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Erschienen in: International Ophthalmology 3/2023

02.09.2022 | Review

Interpenetrating polymeric network (IPNs) in ophthalmic drug delivery: Breaking the barriers

verfasst von: Sachin Rathod

Erschienen in: International Ophthalmology | Ausgabe 3/2023

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Abstract

To maintain the therapeutic drug concentration for a prolonged period of time in aqueous and vitreous humor is primary challenge for ophthalmic drug delivery. Majority of the locally administered drug into the eye is lost as to natural reflexes like blinking and lacrimation resulting in the short span of drug residence. Consequently, less than 5% of the applied drug penetrate through the cornea and reaches the intraocular tissues. The major targets for optimal ophthalmic drug delivery are increasing drug residence time in cul-de-sac of the eye, prolonging intraocular exposure, modulating drug release from the delivery system, and minimizing pre-corneal drug loss. Development of in situ gel, contact lens, intraocular lens, inserts, artificial cornea, scaffold, etc., for ophthalmic drug delivery are few approaches to achieve these major targeted objectives for delivering the drug optimally. Interpenetrating polymeric network (IPN) or smart hydrogels or stimuli sensitive hydrogels are the class of polymers that can help to achieve the targets in ophthalmic drug delivery due to their versatility, biocompatibility and biodegradability. These novel ‘‘smart” materials can alter their molecular configuration and result in volume phase transition in response to environmental stimuli, such as temperature, pH, ionic strength, electric and magnetic field. Hydrogel and tissue interaction, mechanical/tensile properties, pore size and surface chemistry of IPNs can also be modulated for tuning the drug release kinetics. Stimuli sensitive IPNs has been widely exploited to prepare in situ gelling formulations for ophthalmic drug delivery. Low refractive index hydrogel biomaterials with high water content, soft tissue-like physical properties, wettability, oxygen, glucose permeability and desired biocompatibility makes IPNs versatile candidate for contact lenses and corneal implants. This review article focuses on the exploration of these smart polymeric networks/IPNs for therapeutically improved ophthalmic drug delivery that has unfastened novel arenas in ophthalmic drug delivery.

Graphical abstract

Literatur
1.
Zurück zum Zitat Li Q et al (2021) Safety assessment of polymeric micelles as an ophthalmic drug delivery system for intravitreal administration of dasatinib. Int J Pharm 596:120226PubMedCrossRef Li Q et al (2021) Safety assessment of polymeric micelles as an ophthalmic drug delivery system for intravitreal administration of dasatinib. Int J Pharm 596:120226PubMedCrossRef
2.
Zurück zum Zitat Noreen S et al (2020) Terminalia arjuna gum/alginate in situ gel system with prolonged retention time for ophthalmic drug delivery. Int J Biol Macromol 152:1056–1067PubMedCrossRef Noreen S et al (2020) Terminalia arjuna gum/alginate in situ gel system with prolonged retention time for ophthalmic drug delivery. Int J Biol Macromol 152:1056–1067PubMedCrossRef
3.
Zurück zum Zitat Chen M-S et al (2008) Blood-ocular barriers. Tzu Chi Med J 20(1):25–34CrossRef Chen M-S et al (2008) Blood-ocular barriers. Tzu Chi Med J 20(1):25–34CrossRef
4.
Zurück zum Zitat Ferreira JA et al (2014) Numerical simulation of aqueous humor flow: From healthy to pathologic situations. Appl Math Comput 226:777–792 Ferreira JA et al (2014) Numerical simulation of aqueous humor flow: From healthy to pathologic situations. Appl Math Comput 226:777–792
5.
Zurück zum Zitat Baig MS et al (2020) Development and evaluation of cationic nanostructured lipid carriers for ophthalmic drug delivery of besifloxacin. J Drug Deliv Sci Technol 55:101496CrossRef Baig MS et al (2020) Development and evaluation of cationic nanostructured lipid carriers for ophthalmic drug delivery of besifloxacin. J Drug Deliv Sci Technol 55:101496CrossRef
6.
Zurück zum Zitat Chan KC et al (2008) GD-DTPA enhanced MRI of ocular transport in a rat model of chronic glaucoma. Exp Eye Res 87(4):334–341PubMedCrossRef Chan KC et al (2008) GD-DTPA enhanced MRI of ocular transport in a rat model of chronic glaucoma. Exp Eye Res 87(4):334–341PubMedCrossRef
7.
Zurück zum Zitat Umapathy A et al (2018) Functional characterisation of glutathione export from the rat lens. Exp Eye Res 166:151–159PubMedCrossRef Umapathy A et al (2018) Functional characterisation of glutathione export from the rat lens. Exp Eye Res 166:151–159PubMedCrossRef
8.
Zurück zum Zitat Cholkar K et al (2013) Eye: anatomy, physiology and barriers to drug delivery. In: Ocular transporters and receptors. Elsevier, pp 1–36 Cholkar K et al (2013) Eye: anatomy, physiology and barriers to drug delivery. In: Ocular transporters and receptors. Elsevier, pp 1–36
9.
10.
Zurück zum Zitat Chu Z et al (2022) Optical coherence tomography measurements of the retinal pigment epithelium to bruch membrane thickness around geographic atrophy correlate with growth. Am J Ophthalmol 236:249–260PubMedCrossRef Chu Z et al (2022) Optical coherence tomography measurements of the retinal pigment epithelium to bruch membrane thickness around geographic atrophy correlate with growth. Am J Ophthalmol 236:249–260PubMedCrossRef
11.
Zurück zum Zitat Khodamoradi M et al (2021) An electro-conductive hybrid scaffold as an artificial Bruch’s membrane. Mater Sci Eng C Mater Biol Appl 126:112180PubMedCrossRef Khodamoradi M et al (2021) An electro-conductive hybrid scaffold as an artificial Bruch’s membrane. Mater Sci Eng C Mater Biol Appl 126:112180PubMedCrossRef
12.
Zurück zum Zitat Lin MC, Svitova TF (2021) Effects of model tear proteins and topical ophthalmic formulations on evaporation inhibition and biophysical property of model tear lipid nanofilm in vitro. JCIS Open 4:100028CrossRef Lin MC, Svitova TF (2021) Effects of model tear proteins and topical ophthalmic formulations on evaporation inhibition and biophysical property of model tear lipid nanofilm in vitro. JCIS Open 4:100028CrossRef
13.
