WO2023080200A1 - Microneedle array for ophthalmology - Google Patents

Microneedle array for ophthalmology Download PDF

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Publication number
WO2023080200A1
WO2023080200A1 PCT/JP2022/041161 JP2022041161W WO2023080200A1 WO 2023080200 A1 WO2023080200 A1 WO 2023080200A1 JP 2022041161 W JP2022041161 W JP 2022041161W WO 2023080200 A1 WO2023080200 A1 WO 2023080200A1
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microneedle array
hyaluronic acid
ophthalmic
weight
microneedle
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PCT/JP2022/041161
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French (fr)
Japanese (ja)
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英淑 権
文男 神山
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コスメディ製薬株式会社
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Publication of WO2023080200A1 publication Critical patent/WO2023080200A1/en

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin

Definitions

  • the present invention relates to ophthalmic microneedle arrays.
  • Microneedle-Based Delivery An Overview of Current Applications and Trends, Pharmaceuticals 2020, 12(6), 569
  • An object of the present invention is to provide an ophthalmic microneedle array that can be applied to the eye.
  • An ophthalmologic microneedle array comprising at least one hyaluronic acid selected from the group consisting of high-molecular-weight hyaluronic acid and crosslinked hyaluronic acid.
  • an ophthalmic microneedle array that can be applied to the eye.
  • FIG. 1 is a photograph of the microneedle array of the present invention produced in Example 1.
  • FIG. 2 is an enlarged photograph of FIG.
  • FIG. 3 is a photograph after the wearing test.
  • FIG. 4 is a photograph of a corneal erosion produced under eye drop anesthesia.
  • FIG. 5 is a photograph at the time of evaluation in the corneal epithelial erosion model.
  • An ophthalmic microneedle array (hereinafter sometimes abbreviated as a microneedle array) of the present invention comprises a substrate and a plurality of microneedles.
  • the microneedles are forested on one surface of the substrate.
  • the base of the substrate and the base of the microneedles may be the same base or different bases, but are preferably the same base.
  • the ophthalmic microneedle array of the present invention is based on at least one hyaluronic acid selected from the group consisting of high-molecular-weight hyaluronic acid and crosslinked hyaluronic acid. Therefore, the ophthalmic microneedle array of the present invention contains at least one hyaluronic acid selected from the group consisting of high molecular weight hyaluronic acid and crosslinked hyaluronic acid.
  • the ophthalmic microneedle array of the present invention may use high molecular weight hyaluronic acid as a base, crosslinked hyaluronic acid as a base, or high molecular weight hyaluronic acid and crosslinked hyaluronic acid as a base. Only one type of the base may be used, or two or more types may be used in combination.
  • the hyaluronic acid not only serves as a base, but may also serve as a drug component.
  • the hyaluronic acid is preferably used as a base and drug component.
  • Hyaluronic acid is known to have a corneal protective effect and a corneal epithelial wound healing effect.
  • eye drops containing hyaluronic acid are known, eye drops have the drawback that hyaluronic acid quickly flows away from the eye.
  • the intraocular residence time of the components such as hyaluronic acid can be lengthened, and the persistence of effects can be improved.
  • the base preferably contains high-molecular-weight hyaluronic acid.
  • high-molecular-weight hyaluronic acid means hyaluronic acid having a molecular weight of 550,000 daltons or more.
  • the above molecular weight is obtained by measuring the intrinsic viscosity of an aqueous solution of hyaluronic acid.
  • the high-molecular-weight hyaluronic acid is preferably hyaluronic acid having a molecular weight of 600,000 daltons or more.
  • the solubility and diffusibility of polymer compounds vary greatly depending on their molecular weight.
  • the high-molecular-weight hyaluronic acid is preferably hyaluronic acid with a molecular weight of less than 3,000,000 daltons.
  • the base preferably contains crosslinked hyaluronic acid (crosslinked hyaluronic acid).
  • crosslinked hyaluronic acid By cross-linking hyaluronic acid, the effect is remarkably exhibited.
  • Hyaluronic acid can be cross-linked using polyfunctional aldehydes such as glutaraldehyde and glyoxal.
  • the crosslinked hyaluronic acid is preferably crosslinked hyaluronic acid crosslinked with glutaraldehyde or glyoxal, and more preferably crosslinked hyaluronic acid crosslinked with glutaraldehyde.
  • solubility and intraocular diffusibility of hyaluronic acid due to intraocular water after being applied to the eye can be effectively suppressed.
  • the content of the high-molecular-weight hyaluronic acid is preferably 60% by weight or more, more preferably 80% by weight or more, even more preferably 90% by weight or more, and still more preferably 95% by weight or more. , particularly preferably 98% by weight or more.
  • the content of the crosslinked hyaluronic acid is preferably 40% by weight or more, more preferably 60% by weight or more, even more preferably 80% by weight or more, still more preferably 90% by weight or more, Still more preferably 95% by weight or more, particularly preferably 98% by weight or more.
  • the microneedle array may contain drug components as a base.
  • the microneedle array may contain a drug component different from hyaluronic acid in the base.
  • the microneedle array may contain a drug component different from hyaluronic acid.
  • As the drug component conventionally known drug components used for dry eye or ophthalmic treatment can be used. Only one type of the drug component may be used, or two or more types may be used in combination.
  • the above drug components include antibiotics such as chloramphenicol and gentamicin sulfate; antibacterial agents such as ofloxacin and norfloxacin; antifungal/antiviral agents such as pimaricin and acyclovir. These drug components are known as therapeutic drugs for corneal infections.
  • the microneedle array preferably corresponds to dry eye or corneal infection.
  • hyaluronic acid itself acts as a drug component for dry eye treatment.
  • a microneedle array impregnated with the above-described drug components such as antibiotics and releasing the drug slowly, frequent administration is not required as in the past, and the patient's QOL can be improved. Contribute to improvement.
  • the above microneedle array may contain, in the base, other components different from both hyaluronic acid and drug components.
  • the microneedle array may contain other ingredients that are different from both hyaluronic acid and drug ingredients.
  • Other components include water-soluble polymers such as hydroxymethylcellulose, polyvinylpyrrolidone and gelatin; stabilizers; UV absorbers and the like. Only one of the other components may be used, or two or more thereof may be used in combination.
  • the outer diameter of the microneedle array is generally 2.0 cm or less.
