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Transcleral drug delivery for posterior segment disease
Abstract
Exciting new treatments are being developed for retinal degenerations and posterior segment eye disease. The successful treatment of these visually devastating diseases will likely require delivering effective doses of pharmacologic agents to the posterior segment, possibly in conjunction with surgical or genetic interventions. Currently, the treatment of diseases affecting the posterior segment is limited by the difficulty in delivering effective doses of drugs to target tissues in the posterior vitreous, retina or choroid. This review summarizes recent laboratory and clinical studies that indicate that transscleral delivery of therapeutic solutes might be an effective means of achieving therapeutic concentrations of these agents in the posterior eye.
... The functional properties and inherent barriers posed by these protective ocular structures represent significant challenges for the systemic drug administration [34,35]. For instance, systemic medications, such as steroidal and nonsteroidal anti-inflammatory drugs and biologic and nonbiologic immunomodulatory agents, can effectively treat uveitic macular edema (UME) but are often recommended for bilateral disease or cases resistant to local therapy due to AEs such as infections and GI disturbances [20,36,37]. Furthermore, nonsteroidal anti-inflammatory drugs and systemic For instance, systemic medications, such as steroidal and nonsteroidal anti-inflammato ry drugs and biologic and nonbiologic immunomodulatory agents, can effectively treat uveitic macular edema (UME) but are often recommended for bilateral disease or cases resistant to local therapy due to AEs such as infections and GI disturbances [20,36,37]. ...
... For instance, systemic medications, such as steroidal and nonsteroidal anti-inflammatory drugs and biologic and nonbiologic immunomodulatory agents, can effectively treat uveitic macular edema (UME) but are often recommended for bilateral disease or cases resistant to local therapy due to AEs such as infections and GI disturbances [20,36,37]. Furthermore, nonsteroidal anti-inflammatory drugs and systemic For instance, systemic medications, such as steroidal and nonsteroidal anti-inflammato ry drugs and biologic and nonbiologic immunomodulatory agents, can effectively treat uveitic macular edema (UME) but are often recommended for bilateral disease or cases resistant to local therapy due to AEs such as infections and GI disturbances [20,36,37]. Furthermore, nonsteroidal anti-inflammatory drugs and systemic immunomodulatory agents may increase the risk of GI disturbances when used alone or combined with steroids [20,36,37]. ...
... Furthermore, nonsteroidal anti-inflammatory drugs and systemic For instance, systemic medications, such as steroidal and nonsteroidal anti-inflammato ry drugs and biologic and nonbiologic immunomodulatory agents, can effectively treat uveitic macular edema (UME) but are often recommended for bilateral disease or cases resistant to local therapy due to AEs such as infections and GI disturbances [20,36,37]. Furthermore, nonsteroidal anti-inflammatory drugs and systemic immunomodulatory agents may increase the risk of GI disturbances when used alone or combined with steroids [20,36,37]. ...
Treating posterior segment and retinal diseases poses challenges due to the complex structures in the eye that act as robust barriers, limiting medication delivery and bioavailability. This necessitates frequent dosing, typically via eye drops or intravitreal injections, to manage diseases, often leading to side effects with long-term use. Suprachoroidal injection is a novel approach for targeted drug delivery to the posterior segment. The suprachoroidal space is the region between the sclera and the choroid and provides a potential route for minimally invasive medication delivery. Through a more targeted delivery to the posterior segment, this method offers advantages over other routes of administration, such as higher drug concentrations, increased bioavailability, and prolonged duration of action. Additionally, this approach minimizes the risk of corticosteroid-related adverse events such as cataracts and intraocular pressure elevation via compartmentalization. This review focuses on preclinical and clinical studies published between 2019 and 2023, highlighting the potential of suprachoroidal injection in treating a variety of posterior segment diseases. However, to fully harness its potential, more research is needed to address current challenges and limitations, such as the need for technological advancements, refinement of injection techniques, and consideration of cost and accessibility factors. Future studies exploring its use in conjunction with biotech products, gene therapies, and cell-based therapies can lead to personalized treatments that can revolutionize the field of ophthalmology.
... In order to treat posterior segment diseases, an effective delivery strategy must be employed due to the inaccessibility of the target tissue. Topically applied medications, such as drops and ointments, suffer from extremely low bioavailability (<5%) [3], which is attributed to the anatomical and physiological mechanisms of drug elimination, including tear fluid turnover, the blinking reflex, and tear drainage. Therefore, large and frequent doses are required to achieve effective concentrations [4]. ...
... This significant difference between MN-Dex and the other dosage forms is attributed to the fact that MNs pierce the tissue surface, partially overcoming the scleral barrier, while Dex suspension permeation was greater than the free MP-Dex, as expected. Dex is able to demonstrate some scleral permeation in all delivery forms, as previous studies have indicated that the relatively porous scleral membrane allows passage of molecules up to 150 kDa [3]. Nevertheless, the well-recognized anatomical and physiological barriers to drug molecules reaching the vitreoretinal region [63] means that conventional topical drug administration achieves a low level of delivery to the inner tissues [64]. ...
... However, this figure is a net amount of Dex released and remaining encapsulated in the deposited particles. However, the major challenge in treating posterior ocular diseases is delivering an effective dose that overcomes the ocular barrier and reaches the target tissue [3]. The data, in this respect, are encouraging, with 19.2% ± 11.9% with MP-Dex found in the VH after 4 h. ...
Microneedles (MNs) have attracted considerable interest as a means of ocular drug delivery, a challenging delivery route due to the limitations imposed by the various biological barriers associated with this organ. In this study, a novel ocular drug delivery system was developed by formulating a dissolvable MN array containing dexamethasone-loaded PLGA microparticles for scleral drug deposition. The microparticles serve as a drug reservoir for controlled transscleral delivery. The MNs displayed sufficient mechanical strength to penetrate the porcine sclera. Dexamethasone (Dex) scleral permeation was significantly higher than in topically instilled dosage forms. The MN system was able to distribute the drug through the ocular globe, with 19.2% of the administered Dex detected in the vitreous humour. Additionally, images of the sectioned sclera confirmed the diffusion of fluorescent-labelled microparticles within the scleral matrix. The system therefore represents a potential approach for minimally invasive Dex delivery to the posterior of the eye, which lends itself to self-administration and hence high patient convenience.
... The sclera is hydrated and has large collagen fibrils arranged haphazardly; therefore, it is opaque and white rather than clear. There is better permeability of substances through the sclera although intraocular delivery might be compromised by the vascular beds in the episcleral [23]. ...
... Invasive trans-scleral routes via the pars planar into the vitreous (intra-vitreal routes) ensure a more efficacious delivery of drugs into the vitreous chamber. These delivery methods have revolutionized management of conditions like diabetic retinopathy where intra-vitreal anti-vascular endothelial growth factors are administered [23]. ...