Zurück zum Zitat Račić A et al (2019) Development of polysaccharide-based mucoadhesive ophthalmic lubricating vehicles: the effect of different polymers on physicochemical properties and functionality. J Drug Deliv Sci Technol 49:50–57CrossRef Račić A et al (2019) Development of polysaccharide-based mucoadhesive ophthalmic lubricating vehicles: the effect of different polymers on physicochemical properties and functionality. J Drug Deliv Sci Technol 49:50–57CrossRef
14.
Zurück zum Zitat Silvani L et al (2020) Arabinogalactan and hyaluronic acid in ophthalmic solution: experimental effect on xanthine oxidoreductase complex as key player in ocular inflammation (in vitro study). Exp Eye Res 196:108058PubMedCrossRef Silvani L et al (2020) Arabinogalactan and hyaluronic acid in ophthalmic solution: experimental effect on xanthine oxidoreductase complex as key player in ocular inflammation (in vitro study). Exp Eye Res 196:108058PubMedCrossRef
15.
Zurück zum Zitat Wu X-G et al (2011) The biological characteristics and pharmacodynamics of a mycophenolate mofetil nanosuspension ophthalmic delivery system in rabbits. J Pharm Sci 100(4):1350–1361PubMedCrossRef Wu X-G et al (2011) The biological characteristics and pharmacodynamics of a mycophenolate mofetil nanosuspension ophthalmic delivery system in rabbits. J Pharm Sci 100(4):1350–1361PubMedCrossRef
16.
Zurück zum Zitat Al-Ghabeish M et al (2015) Influence of drug loading and type of ointment base on the in vitro performance of acyclovir ophthalmic ointment. Int J Pharm 495(2):783–791PubMedCrossRef Al-Ghabeish M et al (2015) Influence of drug loading and type of ointment base on the in vitro performance of acyclovir ophthalmic ointment. Int J Pharm 495(2):783–791PubMedCrossRef
17.
Zurück zum Zitat Dave V et al (2020) Folic acid modified gold nanoparticle for targeted delivery of Sorafenib tosylate towards the treatment of diabetic retinopathy. Colloids Surf B Biointerfaces 194:111151PubMedCrossRef Dave V et al (2020) Folic acid modified gold nanoparticle for targeted delivery of Sorafenib tosylate towards the treatment of diabetic retinopathy. Colloids Surf B Biointerfaces 194:111151PubMedCrossRef
19.
Zurück zum Zitat Moustafa MA et al (2018) Gel in core carbosomes as novel ophthalmic vehicles with enhanced corneal permeation and residence. Int J Pharm 546(1–2):166–175PubMedCrossRef Moustafa MA et al (2018) Gel in core carbosomes as novel ophthalmic vehicles with enhanced corneal permeation and residence. Int J Pharm 546(1–2):166–175PubMedCrossRef
20.
Zurück zum Zitat Garg V et al (2022) Topical tacrolimus progylcosomes nano-vesicles as a potential therapy for experimental dry eye syndrome. J Pharm Sci 111(2):479–484PubMedCrossRef Garg V et al (2022) Topical tacrolimus progylcosomes nano-vesicles as a potential therapy for experimental dry eye syndrome. J Pharm Sci 111(2):479–484PubMedCrossRef
21.
Zurück zum Zitat Elmotasem H, Awad GEA (2020) A stepwise optimization strategy to formulate in situ gelling formulations comprising fluconazole-hydroxypropyl-beta-cyclodextrin complex loaded niosomal vesicles and Eudragit nanoparticles for enhanced antifungal activity and prolonged ocular delivery. Asian J Pharm Sci 15(5):617–636PubMedCrossRef Elmotasem H, Awad GEA (2020) A stepwise optimization strategy to formulate in situ gelling formulations comprising fluconazole-hydroxypropyl-beta-cyclodextrin complex loaded niosomal vesicles and Eudragit nanoparticles for enhanced antifungal activity and prolonged ocular delivery. Asian J Pharm Sci 15(5):617–636PubMedCrossRef
22.
Zurück zum Zitat Hassan N et al (2021) Doe guided chitosan based nano-ophthalmic preparation against fungal keratitis. Mater Today Proc 41:19–29CrossRef Hassan N et al (2021) Doe guided chitosan based nano-ophthalmic preparation against fungal keratitis. Mater Today Proc 41:19–29CrossRef
23.
Zurück zum Zitat Wu B et al (2022) Flurbiprofen loaded thermosensitive nanohydrogel for ophthalmic anti-inflammatory therapy. J Drug Deliv Sci Technol 70:103253CrossRef Wu B et al (2022) Flurbiprofen loaded thermosensitive nanohydrogel for ophthalmic anti-inflammatory therapy. J Drug Deliv Sci Technol 70:103253CrossRef
24.
Zurück zum Zitat Gudnason K, Sigurdsson S, Jonsdottir FJMB (2021) Multi-region finite element modelling of drug release from hydrogel based ophthalmic lenses. Math Biosci 331:108497PubMedCrossRef Gudnason K, Sigurdsson S, Jonsdottir FJMB (2021) Multi-region finite element modelling of drug release from hydrogel based ophthalmic lenses. Math Biosci 331:108497PubMedCrossRef
25.
Zurück zum Zitat Zhang J et al (2022) Antifouling and antibacterial zwitterionic hydrogels as soft contact lens against ocular bacterial infections. Eur Polym J 167:111037CrossRef Zhang J et al (2022) Antifouling and antibacterial zwitterionic hydrogels as soft contact lens against ocular bacterial infections. Eur Polym J 167:111037CrossRef
26.
Zurück zum Zitat Xue Y et al (2022) Extended ocular delivery of latanoprost from niosome-laden contact lenses: In vitro characterization and in vivo studies. J Drug Deliv Sci Technol 68:103044CrossRef Xue Y et al (2022) Extended ocular delivery of latanoprost from niosome-laden contact lenses: In vitro characterization and in vivo studies. J Drug Deliv Sci Technol 68:103044CrossRef
27.