  • the external shape of the microneedle array is preferably circular or elliptical.
  • the microneedle array preferably has a donut shape with no center when viewed from above. That is, the microneedle array preferably has an opening in the center. The diameter of the central opening is preferably 4 mm or more and 7 mm or less.
  • the microneedle array is preferably attached to a contact lens for use, and more preferably attached to a soft contact lens.
  • Combined administration with a soft contact lens improves the patient's wearing comfort, and the soft contact lens controls the intraocular diffusion of the drug component (including hyaluronic acid), thereby improving the persistence of the effect.
  • the thickness of the microneedle array substrate is preferably 50 ⁇ m or more and 300 ⁇ m or less, more preferably 50 ⁇ m or more and 200 ⁇ m or less, from the viewpoint of safety and durability of the effect.
  • the thickness of the substrate is equal to or greater than the lower limit, the effect of swelling due to moisture can be reduced when the device is placed in the eye.
  • the thickness of the substrate is equal to or less than the upper limit, discomfort to the eyes can be effectively suppressed. In particular, when the thickness of the substrate is 200 ⁇ m or less, it is possible to more effectively suppress discomfort to the eyes.
  • the microneedles of the microneedle array preferably have a needle length of 70 ⁇ m or more and 2000 ⁇ m or less, more preferably 100 ⁇ m or more and 2000 ⁇ m or less, and 200 ⁇ m or more and 1000 ⁇ m or less. more preferably, and particularly preferably 200 ⁇ m or more and 500 ⁇ m or less.
  • the diameter of the apex of the tip of the microneedle is preferably 80 ⁇ m or less, more preferably 50 ⁇ m or less, and even more preferably 30 ⁇ m or less.
  • each microneedle is cylindrical or conical with a circular base, elliptical column or elliptical cone with an elliptical base, triangular prism or triangular pyramid with a triangular base, square column or quadrilateral with a square base.
  • a pyramid shape, or a polygonal prism or polygonal pyramid having a polygonal base can be mentioned. If the base is elliptical, the major axis is expressed as the diameter, and the minor axis is shorter than the major axis as long as the ellipse can be formed.
  • the base is triangular or polygonal, one side may be represented as a representative, and a diagonal line may be represented as a representative.
  • the diameter at the bottom thereof is about 100 ⁇ m to 400 ⁇ m, preferably about 150 ⁇ m to 300 ⁇ m.
  • the microneedles may have steps.
  • a step refers to a shape in which the cross-sectional area of the microneedle is discontinuously reduced from the position where the microneedle is present toward the tip direction.
  • the needle density of the microneedles is preferably 100/cm 2 or more, preferably 200/cm 2 or more, and preferably 800/cm 2 or less.
  • the microneedle array can be mass-produced using a template (mold).
  • the mold is manufactured by wet etching or dry etching using a silicon substrate, precision machining using metal or resin (electric discharge machining, laser machining, hot embossing, injection molding, etc.), mechanical cutting, etc. be able to.
  • Examples of the mold include a mold having 100 to 1500 recesses per square cm corresponding to the shape of the microneedles.
  • a raw material aqueous solution containing at least one hyaluronic acid selected from the group consisting of high-molecular-weight hyaluronic acid and crosslinked hyaluronic acid, and optionally drug components and other components is poured into the mold.
  • hyaluronic acid selected from the group consisting of high-molecular-weight hyaluronic acid and crosslinked hyaluronic acid, and optionally drug components and other components
  • the raw material aqueous solution There is a method of spreading, drying and then peeling off (Japanese Unexamined Patent Application Publication No. 2009-273872 [0031]-[0033]).
  • the raw material aqueous solution may contain an organic solvent such as ethanol in order to improve the solubility of the drug component and the other components.
  • Example 1 Fabrication of microneedle arrays: A 10% by weight aqueous solution of hyaluronic acid (FCH-60, manufactured by Kikkoman Biochemifa, molecular weight: 600,000 daltons) was poured into a Konide mold and dried overnight. Then, it was punched out with a punch to produce a donut-shaped microneedle array having an opening in the center in plan view and having the following dimensions and shape. A photograph of the obtained microneedle array is shown in FIG. FIG. 2 is an enlarged view of FIG.
  • FCH-60 hyaluronic acid
  • microneedle array 1.1 cm Diameter of central opening: 5mm Needle length and shape of microneedle: 250 ⁇ m Conide type Substrate thickness: 80 ⁇ m Needle density: 270 needles/cm 2
  • Example 1 A microneedle array was produced in the same manner as in Example 1, except that hyaluronic acid having a molecular weight of 80,000 daltons (manufactured by Kikkoman Biochemifa) was used.
  • Example 1 (Evaluation of Example 1 and Comparative Example 1)
  • the microneedle array obtained in Example 1 was attached to the hollow side (eye contact side) of a soft contact lens (menicon 1D), and then attached to the right eye of a rabbit (Japanese White).
  • the microneedle array obtained in Comparative Example 1 was attached to the hollow side (eye contact side) of a soft contact lens (menicon 1D), and then attached to the left eye of a rabbit (Japanese White).
  • the soft contact lens was taken out one day after wearing on the rabbit's eye and observed, the microneedle array obtained in Comparative Example 1 had completely disappeared, but the microneedle array obtained in Example 1 had disappeared. Detected on contact lenses.
  • Example 2 The microneedle array obtained in Comparative Example 1 (microneedle array containing hyaluronic acid with a molecular weight of 80,000 daltons) was treated with 0.1 N hydrochloric acid acid ethanol-water mixed solvent containing 0.2 mol of glutaraldehyde (ethanol concentration: 80% by weight) and allowed to react for 24 hours. After 24 hours, the microneedle array was removed and dried. Thus, a microneedle array containing crosslinked hyaluronic acid was produced.
  • a corneal epithelial erosion model was prepared as follows.
  • FIG. 4 shows the results of preparing corneal erosion under eye drop anesthesia. Note that FIG. 4 is HE-stained. Figure 4(a) is a normal control (companion eye) and Figure 4(b) is an erosive eye.
  • Microneedle arrays based on non-crosslinked low-molecular-weight hyaluronic acid dissolve immediately upon contact with tear fluid, but microneedle arrays based on high-molecular-weight hyaluronic acid or crosslinked hyaluronic acid dissolve on the cornea. , the microneedle array can be maintained for a relatively long period of time, thus enhancing the durability of the effect.