Optimal vision remains one of the most essential elements of the sensory system continu-
ously threatened by many ocular pathologies. Various pharmacological agents possess the potential
to effectively treat these ophthalmic conditions; however, the use and efficacy of conventional oph-
thalmic formulations is hindered by ocular anatomical barriers. Recent novel designs of ophthalmic
drug delivery systems (DDS) using nanotechnology show promising prospects, and ophthalmic
formulations based on nanotechnology are currently being investigated due to their potential to
bypass these barriers to ensure successful ocular drug delivery. More recently, stimuli-responsive
nano drug carriers have gained more attention based on their great potential to effectively treat and
alleviate many ocular diseases. The attraction is based on their biocompatibility and biodegradabil-
ity, unique secondary conformations, varying functionalities, and, especially, the stimuli-enhanced
therapeutic efficacy and reduced side effects. This review introduces the design and fabrication of
stimuli-responsive nano drug carriers, including those that are responsive to endogenous stimuli,
viz., pH, reduction, reactive oxygen species, adenosine triphosphate, and enzymes or exogenous
stimuli such as light, magnetic field or temperature, which are biologically related or applicable in
clinical settings. Furthermore, the paper discusses the applications and prospects of these stimuli-
responsive nano drug carriers that are capable of overcoming the biological barriers of ocular disease
alleviation and/or treatment for in vivo administration. There remains a great need to accelerate the
development of stimuli-responsive nano drug carriers for clinical transition and applications in the
treatment of ocular diseases and possible extrapolation to other topical applications such as ungual
or otic drug delivery.
... Local administration to the eye is effective in treating the surface of the eye and diseases of the anterior part of the eye such as conjunctivitis, blepharitis, keratitis, and dry eyes; it is of no value for posterior eye diseases. It has been estimated that typically less than 5% of a topically applied drug actually permeates the cornea and reaches intraocular tissues [72]. An overview of the ocular IDDSs is given in Table 3. ...
... Intraocular implants, which are usually classified as non-biodegradable and biodegradable IDDS devices, are transplanted directly into the vitreous body. The installation of the IDDS device is invasive and can cause complications similar to those caused by intravitreal injections [72]. ...
Precise delivery of therapeutics to the target structures is essential for treatment efficiency and safety. Drug administration via conventional routes requires overcoming multiple transport barriers to achieve and maintain the local drug concentration and commonly results in unwanted off-target effects. Patients’ compliance with the treatment schedule remains another challenge. Implantable drug delivery systems (IDDSs) provide a way to solve these problems. IDDSs are bioengineering devices surgically placed inside the patient’s tissues to avoid first-pass metabolism and reduce the systemic toxicity of the drug by eluting the therapeutic payload in the vicinity of the target tissues. IDDSs present an impressive example of successful translation of the research and engineering findings to the patient’s bedside. It is envisaged that the IDDS technologies will grow exponentially in the coming years. However, to pave the way for this progress, it is essential to learn lessons from the past and present of IDDSs clinical applications. The efficiency and safety of the drug-eluting implants depend on the interactions between the device and the hosting tissues. In this review, we address this need and analyze the clinical landscape of the FDA-approved IDDSs applications in the context of the foreign body reaction, a key aspect of implant–tissue integration.
... Water is the main constituent of the extracellular matrix containing few cells and unchanging permeability during aging (Olsen et al. 1998;Olsen et al. 1995;Boubriak et al. 2000). The use of this route of administration could avoid problems and limitations of other delivery approaches in the treatment of viral and systemic diseases (Kamei et al. 1999;Dayle, 2001;Lang, 1995). Since some transscleral delivery systems may be destructive (i.e. ...
... The sclera, continuous with the cornea, arises from the limbus and expands posteriorly throughout the remainder of the globe. Collagen fibers and proteoglycans embedded in an extracellular matrix make up the majority of the sclera (Geroski and Edelhauser, 2001). The permeability of sclera is comparable to that of the corneal stroma. ...
According to the World Health Organization (WHO) report, people go blind every 5 seconds and a child loses its vision ability every minute throughout the world (Gorantla et al., 2020). According to the latest report of the WHO, about 2.2
billion people are suffering from the vision impairment; among these about one billion cases could have been prevented if
properly addressed. Hence, extensive research in the field of ophthalmology is essential to provide efficient therapeutics for various ocular diseases. Despite extensive research in this field, ophthalmic scientists are facing a major challenge of
efficient drug delivery to the eye due to distinct anatomy and physiology of the eye (Rozi and Sabere, 2021). Various traditional drug delivery forms like eye drops, eye ointments, ocular gels, ocular injections, etc., are available
commercially to treat ocular diseases (Baranowski et al., 2014), but these dosage forms suffer from drawbacks of poor contact time of the drug to the ocular surface, high drainage of solution from eye, tear turnover leading to reduced
bioavailability, high ocular adverse effects, and poor patient compliance (Arribada et al., 2022). Despite these issues, 90%
of the drugs are administered in form of eye drops and only 5% of the total administered drug is absorbed due to the
presence of various anatomical and physiological barriers present in the eye (Patel et al., 2013). Due to the drawbacks
associated with traditional dosage forms, drug administration to the posterior portion of the eye using conventional eye
drops is unable to achieve desired therapeutic concentration (Xue et al., 2022). The delivery to the posterior portion of the eye through intravitreal and periocular routes also imposes various drawbacks like painful repeated injections through intravitreal route causing poor patient compliance, in addition to the inherent infectious risk caused by intravitreal injections. However, ease of administration is possible in the periocular route, but this approach might not result in therapeutic drug levels in the target site due to the requirement of crossing several barriers to reach the intended site of action(Fernandez et al., 2020).
Taking into consideration the abovementioned facts, novel approaches that facilitate considerable drug absorption into the eye are constantly being developed. Nanotechnology-based approaches have proven their efficacy to overcome the
drawbacks associated with traditional dosage forms attributing to prolongation of drug action due to controlled release of
the drug, enhanced contact time of the drug to eye surface, improved drug penetrability through various static and dynamic
barriers leading to improved absorption, and reduced adverse effects (Weng et al., 2017; Khiev et al., 2021). Some of these
approaches include liposomes, solid lipid nanoparticles (SLNs), nanoemulsions, dendrimers, hydrogels, and polymeric
micelles (Kumar et al., 2022).
... A wide variety of literature suggests that periocular administration can achieve therapeutic drug concentration in the retina via transscleral route [43,44], because of the nature of loose scleral organisation and an unaltered scleral permeability to a range of compounds with age [45]. Nevertheless, the fate of subconjunctivally injected drugs largely depends on conjunctival, episcleral and lymphatic blood flows with minimum role of choroidal clearance [46], though the effect of choroidal blood flow is still debatable [47]. ...
... A wide variety of literature suggests that periocular administration can achieve therapeutic drug concentration in the retina via transscleral route [43,44], because of the nature of loose scleral organisation and an unaltered scleral permeability to a range of compounds with age [45]. ...
Age-related macular degeneration (AMD) is a major health concern in the ageing human population. Though existing therapeutics have shown some efficacy, low retinal bioavailability of drugs continues to be a hindrance in ocular drug delivery system. Sirolimus (SIR) is one such drug. In this study, we developed chitosan functionalized PLGA nanoparticles (NP), (<300 nm), for effective and sustained SIR delivery to retina via single subconjunctival injection. Confocal laser microscopy demonstrated superiority of NP for delivering the model cargo, Rhodamine-B, to the posterior segment of eye as opposed to plain dye owing to bioadhesive and permeation enhancer property of chitosan coat. Further, we investigated the protective effect of sirolimus loaded chitosan functionalized PLGA nanoparticles (SIR-NP) vs plain sirolimus suspension (SIR) against sodium iodate-induced retinal degeneration model. Results revealed that SIR-NP enhanced the delivery of SIR in retina and significantly attenuated inflammatory and structural changes in comparison to plain SIR. SIR-NP more This preprint research paper has not been peer reviewed. Electronic copy available at: https://ssrn.com/abstract=4270023 P r e p r i n t n o t p e e r r e v i e w e d efficiently prevented outer nuclear layer thinning and photoreceptor degeneration post sodium iodate-induced toxicity. Moreover, SIR-NP upregulated the levels of anti-oxidants, induced autophagy and inhibited apoptosis in the damaged retina over a period of 21 days which was not seen with plain SIR. Also, no toxic effects on blood, liver or kidney were observed with SIR-NP treatment. Thus, SIR-NP could be a potential strategy to target AMD.