Zurück zum Zitat Kim YJ, Min JJI (2021) Property modulation of the alginate-based hydrogel via semi-interpenetrating polymer network (semi-IPN) with poly (vinyl alcohol). Int J Biol Macromol 193:1068–1077PubMedCrossRef Kim YJ, Min JJI (2021) Property modulation of the alginate-based hydrogel via semi-interpenetrating polymer network (semi-IPN) with poly (vinyl alcohol). Int J Biol Macromol 193:1068–1077PubMedCrossRef
28.
Zurück zum Zitat Liu L, Sheardown HJB (2005) Glucose permeable poly (dimethyl siloxane) poly (N-isopropyl acrylamide) interpenetrating networks as ophthalmic biomaterials. Biomaterials 26(3):233–244PubMedCrossRef Liu L, Sheardown HJB (2005) Glucose permeable poly (dimethyl siloxane) poly (N-isopropyl acrylamide) interpenetrating networks as ophthalmic biomaterials. Biomaterials 26(3):233–244PubMedCrossRef
29.
Zurück zum Zitat Yang M-C, Tran-Nguyen PLJC, Biointerfaces SB (2021) Evaluation of silicone hydrogel contact lenses based on poly (dimethylsiloxane) dialkanol and hydrophilic polymers. Colloids Surf B 206:111957CrossRef Yang M-C, Tran-Nguyen PLJC, Biointerfaces SB (2021) Evaluation of silicone hydrogel contact lenses based on poly (dimethylsiloxane) dialkanol and hydrophilic polymers. Colloids Surf B 206:111957CrossRef
30.
Zurück zum Zitat Chen F et al (2020) Simultaneous interpenetrating polymer network of collagen and hyaluronic acid as an in situ-forming corneal defect filler. Chem Mater 32(12):5208–5216PubMedPubMedCentralCrossRef Chen F et al (2020) Simultaneous interpenetrating polymer network of collagen and hyaluronic acid as an in situ-forming corneal defect filler. Chem Mater 32(12):5208–5216PubMedPubMedCentralCrossRef
31.
Zurück zum Zitat Feng L et al (2021) Thermo-gelling dendronized chitosans as biomimetic scaffolds for corneal tissue engineering. ACS Appl Mater Interfaces 13(41):49369–49379PubMedCrossRef Feng L et al (2021) Thermo-gelling dendronized chitosans as biomimetic scaffolds for corneal tissue engineering. ACS Appl Mater Interfaces 13(41):49369–49379PubMedCrossRef
32.
Zurück zum Zitat Li J, Stachowski M, Zhang Z (2015) Application of responsive polymers in implantable medical devices and biosensors. Switch Respon Surf Mater Biomed Appl 15:259–298 Li J, Stachowski M, Zhang Z (2015) Application of responsive polymers in implantable medical devices and biosensors. Switch Respon Surf Mater Biomed Appl 15:259–298
33.
Zurück zum Zitat Shivashankar M, Mandal BK (2012) A review on interpenetrating polymer network. Int J Phram Phram Sci 4(5):1–7 Shivashankar M, Mandal BK (2012) A review on interpenetrating polymer network. Int J Phram Phram Sci 4(5):1–7
34.
Zurück zum Zitat Lohani A et al (2014) Interpenetrating polymer networks as innovative drug delivery systems. J Drug Deliv 2014:528CrossRef Lohani A et al (2014) Interpenetrating polymer networks as innovative drug delivery systems. J Drug Deliv 2014:528CrossRef
35.
Zurück zum Zitat Pal K, Paulson AT, Rousseau D (2009) Biopolymers in controlled-release delivery systems. In: Modern biopolymer science. Elsevier, pp 519–557 Pal K, Paulson AT, Rousseau D (2009) Biopolymers in controlled-release delivery systems. In: Modern biopolymer science. Elsevier, pp 519–557
36.
Zurück zum Zitat Wu B et al (2021) Cell penetrating peptide TAT-functionalized liposomes for efficient ophthalmic delivery of flurbiprofen: penetration and its underlying mechanism, retention, anti-inflammation and biocompatibility. Int J Pharm 598:120405PubMedCrossRef Wu B et al (2021) Cell penetrating peptide TAT-functionalized liposomes for efficient ophthalmic delivery of flurbiprofen: penetration and its underlying mechanism, retention, anti-inflammation and biocompatibility. Int J Pharm 598:120405PubMedCrossRef
37.
Zurück zum Zitat Sun X et al (2022) Mucoadhesive phenylboronic acid conjugated chitosan oligosaccharide-vitamin E copolymer for topical ocular delivery of voriconazole: synthesis, in vitro/vivo evaluation, and mechanism. Acta Biomater 138:193–207PubMedCrossRef Sun X et al (2022) Mucoadhesive phenylboronic acid conjugated chitosan oligosaccharide-vitamin E copolymer for topical ocular delivery of voriconazole: synthesis, in vitro/vivo evaluation, and mechanism. Acta Biomater 138:193–207PubMedCrossRef
38.
Zurück zum Zitat Sweeney C et al (2022) Impact of mucoadhesive agent inclusion on the intraocular pressure lowering profile of Δ9-tetrahydrocannabinol-valine-hemisuccinate loaded nanoemulsions in New Zealand white rabbits. Int J Pharm 616:121564PubMedCrossRef Sweeney C et al (2022) Impact of mucoadhesive agent inclusion on the intraocular pressure lowering profile of Δ9-tetrahydrocannabinol-valine-hemisuccinate loaded nanoemulsions in New Zealand white rabbits. Int J Pharm 616:121564PubMedCrossRef
39.
Zurück zum Zitat Chetoni P et al (1998) Silicone rubber/hydrogel composite ophthalmic inserts: preparation and preliminary in vitro/in vivo evaluation. Eur J Pharm Biopharm 46(1):125–132PubMedCrossRef Chetoni P et al (1998) Silicone rubber/hydrogel composite ophthalmic inserts: preparation and preliminary in vitro/in vivo evaluation. Eur J Pharm Biopharm 46(1):125–132PubMedCrossRef
40.