  • the microneedle array can be stably attached. For example, wearing a soft contact lens for the purpose of preventing detachment after placing a microneedle array on the cornea, or using a soft contact lens with a microneedle array obtained by placing a microneedle array on a soft contact lens. Therefore, the microneedle array can be attached stably.

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Abstract

Provided is a microneedle array for ophthalmology that can be used on the eye.　A microneedle array for ophthalmology that has, as a base material, at least one type of hyaluronic acid selected from the group consisting of high-molecular-weight hyaluronic acid and crosslinked hyaluronic acid.

Description

眼科用マイクロニードルアレイophthalmic microneedle array
　本発明は、眼科用マイクロニードルアレイに関するものである。 The present invention relates to ophthalmic microneedle arrays.
　マイクロニードルの眼科への応用については、ステンレススチール又はガラスからなるマイクロニードルに塗布された薬物を角膜に投与する報告、あるいは水溶性高分子からなるマイクロニードルをドライアイ治療の目的で角膜上に投与する報告がある（例えば、下記の特許文献１）。また、マイクロニードルを用いて、角膜を介して、眼科疾患の治療用の薬物を投与する報告もある（例えば、下記の非特許文献１）。しかしながら、毒性の問題があったり、効果の持続性の問題があったりして、実用化には至っていない。 Regarding the application of microneedles in ophthalmology, there are reports of administering drugs coated on microneedles made of stainless steel or glass to the cornea, or administering microneedles made of water-soluble polymers onto the cornea for the purpose of treating dry eye. There is a report to do (for example, Patent Document 1 below). There is also a report of administration of drugs for treatment of ophthalmic diseases through the cornea using microneedles (for example, Non-Patent Document 1 below). However, it has not been put to practical use because of problems of toxicity and persistence of effects.
ＷＯ２０１８／００３９５２Ａ１WO2018/003952A1
　本発明の目的は、眼に適用可能な眼科用マイクロニードルアレイを提供することである。 An object of the present invention is to provide an ophthalmic microneedle array that can be applied to the eye.
　本発明は、以下に示す通りである。
［１］　高分子量ヒアルロン酸及び架橋ヒアルロン酸からなる群より選ばれる少なくとも１種のヒアルロン酸を基剤とする、眼科用マイクロニードルアレイ。
［２］　前記高分子量ヒアルロン酸の分子量が６０万ダルトン以上であり、前記架橋ヒアルロン酸がグルタルアルデヒド又はグリオキサールで架橋された架橋ヒアルロン酸である、［１］に記載の眼科用マイクロニードルアレイ。
［３］　薬剤成分を前記基剤に含有する、［１］又は［２］に記載の眼科用マイクロニードルアレイ。
［４］　ソフトコンタクトレンズに装着して用いられる、［１］～［３］のいずれかに記載の眼科用マイクロニードルアレイ。
［５］　平面視にて、中心部がないドーナッツ形状である、［１］～［４］のいずれかに記載の眼科用マイクロニードルアレイ。
［６］　ドライアイ又は角膜感染症に対応する、［１］～［５］のいずれかに記載の眼科用マイクロニードルアレイ。 The present invention is as described below.
[1] An ophthalmologic microneedle array comprising at least one hyaluronic acid selected from the group consisting of high-molecular-weight hyaluronic acid and crosslinked hyaluronic acid.
[2] The ophthalmic microneedle array according to [1], wherein the molecular weight of the high molecular weight hyaluronic acid is 600,000 daltons or more, and the crosslinked hyaluronic acid is crosslinked hyaluronic acid crosslinked with glutaraldehyde or glyoxal.
[3] The ophthalmic microneedle array according to [1] or [2], which contains a drug component in the base.
[4] The ophthalmic microneedle array according to any one of [1] to [3], which is attached to a soft contact lens.
[5] The ophthalmic microneedle array according to any one of [1] to [4], which has a donut shape with no center in plan view.
[6] The ophthalmic microneedle array according to any one of [1] to [5], which is for dry eye or corneal infection.
　本発明によれば、眼に適用可能な眼科用マイクロニードルアレイを提供することができる。 According to the present invention, it is possible to provide an ophthalmic microneedle array that can be applied to the eye.
図１は、実施例１で作製した本発明のマイクロニードルアレイの写真である。FIG. 1 is a photograph of the microneedle array of the present invention produced in Example 1. FIG. 図２は、図１の拡大写真である。FIG. 2 is an enlarged photograph of FIG. 図３は、装着試験後の写真である。FIG. 3 is a photograph after the wearing test. 図４は、点眼麻酔下で角膜びらんを作製した写真である。FIG. 4 is a photograph of a corneal erosion produced under eye drop anesthesia. 図５は、角膜上皮びらんモデルでの評価時の写真である。FIG. 5 is a photograph at the time of evaluation in the corneal epithelial erosion model.
　（眼科用マイクロニードルアレイ）
　本発明の眼科用マイクロニードルアレイ（以下、マイクロニードルアレイと略記することがある）は、基板と、複数本のマイクロニードルとを備える。上記マイクロニードルは、基板の一方の表面上に林立している。なお、基板の基剤とマイクロニードルの基剤とは、同一の基剤であってもよく、異なる基剤であってもよいが、同一の基剤であることが好ましい。 (Microneedle array for ophthalmology)
An ophthalmic microneedle array (hereinafter sometimes abbreviated as a microneedle array) of the present invention comprises a substrate and a plurality of microneedles. The microneedles are forested on one surface of the substrate. The base of the substrate and the base of the microneedles may be the same base or different bases, but are preferably the same base.
