or press working, and is not particularly limited, but is preferably a thermocompression bonding method. There is no restriction | limiting in particular about the conditions to adhere | attach, An adhesive agent can also be used if desired.
The honeycomb structure described above may be formed on a part or all of the surface of the drug-containing matrix (B) in the first invention and the surface of the drug-containing layer in the second invention.
The drug is contained in the drug-containing matrix (B) in the first invention and the drug-containing layer (D) in the second invention. Such drugs are preferably those having the effect of suppressing the growth of fibroblasts and cancer cells. Taxanes such as paclitaxel, doxetaxel, DHA-paclitaxel, Abraxane, polyglutamated paclitaxel, 5-fluorouracil, mitozantrone, daunorubicin, doxorubicin , Anticancer agents such as cisplatin, carboplatin, methotrexate, and bevacizumab, tacrolimus or analogs thereof, and statins, and paclitaxel and doxetaxel are preferably used. Moreover, a protein formulation and a nucleic acid medicine may be sufficient as long as it can maintain activity in a volatile solvent. The content of the drug is not particularly limited, but is preferably in the range of 0.01 to 10% with respect to the biodegradable polymer. The mixing method of the biodegradable polymer and the drug is not particularly limited, and a uniform mixed solution may be prepared using a solvent that can dissolve both, and this may be molded. The drug may be dispersed and molded into a film shape, or the powder may be mixed and compressed to be molded. In addition, things other than a chemical | medical agent, for example, a metal, polysaccharide, a fatty acid, phospholipid, and surfactant, may be further included.
The laminate (A) and drug-containing matrix (B) in the first invention, and the adhesive layer (C) and drug-containing layer (D) in the second invention can be prepared by using a suture or a fixture as desired. You may fix to. A suture can be used for suturing, and examples of the fixture include a stapler and a pin.
The glaucoma treatment material of the present invention is gradually decomposed and absorbed when applied to a patient. Although there is no restriction | limiting in particular about the decomposition | disassembly period, The thing completely absorbed in about 3 months to 1 year is good. The release rate of the drug is not particularly limited, but it is preferable that the drug is released for a period of about one month after the operation.
実施例１ ハニカムフィルム（接着層）の作製
ポリ乳酸−ポリカプロラクトン共重合体（乳酸：カプロラクトン＝８８：１２（モル比）、Ｍｗ＝１８．９万、（株）多木化学製）のクロロホルム溶液（５ｇ／Ｌ）に、ホスファチジルエタノールアミンジオレオイル（日油（株）製）をポリマーに対して０．５％の割合（重量）で混合し、ポリマー溶液を調製した。ポリマー溶液をガラス基板上にキャストした。この液状膜に室温、湿度７０％の水蒸気を吹き付け、溶媒を徐々に蒸発させると共に水蒸気を液状膜表面に結露させて水滴を形成し、ついで水滴を蒸発させてフィルムを調製した。得られたフィルムは、孔径約５．５μｍの細孔が均一にハニカム状に配置された凹凸部を有し、裏面は平滑で、厚さ７μｍの非貫通フィルムであった。
実施例２ キャストフィルム（バリア層）の作製
実施例１において調製したポリマー溶液に、法定色素緑色２０２号をポリマーに対して０．３％の割合で混合し、それをガラス板上に流しこみ、湿度を加えずに乾燥することで、凹凸構造が観察されない青色のキャストフィルムを得た。
実施例３ ハニカムフィルムとバリア層の積層化
実施例１で作製したハニカムフィルムの平滑面に、実施例２で作製したキャストフィルムを重ね、７０℃で１０分間処理することで、積層体（Ａ）を得た。
実施例４ 薬物を担持したマトリクス（複合フィルム）の作製
実施例２において調製した青色色素を含んだポリマー溶液に、パクリタキセル（Ｅｎｚｏ Ｌｉｆｅ Ｓｃｉｅｎｃｅｓ製）を５μｇとなるように加え、混合し、均一な溶液を得た。これをガラス板上に流しこみ、湿度を加えずに乾燥することで、パクリタキセルを含む青色のキャストフィルムを得た。
このフィルムの表面に、実施例１で作製したハニカムフィルムを積層し、ハニカム構造を片面にもつパクリタキセル含有マトリクスを作製した。
実施例５ 緑内障濾過手術