Zurück zum Zitat Yanez F et al (2008) Macromolecule release and smoothness of semi-interpenetrating PVP–pHEMA networks for comfortable soft contact lenses. Eur J Pharm Biopharm 69(3):1094–1103PubMedCrossRef Yanez F et al (2008) Macromolecule release and smoothness of semi-interpenetrating PVP–pHEMA networks for comfortable soft contact lenses. Eur J Pharm Biopharm 69(3):1094–1103PubMedCrossRef
42.
Zurück zum Zitat Hasnain MS, Nayak AK (2018) Chitosan as responsive polymer for drug delivery applications. Stimuli responsive polymeric nanocarriers for drug delivery applications, vol 1. Elsevier, pp 581–605CrossRef Hasnain MS, Nayak AK (2018) Chitosan as responsive polymer for drug delivery applications. Stimuli responsive polymeric nanocarriers for drug delivery applications, vol 1. Elsevier, pp 581–605CrossRef
43.
Zurück zum Zitat Gupta P, Vermani K, Garg S (2002) Hydrogels: from controlled release to pH-responsive drug delivery. Drug Discov Today 7(10):569–579PubMedCrossRef Gupta P, Vermani K, Garg S (2002) Hydrogels: from controlled release to pH-responsive drug delivery. Drug Discov Today 7(10):569–579PubMedCrossRef
44.
Zurück zum Zitat Wu W, Wang D-S (2010) A fast pH-responsive IPN hydrogel: Synthesis and controlled drug delivery. React Funct Polym 70(9):684–691CrossRef Wu W, Wang D-S (2010) A fast pH-responsive IPN hydrogel: Synthesis and controlled drug delivery. React Funct Polym 70(9):684–691CrossRef
45.
Zurück zum Zitat Wang W, Wang A (2010) Synthesis and swelling properties of pH-sensitive semi-IPN superabsorbent hydrogels based on sodium alginate-g-poly (sodium acrylate) and polyvinylpyrrolidone. Carbohyd Polym 80(4):1028–1036CrossRef Wang W, Wang A (2010) Synthesis and swelling properties of pH-sensitive semi-IPN superabsorbent hydrogels based on sodium alginate-g-poly (sodium acrylate) and polyvinylpyrrolidone. Carbohyd Polym 80(4):1028–1036CrossRef
46.
Zurück zum Zitat Lim LS et al (2017) Synthesis and swelling behavior of pH-sensitive semi-IPN superabsorbent hydrogels based on poly (acrylic acid) reinforced with cellulose nanocrystals. Nanomaterials 7(11):399PubMedPubMedCentralCrossRef Lim LS et al (2017) Synthesis and swelling behavior of pH-sensitive semi-IPN superabsorbent hydrogels based on poly (acrylic acid) reinforced with cellulose nanocrystals. Nanomaterials 7(11):399PubMedPubMedCentralCrossRef
47.
Zurück zum Zitat Mohamadnia Z et al (2007) pH-sensitive IPN hydrogel beads of carrageenan-alginate for controlled drug delivery. J Bioact Compat Polym 22(3):342–356CrossRef Mohamadnia Z et al (2007) pH-sensitive IPN hydrogel beads of carrageenan-alginate for controlled drug delivery. J Bioact Compat Polym 22(3):342–356CrossRef
48.
Zurück zum Zitat Kim SJ et al (2003) Electrical/pH-sensitive swelling behavior of polyelectrolyte hydrogels prepared with hyaluronic acid–poly (vinyl alcohol) interpenetrating polymer networks. React Funct Polym 55(3):291–298CrossRef Kim SJ et al (2003) Electrical/pH-sensitive swelling behavior of polyelectrolyte hydrogels prepared with hyaluronic acid–poly (vinyl alcohol) interpenetrating polymer networks. React Funct Polym 55(3):291–298CrossRef
49.
Zurück zum Zitat Kozhunova EY, Vyshivannaya OV, Nasimova IR (2019) “Smart” IPN microgels with different network structures: self-crosslinked vs conventionally crosslinked. Polymer 176:127–134CrossRef Kozhunova EY, Vyshivannaya OV, Nasimova IR (2019) “Smart” IPN microgels with different network structures: self-crosslinked vs conventionally crosslinked. Polymer 176:127–134CrossRef
50.
Zurück zum Zitat Morimoto N, Yamamoto MJL (2021) Design of an LCST–UCST-like thermoresponsive zwitterionic copolymer. Langmuir 37(11):3261–3269PubMedCrossRef Morimoto N, Yamamoto MJL (2021) Design of an LCST–UCST-like thermoresponsive zwitterionic copolymer. Langmuir 37(11):3261–3269PubMedCrossRef
51.
Zurück zum Zitat Fu X, Xing C, Sun JJB (2020) Tunable LCST/UCST-type polypeptoids and their structure-property relationship. Biomacromol 21(12):4980–4988CrossRef Fu X, Xing C, Sun JJB (2020) Tunable LCST/UCST-type polypeptoids and their structure-property relationship. Biomacromol 21(12):4980–4988CrossRef
52.
Zurück zum Zitat Wałach W et al (2021) Alternative to poly (2-isopropyl-2-oxazoline) with a reduced ability to crystallize and physiological LCST. Int J Mol Sci 22(4):2221PubMedPubMedCentralCrossRef Wałach W et al (2021) Alternative to poly (2-isopropyl-2-oxazoline) with a reduced ability to crystallize and physiological LCST. Int J Mol Sci 22(4):2221PubMedPubMedCentralCrossRef
53.
Zurück zum Zitat d’Oliveira H et al (2017) Test-area surface tension calculation of the graphene-methane interface: fluctuations and commensurability. J Chem Phys 146(21):214112PubMedPubMedCentralCrossRef d’Oliveira H et al (2017) Test-area surface tension calculation of the graphene-methane interface: fluctuations and commensurability. J Chem Phys 146(21):214112PubMedPubMedCentralCrossRef
54.
Zurück zum Zitat Liu R et al (2022) Preparation of LCST regulable DES-lignin-g-PNVCL thermo-responsive polymer by ARGET-ATRP. Int J Biol Macromol 194:358–365PubMedCrossRef Liu R et al (2022) Preparation of LCST regulable DES-lignin-g-PNVCL thermo-responsive polymer by ARGET-ATRP. Int J Biol Macromol 194:358–365PubMedCrossRef
55.