... Formal therapy is widely employed, but it has harmful side effects since it frequently fails to identify the eye due to its distinct physical and biological structure and inherent barrier to eye protection [75]. Several attempts have been undertaken to improve drug retention and sclerosis in order to improve the therapeutic impact [76][77][78][79][80][81][82][83][84]. A bioavailability discovery event and a controlled release system are frequently separated into two phases in these attempts. ...
Silk is a wonderful biopolymer that has a long history of medical applications. Surgical cords and medically authorised human analogues made of silk have a long history of use in management. We describe the use of silk in the treatment of eye diseases in this review by looking at the usage of silk fibroin for eye-related drug delivery applications and medication transfer to the eyes. During this ancient art endeavour, a reduced engineering project that employed silk as a platform for medicine delivery or a cell-filled matrix helped reignite interest. With considerable attention, this study explores the present usage of silk in ocular-based drug delivery. This paper also examines emerging developments with the use of silk as a biopolymer for the treatment of eye ailments. As treatment options for glaucoma, diabetic retinopathy, retinitis pigmentosa, and other retinal diseases and degenerations are developed, the trans-scleral route of drug delivery holds great promise for the selective, sustained-release delivery of these novel therapeutic compounds. We should expect a swarm of silk-inspired materials to enter clinical testing and use on the surface as the secrets of silk are unveiled. This article finishes with a discussion on potential silk power, which adds to better ideas and enhanced ocular medicine delivery.
... Periocular implants are usually placed on the surface of the eyeball, which includes the subtenon, subconjunctival, retrobulbar, posterior juxta-scleral, and peribulbar spaces. These implants utilize the trans-scleral route for drug delivery into the vitreous, retina, and choroid [36][37][38][39]. The trans-scleral route has some advantages, including a high hydration level of the sclera, a large surface area, and the high permeability of larger drugs. ...
Ocular drug delivery is one of the most challenging endeavors among the various available drug delivery systems. Despite having suitable drugs for the treatment of ophthalmic disease, we have not yet succeeded in achieving a proper drug delivery approach with the least adverse effects. Nanotechnology offers great opportunities to overwhelm the restrictions of common ocular delivery systems, including low therapeutic effects and adverse effects because of invasive surgery or systemic exposure. The present review is dedicated to highlighting and updating the recent achievements of nano-based technologies for ocular disease diagnosis and treatment. While further effort remains, the progress illustrated here might pave the way to new and very useful ocular nanomedicines.
... 11 Geroski et al concluded that trans-scleral route was beneficial in placement of drug in retina. 12 Weijtens et al reported peribulbar injection of corticosteroids provided higher intravitreal concentrations. 13 Summarizing all these reports effective concentrations of TA in retina can be attained through sub-tenon route. ...
Purpose Aim of this study was to evaluate and compare the effects of combined simultaneous injection of intravitreal triamcinolone acetonide and bevacizumab versus intravitreal bevacizumab and posterior subtenon triamcinolone acetonide in treatment of persistent refractory diabetic macular edema after intravitreal bevacizumab injection failure Methods 40 pseudophakic diabetic patients were enrolled in quasi experimental study conducted at ophthalmology department. All eyes were specifically diagnosed with persistent refractory diabetic macular edema with central retinal thickness of _____on OCT. Patients were divided into two groups. Group A was given simultaneous injection of intravitreal bevacizumab 1.25mg/0.05ml with posterior subtenon triamcinolone 40mg and group B was given intravitreal bevacizumab in conjunction with simultaneous intravitreal triamcinolone 2mg/0.05 ml.Patients were followed upmonthly till three months. Changes in the best corrected visual acuity, intraocular pressure and central retinal thickness by optical coherence tomography were evaluated in both groups. Retreatment was given at 12 weeks interval whenever indicated by OCT. Results Group B showed a more significant decrease in the median CRT at 1month (p =0.0002)but after 3 months both groups showed a reduction in CRT which was not statistically significant between two groups _____. Both groups had significant improvement in BCVA compared to pre-injection baseline visual acuity.Between two groups BCVA changes were not statistically significant at 3 months _____.Five eyes in group B developed IOP beyond 22mmHg, which was treated with anti glaucoma medications within 2 weeks. No eye in group A developed IOP greater than 21mmHg. At 12 weeks, 7 of group A patients and 6 of group B patients developed recurrent macular edema and required repeated injections. Conclusion While treating persistent refractory diabetic macular edema, posterior subtenon triamcinolone is as effective as intravitreal triamcinolone in conjunction with intravitreal bevacizumab in reducing CRT and improving and stabilizing BCVA but in terms of IOP rise posterior subtenon injection is safer as compared to intravitreal injection. Both treatments are cost effective and combined simultaneous injections decrease the number of repeated injections.
... 5 However, these treatment methods are inconvenient for the patient because of their invasive nature, rapid drug elimination followed by repeated administration, and increased post-treatment complications, including retinal detachment, retinal rupture, macular edema, and fibrosis. [5][6][7] Nanocarriers are distinct particulate systems in the nanosize range (10-1000 nm) that have gained attention in recent years to overcome the limitations of the currently available treatments for PSEDs. 8,9 Among the different nanocarriers, nanoemulsion has been explored as a suitable alternative owing to its enhanced bioavailability, improved stability, high retention time, and ease of formulation as eye drops or injection. ...
Purpose:
The aim of this study was to develop a nanogel emulsion as a minimally invasive, safe, and effective treatment alternative for posterior ocular diseases.
Methods:
A gel-in-water (G/W) nanoemulsion was developed by ultrasonication using beeswax as an organogelator. Different physicochemical properties were evaluated along with particle size analysis by dynamic light scattering. In vitro biocompatibility of G/W nanoemulsion using rat hepatocytes and human umbilical vein endothelial cells (HUVECs) and in vivo corneal permeability as eye drops were investigated.
Results:
The nanogel emulsion was monodispersed with a polydispersity index and particle diameter of approximately 0.2 and 200 nm, respectively. The zeta potential value of -8.1 mV suggested enhanced stability and improved retinal permeability of nanoparticles. The prepared nanoemulsion was found to be biocompatible with hepatocytes and HUVECs in vitro. Moreover, in vivo study demonstrated high permeability of G/W nanoemulsion to the retinal layer with no ocular irritation.
Conclusions:
G/W nanoemulsions have the potential for topical drug delivery in the posterior eye segment with maximum therapeutic efficacy.
Translational relevance:
Organogel nanodispersion is a new concept to deliver hydrophobic drugs to the posterior segment of eyes as a novel drug delivery system.
... In general, the conjunctiva is more leaky epithelium than the cornea and its surface area is also nearly 20 times greater than that of the cornea [12,13]. Drug absorption across the bulbar conjunctiva has gained increasing attention recently, since conjunctiva is also fairly permeable to the hydrophilic and large molecules [14]. Therefore, it may serve as a route of absorption for larger bio-organic compounds such as proteins and peptides. ...
Shalakya Tantra, the potent branch of Ayurveda, which deals with the Urdhwajatru vikaras gives prime importance to eye diseases. Kriyakalpas, the specialized ocular treatment modalities, affirms the absolute necessity of unique approach towards netra rogas, thus highlighting the gravitates of eye and eye diseases. The probable mode of action and possible drug route of Kriyakalpas are yet to be explored. In this era of escalating of eye diseases, such an attempt is highly essential to uphold the scientific credibility of Kriyakalpa.