　本発明の眼科用マイクロニードルアレイでは、高分子量ヒアルロン酸及び架橋ヒアルロン酸からなる群より選ばれる少なくとも１種のヒアルロン酸を基剤とする。したがって、本発明の眼科用マイクロニードルアレイは、高分子量ヒアルロン酸及び架橋ヒアルロン酸からなる群より選ばれる少なくとも１種のヒアルロン酸を含む。本発明の眼科用マイクロニードルアレイでは、高分子量ヒアルロン酸を基剤としてもよく、架橋ヒアルロン酸を基剤としてもよく、高分子量ヒアルロン酸と架橋ヒアルロン酸とを基剤としてもよい。上記基剤は、１種のみが用いられてもよく、２種以上が併用されてもよい。 The ophthalmic microneedle array of the present invention is based on at least one hyaluronic acid selected from the group consisting of high-molecular-weight hyaluronic acid and crosslinked hyaluronic acid. Therefore, the ophthalmic microneedle array of the present invention contains at least one hyaluronic acid selected from the group consisting of high molecular weight hyaluronic acid and crosslinked hyaluronic acid. The ophthalmic microneedle array of the present invention may use high molecular weight hyaluronic acid as a base, crosslinked hyaluronic acid as a base, or high molecular weight hyaluronic acid and crosslinked hyaluronic acid as a base. Only one type of the base may be used, or two or more types may be used in combination.
　本発明において、上記ヒアルロン酸は、基剤としての役割を果たすだけでなく、薬剤成分としての役割を果たすこともある。本発明において、上記ヒアルロン酸は、基剤兼薬剤成分として好適に用いられる。ヒアルロン酸は、角膜保護作用を有していたり、角膜上皮創傷治癒効果を有していたりすることが知られている。なお、ヒアルロン酸を含有する点眼薬が知られているものの、点眼薬では、ヒアルロン酸が速やかに目から流れ去るという欠点がある。これに対して、本発明の眼科用マイクロニードルアレイでは、上記ヒアルロン酸等の成分の眼内滞留時間を長くすることができ、効果の持続性を向上させることができる。 In the present invention, the hyaluronic acid not only serves as a base, but may also serve as a drug component. In the present invention, the hyaluronic acid is preferably used as a base and drug component. Hyaluronic acid is known to have a corneal protective effect and a corneal epithelial wound healing effect. Although eye drops containing hyaluronic acid are known, eye drops have the drawback that hyaluronic acid quickly flows away from the eye. In contrast, in the ophthalmic microneedle array of the present invention, the intraocular residence time of the components such as hyaluronic acid can be lengthened, and the persistence of effects can be improved.
　上記基剤は、高分子量ヒアルロン酸を含むことが好ましい。なお、本明細書において、高分子量ヒアルロン酸とは、分子量が５５万ダルトン以上のヒアルロン酸を意味する。上記分子量は、ヒアルロン酸の水溶液の極限粘度測定により求められる。上記高分子量ヒアルロン酸は、分子量が６０万ダルトン以上のヒアルロン酸であることが好ましい。高分子化合物の溶解性及び拡散性は、その分子量により大きく異なる。分子量が６０万ダルトン以上のヒアルロン酸を用いることにより、眼へ装着した後のヒアルロン酸の眼内水分による溶解性及び眼内拡散性を著しく抑えることができる。また、上記高分子量ヒアルロン酸の分子量が３００万ダルトン以上の場合には、分子量が３００万ダルトン未満である場合と比べて、溶解性及び拡散性が低く取り扱いに不便である。そのため、上記高分子量ヒアルロン酸は、分子量が３００万ダルトン未満のヒアルロン酸であることが好ましい。 The base preferably contains high-molecular-weight hyaluronic acid. In the present specification, high-molecular-weight hyaluronic acid means hyaluronic acid having a molecular weight of 550,000 daltons or more. The above molecular weight is obtained by measuring the intrinsic viscosity of an aqueous solution of hyaluronic acid. The high-molecular-weight hyaluronic acid is preferably hyaluronic acid having a molecular weight of 600,000 daltons or more. The solubility and diffusibility of polymer compounds vary greatly depending on their molecular weight. By using hyaluronic acid with a molecular weight of 600,000 daltons or more, the solubility and intraocular diffusibility of hyaluronic acid due to intraocular water after being applied to the eye can be remarkably suppressed. In addition, when the molecular weight of the high-molecular-weight hyaluronic acid is 3,000,000 daltons or more, the solubility and diffusibility are lower than when the molecular weight is less than 3,000,000 daltons, and handling is inconvenient. Therefore, the high-molecular-weight hyaluronic acid is preferably hyaluronic acid with a molecular weight of less than 3,000,000 daltons.
　上記基剤は、架橋ヒアルロン酸（架橋されたヒアルロン酸）を含むことが好ましい。ヒアルロン酸を架橋させることにより、その効果が顕著に表れる。 The base preferably contains crosslinked hyaluronic acid (crosslinked hyaluronic acid). By cross-linking hyaluronic acid, the effect is remarkably exhibited.
　ヒアルロン酸の架橋は、グルタルアルデヒド及びグリオキサール等の多官能アルデヒドを用いて行うことができる。上記架橋ヒアルロン酸は、グルタルアルデヒド又はグリオキサールで架橋された架橋ヒアルロン酸であることが好ましく、グルタルアルデヒドで架橋された架橋ヒアルロン酸であることがより好ましい。この場合には、眼へ装着した後のヒアルロン酸の眼内水分による溶解性及び眼内拡散性を効果的に抑えることができる。 　Hyaluronic acid can be cross-linked using polyfunctional aldehydes such as glutaraldehyde and glyoxal. The crosslinked hyaluronic acid is preferably crosslinked hyaluronic acid crosslinked with glutaraldehyde or glyoxal, and more preferably crosslinked hyaluronic acid crosslinked with glutaraldehyde. In this case, the solubility and intraocular diffusibility of hyaluronic acid due to intraocular water after being applied to the eye can be effectively suppressed.
　上記マイクロニードルアレイ１００重量％中、上記高分子量ヒアルロン酸の含有量は、好ましくは６０重量％以上、より好ましくは８０重量％以上、より一層好ましくは９０重量％以上、更に好ましくは９５重量％以上、特に好ましくは９８重量％以上である。上記マイクロニードルアレイ１００重量％中、上記架橋ヒアルロン酸の含有量は、好ましくは４０重量％以上、より好ましくは６０重量％以上、より一層好ましくは８０重量％以上、更に好ましくは９０重量％以上、更に一層好ましくは９５重量％以上、特に好ましくは９８重量％以上である。 In 100% by weight of the microneedle array, the content of the high-molecular-weight hyaluronic acid is preferably 60% by weight or more, more preferably 80% by weight or more, even more preferably 90% by weight or more, and still more preferably 95% by weight or more. , particularly preferably 98% by weight or more. In 100% by weight of the microneedle array, the content of the crosslinked hyaluronic acid is preferably 40% by weight or more, more preferably 60% by weight or more, even more preferably 80% by weight or more, still more preferably 90% by weight or more, Still more preferably 95% by weight or more, particularly preferably 98% by weight or more.