Zurück zum Zitat Xie B et al (2015) An injectable thermosensitive polymeric hydrogel for sustained release of Avastin® to treat posterior segment disease. Int J Pharm 490(1–2):375–383PubMedCrossRef Xie B et al (2015) An injectable thermosensitive polymeric hydrogel for sustained release of Avastin® to treat posterior segment disease. Int J Pharm 490(1–2):375–383PubMedCrossRef
56.
Zurück zum Zitat Cao Y et al (2007) Poly (N-isopropylacrylamide)–chitosan as thermosensitive in situ gel-forming system for ocular drug delivery. J Control Release 120(3):186–194PubMedCrossRef Cao Y et al (2007) Poly (N-isopropylacrylamide)–chitosan as thermosensitive in situ gel-forming system for ocular drug delivery. J Control Release 120(3):186–194PubMedCrossRef
57.
Zurück zum Zitat Jung SW et al (2018) Multivalent ion-based in situ gelling polysaccharide hydrogel as an injectable bone graft. Carbohyd Polym 180:216–225CrossRef Jung SW et al (2018) Multivalent ion-based in situ gelling polysaccharide hydrogel as an injectable bone graft. Carbohyd Polym 180:216–225CrossRef
58.
Zurück zum Zitat Tsuru T, Sugimura K, Nishio YJ (2017) Superparamagnetic IPN gels of carrageenan/PHEMA excelling in shape retention. Carbohyd Polym 178:1–7CrossRef Tsuru T, Sugimura K, Nishio YJ (2017) Superparamagnetic IPN gels of carrageenan/PHEMA excelling in shape retention. Carbohyd Polym 178:1–7CrossRef
59.
Zurück zum Zitat Wang W-B et al (2013) One-step in situ fabrication of a granular semi-IPN hydrogel based on chitosan and gelatin for fast and efficient adsorption of Cu2+ ion. Colloids Surf B Biointerfaces 106:51–59PubMedCrossRef Wang W-B et al (2013) One-step in situ fabrication of a granular semi-IPN hydrogel based on chitosan and gelatin for fast and efficient adsorption of Cu2+ ion. Colloids Surf B Biointerfaces 106:51–59PubMedCrossRef
60.
Zurück zum Zitat Jana S et al (2015) Metal ion-induced alginate–locust bean gum IPN microspheres for sustained oral delivery of aceclofenac. Int J Biol Macromol 72:47–53PubMedCrossRef Jana S et al (2015) Metal ion-induced alginate–locust bean gum IPN microspheres for sustained oral delivery of aceclofenac. Int J Biol Macromol 72:47–53PubMedCrossRef
61.
Zurück zum Zitat Zeng L et al (2020) Anion exchange membrane based on interpenetrating polymer network with ultrahigh ion conductivity and excellent stability for alkaline fuel cell. Research 2020:5248CrossRef Zeng L et al (2020) Anion exchange membrane based on interpenetrating polymer network with ultrahigh ion conductivity and excellent stability for alkaline fuel cell. Research 2020:5248CrossRef
62.
Zurück zum Zitat Singha NR et al (2017) Synthesis of guar gum-g-(acrylic acid-co-acrylamide-co-3-acrylamido propanoic acid) IPN via in situ attachment of acrylamido propanoic acid for analyzing superadsorption mechanism of Pb (II)/Cd (II)/Cu (II)/MB/MV. Polym Chem 8(44):6750–6777CrossRef Singha NR et al (2017) Synthesis of guar gum-g-(acrylic acid-co-acrylamide-co-3-acrylamido propanoic acid) IPN via in situ attachment of acrylamido propanoic acid for analyzing superadsorption mechanism of Pb (II)/Cd (II)/Cu (II)/MB/MV. Polym Chem 8(44):6750–6777CrossRef
63.
Zurück zum Zitat Loghin DFA et al (2017) Preparation and characterization of oxidized starch/poly (N, N-dimethylaminoethyl methacrylate) semi-IPN cryogels and in vitro controlled release evaluation of indomethacin. Int J Biol Macromol 96:589–599CrossRef Loghin DFA et al (2017) Preparation and characterization of oxidized starch/poly (N, N-dimethylaminoethyl methacrylate) semi-IPN cryogels and in vitro controlled release evaluation of indomethacin. Int J Biol Macromol 96:589–599CrossRef
64.
Zurück zum Zitat Hu X et al (2015) Mechanically tough biomacromolecular IPN hydrogel fibers by enzymatic and ionic crosslinking. Int J Biol Macromol 72:403–409PubMedCrossRef Hu X et al (2015) Mechanically tough biomacromolecular IPN hydrogel fibers by enzymatic and ionic crosslinking. Int J Biol Macromol 72:403–409PubMedCrossRef
65.
Zurück zum Zitat Paulsson M, Hägerström H, Edsman K (1999) Rheological studies of the gelation of deacetylated gellan gum (Gelrite®) in physiological conditions. Eur J Pharm Sci 9(1):99–105PubMedCrossRef Paulsson M, Hägerström H, Edsman K (1999) Rheological studies of the gelation of deacetylated gellan gum (Gelrite®) in physiological conditions. Eur J Pharm Sci 9(1):99–105PubMedCrossRef
66.
Zurück zum Zitat Shelley H et al (2018) In situ gel formulation for enhanced ocular delivery of nepafenac. J Pharm Sci 107(12):3089–3097PubMedCrossRef Shelley H et al (2018) In situ gel formulation for enhanced ocular delivery of nepafenac. J Pharm Sci 107(12):3089–3097PubMedCrossRef
67.
Zurück zum Zitat Krtalić I et al (2018) D-optimal design in the development of rheologically improved in situ forming ophthalmic gel. J Pharm Sci 107(6):1562–1571PubMedCrossRef Krtalić I et al (2018) D-optimal design in the development of rheologically improved in situ forming ophthalmic gel. J Pharm Sci 107(6):1562–1571PubMedCrossRef
68.
Zurück zum Zitat Fang G et al (2021) Hydrogels-based ophthalmic drug delivery systems for treatment of ocular diseases. Mater Sci Eng C 127:112212CrossRef Fang G et al (2021) Hydrogels-based ophthalmic drug delivery systems for treatment of ocular diseases. Mater Sci Eng C 127:112212CrossRef
69.
