pharmaceutics Review Novel Drug Delivery Systems Fighting Glaucoma: Formulation Obstacles and Solutions Ognjenka Rahi´c 1,* , Amina Tucak 1 , Naida Omerovi´c 2 , Merima Sirbubalo 1 , Lamija Hindija 1 , Jasmina Hadžiabdi´c 1 and Edina Vrani´c 1,* 1 Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Sarajevo, Zmaja od Bosne 8, 71000 Sarajevo, Bosnia and Herzegovina; [email protected] (A.T.); [email protected] (M.S.); [email protected] (L.H.); [email protected] (J.H.) 2 Department of Clinical Pharmacy, Faculty of Pharmacy, University of Sarajevo, Zmaja od Bosne 8, 71000 Sarajevo, Bosnia and Herzegovina; [email protected] * Correspondence: [email protected] (O.R.); [email protected] (E.V.) Abstract: Glaucoma is considered to be one of the biggest health problems in the world. It is the main cause of preventable blindness due to its asymptomatic nature in the early stages on the one hand and patients’ non-adherence on the other. There are several approaches in glaucoma treatment, whereby this has to be individually designed for each patient. The first-line treatment is medication therapy. However, taking into account numerous disadvantages of conventional ophthalmic dosage forms, intensive work has been carried out on the development of novel drug delivery systems for glaucoma. This review aims to provide an overview of formulation solutions and strategies in the development of in situ gel systems, nanosystems, ocular inserts, contact lenses, collagen corneal shields, ocular implants, microneedles, and iontophoretic devices. The results of studies confirming the effectiveness of the aforementioned drug delivery systems were also briefly presented. Keywords: glaucoma; novel ocular drug delivery systems; formulation Citation: Rahi´c,O.; Tucak, A.; Omerovi´c,N.; Sirbubalo, M.; Hindija, L.; Hadžiabdi´c,J.; Vrani´c,E. Novel Drug Delivery 1. Introduction Systems Fighting Glaucoma: Glaucoma Formulation Obstacles and Glaucoma is a chronic disease that affected approximately 60.5 million people world- Solutions. Pharmaceutics 2021, 13, 28. wide in 2010 [1]. This number is expected to rise approximately to 76.0 million by 2020 and https://dx.doi.org/10.3390/ 112.0 million by 2040 [2,3]. Glaucoma is the second most common eye disease after pharmaceutics13010028 cataracts [4]. It is known as the “silent thief of vision” because its symptoms are usually Received: 13 November 2020 only felt in the late stages of the disease when the visual field and vision are seriously Accepted: 22 December 2020 impaired [5]. Yet, it is the most common cause of vision loss internationally [2,6,7]. Published: 26 December 2020 Glaucoma is a neurodegenerative disorder of the optic nerve. It is a form of optic neuropathy, characterized by damage of the optic disc, the place where the optic nerve and Publisher’s Note: MDPI stays neu- blood vessels enter the retina (Figure1a) [ 8]. The retina is a thin layer on the rear eye part tral with regard to jurisdictional claims that collects light and it consists of neuronal and non-neuronal parts. One of five types of in published maps and institutional retinal neurons are ganglion cells [9]. These are unique retinal cells, which can produce affiliations. action potentials that are transmitted to the brain through the optic nerve, thus enabling vision. Of all retinal cells, only ganglion cells, in particular their axons, are affected by glaucomatous changes. This sensitivity is because: (1) a part of ganglion cell axons, between the retina and the lamina cribrosa, is not myelinated, and (2) ganglion cell axons Copyright: © 2020 by the authors. Li- are very long and susceptible to numerous disorders [10]. Although glaucomatous havoc censee MDPI, Basel, Switzerland. This affects the retinal ganglion cell stroma, photoreceptors, the lateral geniculate body, and the article is an open access article distributed visual cortex, the main reason for vision loss is the impairment of retinal ganglion cell under the terms and conditions of the lamina cribrosa Creative Commons Attribution (CC BY) axons within the of the optic nerve head [11]. license (https://creativecommons.org/ licenses/by/4.0/). Pharmaceutics 2021, 13, 28. https://dx.doi.org/10.3390/pharmaceutics13010028 https://www.mdpi.com/journal/pharmaceutics Pharmaceutics 2021,, 1313,, 28x FOR PEER REVIEW 2 of 58 The change change of of the the optic optic disc, disc, known known as “cupping as “cupping of the of optic the optic disc” disc” is its isvertical its vertical elon‐ gationelongation and andis accompanied is accompanied by the by loss the lossof the of neuroretinal the neuroretinal rim, rim, which which can can be visualized be visualized on theon thesuperior superior and and inferior inferior poles poles of