... Topical instillation is the preferred route of drug administration to the eye due to the ease of application, low cost, few systemic effects and good patient compliance (Geroski and Edelhauser, 2001). In fact, 90% of all ophthalmic formulations available on the market are administered through this route and they mainly target the anterior segment eye diseases (Edelhauser et al., 2010). ...
Age-related eye disorders are chronic diseases that affect millions of people worldwide. They cause visual impairment and, in some cases, irreversible blindness. Drug targeting to the retina is still a challenge due to the difficulties with drug distribution, crossing eye barriers, and reaching intraocular tissues in an effective therapeutic concentration. Although intravitreal injections can directly deliver drugs to the posterior segment of the eye, it remains an invasive technique and leads to several side effects. Conventional formulations such as emulsions, suspensions, or ointments have been related to frequent instillation and inability to reach intraocular tissues. New drug delivery systems and medical devices have also been designed. Nevertheless, these treatments are not always effective and sometimes require the presence of a specialist for the administration of the dose. Therefore, treatments for age-related ocular diseases remain as one of the major unmet clinical needs to manage these widespread eye conditions. Nanotechnology may become the adequate tool for developing effective and non-invasive therapies suitable for self-administration. In this review, we discuss emerging therapeutic options based on nanoengineering of cyclodextrin nanocarriers for the treatment of age-related eye disorders, including their pathophysiology, pharmacological options, and feasibility of clinical translation.
... Topical ocular delivery suffers from low ocular BA, typically amounting to <5% of the applied dose. The remaining 95% of the treatment gets eliminated by nasolacrimal drainage and systemic absorption through the conjunctival route [12]. The intravitreal injections are employed to bypass the ocular anatomical and physiological barriers and to deliver the drug directly into the vitreous humor of the posterior compartment. ...
In contrast to the conventional ocular formulations, contact lenses are well known for their diverse applications ranging from bio-sensing, prevention of myopia, cosmetics, and drug delivery. With a tremendous change in the lifestyle, contact lenses for therapeutic purposes have increased several fold. Contact lenses as medicated lenses suffer from several disadvantages, and to overcome the same numerous approaches have been explored. Researches worldwide have come a long way from cyclodextrin-based and vitamin E-based modified contact lenses to bioinspired approaches to enhance the effectiveness of the drug-eluting contact lenses. The bioinspired approach exploits bioinspired polymeric systems to enhance biocompatibility, specific molecule recognition technique by molecular imprinting, or stimuli-responsive system to improve the biocompatibility, drug loading, and drug delivery efficacy of the drug-eluting contact lenses. Moreover, recent innovations in ocular therapeutics such as nanowafers and microneedle contact lenses, and ocular patches have gained tremendous attention in ocular therapeutics. Another potential application of the contact lenses are smart lenses applied in the biosensing and diagnosis of various ocular disorders. The review summarizes and discusses the widespread therapeutic applications of next-generation contact lenses and various fabrication approaches, including its clinical implications, efforts taken by researchers in exploring the novel materials and diverse forms of the lenses, mechanisms of drug release, clinical trials, and their toxicity and safety concerns.
... While traditionally not considered a major drug delivery route, ocular drug penetration may also occur via the conjunctival-scleral pathway which provides a much larger surface area for drug absorption than the cornea [28]. The conjunctival epithelium is relatively leaky and hydrophilic, with intercellular spaces being approximately 230-fold larger than those in the cornea, rendering it permeable even to large biomolecules, such as proteins and peptides [30,31]. The conjunctival epithelium is more permeable to hydrophilic drugs with the permeability of hydrophilic polyethylene glycol mixtures reportedly being the highest in the conjunctiva, followed by the sclera and cornea, respectively [31]. ...
Dry eye disease (DED) is one of the most common ocular surface disorders characterised by a deficiency in quality and/or quantity of the tear fluid. Due to its multifactorial nature involving several inter-related underlying pathologies, it can rapidly accelerate to become a chronic refractory condition. Therefore, several therapeutic interventions are often simultaneously recommended to manage DED efficiently. Typically, artificial tear supplements are the first line of treatment, followed by topical application of medicated eyedrops. However, the bioavailability of topical eyedrops is generally low as the well-developed protective mechanisms of the eye ensure their rapid clearance from the precorneal space, thus limiting ocular penetration of the incorporated drug. Moreover, excipients commonly used in eyedrops can potentially exhibit ocular toxicity and further exacerbate the signs and symptoms of DED. Therefore, formulation development of topical eyedrops is rather challenging. This review highlights the challenges typically faced in eyedrop development, in particular, those intended for the management of DED. Firstly, various artificial tear supplements currently on the market, their mechanisms of action, as well as their application, are discussed. Furthermore, formulation strategies generally used to enhance ocular drug delivery, their advantages and limitations, as well as their application in commercially available DED eyedrops are described.
... Ophthalmic formulations have very less bioavailability as they may not be completely eliciting therapeutic action because of reasons such as rapid tear drainage, blinking of eye, lower residence time of ophthalmic formulation in eye and lower cul-de sac volume [1,2]. Various attempts have been tried to improve the bioavailability by formulating different dosage forms however all these require specialized manufacturing equipment. ...
... Instead, treatments can only reduce progression of the disease. The main challenge of treating these posterior eye diseases lies in the delicacy of the eye tissue and the many ocular barriers that may prevent access to the virtuous humor [5][6][7]. Topical or oral drug delivery fails to quickly and accurately localize the drug to desired areas, and thus, requires administering higher doses, leading to waste, high toxicity, or additional side effects [8,9]. To localize the drug delivery and overcome the scleral barriers in the eye, intravitreal injections are commonly used to deliver drugs to the vitreous humor. ...
Microneedles (MNs) provide a minimally invasive alternative to intravitreal injections and a promising means to sustainable ocular drug delivery. To optimize the sustained drug release profile and to ease the administration of the MN array to the eye, the number of MNs in an MN array and their layout need to be carefully selected. In this study, the drug release kinetics of MN arrays with varying numbers of MNs (8, 12, and 16) is studied over a four-week period. The MN arrays show a much more uniform drug release profile than the single injections. Only the 16-needle MN array fully released all the amount of loaded drug at the end of the 4-week period. Both 8- and 12-needle arrays showed a steady release rate over the 4-week period, which is the longest sustained release duration that has been reported. Zero-order models are created to predict drug release profiles for the three MN arrays. It is estimated that the MN array with 8 needles can deliver the drug for up to 6 weeks. The models can be used to design MN arrays with a given targeted therapeutic index for sustained drug delivery.
... Consequently, administrated drugs experience rapid clearance either through the blood stream or the lymphatic system (Kuno and Fujii, 2011). The conjunctival veins represent a loose boundary (Raviola, 1983), which allows drugs, specially the high molecular weights proteins and peptides, to pass into the blood stream by pinocytosis as well as convective transport through the paracellular pores in the vascular endothelial layer (Geroski andEdelhauser, 2001, Hämäläinen et al., 1997). In addition, some drugs may experience transscleral penetration into the posterior segment during an attempt to enter the conjunctiva. ...
Glaucoma, being asymptomatic for relatively late stage, is recognized as a worldwide cause of irreversible vision loss. The eye is an impervious organ that exhibits natural anatomical and physiological barriers which renders the design of an efficient ocular delivery system a formidable task and challenge scientists to find alternative formulation approaches. In the field of glaucoma treatment, smart delivery systems for targeting have aroused interest in the topical ocular delivery field owing to its potentiality to oppress many treatment challenges associated with many of glaucoma types. The current momentum of nano-pharmaceuticals, in the development of advanced drug delivery systems, hold promises for much improved therapies for glaucoma to reduce its impact on vision loss.