Zurück zum Zitat Elbahwy IA et al (2018) Mucoadhesive self-emulsifying delivery systems for ocular administration of econazole. Int J Pharm 541(1–2):72–80PubMedCrossRef Elbahwy IA et al (2018) Mucoadhesive self-emulsifying delivery systems for ocular administration of econazole. Int J Pharm 541(1–2):72–80PubMedCrossRef
70.
Zurück zum Zitat Del Amo EM, Urtti A (2008) Current and future ophthalmic drug delivery systems: a shift to the posterior segment. Drug Discov Today 13(3–4):135–143PubMed Del Amo EM, Urtti A (2008) Current and future ophthalmic drug delivery systems: a shift to the posterior segment. Drug Discov Today 13(3–4):135–143PubMed
71.
Zurück zum Zitat Rafie F et al (2010) In vivo evaluation of novel nanoparticles containing dexamethasone for ocular drug delivery on rabbit eye. Curr Eye Res 35(12):1081–1089PubMedCrossRef Rafie F et al (2010) In vivo evaluation of novel nanoparticles containing dexamethasone for ocular drug delivery on rabbit eye. Curr Eye Res 35(12):1081–1089PubMedCrossRef
73.
Zurück zum Zitat Awwad S et al (2019) In situ antibody-loaded hydrogel for intravitreal delivery. Eur J Pharm Sci 137:104993PubMedCrossRef Awwad S et al (2019) In situ antibody-loaded hydrogel for intravitreal delivery. Eur J Pharm Sci 137:104993PubMedCrossRef
74.
Zurück zum Zitat Al-Kinani AA et al (2018) Ophthalmic gels: past, present and future. Adv Drug Deliv Rev 126:113–126PubMedCrossRef Al-Kinani AA et al (2018) Ophthalmic gels: past, present and future. Adv Drug Deliv Rev 126:113–126PubMedCrossRef
75.
Zurück zum Zitat del Amo EM et al (2015) Intravitreal clearance and volume of distribution of compounds in rabbits: in silico prediction and pharmacokinetic simulations for drug development. Eur J Pharm Biopharm 95:215–226PubMedCrossRef del Amo EM et al (2015) Intravitreal clearance and volume of distribution of compounds in rabbits: in silico prediction and pharmacokinetic simulations for drug development. Eur J Pharm Biopharm 95:215–226PubMedCrossRef
76.
Zurück zum Zitat Hou Y et al (2019) Ultra-small micelles based on polyoxyl 15 hydroxystearate for ocular delivery of myricetin: optimization, in vitro, and in vivo evaluation. Drug Deliv 26(1):158–167PubMedPubMedCentralCrossRef Hou Y et al (2019) Ultra-small micelles based on polyoxyl 15 hydroxystearate for ocular delivery of myricetin: optimization, in vitro, and in vivo evaluation. Drug Deliv 26(1):158–167PubMedPubMedCentralCrossRef
77.
Zurück zum Zitat Myung D et al (2009) Bioactive interpenetrating polymer network hydrogels that support corneal epithelial wound healing. J Biomed Mater Res A 90(1):70–81PubMedPubMedCentralCrossRef Myung D et al (2009) Bioactive interpenetrating polymer network hydrogels that support corneal epithelial wound healing. J Biomed Mater Res A 90(1):70–81PubMedPubMedCentralCrossRef
78.
Zurück zum Zitat Rodriguez-Tenreiro C et al (2007) Cyclodextrin/carbopol micro-scale interpenetrating networks (ms-IPNs) for drug delivery. J Control Release 123(1):56–66PubMedCrossRef Rodriguez-Tenreiro C et al (2007) Cyclodextrin/carbopol micro-scale interpenetrating networks (ms-IPNs) for drug delivery. J Control Release 123(1):56–66PubMedCrossRef
79.
Zurück zum Zitat Agrawal AK, Das M, Jain S (2012) In situ gel systems as ‘smart’ carriers for sustained ocular drug delivery. Expert Opin Drug Deliv 9(4):383–402PubMedCrossRef Agrawal AK, Das M, Jain S (2012) In situ gel systems as ‘smart’ carriers for sustained ocular drug delivery. Expert Opin Drug Deliv 9(4):383–402PubMedCrossRef
80.
Zurück zum Zitat Lin H-R, Sung K, Vong W-J (2004) In situ gelling of alginate/pluronic solutions for ophthalmic delivery of pilocarpine. Biomacromol 5(6):2358–2365CrossRef Lin H-R, Sung K, Vong W-J (2004) In situ gelling of alginate/pluronic solutions for ophthalmic delivery of pilocarpine. Biomacromol 5(6):2358–2365CrossRef
81.
Zurück zum Zitat Egbu R et al (2018) Antibody loaded collapsible hyaluronic acid hydrogels for intraocular delivery. Eur J Pharm Biopharm Egbu R et al (2018) Antibody loaded collapsible hyaluronic acid hydrogels for intraocular delivery. Eur J Pharm Biopharm
82.
Zurück zum Zitat Jiang L et al (2019) Scaffold hopping-driven optimization of 4-(quinazolin-4-yl)-3, 4-dihydroquinoxalin-2 (1 H)-ones as novel tubulin inhibitors. ACS Med Chem Lett 11(1):83–89PubMedPubMedCentralCrossRef Jiang L et al (2019) Scaffold hopping-driven optimization of 4-(quinazolin-4-yl)-3, 4-dihydroquinoxalin-2 (1 H)-ones as novel tubulin inhibitors. ACS Med Chem Lett 11(1):83–89PubMedPubMedCentralCrossRef
83.
Zurück zum Zitat Bhardwaj V, Harit G, Kumar S (2012) Interpenetrating polymer network (IPN): novel approach in drug delivery. Int J Drug Dev Res 4(3):41–54 Bhardwaj V, Harit G, Kumar S (2012) Interpenetrating polymer network (IPN): novel approach in drug delivery. Int J Drug Dev Res 4(3):41–54
85.