　上記マイクロニードルアレイは、薬剤成分を基剤に含有していてもよい。上記マイクロニードルアレイは、ヒアルロン酸とは異なる薬剤成分を基剤に含有してもよい。上記マイクロニードルアレイは、ヒアルロン酸とは異なる薬剤成分を含有していてもよい。上記薬剤成分として、ドライアイ又は眼科治療に用いられる従来公知の薬剤成分を使用可能である。上記薬剤成分は、１種のみが用いられてもよく、２種以上が併用されてもよい。 The microneedle array may contain drug components as a base. The microneedle array may contain a drug component different from hyaluronic acid in the base. The microneedle array may contain a drug component different from hyaluronic acid. As the drug component, conventionally known drug components used for dry eye or ophthalmic treatment can be used. Only one type of the drug component may be used, or two or more types may be used in combination.
　上記薬剤成分としては、クロラムフェニコール及び硫酸ゲンタマイシン等の抗生物質；オフロキサシン及びノルフロキサシン等の抗菌剤；ピマリシン及びアシクロビル等の抗真菌・抗ウイルス剤等が挙げられる。これらの薬剤成分は、角膜感染症治療薬として知られている。 The above drug components include antibiotics such as chloramphenicol and gentamicin sulfate; antibacterial agents such as ofloxacin and norfloxacin; antifungal/antiviral agents such as pimaricin and acyclovir. These drug components are known as therapeutic drugs for corneal infections.
　上記マイクロニードルアレイは、ドライアイ又は角膜感染症に対応することが好ましい。 The microneedle array preferably corresponds to dry eye or corneal infection.
　なお、ドライアイ治療には、ヒアルロン酸自体が薬剤成分として作用する。また、角膜感染症治療には、抗生物質等の上述した薬剤成分を含浸したマイクロニードルアレイを投与し薬物を徐放させることにより、従来のように頻回の投与を必要とせず、患者のＱＯＬ向上に資する。 In addition, hyaluronic acid itself acts as a drug component for dry eye treatment. In addition, in the treatment of corneal infections, by administering a microneedle array impregnated with the above-described drug components such as antibiotics and releasing the drug slowly, frequent administration is not required as in the past, and the patient's QOL can be improved. Contribute to improvement.
　上記マイクロニードルアレイは、ヒアルロン酸及び薬剤成分の双方とは異なる他の成分を基剤に含有していてもよい。上記マイクロニードルアレイは、ヒアルロン酸及び薬剤成分の双方とは異なる他の成分を含有していてもよい。上記他の成分としては、ヒドロキシメチルセルロース、ポリビニルピロリドン及びゼラチン等の水溶性高分子；安定剤；紫外線吸収剤等が挙げられる。上記他の成分は、１種のみが用いられてもよく、２種以上が併用されてもよい。 The above microneedle array may contain, in the base, other components different from both hyaluronic acid and drug components. The microneedle array may contain other ingredients that are different from both hyaluronic acid and drug ingredients. Other components include water-soluble polymers such as hydroxymethylcellulose, polyvinylpyrrolidone and gelatin; stabilizers; UV absorbers and the like. Only one of the other components may be used, or two or more thereof may be used in combination.
　マイクロニードルアレイは眼内に投与されるので、一般に、マイクロニードルアレイの外径は２．０ｃｍ以下である。また、マイクロニードルアレイは眼内に投与されるので、マイクロニードルアレイの外形は円形又は楕円形であることが好ましい。投与後の視野を確保するために、マイクロニードルアレイの平面視にて、中心部がないドーナッツ形状であることが好ましい。すなわち、マイクロニードルアレイは、中央部に開口を有することが好ましい。中央部の開口の直径は、４ｍｍ以上、７ｍｍ以下が好ましい。 Since the microneedle array is administered intraocularly, the outer diameter of the microneedle array is generally 2.0 cm or less. Moreover, since the microneedle array is administered intraocularly, the external shape of the microneedle array is preferably circular or elliptical. In order to secure a field of view after administration, the microneedle array preferably has a donut shape with no center when viewed from above. That is, the microneedle array preferably has an opening in the center. The diameter of the central opening is preferably 4 mm or more and 7 mm or less.
　マイクロニードルアレイを直接眼内投与するためには、高い技術性が必要である。また、装着後も患者によっては不快感を持つことがある。これらの課題を効果的に解決する観点からは、上記マイクロニードルアレイは、コンタクトレンズに装着して用いられることが好ましく、ソフトコンタクトレンズに装着して用いられることがより好ましい。なおこの場合に、コンタクトレンズの内側（角膜へ接触する側）にマイクロニードルアレイを装着（固定）し、その状態で眼内投与することが好ましい。ソフトコンタクトレンズとの合体投与により、患者の装着感も改善され、さらにソフトコンタクトレンズにより薬剤成分（ヒアルロン酸を含む）の眼内拡散が制御されるので効果の持続性が改善される。 A high degree of technical skill is required for direct intraocular administration of microneedle arrays. In addition, some patients may feel discomfort even after wearing the device. From the viewpoint of effectively solving these problems, the microneedle array is preferably attached to a contact lens for use, and more preferably attached to a soft contact lens. In this case, it is preferable to attach (fix) the microneedle array to the inner side of the contact lens (the side in contact with the cornea) and administer the drug intraocularly in that state. Combined administration with a soft contact lens improves the patient's wearing comfort, and the soft contact lens controls the intraocular diffusion of the drug component (including hyaluronic acid), thereby improving the persistence of the effect.
　安全性の観点及び効果の持続性の観点から、マイクロニードルアレイの基板の厚さは、好ましくは５０μｍ以上３００μｍ以下であり、より好ましくは５０μｍ以上２００μｍ以下である。上記基板の厚さが上記下限以上であると、眼内へ装着したときに水分による膨張の影響を小さくすることができる。上記基板の厚さが上記上限以下であると、目に対する違和感を効果的に抑えることができる。特に、上記基板の厚さが２００μｍ以下の場合には、目に対する違和感をより効果的に抑えることができる。 The thickness of the microneedle array substrate is preferably 50 μm or more and 300 μm or less, more preferably 50 μm or more and 200 μm or less, from the viewpoint of safety and durability of the effect. When the thickness of the substrate is equal to or greater than the lower limit, the effect of swelling due to moisture can be reduced when the device is placed in the eye. When the thickness of the substrate is equal to or less than the upper limit, discomfort to the eyes can be effectively suppressed. In particular, when the thickness of the substrate is 200 μm or less, it is possible to more effectively suppress discomfort to the eyes.