図２に示すように、家兎の片眼に緑内障濾過手術を行った。角膜輪部基底の結膜を切開し、３ｍｍ×３ｍｍの強膜半層フラップを作成し、線維柱帯を切除した。実施例４で作製したパクリタキセル含有複合フィルム（３×６ｍｍの大きさ）をハニカム面が内側を向くように設置し、フィルムが動かないように１０−０ナイロン縫合糸で２箇所縫合し、固定した。
強膜弁を残したまま、実施例３で作製した積層体（Ａ）を、ハニカム面が外側を向くように設置し、フィルムが動かないように縫合しで５箇所固定し、結膜を閉じて縫合した。
術後、７日、１４日、２１日、および２８日において、点眼麻酔下でのトノペンによる眼圧測定と超音波生態顕微鏡（ＵＢＭ）による濾過胞観察を行った。
その結果、術後２８日までの間、ＵＢＭでは結膜下に濾過のスペースが観察され、濾過胞が消失することはなく、眼圧は低い状態で一定のままであった。手術をした結膜周辺を肉眼で観察すると、健常な結膜組織と何ら遜色ない状態であることが観察され、毛細血管の再生も観察された。
ヘマトキシリン−エオジン染色により作製した病理学的切片を解析した結果、ハニカムフィルムは組織表面に密着しており、結膜上皮は薄肉化や部分的欠如は見られず、健常な状態であることが観察された。
実施例６
実施例５の緑内障濾過手術において、パクリタキセル含有マトリクスを使わず、さらに積層体（Ａ）の代わりに実施例４で作製したパクリタキセル含有マトリクスを設置した。
その結果、術後２８日までの間、ＵＢＭでは結膜下に濾過のスペースが観察され、濾過胞が消失することはなく、眼圧は低い状態で一定のままであった。しかしながら、手術をした結膜周辺は色白で、毛細血管が消えたような状態であり、手術を行っていない健常組織とは明らかに異なる状態であることが観察された。
ヘマトキシリン−エオジン染色により作製した病理学的切片を解析した結果、ハニカムフィルムは組織表面に密着しているものの、結膜上皮は薄くなり、部分的に欠如している状態で、線維芽細胞の浸潤もみられないことが観察された。
比較例１
実施例５の緑内障濾過手術において、パクリタキセル含有複合フィルムの代わりに実施例３で作製した積層体（Ａ）（パクリタキセルを含まないハニカムフィルム）のみを設置した。
その結果、術後２８日までの間、ＵＢＭでは結膜下に濾過のスペースが観察され、濾過胞が消失することはなく、眼圧は低い状態で一定のままであった。
ヘマトキシリン−エオジン染色により作製した病理学的切片を解析した結果、ハニカムフィルムを設置した強膜周辺の組織は炎症瘢痕化が観察された。
実施例７ キャストフィルム（薬物含有層）の作製
実施例１で作製したポリマードープに、法定色素緑色２０２号をポリマーに対して０．３％の割合で混合し、パクリタキセル（Ｅｎｚｏ Ｌｉｆｅ Ｓｃｉｅｎｃｅｓ製）を５μｇとなるように加え、混合し、均一な溶液を得た。これをガラス板上に流しこみ、湿度を加えずに乾燥することで、パクリタキセルを含む青色のキャストフィルムを得た。
実施例８ パクリタキセル含有積層フィルムの作製
実施例７で得られたフィルムの表面に、実施例１で作製したハニカムフィルムを積層し、ハニカム構造を片面にもつパクリタキセル含有積層フィルムを作製した。
実施例９ 緑内障濾過手術
図３に示すように、家兎の片眼に緑内障濾過手術を行った。角膜輪部基底の結膜を切開し、３ｍｍ×３ｍｍの半層強膜弁を作成し、線維柱帯を切除した。強膜弁を残したまま、実施例８で作製したパクリタキセル含有積層フィルムを、ハニカム面が外側（濾過胞壁側）を向くように設置し、フィルムが動かないように１０−０ナイロン縫合糸で５箇所固定し、結膜を閉じて縫合した。術後７日、１４日、２１日、および２８日において、点眼麻酔下でのトノペンによる眼圧測定と超音波生態顕微鏡（ＵＢＭ）による濾過胞観察を行った。
その結果、術後２８日までの間、超音波生体顕微鏡では濾過胞壁側のフィルムは濾過胞壁に接しており、結膜下に濾過のスペースが観察され、濾過胞が消失することはなかった。眼圧は手術前よりも低い状態で一定のままであった。
ヘマトキシリン−エオジン染色により作製した病理学的切片を解析した結果、強膜弁の周辺組織の瘢痕化はみられず、健常な状態であることが観察された。
比較例２
実施例９の緑内障濾過手術において、実施例３にて作製したパクリタキセルを含まない積層体を設置した。
その結果、術後２８日までの間、超音波生体顕微鏡ではフィルムは濾過胞壁に部分的に接しており、結膜下に濾過のスペースが観察され、濾過胞が消失することはなかった。眼圧は手術前よりも低い状態で一定のままであった。しかしながら、ヘマトキシリン−エオジン染色により作製した病理学的切片を解析した結果、強膜弁周囲の線維芽細胞の浸潤が著しく、瘢痕組織の形成が観察された。
以上の結果から、第一の本発明の緑内障治療材と、第二の本発明の緑内障治療材とでは、前者の方が優れているものの（実施例６参照）、いずれによっても薬剤による結膜上皮細胞の脆弱化が起こらず、強膜弁の瘢痕組織の形成が抑制され、濾過胞の形成維持に優れていることがわかる。よって、いずれの本発明によっても、ＭＭＣの副作用の問題から開放された、理想的な緑内障治療が達成される。Example 1 Preparation of Honeycomb Film (Adhesive Layer) Chloroform solution of polylactic acid-polycaprolactone copolymer (lactic acid: caprolactone = 88: 12 (molar ratio), Mw = 18.9 million, manufactured by Taki Chemical Co., Ltd.) (5 g / L) was mixed with phosphatidylethanolamine dioleoyl (manufactured by NOF Corporation) at a ratio (weight) of 0.5% with respect to the polymer to prepare a polymer solution. The polymer solution was cast on a glass substrate. Water vapor at room temperature and 70% humidity was sprayed on the liquid film to gradually evaporate the solvent and to condense the water vapor on the surface of the liquid film to form water droplets, and then the water droplets were evaporated to prepare a film. The obtained film had a concavo-convex portion in which pores having a pore diameter of about 5.5 μm were uniformly arranged in a honeycomb shape, the back surface was smooth, and was a non-penetrating film having a thickness of 7 μm.
Example 2 Production of Cast Film (Barrier Layer) In the polymer solution prepared in Example 1, legal dye green No. 202 was mixed at a ratio of 0.3% with respect to the polymer, and was poured onto a glass plate. By drying without applying humidity, a blue cast film in which an uneven structure was not observed was obtained.