Zurück zum Zitat Elkhouly H, Mamdouh W, El-Korashy DIJ (2021) Electrospun nano-fibrous bilayer scaffold prepared from polycaprolactone/gelatin and bioactive glass for bone tissue engineering. J Mater Sci Mater Med 32(9):1–15CrossRef Elkhouly H, Mamdouh W, El-Korashy DIJ (2021) Electrospun nano-fibrous bilayer scaffold prepared from polycaprolactone/gelatin and bioactive glass for bone tissue engineering. J Mater Sci Mater Med 32(9):1–15CrossRef
87.
Zurück zum Zitat Sharma R et al (2019) Clinical-grade stem cell–derived retinal pigment epithelium patch rescues retinal degeneration in rodents and pigs. Sci Transl Med 11(475):eaat5580PubMedPubMedCentralCrossRef Sharma R et al (2019) Clinical-grade stem cell–derived retinal pigment epithelium patch rescues retinal degeneration in rodents and pigs. Sci Transl Med 11(475):eaat5580PubMedPubMedCentralCrossRef
88.
Zurück zum Zitat Weiss MD et al (2006) Sleep hygiene and melatonin treatment for children and adolescents with ADHD and initial insomnia. J Am Acad Child Adolesc Psychiatry 45(5):512–519PubMedCrossRef Weiss MD et al (2006) Sleep hygiene and melatonin treatment for children and adolescents with ADHD and initial insomnia. J Am Acad Child Adolesc Psychiatry 45(5):512–519PubMedCrossRef
89.
Zurück zum Zitat Albon J (2003) Corneal transplantation and the artificial cornea. J Mech Med Biol 3(01):95–106CrossRef Albon J (2003) Corneal transplantation and the artificial cornea. J Mech Med Biol 3(01):95–106CrossRef
90.
91.
Zurück zum Zitat Polisetti N et al (2021) A decellularized human corneal scaffold for anterior corneal surface reconstruction. Sci Rep 11(1):1–15CrossRef Polisetti N et al (2021) A decellularized human corneal scaffold for anterior corneal surface reconstruction. Sci Rep 11(1):1–15CrossRef
92.
Zurück zum Zitat Soleimannejad M et al (2018) Fibrin gel as a scaffold for photoreceptor cells differentiation from conjunctiva mesenchymal stem cells in retina tissue engineering. Artif Cells Nanomed Biotechnol 46(4):805–814PubMedCrossRef Soleimannejad M et al (2018) Fibrin gel as a scaffold for photoreceptor cells differentiation from conjunctiva mesenchymal stem cells in retina tissue engineering. Artif Cells Nanomed Biotechnol 46(4):805–814PubMedCrossRef
93.
Zurück zum Zitat Hotaling NA et al (2016) Nanofiber scaffold-based tissue-engineered retinal pigment epithelium to treat degenerative eye diseases. J Ocul Pharmacol Ther 32(5):272–285PubMedPubMedCentralCrossRef Hotaling NA et al (2016) Nanofiber scaffold-based tissue-engineered retinal pigment epithelium to treat degenerative eye diseases. J Ocul Pharmacol Ther 32(5):272–285PubMedPubMedCentralCrossRef
94.
Zurück zum Zitat Brunette I et al (2017) Alternatives to eye bank native tissue for corneal stromal replacement. Prog Retin Eye Res 59:97–130PubMedCrossRef Brunette I et al (2017) Alternatives to eye bank native tissue for corneal stromal replacement. Prog Retin Eye Res 59:97–130PubMedCrossRef
95.
Zurück zum Zitat Chung C-W et al (2011) Interpenetrating polymer network (IPN) scaffolds of sodium hyaluronate and sodium alginate for chondrocyte culture. Colloids Surf B Biointerfaces 88(2):711–716PubMedCrossRef Chung C-W et al (2011) Interpenetrating polymer network (IPN) scaffolds of sodium hyaluronate and sodium alginate for chondrocyte culture. Colloids Surf B Biointerfaces 88(2):711–716PubMedCrossRef
96.
Zurück zum Zitat Griffith M et al. Biomimetic corneal substitutes for transplantation: from benchtop to bedside Griffith M et al. Biomimetic corneal substitutes for transplantation: from benchtop to bedside
97.
Zurück zum Zitat Liu W et al (2009) Collagen–phosphorylcholine interpenetrating network hydrogels as corneal substitutes. Biomaterials 30(8):1551–1559PubMedCrossRef Liu W et al (2009) Collagen–phosphorylcholine interpenetrating network hydrogels as corneal substitutes. Biomaterials 30(8):1551–1559PubMedCrossRef
98.
Zurück zum Zitat Hartmann L et al (2011) Toward the development of an artificial cornea: improved stability of interpenetrating polymer networks. J Biomed Mater Res B Appl Biomater 98(1):8–17PubMedCrossRef Hartmann L et al (2011) Toward the development of an artificial cornea: improved stability of interpenetrating polymer networks. J Biomed Mater Res B Appl Biomater 98(1):8–17PubMedCrossRef
99.
Zurück zum Zitat Deng C et al (2010) Collagen and glycopolymer based hydrogel for potential corneal application. Acta Biomater 6(1):187–194PubMedCrossRef Deng C et al (2010) Collagen and glycopolymer based hydrogel for potential corneal application. Acta Biomater 6(1):187–194PubMedCrossRef
100.
Zurück zum Zitat Chirila TV et al (1998) Hydrophilic sponges based on 2-hydroxyethyl methacrylate. VI. Effect of phase sequence inversion on the characteristics of IPN between sponges and homogeneous gels. J Mater Sci Mater Med 40(1–2):97–104 Chirila TV et al (1998) Hydrophilic sponges based on 2-hydroxyethyl methacrylate. VI. Effect of phase sequence inversion on the characteristics of IPN between sponges and homogeneous gels. J Mater Sci Mater Med 40(1–2):97–104
101.
Zurück zum Zitat Hicks CR et al (1996) Keratoprosthesis: preliminary results of an artificial corneal button as a full-thickness implant in the rabbit model. Aust N Z J Ophthalmol 24(3):297–303PubMedCrossRef Hicks CR et al (1996) Keratoprosthesis: preliminary results of an artificial corneal button as a full-thickness implant in the rabbit model. Aust N Z J Ophthalmol 24(3):297–303PubMedCrossRef
102.