　安全性の観点及び効果の持続性の観点から、マイクロニードルアレイのマイクロニードルは、針長さが、７０μｍ以上２０００μｍ以下であること好ましく、１００μｍ以上２０００μｍ以下であることがより好ましく、２００μｍ以上１０００μｍ以下であることが更に好ましく、２００μｍ以上５００μｍ以下であることが特に好ましい。 From the viewpoint of safety and durability of the effect, the microneedles of the microneedle array preferably have a needle length of 70 μm or more and 2000 μm or less, more preferably 100 μm or more and 2000 μm or less, and 200 μm or more and 1000 μm or less. more preferably, and particularly preferably 200 μm or more and 500 μm or less.
　マイクロニードルの先端部頂点の大きさを直径として表すと、好ましくは８０μｍ以下、より好ましくは５０μｍ以下、更に好ましくは３０μｍ以下である。 The diameter of the apex of the tip of the microneedle is preferably 80 μm or less, more preferably 50 μm or less, and even more preferably 30 μm or less.
　各マイクロニードルの形状としては、底面が円である円柱状もしくは円錐状、底面が楕円である楕円柱状もしくは楕円錐状、底面が三角形である三角柱もしくは三角錐、底面が四角形である四角柱状もしくは四角錐状、又は底面が多角形である多角柱もしくは多角錐が挙げられる。底面が楕円の場合、長径を直径として表し、短径は楕円を形成できる限りにおいて長径より短い。底面が三角形ないし多角形の場合、一辺を代表として表してもよく、対角線を代表として表してもよい。マイクロニードルが円錐状である場合には、その底面における直径は、１００μｍ～４００μｍ程度であり、１５０μｍ～３００μｍ程度が好ましい。 The shape of each microneedle is cylindrical or conical with a circular base, elliptical column or elliptical cone with an elliptical base, triangular prism or triangular pyramid with a triangular base, square column or quadrilateral with a square base. A pyramid shape, or a polygonal prism or polygonal pyramid having a polygonal base can be mentioned. If the base is elliptical, the major axis is expressed as the diameter, and the minor axis is shorter than the major axis as long as the ellipse can be formed. When the base is triangular or polygonal, one side may be represented as a representative, and a diagonal line may be represented as a representative. When the microneedle is conical, the diameter at the bottom thereof is about 100 μm to 400 μm, preferably about 150 μm to 300 μm.
　マイクロニードルは、段差を有していてもよい。段差とは、マイクロニードルのある位置から先端方向に向かって、マイクロニードルの断面積が不連続的に縮小する形状をいう。 The microneedles may have steps. A step refers to a shape in which the cross-sectional area of the microneedle is discontinuously reduced from the position where the microneedle is present toward the tip direction.
　マイクロニードルの針密度は、好ましくは１００本／ｃｍ２以上、好ましくは２００本／ｃｍ２以上、好ましくは８００本／ｃｍ２以下である。 The needle density of the microneedles is preferably 100/cm 2 or more, preferably 200/cm 2 or more, and preferably 800/cm 2 or less.
　（マイクロニードルアレイの製造方法）
　上記マイクロニードルアレイは、鋳型（金型）を用いて大量生産することができる。上記鋳型は、シリコン基板を用いたウエットエッチング加工又はドライエッチング加工、金属若しくは樹脂を用いた精密機械加工（放電加工、レーザー加工、ホットエンボス加工、射出成型加工等）、機械切削加工等により製造することができる。鋳型としては、マイクロニードルの形状に対応した、１平方ｃｍ当たり１００個～１５００個の凹部を有する鋳型等が挙げられる。 (Method for producing microneedle array)
The microneedle array can be mass-produced using a template (mold). The mold is manufactured by wet etching or dry etching using a silicon substrate, precision machining using metal or resin (electric discharge machining, laser machining, hot embossing, injection molding, etc.), mechanical cutting, etc. be able to. Examples of the mold include a mold having 100 to 1500 recesses per square cm corresponding to the shape of the microneedles.
　マイクロニードルアレイの製造方法としては、上記鋳型に、高分子量ヒアルロン酸及び架橋ヒアルロン酸からなる群より選ばれる少なくとも１種のヒアルロン酸、必要に応じて薬剤成分及び他の成分を含む原料水溶液を流延し、乾燥した後剥離する方法が挙げられる（特開２００９－２７３８７２号公報［００３１］－［００３３］）。上記原料水溶液における上記薬剤成分及び上記他の成分としては、上述した成分が挙げられる。また、上記原料水溶液は、上記薬剤成分及び上記他の成分の溶解性を向上させるために、エタノール等の有機溶媒を含んでいてもよい。 As a method for producing a microneedle array, a raw material aqueous solution containing at least one hyaluronic acid selected from the group consisting of high-molecular-weight hyaluronic acid and crosslinked hyaluronic acid, and optionally drug components and other components is poured into the mold. There is a method of spreading, drying and then peeling off (Japanese Unexamined Patent Application Publication No. 2009-273872 [0031]-[0033]). Examples of the drug component and the other component in the raw material aqueous solution include the components described above. In addition, the raw material aqueous solution may contain an organic solvent such as ethanol in order to improve the solubility of the drug component and the other components.
　本発明の実施例を以下に示すが、本発明は実施例に限定されるわけではない。 Examples of the present invention are shown below, but the present invention is not limited to the examples.
　（実施例１）
　マイクロニードルアレイの作製：
　ヒアルロン酸（ＦＣＨ－６０，キッコーマンバイオケミファ製、分子量：６０万ダルトン）の１０重量％水溶液を、コニーデ型の鋳型に流涎して、１夜乾燥させた。次いで、ポンチで打ち抜いて、平面視にて中央部に開口を有し、以下の寸法及び形状を有するドーナッツ形状のマイクロニードルアレイを作製した。得られたマイクロニードルアレイの写真を図１に示す。図２は、図１の拡大図である。 (Example 1)
Fabrication of microneedle arrays:
A 10% by weight aqueous solution of hyaluronic acid (FCH-60, manufactured by Kikkoman Biochemifa, molecular weight: 600,000 daltons) was poured into a Konide mold and dried overnight. Then, it was punched out with a punch to produce a donut-shaped microneedle array having an opening in the center in plan view and having the following dimensions and shape. A photograph of the obtained microneedle array is shown in FIG. FIG. 2 is an enlarged view of FIG.