In this review, a brief about glaucoma; its etiology, predisposing factors and different treatment modalities has been reviewed. The diverse ocular drug delivery systems currently available or under investigations have been presented. Additionally, future foreseeing of new drug delivery systems that may represent potential means for more efficient glaucoma management are overviewed. Finally, a gab-analysis for the required investigation to pave the road for commercialization of ocular novel-delivery systems based on the nano-technology are discussed.
... For instance, oral prednisolone is approved for ocular adnexal IgG4-related disease [149]. The intravenous methylprednisolone administration has been recommended in case of severe uveitis when rapid control of the inflammation is required [150]. Keratoplasty (corneal transplant) rejections and chronic bilateral uveitis are better treated with systemic corticosteroids (prednisolone 1 mg/kg/day) than other routes of administration [151]. ...
... For instance, oral prednisolone is approved for ocular adnexal IgG4-related disease [149]. The intravenous methylprednisolone administration has been recommended in case of severe uveitis when rapid control of the inflammation is required [150]. Keratoplasty (corneal transplant) rejections and chronic bilateral uveitis are better treated with systemic corticosteroids (prednisolone 1 mg/kg/day) than other routes of administration [151]. ...
Corticosteroids remain the mainstay of the treatment for various ocular conditions affecting the ocular surface, anterior and posterior segments of the eye due to their anti-inflammatory, anti-oedematous, and anti-neovascularization properties. Prednisolone, prednisolone acetate, dexamethasone, triamcinolone acetonide, fluocinolone acetonide, and loteprednol etabonate are amongst the most widely used ophthalmic corticosteroids. Corticosteroids differ in their activity and potency in the eye due to their inherent pharmacological and pharmaceutical differences. Different routes and regimens are available for ocular administration of corticosteroids. Conventional topical application to the eye is the route of choice when targeting diseases affecting the ocular surface and anterior segment, while periocular, intravitreal, and suprachoroidal injections can be potentially effective for posterior segment diseases. Corticosteroid-induced intraocular pressure elevation and cataract formation remain the most significant local risks following topical as well as systemic corticosteroid administration. Invasive drug administration via intracameral, subconjunctival, and intravitreal injection can enhance ocular bioavailability and minimize dose and dosing frequency of administration, yet may exacerbate ocular side effects of corticosteroids. This review provides a critical appraisal of the oph-thalmic uses of corticosteroid, routes of administration, drug delivery fundamentals and novel ocular implantable steroid delivery systems, factors influencing side effects, and future perspectives for ocular corticosteroid therapy.
... The permeation speed through the sclera is drug size-dependent [17], where the small molecules movement is constant. Macromolecules permeation is slower [3,150,172,180], although up to 70 kDa size molecules can easily penetrate the sclera [17,33,116,[181][182][183]. Once the sclera is crossed, a rapid elimination caused by the choroidal blood flow takes place due to its large choriocapillaris fenestrations. ...
The treatment of the posterior-segment ocular diseases, such as age-related eye diseases (AMD) or diabetic retinopathy (DR), present a challenge for ophthalmologists due to the complex anatomy and physiology of the eye. This specialized organ is composed of various static and dynamic barriers that restrict drug delivery into the target site of action. Despite numerous efforts, effective intraocular drug delivery remains unresolved and, therefore, it is highly desirable to improve the current treatments of diseases affecting the posterior cavity. This review article gives an overview of pharmacokinetic and biopharmaceutics aspects for the most commonly-used ocular administration routes (intravitreal, topical, systemic, and periocular), including information of the absorption, distribution, and elimination, as well as the benefits and limitations of each one. This article also encompasses different conventional and novel drug delivery systems designed and developed to improve drug pharmacokinetics intended for the posterior ocular segment treatment.
... Trans-scleral delivery [85,107] Choroid Choroidal cells of choroid plexus. Intra-vitreal injection [103,99,45] Additionally, drugs with molecular weight less than 500 Da (when administered intravitreally) are drained off from the site of application with a halflife of less than 3 days [11]. ...
Posterior segment of the human eye
remains the focal target of majority of diseases
and disorders risking reduced visual activity or
blindness. Successful targeting of posterior
segment of the eye has been explored using
various biodegradable and non-biodegradable
implants, and direct intervention using
injections, with exemplary effect. But, often
these models are affiliated with serious
complications, namely vitreous haemorrhage,
retinal detachment, cataract, and
endophthalmitis. Novel lipid and polymer
based carrier loaded drug delivery systems
along with the improved drug delivery
techniques such as dendrimers, iontophoresis,
microneedles etc., more compliant with the
frangible structure of human eye, are part of
the revolutionised targeting strategies to the
posterior eye. These profound, sustained drug
delivery strategies can also be successfully
modulated to improve the bioavailability of the
drug in posterior segment of human eye. As a
result, the uncomplicated topical
administration using such novel drug delivery
systems is currently under vigorous
experimental scrutiny
Ocular diseases profoundly impact patients’ vision and overall quality of life globally. However, effective ocular drug delivery presents formidable challenges within clinical pharmacology and biomaterial science, primarily due to the intricate anatomical and physiological barriers unique to the eye. In this comprehensive review, we aim to shed light on the anatomical and physiological features of the eye, emphasizing the natural barriers it presents to drug administration. Our goal is to provide a thorough overview of various characteristics inherent to each nano-based drug delivery system. These encompass nanomicelles, nanoparticles, nanosuspensions, nanoemulsions, microemulsions, nanofibers, dendrimers, liposomes, niosomes, nanowafers, contact lenses, hydrogels, microneedles, and innovative gene therapy approaches employing nano-based ocular delivery techniques. We delve into the biology and methodology of these systems, introducing their clinical applications over the past decade. Furthermore, we discuss the advantages and challenges illuminated by recent studies. While nano-based drug delivery systems for ophthalmic formulations are gaining increasing attention, further research is imperative to address potential safety and toxicity concerns.
In the field of ocular drug delivery, topical delivery remains the most common treatment option for managing anterior segment diseases, whileintraocular injectionsare the current gold standard treatment option for treating posterior segment diseases. Nonetheless, topical eye drops are associated with low bioavailability (<5%), and theintravitreal administration procedure is highly invasive, yielding poor patient acceptability. In both cases, frequent administration is currently required. As a result, there is a clear unmet need for sustained drug delivery to the eye, particularly in a manner that can be localised. Microneedles, which are patches containing an array of micron-scale needles (< 1 mm), have the potential to meet this need. These platforms can enable localised drug delivery to the eye while enhancing penetration of drug molecules through key ocular barriers, thereby improving overall therapeutic outcomes. Moreover, the minimally invasive manner in which microneedles are applied could provide significant advantages over traditional intravitreal injections regarding patient acceptability. Considering the benefitsofthis novel ocular delivery system, this review provides an in-depth overviewofthe microneedle systems for ocular drug delivery, including the types of microneedles used and therapeutics delivered. Notably, we outline and discuss the current challenges associated with the clinical translation of these platforms and offer opinions on factors which should be considered to improve such transition from lab to clinic.