Example 3 Lamination of Honeycomb Film and Barrier Layer The cast film produced in Example 2 was layered on the smooth surface of the honeycomb film produced in Example 1, and the laminate (A) was treated at 70 ° C. for 10 minutes. Got.
Example 4 Preparation of drug-supported matrix (composite film) To the polymer solution containing the blue pigment prepared in Example 2, paclitaxel (manufactured by Enzo Life Sciences) was added to 5 μg, mixed, and a uniform solution Got. This was poured onto a glass plate and dried without applying humidity to obtain a blue cast film containing paclitaxel.
The honeycomb film prepared in Example 1 was laminated on the surface of this film to prepare a paclitaxel-containing matrix having a honeycomb structure on one side.
Example 5 Glaucoma Filtration Surgery As shown in FIG. 2, glaucoma filtration surgery was performed on one eye of a rabbit. The conjunctiva at the base of the limbus was incised to create a 3 mm × 3 mm scleral half-layer flap, and the trabecular meshwork was excised. The paclitaxel-containing composite film (3 × 6 mm in size) produced in Example 4 was placed so that the honeycomb surface faced inward, and was sutured and fixed with two 10-0 nylon sutures so that the film did not move. .
With the scleral valve remaining, the laminate (A) produced in Example 3 was placed so that the honeycomb surface faced outward, and the film was sewn so as not to move, and fixed at five locations, and the conjunctiva was closed. Sutured.
On the 7th, 14th, 21st, and 28th days after the operation, intraocular pressure measurement with tonopenes under eye drop anesthesia and observation of filter cysts with an ultrasonic ecological microscope (UBM) were performed.
As a result, until 28 days after the operation, filtration space was observed under the conjunctiva in UBM, the filtering vesicles did not disappear, and the intraocular pressure remained constant. When the periphery of the conjunctiva where surgery was performed was observed with the naked eye, it was observed that it was in no way inferior to healthy conjunctival tissue, and regeneration of capillaries was also observed.
As a result of analyzing a pathological section prepared by hematoxylin-eosin staining, it was observed that the honeycomb film was in close contact with the tissue surface and the conjunctival epithelium was not thinned or partially lacked and was in a healthy state. It was.
Example 6
In the glaucoma filtration surgery of Example 5, the paclitaxel-containing matrix was not used, and the paclitaxel-containing matrix prepared in Example 4 was installed instead of the laminate (A).
As a result, until 28 days after the operation, filtration space was observed under the conjunctiva in UBM, the filtering vesicles did not disappear, and the intraocular pressure remained constant. However, it was observed that the area around the conjunctiva that had undergone surgery was fair and the capillaries had disappeared, which was clearly different from normal tissues that had not undergone surgery.
As a result of analyzing a pathological section prepared by staining with hematoxylin and eosin, the honeycomb film was closely attached to the tissue surface, but the conjunctival epithelium was thinned and partially absent, and fibroblast infiltration was observed. Not observed.