　マイクロニードルアレイの外径：１．１ｃｍ
　中央部の開口の直径：５ｍｍ
　マイクロニードルの針長さ及び形状：２５０μｍのコニーデ型
　基板の厚さ：８０μｍ
　針密度：２７０本／ｃｍ２ Outer diameter of microneedle array: 1.1 cm
Diameter of central opening: 5mm
Needle length and shape of microneedle: 250 μm Conide type Substrate thickness: 80 μm
Needle density: 270 needles/cm 2
　（比較例１）
　分子量８万ダルトンのヒアルロン酸（キッコーマンバイオケミファ製）を用いたこと以外は、実施例１と同様にして、マイクロニードルアレイを作製した。 (Comparative example 1)
A microneedle array was produced in the same manner as in Example 1, except that hyaluronic acid having a molecular weight of 80,000 daltons (manufactured by Kikkoman Biochemifa) was used.
　（実施例１及び比較例１の評価）
　実施例１で得られたマイクロニードルアレイを、ソフトコンタクトレンズ（ｍｅｎｉｃｏｎ１Ｄ）の窪み側（眼接触側）に張り付けた後、ウサギ（日本白種）の右目に装着した。比較例１で得られたマイクロニードルアレイを、ソフトコンタクトレンズ（ｍｅｎｉｃｏｎ１Ｄ）の窪み側（眼接触側）に張り付けた後、ウサギ（日本白種）の左目に装着した。ウサギの目に装着してから１日後にソフトコンタクトレンズを取り出し観察したところ、比較例１で得られたマイクロニードルアレイは完全に消失していたが、実施例１で得られたマイクロニードルアレイはコンタクトレンズ上に確認された。 (Evaluation of Example 1 and Comparative Example 1)
The microneedle array obtained in Example 1 was attached to the hollow side (eye contact side) of a soft contact lens (menicon 1D), and then attached to the right eye of a rabbit (Japanese White). The microneedle array obtained in Comparative Example 1 was attached to the hollow side (eye contact side) of a soft contact lens (menicon 1D), and then attached to the left eye of a rabbit (Japanese White). When the soft contact lens was taken out one day after wearing on the rabbit's eye and observed, the microneedle array obtained in Comparative Example 1 had completely disappeared, but the microneedle array obtained in Example 1 had disappeared. Detected on contact lenses.
　（実施例２）
　比較例１で得られたマイクロニードルアレイ（分子量８万ダルトンのヒアルロン酸を含むマイクロニードルアレイ）を、０．２モルのグルタルアルデヒドを含む、０．１Ｎ塩酸酸性エタノール－水混合溶媒（エタノール濃度：８０重量％）中に浸漬し、２４時間反応させた。２４時間後、マイクロニードルアレイを取り出し乾燥させた。このようにして、架橋ヒアルロン酸を含むマイクロニードルアレイを作製した。 (Example 2)
The microneedle array obtained in Comparative Example 1 (microneedle array containing hyaluronic acid with a molecular weight of 80,000 daltons) was treated with 0.1 N hydrochloric acid acid ethanol-water mixed solvent containing 0.2 mol of glutaraldehyde (ethanol concentration: 80% by weight) and allowed to react for 24 hours. After 24 hours, the microneedle array was removed and dried. Thus, a microneedle array containing crosslinked hyaluronic acid was produced.
　なお、以下のようにして角膜上皮びらんモデルを作製した。 A corneal epithelial erosion model was prepared as follows.
　使用動物：雄性ニュージーランド白色家兎
　全身麻酔下で瞬膜を切除
　７日目以降に点眼麻酔下で片眼の角膜全体の上皮を全身麻酔下でスパーテルを用いて掻把。感染症が認められなかったものを「角膜上皮びらんモデル」として使用。 Animals used: Male New Zealand white rabbits Under general anesthesia, the nictitating membrane was excised. After 7 days, under general anesthesia, the epithelium of the entire cornea of one eye was scraped with a spatula under general anesthesia. Those in which no infection was observed were used as "corneal epithelial erosion models."
　（実施例２の評価）
　（１）装着試験
　ソフトコンタクトレンズとして、市販のソフトコンタクトレンズ（ＳＣＬ　ｓｅｎｏｆｉｌｃｏｎ　Ａ　ｐｏｌｙｍａｃｏｎ）を使用した。また、実施例２で得られたマイクロニードルアレイをソフトコンタクトレンズに接着するためのレンズケース（なだらかな球面を持つ凹面を有するレンズケース）を用意した。このレンズケースに、ソフトコンタクトレンズを置いた。次いで、マイクロニードルアレイの針（マイクロニードル）が設けられている面が角膜に対向する向きとなるように、ソフトコンタクトレンズ上にマイクロニードルアレイを載せた。次いで、マイクロニードルアレイ付きソフトコンタクトレンズを、点眼麻酔前又は後の角膜上に装着したところ、安定的に装着することができた（図３）。 (Evaluation of Example 2)
(1) Wearing Test A commercially available soft contact lens (SCL senofilcon A polymeron) was used as the soft contact lens. A lens case (a lens case having a concave surface with a gentle spherical surface) was also prepared for adhering the microneedle array obtained in Example 2 to a soft contact lens. A soft contact lens was placed in this lens case. Next, the microneedle array was placed on the soft contact lens so that the surface of the microneedle array on which the needles (microneedles) are provided faces the cornea. Next, when a soft contact lens with a microneedle array was placed on the cornea before or after eye drop anesthesia, it could be stably placed (Fig. 3).
　（２）角膜上皮びらんモデルでの評価
　点眼麻酔下で角膜びらんを作製した結果を図４に示す。なお、この図４は、ＨＥ染色したものである。図４（ａ）は、正常対照（僚眼）であり、図４（ｂ）は、びらん作製眼である。 (2) Evaluation by corneal epithelial erosion model FIG. 4 shows the results of preparing corneal erosion under eye drop anesthesia. Note that FIG. 4 is HE-stained. Figure 4(a) is a normal control (companion eye) and Figure 4(b) is an erosive eye.