This study employed superficial ultrasound exposure of good ocular safety and a drug-loaded hydrogel of long residence time to enable transscleral delivery. First, we designed an acoustic adaptor to limit the ultrasound exposure depth to 1.59 mm to protect the posterior eye segments. Then, we optimized the alginate/polyacrylamide ratio (3:7) of a dual-crosslinked hydrogel to enable ultrasound-triggered release of model drug (70-kDa fluorescein isothiocyanate-conjugated dextran). Using fluorescence imaging to quantify the drug release, we showed that the developed method resulted in enhanced transscleral delivery in both ex vivo porcine scleras (2.6-fold) and in vivo rabbit scleras (2.2-fold). We also demonstrated that the method increased the drug penetration depth to the whole thickness of the sclera. In particular, the drug release efficiency increased with increasing ultrasound exposure time (1 and 3 min) and intensity (8, 19, 36, and 61 mW/cm2). Using scanning electron microscopy, we revealed that ultrasound exposure resulted in rougher surfaces and microscale rupture of the hydrogel. Moreover, Masson staining of scleral slices showed that the integrity of the top scleral fibers was disturbed by ultrasound exposure, and this disturbance recovered 3 days later. Our work demonstrates that the developed method holds great potential for mediating ocular drug delivery.
The eye has several dynamic and static barriers in place to limit the entry of foreign substances including therapeutics. As such, efficient drug delivery, especially to posterior segment tissues, has been challenging. This chapter describes the anatomical and physiological challenges associated with ocular drug delivery before discussing constraints with regard to formulation parameters. Finally, it gives an overview of advanced drug delivery technologies with a specific focus on recently marketed and late-stage clinical trial products.KeywordsDynamic barriersEyeEyedropsIntracameral implantsIntravitreal implantsMucus-penetrating particlesOcular drug deliveryPort delivery systemPunctum plugStatic barriersSuprachoroidal injection
Innovative and new drug delivery systems (DDSs) have recently been developed to vehicle treatments and drugs to the ocular posterior segment and the retina. New formulations and technological developments, such as nanotechnology, novel matrices, and non-traditional treatment strategies, open new perspectives in this field. The aim of this mini-review is to highlight promising strategies reported in the current literature based on innovative routes to overcome the anatomical and physiological barriers of the vitreoretinal structures. The paper also describes the challenges in finding appropriate and pertinent treatments that provide safety and efficacy and the problems related to patient compliance, acceptability, effectiveness, and sustained drug delivery. The clinical application of these experimental approaches can help pave the way for standardizing the use of DDSs in developing enhanced treatment strategies and personalized therapeutic options for ocular pathologies.
Recently, the eye drug delivery system has received increasing attention. The in situ ophthalmic gel is a semisolid ophthalmic preparation that can be changed in the eyes immediately after the solution is administered, showing unique advantages as a new drug delivery system. Although there are still some problems to be solved, the in situ ophthalmic gel is a promising drug delivery system to treat ocular diseases, due to its properties in improving the bioavailability, prolonging the retention time of the drug, producing a sustained‐release effect, and possessing little toxicity and irritation. In this review, the characteristics, classification, ocular barrier, and route of administration of in situ ophthalmic gel have been introduced in detail for expanding the horizon of nanoscale technologies in the treatment of ocular diseases in the foreseeable future.
Topical eyedrop application is the preferred route for drug delivery to anterior segment tissues; however, the challenge of overcoming the eye's anatomical and physiological barriers while minimising tissue toxicity has restricted developments in this field. Aqueous vehicles have traditionally been used, which typically require several additives and preservatives to achieve physiologically compatible and sterile eyedrops, elevating their toxicity potential. Non-aqueous vehicles have been suggested as efficient alternatives for topical drug delivery as they can address many of the limitations associated with conventional aqueous eyedrops. However, despite their obvious advantages, non-aqueous eyedrops remain poorly researched and few non-aqueous formulations are currently available in the market. This review challenges the conventional hypothesis that aqueous solubility is a prerequisite to ocular drug absorption and establishes a rationale for using non-aqueous vehicles for ocular drug delivery. Recent advances in the field have been detailed and future research prospects have been explored, pointing towards a paradigm shift in eyedrop formulation in the near future.
Purpose:
Topography of the in vivo anterior segment is of relevance in understanding its role in myopia and in the development of ocular surgical procedures. Using 3D magnetic resonance (MR) images of the human eye, regional variations in surface area (SA) and bulbosity of four anterior segment regions were investigated in association with refractive status (Rx), axial length (AL) and total ocular volume (OV).
Methods:
T2-weighted ocular MR images from 43 adults aged 18-40 years (mean ± SD; 28.65 ± 6.20) comprising 20 non-myopes (≥-0.50) 0.57 ± 1.38 and 23 myopes (<-0.50) -6.37 ± 4.23 MSE (D) were collected. 2D representations of each quadrant (superior-temporal [ST], superior-nasal [SN], inferior-temporal [IT] and inferior-nasal [IN]) of the anterior section (3.5-9 mm) were fitted with second-order polynomials. Polynomials were integrated and rotated about the x-axis to generate SA; dividing the SA by 4 provided relative quadrantial SA. The x2 coefficient provides indices of bulbosity. OV was derived from the 3D MRI scans. Rx and AL were measured using cycloplegic autorefraction and the Zeiss IOLMaster, respectively. One- and two-way repeated-measures ANCOVAs tested differences in SA and bulbosity for Rx, gender, ethnicity and age. Pearson's correlation coefficient tested the relationship between MRI-derived metrics and biometry.
Results:
Significant differences in SA were observed between quadrants (p < 0.001) with differences between ST versus IN, IN versus IT and SN versus IT. An interaction effect (p = 0.01) for Rx suggested smaller temporal (ST and IT) and larger nasal (SN and IN) SA in myopes. AL and myopic Rx were negative correlated (p < 0.05) with SA at IN, SN and IT. OV was significantly associated with SA at ST. Bulbosity showed no regional differences nor an effect of AL or Rx.
Conclusion:
Significant regional variation in SA exists across the anterior segment that is modulated by Rx and AL. It is unclear whether these structural characteristics are a precursor or consequence of myopia and may warrant investigation when developing biomechanical interventions.
Retinoblastoma (RB), a childhood retinal cancer is caused due to RB1 gene mutation which affects the child below 5 years of age. Angiogenesis has been proven its role in RB metastasis due to the presence of vascular endothelial growth factor (VEGF) in RB cells. Therefore, exploring angiogenic pathway by inhibiting VEGF in treating RB would pave the way for future treatment. In preclinical studies, anti-VEGF molecule have shown their efficacy in treating RB. However, treatment requires recurrent intra-vitreal injections causing various side effects along with patient nonadherence. As a result, delivery of anti-VEGF agent to retina requires an ocular delivery system that can transport it in a non-invasive manner to achieve patient compliance. Moreover, development of these type of systems are challenging due to the complicated physiological barriers of eye. Adopting a non-invasive or minimally invasive approach for delivery of anti-VEGF agents would not only address the bioavailability issues but also improve patient adherence to therapy overcoming the side effects associated with invasive approach. The present review focuses on the eye cancer, angiogenesis and various novel ocular drug delivery systems that can facilitate inhibition of VEGF in the posterior eye segment by overcoming the eye barriers.
Sight, or vision, is crucial for human survival. Due to the unique architecture and physiology of the eye, drug delivery scientists and pharmacologists have faced significant difficulties. For the treatment of eye problems, topical administration of both traditional and cutting-edge medication formulations is available. Ophthalmic solutions, suspensions, ointments, gels, and inserts are examples of conventional dosage forms. Microemulsions, nanosuspensions, dendrimers, niosomes, liposomes, etc. are examples of novel dosage forms. Comparing novel drug delivery systems to traditional drug delivery systems, the bioavailability of the medicine is enhanced. The obstacles offered by numerous anterior and posterior segment disorders can be significantly improved, according to recent advancements in the field of ophthalmic drug administration. Here in this article, we are going to discuss the anatomy of the eye, and conventional and novel ophthalmic techniques.