the of the optic optic disc disc (Figure (Figure 1c)1 [3,12].c) [3,12 ]. Figure 1. ((aa)) Morphology Morphology of of the the eye; eye; ( (bb)) Optical Optical nerve nerve head head in in a a healthy healthy eye; eye; (c ()c )The The optical optical nerve nerve head in glaucoma is characterized by vertical elongationelongation ofof thethe cupcup andand lossloss ofof thethe neuroretinal neuroretinal rim. rim. Most frequently, glaucomatous changes of the optic disc occur as a result of elevated intraocularMost frequently, pressure (IOP)glaucomatous [3,13,14]. changes However, of the elevated optic disc IOP occur on its as own a result is not of elevated proof of intraocularglaucoma’s pressure existence. (IOP) On the [3,13,14]. other hand, However, it has elevated been proven IOP thaton its lowering own is IOPnot inproof ocular of glaucoma’shypertension existence. delays or On even the stops other changes hand, it in has optic been nerve proven axons that [13 lowering,14]. IOP in ocular hypertensionOpen-angle delays glaucoma or even is stops a threat changes called in “silent optic nerve thief” axons [5]. Another [13,14]. type of glaucoma, denotedOpen as‐angle “angle-closure glaucoma glaucoma”,is a threat called is characterized “silent thief” by [5]. an Another increase type in IOP of asglaucoma, a conse- denotedquence of as a “angle physical‐closure obstruction glaucoma”, of the is trabecular characterized meshwork by an byincrease the iris in [ 15IOP]. Apartas a conse from‐ quencethese, there of a physical is congenital obstruction or childhood of the trabecular glaucoma, meshwork which is a by result the ofiris inadequate [15]. Apart devel- from these,opment there of the is congenital aqueous outflow or childhood system. glaucoma, It may which be a surprise, is a result but of inadequate there is also develop normal‐ mentor low of tension the aqueous glaucoma, outflow with system. normal It may IOP be levels, a surprise, but it but is believedthere is also that normal vascular or andlow tensiongenetic glaucoma, factors influence with normal its occurrence IOP levels, [10 but,16 it]. is There believed is also that drug-induced vascular and genetic glaucoma, fac‐ torssecondary influence glaucoma its occurrence that is induced [10,16]. by There topical is andalso systemic drug‐induced medications, glaucoma, especially secondary corti- glaucomacosteroids that [10,16 is]. induced There are by types topical of glaucomaand systemic associated medications, with other especially systemic corticosteroids eye diseases [10,16].and conditions, There are such types as of pigmentary glaucoma associated glaucoma, with and other the list systemic continues eye [16 diseases]. and con‐ ditions, such as pigmentary glaucoma, and the list continues [16]. 2. Glaucoma Treatment 2.2.1. Glaucoma IOP Lowering Treatment Agents 2.1. IOPThe Lowering treatment Agents of glaucoma depends on several factors that are related to a patient or his environment. The outcome of these factors’ action varies from person to person, The treatment of glaucoma depends on several factors that are related to a patient or and the treatment must be individualized for each patient. It is very important to his environment. The outcome of these factors’ action varies from person to person, and notice that there are many cases of vision loss in patients with glaucoma because of non- theadherence. treatment Therefore, must be individualized there are several for approaches each patient. to glaucomaIt is very important treatment to such notice as laser that theretherapy, are incisional many cases surgery, of vision or medication loss in patients use. The with first-line glaucoma treatment because is mostlyof non‐ medicationadherence. Therefore,therapy. The there failure are several of this therapyapproaches implies to glaucoma the application treatment of other such methods as laser [therapy,17]. in‐ cisionalThe surgery, IOP is currently or medication the only use. known The first modifiable‐line treatment risk factor is mostly for glaucoma. medication It hastherapy. been Theproven failure that of reducing this therapy IOP implies can slow the down application the deterioration of other methods of the visual [17]. field, and thus preventThe theIOP development is currently the and only progression known modifiable of glaucoma risk factor [18–20 for]. Havingglaucoma. this It has in mind, been proven that reducing IOP can slow down the deterioration of the visual field, and thus Pharmaceutics 2021, 13, 28 3 of 58 the therapy aims to decrease IOP to an individual target level at which further progression of glaucomatous optic nerve damage is unlikely. The target IOP level for a particular eye is estimated based on the pre-treated