　エバンスブルー含有のマイクロニードルアレイを乗せて、直ちにソフトコンタクトレンズを装用することにより、装着が安定化した（図５）。そのまま、３日間連続して装着して用いた。 Wearing was stabilized by placing a microneedle array containing Evans blue and immediately wearing a soft contact lens (Fig. 5). The device was worn continuously for 3 days as it was.
　１日目にソフトコンタクトレンズを外して観察したところ、右目に装着した実施例２のマイクロニードルアレイでは、ヒアルロン酸膜を確認することができた。実施例２のマイクロニードルアレイでは架橋ヒアルロン酸が用いられているので、眼内滞留時間を長くすることができた。なお、３日目にソフトコンタクトレンズを外して観察したところ、実施例２のマイクロニードルアレイでは、該マイクロニードルアレイを確認できなかった。 When the soft contact lens was removed on the first day and observed, a hyaluronic acid film could be confirmed in the microneedle array of Example 2 worn on the right eye. Since crosslinked hyaluronic acid was used in the microneedle array of Example 2, it was possible to lengthen the retention time in the eye. In addition, when the soft contact lens was removed and observed on the third day, the microneedle array of Example 2 could not be confirmed.
　以上の結果より、以下が考察される。 From the above results, the following can be considered.
　１）架橋されていない低分子量ヒアルロン酸を基剤とするマイクロニードルアレイでは、涙液に触れると直ちに溶解するものの、高分子量ヒアルロン酸又は架橋ヒアルロン酸を基剤とするマイクロニードルアレイでは、角膜上に該マイクロニードルアレイを比較的長い時間保持することができ、従って、効果の持続性を高めることができる。 1) Microneedle arrays based on non-crosslinked low-molecular-weight hyaluronic acid dissolve immediately upon contact with tear fluid, but microneedle arrays based on high-molecular-weight hyaluronic acid or crosslinked hyaluronic acid dissolve on the cornea. , the microneedle array can be maintained for a relatively long period of time, thus enhancing the durability of the effect.
　２）マイクロニードルアレイとコンタクトレンズとを組み合わせて用いることにより、マイクロニードルアレイを安定的に装着することができる。例えば、マイクロニードルアレイを角膜上に置いた後の脱落防止目的でソフトコンタクトレンズを装用したり、マイクロニードルアレイをソフトコンタクトレンズ上に置いて得られるマイクロニードルアレイ付きソフトコンタクトレンズを用いたりすることにより、マイクロニードルアレイを安定的に装着することができる。 2) By using the microneedle array and the contact lens in combination, the microneedle array can be stably attached. For example, wearing a soft contact lens for the purpose of preventing detachment after placing a microneedle array on the cornea, or using a soft contact lens with a microneedle array obtained by placing a microneedle array on a soft contact lens. Therefore, the microneedle array can be attached stably.
　マイクロニードルアレイに、他の薬剤成分を含有させることによる他の角膜疾患への応用が見出される。 Applications to other corneal diseases can be found by incorporating other drug components into the microneedle array.

Claims (6)

  1. 　高分子量ヒアルロン酸及び架橋ヒアルロン酸からなる群より選ばれる少なくとも１種のヒアルロン酸を基剤とする、眼科用マイクロニードルアレイ。 An ophthalmic microneedle array based on at least one hyaluronic acid selected from the group consisting of high-molecular-weight hyaluronic acid and crosslinked hyaluronic acid.
  2. 　前記高分子量ヒアルロン酸の分子量が６０万ダルトン以上であり、
    　前記架橋ヒアルロン酸がグルタルアルデヒド又はグリオキサールで架橋された架橋ヒアルロン酸である、請求項１に記載の眼科用マイクロニードルアレイ。     The molecular weight of the high-molecular-weight hyaluronic acid is 600,000 daltons or more,
    The ophthalmic microneedle array according to claim 1, wherein the crosslinked hyaluronic acid is crosslinked hyaluronic acid crosslinked with glutaraldehyde or glyoxal.
  3. 　薬剤成分を前記基剤に含有する、請求項１に記載の眼科用マイクロニードルアレイ。 The ophthalmic microneedle array according to claim 1, wherein the base contains a drug component.
  4. 　ソフトコンタクトレンズに装着して用いられる、請求項１に記載の眼科用マイクロニードルアレイ。 The ophthalmic microneedle array according to claim 1, which is used by attaching to a soft contact lens.
  5. 　平面視にて、中心部がないドーナッツ形状である、請求項１に記載の眼科用マイクロニードルアレイ。 The ophthalmic microneedle array according to claim 1, which has a donut shape with no central portion in plan view.
  6. 　ドライアイ又は角膜感染症に対応する、請求項１～５のいずれか１項に記載の眼科用マイクロニードルアレイ。
          The ophthalmic microneedle array according to any one of claims 1 to 5, which is for dry eye or corneal infection.
PCT/JP2022/041161 2021-11-05 2022-11-04 Microneedle array for ophthalmology WO2023080200A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08259604A (en) * 1983-10-11 1996-10-08 Fidia Spa Pharmacologically active fraction of hyaluronic acid,its production,and its medicine composition
JP2009201956A (en) * 2008-02-28 2009-09-10 Kosumedei Seiyaku Kk Microneedle array
JP2016502130A (en) * 2012-10-30 2016-01-21 キム， ソン ホＫＩＭ， ＳｅｏｎＨｏ Therapeutic contact lenses
JP2019513459A (en) * 2016-04-05 2019-05-30 エルジー ハウスホールド アンド ヘルスケア リミテッド Micro-noodle construction for efficient skin perforation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08259604A (en) * 1983-10-11 1996-10-08 Fidia Spa Pharmacologically active fraction of hyaluronic acid,its production,and its medicine composition
JP2009201956A (en) * 2008-02-28 2009-09-10 Kosumedei Seiyaku Kk Microneedle array
JP2016502130A (en) * 2012-10-30 2016-01-21 キム， ソン ホＫＩＭ， ＳｅｏｎＨｏ Therapeutic contact lenses
JP2019513459A (en) * 2016-04-05 2019-05-30 エルジー ハウスホールド アンド ヘルスケア リミテッド Micro-noodle construction for efficient skin perforation

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