Zurück zum Zitat Myung D et al (2008) Glucose-permeable interpenetrating polymer network hydrogels for corneal implant applications: a pilot study. Curr Eye Res 33(1):29–43PubMedCrossRef Myung D et al (2008) Glucose-permeable interpenetrating polymer network hydrogels for corneal implant applications: a pilot study. Curr Eye Res 33(1):29–43PubMedCrossRef
103.
Zurück zum Zitat Zhang Q et al (2012) High refractive index inorganic–organic interpenetrating polymer network (IPN) hydrogel nanocomposite toward artificial cornea implants. ACS Macro Lett 1(7):876–881PubMedCrossRef Zhang Q et al (2012) High refractive index inorganic–organic interpenetrating polymer network (IPN) hydrogel nanocomposite toward artificial cornea implants. ACS Macro Lett 1(7):876–881PubMedCrossRef
104.
Zurück zum Zitat Parke-Houben R et al (2015) Interpenetrating polymer network hydrogel scaffolds for artificial cornea periphery. J Mater Sci Mater Med 26(2):1–12CrossRef Parke-Houben R et al (2015) Interpenetrating polymer network hydrogel scaffolds for artificial cornea periphery. J Mater Sci Mater Med 26(2):1–12CrossRef
105.
Zurück zum Zitat Liu J, Wang XJAP (2022) Ofloxacin-loaded niosome-laden contact lens: improved properties of biomaterial for ocular drug delivery. AAPS PharmSciTech 23(1):1–9 Liu J, Wang XJAP (2022) Ofloxacin-loaded niosome-laden contact lens: improved properties of biomaterial for ocular drug delivery. AAPS PharmSciTech 23(1):1–9
106.
Zurück zum Zitat Ding X et al (2020) Soft contact lens with embedded microtubes for sustained and self-adaptive drug delivery for glaucoma treatment. ACS Appl Mater Interfaces 12(41):45789–45795PubMedCrossRef Ding X et al (2020) Soft contact lens with embedded microtubes for sustained and self-adaptive drug delivery for glaucoma treatment. ACS Appl Mater Interfaces 12(41):45789–45795PubMedCrossRef
107.
Zurück zum Zitat Wei Y et al (2020) Design of circular-ring film embedded contact lens for improved compatibility and sustained ocular drug delivery. Eur J Pharm Biopharm 157:28–37PubMedCrossRef Wei Y et al (2020) Design of circular-ring film embedded contact lens for improved compatibility and sustained ocular drug delivery. Eur J Pharm Biopharm 157:28–37PubMedCrossRef
108.
Zurück zum Zitat Zhu Q et al (2018) Inner layer-embedded contact lenses for ion-triggered controlled drug delivery. Mater Sci Eng C Mater Biol Appl 93:36–48PubMedCrossRef Zhu Q et al (2018) Inner layer-embedded contact lenses for ion-triggered controlled drug delivery. Mater Sci Eng C Mater Biol Appl 93:36–48PubMedCrossRef
109.
Zurück zum Zitat Zhu Q et al (2018) Inner layer-embedded contact lenses for pH-triggered controlled ocular drug delivery. Eur J Pharm Biopharm 128:220–229PubMedCrossRef Zhu Q et al (2018) Inner layer-embedded contact lenses for pH-triggered controlled ocular drug delivery. Eur J Pharm Biopharm 128:220–229PubMedCrossRef
110.
111.
Zurück zum Zitat Xu J et al (2014) Simultaneous interpenetrating silicone hydrogel based on radical/addition polymerization for extended release of ocular therapeutics. J Biomater Sci Polym Ed 25(2):121–135PubMedCrossRef Xu J et al (2014) Simultaneous interpenetrating silicone hydrogel based on radical/addition polymerization for extended release of ocular therapeutics. J Biomater Sci Polym Ed 25(2):121–135PubMedCrossRef
112.
Zurück zum Zitat Karlgard C et al (2003) In vitro uptake and release studies of ocular pharmaceutical agents by silicon-containing and p-HEMA hydrogel contact lens materials. Int J Pharm 257(1–2):141–151PubMedCrossRef Karlgard C et al (2003) In vitro uptake and release studies of ocular pharmaceutical agents by silicon-containing and p-HEMA hydrogel contact lens materials. Int J Pharm 257(1–2):141–151PubMedCrossRef
113.
Zurück zum Zitat Zheng Y, Zheng SJR, Polymers F (2012) Poly (ethylene oxide)-grafted poly (N-isopropylacrylamide) networks: preparation, characterization and rapid deswelling and reswelling behavior of hydrogels. React Funct Polym 72(3):176–184CrossRef Zheng Y, Zheng SJR, Polymers F (2012) Poly (ethylene oxide)-grafted poly (N-isopropylacrylamide) networks: preparation, characterization and rapid deswelling and reswelling behavior of hydrogels. React Funct Polym 72(3):176–184CrossRef
114.
Zurück zum Zitat Shimizu T et al (2010) Super-hydrophilic silicone hydrogels with interpenetrating poly (2-methacryloyloxyethyl phosphorylcholine) networks. Biomaterials 31(12):3274–3280PubMedCrossRef Shimizu T et al (2010) Super-hydrophilic silicone hydrogels with interpenetrating poly (2-methacryloyloxyethyl phosphorylcholine) networks. Biomaterials 31(12):3274–3280PubMedCrossRef
115.
Zurück zum Zitat McElroy DM et al (2014) The effect of photoinitiator concentration on the physicochemical properties of hydrogel contact lenses. Appl Mech Mater McElroy DM et al (2014) The effect of photoinitiator concentration on the physicochemical properties of hydrogel contact lenses. Appl Mech Mater
Metadaten
Titel
Interpenetrating polymeric network (IPNs) in ophthalmic drug delivery: Breaking the barriers
verfasst von
Sachin Rathod
Publikationsdatum
02.09.2022
Verlag
Springer Netherlands
Erschienen in
International Ophthalmology / Ausgabe 3/2023
Print ISSN: 0165-5701
Elektronische ISSN: 1573-2630
DOI
https://doi.org/10.1007/s10792-022-02482-4

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