In recent years, dendrimers as a new class of polymeric materials have attracted much attention due to their unique properties, especially as drug delivery systems. In this process, dendrimers can deliver medicine directly to the affected part of the patient's body. Dendrimers can be defined as macromolecular structures with several advantages that may change depending on the chemical nature of the drug to be delivered. Dendrimers can be defined as macromolecular structures with several advantages that depending on the chemical nature of the drug to be delivered, may change. The reason dendrimers are so popular in drug delivery is that they have properties such as uniform size, water-solubility, modifiable surface performance, high degree of branching, being multivalent, well-defined molecular weight, and available internal cavities. In addition, the high level of control over dendritic architecture distinguishes them as ideal carriers. Also, the use of dendrimers in biomedicine has attracted the attention of many scientists. Biomedicine is one of the main fields of study for dendrimers because of its capacity to improve solubility, uptake, bioavailability, and targeted distribution, and their value in diagnosis and treatment. In the last decade, anti-neoplastic research on dendrimers has been extensively developed, and several types of poly amidoamine (PAMAM) and polypropylene imine (PPI) dendrimer complexes with doxorubicin, paclitaxel, cisplatin, melphalan, and methotrexate have been improved compared to the drug molecule alone.
The human eye is a complex biomechanical structure with a range of biomechanical processes involved in various physiological as well as pathological conditions. Fluid flow inside different domains of the eye is one of the most significant biomechanical processes that tend to perform a wide variety of functions and when combined with other biophysical processes play a crucial role in ocular drug delivery. However, it is quite difficult to comprehend the effect of these processes on drug transport and associated treatment experimentally because of ethical constraints and economic feasibility. Computational modeling on the other hand is an excellent means to understand the associated complexity between these aforementioned processes and drug delivery. A wide range of computational models specific to different types of fluids present in different domains of the eye as well as varying drug delivery modes has been established to understand the fluid flow behavior and drug transport phenomenon in an insilico manner. These computational models have been used as a non-invasive tool to aid ophthalmologists in identifying the challenges associated with a particular drug delivery mode while treating particular eye diseases and to advance the understanding of the biomechanical behavior of the eye. In this regard, the author attempts to summarize the existing computational and mathematical approaches proposed in the last two decades for understanding the fluid mechanics and drug transport associated with different domains of the eye, together with their application to modify the existing treatment processes.
The prevalence of chronic fundus diseases is increasing with the aging of the general population. The treatment of these intraocular diseases relies on invasive drug delivery because of the globular structure and multiple barriers of the eye. Frequent intraocular injections bring heavy burdens to the medical care system and patients. The use of topical drugs to treat retinal diseases has always been an attractive solution. The fast development of new materials and technologies brings the possibility to develop innovative topical formulations. This article reviews anatomical and physiological barriers of the eye which affect the bioavailability of topical drugs. In addition, we summarize innovative topical formulations which enhance the permeability of drugs through the ocular surface and/or extend the drug retention time in the eye. This article also reviews the differences of eyes between different laboratory animals to address the translational challenges of preclinical models. The fast development of in vitro eye models may provide more tools to increase the clinical translationality of topical formulations for intraocular diseases. Clinical successes of topical formulations rely on continuous and collaborative efforts between different disciplines.
Treatment of neovascular ocular diseases involves intravitreal injections of therapeutic proteins using conventional hypodermic needles every 4-6 weeks. Due to the chronic nature of these diseases, these injections will be administrated to patients for the rest of their lives and their frequent nature can potentially pose a risk of sight-threatening complications and poor patient compliance. Therefore, we propose to develop nanoparticle (NP)-loaded bilayer dissolving microneedle (MN) arrays, to sustain delivery of protein drugs in a minimally invasive manner. In this research, a model protein, ovalbumin (OVA)-encapsulated PLGA NPs were prepared and optimised using a water-in-oil-in-water (W/O/W) double emulsion method. The impact of stabilisers and primary sonication time on the stability of encapsulated OVA was evaluated using an enzyme-linked immunosorbent assay (ELISA). Results showed that the lower primary sonication time was capable of sustaining release (77 days at 28.5% OVA loading) and improving the OVA bioactivity. The optimised NPs were then incorporated into a polymeric matrix to fabricate bilayer MNs and specifically concentrated into MN tips by high-speed centrifugation. Optimised bilayer MNs exhibited good mechanical and insertion properties and rapid dissolution kinetics (less than 3 min) in excised porcine sclera. Importantly, ex vivo transscleral distribution studies conducted using a multiphoton microscope confirmed the important function of MN arrays in the localisation of proteins and NPs in the scleral tissue. Furthermore, the polymers selected to prepare bilayer MNs and OVA NPs were determined to be biocompatible with retinal cells (ARPE-19). This delivery approach could potentially sustain the release of encapsulated proteins for more than two months and effectively bypass the scleral barrier, leading to a promising therapy for treating neovascular ocular diseases.
The purpose of this study is to investigate the effect of vitreous sloshing induced by saccades on the intravitreal delivery of large molecule drugs. The vitreous body was considered in its age-related liquefaction condition. Fluid dynamics and large molecule distribution were described by the coupling of mass conservation's and Fick's laws with continuity and momentum equations for a Newtonian incompressible fluid in a 3D unsteady analysis. Two injection sites were analyzed, in both the mixing effect of a 50° periodic saccade leads to uniform drug distribution in 30 seconds of simulation, the initial bolus site being left after 3 seconds of simulation. In absence of saccadic movements, the dominant transport contribution is the diffusive one and large molecules hardly reach their uniform distribution inside the vitreous cavity. A model describing the intravitreal distribution of large molecules in presence of saccades was developed, improving the understanding of drug transport mechanism after an intravitreal injection and highlighting how advection contribution enhances its distribution in the vitreous chamber.
Purpose:
To compare the neuroprotective properties of retinalamin administered in different ways among open-angle glaucoma patients with compensated intraocular pressure.
Material and methods:
The study included 498 patients (eyes) with initial, moderate and advanced stages of glaucoma. Patients were divided into 3 groups: group I (n=110) received 5 mg intramuscular and 5 mg retrobulbar injections of retinalamin; group II (n=171) received 5 mg retrobulbar injection of retinalamin; group III received 5 mg intramuscular injection of retinalamin. The overall treatment dose contained 50 mg of retinalamin. All the patients underwent tonometry and static perimetry. Patients of group II with initial glaucoma and patients of group III with moderate glaucoma also underwent contrast sensitivity tests. The examinations were conducted before the treatment, and on months 3 and 6.
Results:
Visual acuity did not change significantly. In group I, after 3 months of treatment total threshold retinal sensitivity increased by 122 dB in patients with initial glaucoma, by 166 dB in moderate and by 124 dB in advanced glaucoma. Positive trend was observed in patients with initial and moderate stages of glaucoma by month 6. In group II, total threshold retinal sensitivity increased by 123 dB in initial glaucoma and by 110 dB in moderate; the result did not change by month 6. No significant changes were observed in patients with advanced glaucoma. In group III, total threshold retinal sensitivity increased by 142 dB in initial glaucoma, by 274 dB in moderate and by 148 dB in advanced glaucoma. Regression began on the sixth month. In group II, patients with initial glaucoma were observed to have decreased sensorimotor reaction times to achromatic stimuli within the studied areas of central visual field. In group III, patients with advanced glaucoma were also observed to have decreased sensorimotor reaction times to achromatic stimuli detected within 1° and 5° areas from the fixation point, but not in the 10° area.
