Ophthalmic drug delivery device and method for fabricating the same

Patent metadata

Field	Value
Publication number	US-11103446-B2
Application number	US-201916731966-A
Country	US
Kind code	B2
Filing date	Dec 31, 2019
Priority date	Dec 31, 2019
Publication date	Aug 31, 2021
Grant date	Aug 31, 2021

Abstract

An ophthalmic drug delivery device and a method for fabricating the same are provided. The ophthalmic drug delivery device includes a shield element and a drug release element. The shield element has a light transmittance more than or equal to 80%. The drug release element is an annular body so that the drug release element surrounds the shield element. The drug release element is neutral and includes a cross-linked neutral collagen, a first hydrophilic biodegradable polymer and a drug. The shield element is acidic and includes a cross-linked acidic collagen and a second hydrophilic biodegradable polymer.

First claim

What is claimed is:

1. An ophthalmic drug delivery device, comprising:
a shield element, which is adapted to be positioned onto a visual region of a cornea, wherein the shield element has a light transmittance more than or equal to 80%; and
a drug release element, which is adapted to be positioned onto a region surrounding the cornea, wherein the region is outside the cornea, wherein the drug release element is an annular body, and the drug release element surrounds the shield element,
wherein the drug release element is neutral and comprises a cross-linked neutral collagen, a first hydrophilic biodegradable polymer and a drug, and wherein the shield element is acidic and comprises a cross-linked acidic collagen and a second hydrophilic biodegradable polymer.

2. The ophthalmic drug delivery device as claimed in claim 1 , wherein the weight ratio of the cross-linked neutral collagen to the first hydrophilic biodegradable polymer is ranging from 1:3 to 9:1.

3. The ophthalmic drug delivery device as claimed in claim 1 , wherein the weight ratio of the cross-linked neutral collagen to the second hydrophilic biodegradable polymer is ranging from 1:3 to 9:1.

4. The ophthalmic drug delivery device as claimed in claim 1 , wherein the amount of the drug is ranging from 0.01 wt % to 20 wt %, based on the total weight of the neutral collagen and the first hydrophilic biodegradable polymer.

5. The ophthalmic drug delivery device as claimed in claim 1 , wherein the ophthalmic drug release element is a product obtained by subjecting a first layer to a cross-linking process in the presence of a cross-linking agent, wherein the first layer is a product obtained by solidifying a neutral aqueous solution, and the neutral aqueous solution includes water, a first collagen, the first hydrophilic biodegradable polymer, and the drug.

6. The ophthalmic drug delivery device as claimed in claim 5 , wherein the neutral aqueous solution has a pH value of 6.5 to 7.5.

7. The ophthalmic drug delivery device as claimed in claim 1 , wherein the shield element is a product obtained by subjecting a second layer to a cross-linking process in the presence of a cross-linking agent, wherein the second layer is formed by drying an acidic aqueous solution, and the acidic aqueous solution includes water, a second collagen and the second hydrophilic biodegradable polymer.

8. The ophthalmic drug delivery device as claimed in claim 7 , wherein the acidic aqueous solution has a pH value of 2 to 5.

9. The ophthalmic drug delivery device as claimed in claim 1 , wherein the first hydrophilic biodegradable polymer and the second hydrophilic biodegradable polymer are independently selected from a group consisting of polyvinyl alcohol (PVA), polyethylene glycol/polyethylene oxide (PEG/PEO) and polyvinylpyrrolidone (PVP).

10. The ophthalmic drug delivery device as claimed in claim 1 , wherein the ophthalmic drug release element comprises a metal oxide doped in the drug release element, wherein the metal oxide is zinc oxide, iron oxide, or a combination thereof.

11. The ophthalmic drug delivery device as claimed in claim 5 , wherein the cross-linking agent is formaldehyde, glutaraldehyde, glyoxal, malonaldehyde, succinaldehyde, phthalaldehyde, dialdehyde starch, polyacrolein, polymethacrolein, or a combination thereof.