Comparative Example 1
In the glaucoma filtration operation of Example 5, only the laminate (A) (honeycomb film not containing paclitaxel) prepared in Example 3 was installed instead of the paclitaxel-containing composite film.
As a result, until 28 days after the operation, filtration space was observed under the conjunctiva in UBM, the filtering vesicles did not disappear, and the intraocular pressure remained constant.
As a result of analyzing a pathological section prepared by staining with hematoxylin and eosin, inflammation scarring was observed in the tissue around the sclera where the honeycomb film was placed.
Example 7 Production of cast film (drug-containing layer) Legal dye green No. 202 was mixed with the polymer dope produced in Example 1 at a ratio of 0.3% with respect to the polymer, and paclitaxel (produced by Enzo Life Sciences) was added. It was added to 5 μg and mixed to obtain a uniform solution. This was poured onto a glass plate and dried without applying humidity to obtain a blue cast film containing paclitaxel.
Example 8 Production of Paclitaxel-Containing Laminated Film The honeycomb film produced in Example 1 was laminated on the surface of the film obtained in Example 7, and a paclitaxel-containing laminated film having a honeycomb structure on one side was produced.
Example 9 Glaucoma Filtration Surgery As shown in FIG. 3, glaucoma filtration surgery was performed on one eye of a rabbit. The conjunctiva at the base of the limbus was incised to create a 3 mm × 3 mm semi-scleral flap, and the trabecular meshwork was excised. With the scleral valve remaining, the laminated film containing paclitaxel prepared in Example 8 was placed so that the honeycomb surface faced the outside (filtered cell wall side), and 10-0 nylon suture thread was used so that the film did not move. Five places were fixed, the conjunctiva was closed and sutured. On the 7th, 14th, 21st, and 28th days after the operation, intraocular pressure measurement with tonopene under eye drop anesthesia and observation of filter cysts with an ultrasonic ecological microscope (UBM) were performed.
As a result, until 28 days after the operation, the film on the filtration follicle wall side was in contact with the filtration follicle wall in the ultrasonic biomicroscope, and a filtration space was observed under the conjunctiva, and the filtration follicle did not disappear. . Intraocular pressure remained constant at a lower level than before surgery.
As a result of analyzing a pathological section prepared by staining with hematoxylin and eosin, it was observed that the tissue around the scleral flap was not scarred and was in a healthy state.
Comparative Example 2
In the glaucoma filtration operation of Example 9, the laminate not including paclitaxel prepared in Example 3 was installed.
As a result, until 28 days after the operation, the film was in partial contact with the wall of the filtering bleb in the ultrasonic biomicroscope, and a filtration space was observed under the conjunctiva, and the filtering vesicle did not disappear. Intraocular pressure remained constant at a lower level than before surgery. However, as a result of analyzing pathological sections prepared by hematoxylin-eosin staining, infiltration of fibroblasts around the scleral flap was remarkable, and formation of scar tissue was observed.
From the above results, the glaucoma treatment material of the first invention and the glaucoma treatment material of the second invention are superior to the former (see Example 6). It can be seen that cell weakening does not occur, the formation of scar tissue of the scleral flap is suppressed, and it is excellent in maintaining the formation of filtration bleb. Therefore, according to any of the present inventions, an ideal glaucoma treatment that is free from the problem of side effects of MMC is achieved.
本発明の緑内障治療材は、例えば医療用材料の製造業において利用される。 The glaucoma treatment material of the present invention is used, for example, in the manufacturing industry of medical materials.
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| JP2011106716 | 2011-05-11 | ||
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| JP2011106716 | 2011-05-11 | ||
| PCT/JP2012/062723 WO2012153870A1 (en) | 2011-05-11 | 2012-05-11 | Therapeutic material for glaucoma |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005533106A (en) * | 2002-07-15 | 2005-11-04 | アルコン，インコーポレイテッド | Bioerodible film for ophthalmic drug delivery |
| JP2008136770A (en) * | 2006-12-05 | 2008-06-19 | Teijin Ltd | Glaucoma treatment material |
| JP2008533204A (en) * | 2005-03-21 | 2008-08-21 | マクサイト， インコーポレイテッド | Drug delivery system for treatment of disease or condition |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005533106A (en) * | 2002-07-15 | 2005-11-04 | アルコン，インコーポレイテッド | Bioerodible film for ophthalmic drug delivery |
| JP2008533204A (en) * | 2005-03-21 | 2008-08-21 | マクサイト， インコーポレイテッド | Drug delivery system for treatment of disease or condition |
| JP2008136770A (en) * | 2006-12-05 | 2008-06-19 | Teijin Ltd | Glaucoma treatment material |
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