12. The ophthalmic drug delivery device as claimed in claim 1 , wherein the drug is apraclonidine, timolol maleate, betaxolol, levobunolol, atenolol, metipranolol, timolol hemihydrate, pilocarpine, carbachol, travoprost, bimatoprost, tafluprost, latanoprost, netarsudil, polyvinyl alcohol hypromellose, glycerine, pegaptanib, propylene glycol, tetryzoline, cyclosporine, doxycicine, vitamin D3, quinethazone, hydroxypropyl cellulose, polyvinylpyrrolidone, chlorobutanol, bepotastine besilate, lifitegrast, omega-3 fatty acids, flaxseed oil, carboxymethyl cellulose, hyaluronic acid, hydroxypropyl-guar, macrolide, tetracycline, tacrolimus, acetylcysteine, vitamin A, carbomer, triglycerides, fluorometholone, loteprednol, fluocinolone, dexamethasone, difluprednate, triamcinolone, prednisolone, rimexolone, gentamicin, tobramycin, besifloxacin, ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, ofloxacin, azithromycin, erythromycin, bacitracin, natamycin, neomycin, polymyxin B, trimethoprim, sulfacetamide, bromfenac, ketorolac, nepafenac, flurbiprofen, or diclofenac.

13. A method for fabricating an ophthalmic drug delivery device, which is the ophthalmic drug delivery device as claimed in claim 1 , comprising:
providing a first aqueous solution, wherein the first aqueous solution comprises water, a first collagen, a first hydrophilic biodegradable polymer, a first acidic substance, and a drug, and the first aqueous solution has a pH value of 2 to 5;
pouring the first aqueous solution into a first mold, and then the first mold is cooled down to a temperature of 1° C. to 10° C.;
pouring a second aqueous solution into the first mold, wherein the second aqueous solution comprises an alkali metal hydroxide and water, and the second aqueous solution has a pH value of 9 to 11;
standing the first mold to transfer the first aqueous solution into a first layer, wherein the first layer has a central region and an annular region, and the annular region surrounds the central region and is coaxial with the central region;
removing the central region from the first layer so that the remaining first layer has a through hole after removing the second aqueous solution from the first mold;
filling the through hole with the third aqueous solution, wherein the third aqueous solution comprises water, a second collagen, a second acidic substance, and a second hydrophilic biodegradable polymer, wherein the third aqueous solution has a pH value of 2 to 5;
subjecting the third aqueous solution to a drying process to obtain a second layer, wherein the first layer and the second layer constitute a composite film;
disposing the composite film in a second mold to obtain a molded film after molding; and
subjecting the composite film to a cross-linking process by a cross-linking agent to obtain the ophthalmic drug delivery device.

14. The method as claimed in claim 13 , wherein a step for preparing the first aqueous solution comprises:
dissolving the first collagen, the first hydrophilic biodegradable polymer and the drug in water to obtain a first mixture, wherein the weight ratio of the first collagen to the first hydrophilic biodegradable polymer is ranging from 1:3 to 9:1, and the amount of the drug is ranging from 0.01 wt % to 20 wt %, based on the total weight of the first collagen and the first hydrophilic biodegradable polymer; and
adding the first acidic substance to the first mixture until the obtained first aqueous solution has a pH value of 2 to 5, wherein the first aqueous solution has a solid content ranging from 0.5 wt % to 10 wt %.

15. The method as claimed in claim 13 , wherein the second aqueous solution further comprises a metal oxide.

16. The method as claimed in claim 15 , wherein a step for preparing the second aqueous solution comprises:
providing an alkali metal hydroxide aqueous solution, wherein the alkali metal hydroxide aqueous solution has a concentration ranging from 0.1 M to 2 M;
dissolving the metal oxide in the alkali metal hydroxide aqueous solution to obtain the second aqueous solution, wherein the amount of the metal oxide is ranging from 0.5 wt % to 2 wt %, based on the weight of the second aqueous solution, wherein the second aqueous solution has a pH value of 9 to 11.

17. The method as claimed in claim 13 ,

Assignees

• Ind Tech Res Inst

Inventors

• Liou Yu-Bing
• Hsu Hsin-Yi
• Shen Ying-Wen
• Teng Yun-Chung
• Wang Yuchi
• Shen Hsin-Hsin

Classifications

• A61K47/32

  Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers {, poly(meth)acrylates, or polyvinyl pyrrolidone} · CPC title

• A61K9/0048 Primary

  Eye, e.g. artificial tears · CPC title

• A61K9/0051 Primary

  Ocular inserts or implants · CPC title

• A61K31/5575

  having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha · CPC title

• A61K47/42

  Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein (oligopeptides having up to five amino acids {A61K47/183}; polyamino acids A61K47/34) · CPC title