Conclusion:
Retinalamin is most effective in initial and moderate glaucoma stages. Intramuscular, retrobulbar and combined administration methods have comparable efficacy.
Age‐related macular degeneration (AMD) and glaucoma are global ocular diseases with high blindness rate. RNA interference (RNAi) is being increasingly used in the treatment of these disorders with siRNA drugs, bevasiranib, AGN211745 and PF‐04523655 for AMD, and SYL040012 and QPI‐1007 for glaucoma. Administration routes and vectors of gene drugs affect their therapeutic effect. Compared with the non‐viral vectors, viral vectors have limited payload capacity and potential immunogenicity. This review summarizes the progress of the ocular siRNA gene silencing therapy by focusing on siRNA drugs for AMD and glaucoma already used in clinical research, the main routes of drug delivery, and the non‐viral vectors for siRNA drugs.
Efficient ocular drug delivery to the posterior segment of the eye by topical administration is a great challenge to pharmacologists. To explore drug delivery system of organic-inorganic hybrid nanocomposites for the efficient delivery of dexamethasone disodium phosphate (DEXP), a targeted hybrid nanocomposite based on layered double hydroxide (LDH) and functional carboxymethyl chitosan (CMCS) derivatives was designed. A special substrate of peptide transporter-1 (PepT-1) and glutathione was modified on CMCS. CMCS-glutathione-glycylsarcosine (CMCG-GS) and CMCS-glutathione-valyl-valine (CMCG-VV)-LDH hybrid nanocomposites were prepared and structurally confirmed. The in vitro experiments on human conjunctival epithelial cells showed noncytotoxicity (LDH concentration ≤100.0 µg/mL) and enhanced permeability for hybrid nanocomposites. Additionally, cellular uptake of the CMCG-GS-DEXP-LDH (10:1) nanocomposite eye drops involved clathrin-mediated endocytosis and PepT-1 mediated actively targeting transport. Results of the in vivo precorneal retention study showed an 8.35-fold, 2.87-fold and 2.58-fold increase of AUC0–6 h, Cmax and MRT for CMCG-GS-DEXP-LDH (10:1) hybrid nanocomposite eye drops, respectively, compared to that of the commercial product. Fluorescence imaging of fluorescein isothiocyanate isome (FITC)-loaded LDH hybrid nanocomposites demonstrated that FITC could diffuse into the choroid-retina with the shelter of LDH and CMCG-GS. The presence of a strong fluorescence signal of FITC-conjugated LDH hybrid nanocomposites in the sclera revealed that integral LDH nanocarrier reached the sclera. In the tissue distribution evaluation of rabbit's eyes, DEXP of CMCG-GS-DEXP-LDH (10:1) nanocomposites group retained in the target of the choroid-retina for 3 h with final concentration at 120.04 ng/g. Furthermore, the results of fluorescence imaging and tissue distribution suggested that the intraocular transport pathway for the hybrid nanocomposites is the conjunctival-scleral route. Consequently, the developed hybrid nanocomposites offer a simple and efficient strategy for topically administered drug delivery to the posterior segment of the eye.
Statement of Significance
Efficient ocular drug delivery to the posterior segment of the eye by topical administration is a great challenge to pharmacologists. In this manuscript, hybrid nanocomposite based on layered double hydroxide (LDH) and functional carboxymethyl chitosan (CMCS) derivatives were designed. The multifunctional properties of these hybrid nanocomposites were attributed to active targeting, bioadhesive capacity and penetration enhancement. Visualization of transport routes of fluorescein isothiocyanate-conjugated LDH hybrid nanocomposites demonstrated that the integral LDH nanocarrier reached the sclera through the conjunctival-scleral pathway, and the loaded drug could further diffuse to the retina. The multifunctional CMCS derivatives-LDH hybrid nanocomposites could be applied for the efficient drug delivery to the posterior segment of the eye through noninvasive topical instillation.
The sealed anatomical features of the eye and its physiological activity that removes rapidly drugs is called anatomical and physiological barriers, which is the cause of more than 90% of drug loss. This aspect remains a critical issue in eye surface medication. Thus, promoting tissue permeability of drugs as well as prolong their retention on eye surface can improve their bioavailability and enhance their therapeutic effects. Thanks to the existence of a negative charged mucin layer on the eye surface, several peptide-decorated-polymeric micelles were prepared to enhance the interaction between the micelle and eye surface, thus prolonging the drug retention on the eye surface and promoting its tissue permeability. Tacrolimus (also known as FK506) is a hydrophobic macrolide immunosuppressant used to treat dry eye syndrome and other eye diseases. However, its hydrophobic nature makes its delivery as topical eye surface medication difficult, with the risk of side effects due to overdoses. Therefore, the aim of this work was to evaluate the ability of FK506 micelles in promoting its permeability on the eye surface. Our results showed that the positive charged nano-micelles could significantly prolong FK506 retention on the eye surface and enhance its corneal permeability in an ex-vivo and in vivo condition. FK506 nano-micelles exhibited superior curing effects against dry eye diseases than FK506 suspension and a commercial FK506 formula. It exerted better inhibition effects on eye surface inflammation and corneal epithelium apoptosis when examined by slip lamp and TUNEL assay respectively. Further assays revealed the higher suppressive effects on the expression of several inflammation related factors at an mRNA and protein level. Hence, our results suggested that this positive charged nano-micelle might be a good drug delivery system for ocular surface medication.
The vascular endothelial growth factor (VEGF) induces pathological angiogenetic ocular diseases. It is a scientific challenge to develop carriers for the controlled release of inhibitors for VEGF present in the back of the eye domain. Carbon dots (C‐dots) functionalized with the VEGF aptamer are introduced and the hybrid nanoparticles are used for ocular nanomedicine. The C‐dots are applied as effective carriers of the anti‐VEGF aptamer across the cornea, yielding therapeutic levels upon topical administration. The hybrids show no toxicity for both in vitro and in vivo murine animal model, and further enable noninvasive intraocular concentration monitoring through the C‐dots inherent fluorescence. In addition, the hybrid C‐dots effectively inhibit VEGF‐stimulated angiogenesis in choroidal blood vessels. This inhibition is comparable to two commercially available anti‐VEGF drugs, bevacizumab and aflibercept. The hybrid aptamer‐modified C‐dots provide a versatile nanomaterial to treat age‐related macular degeneration and diabetic retinopathy. Age‐related macular degeneration and diabetic retinopathy are macular diseases induced by the vascular endothelial growth factor (VEGF). Nontoxic anti‐VEGF aptamer‐functionalized C‐dots penetrate the cornea into the intravitreal space, where the VEGF‐driven angiogenesis is effectively inhibited. The aptamer C‐dots conjugates provide promising therapeutic materials for ocular nanomedicines.
Minimally invasive delivery of a sustained drug release device to the body is a promising approach for treating chronic conditions such as retinal diseases. Herein, we describe a sheet-type device capable of sustained drug release and deployment control after being applied to the body through a small opened hole via a syringe-type injector. Such device consists of a four-layered structure of thin photopolymerized sheets, which are in turn made of different ratios of a mixture of polyethylene glycol dimethacrylate (PEGDM) and triethylene glycol dimethacrylate (TEGDM). A layer containing a model drug, i.e., fluorescein, was sandwiched between a controlled release and guard layer to achieve sustained unidirectional drug release. A deployment layer was then attached onto the guard layer to control the curvature of the device following deployment. The sheet-type device was sufficiently flexible to be rolled up and could be inserted into a syringe-type injector. When the device was injected into the subconjunctival space of a rabbit eye through a small opened hole, it unfolded to fit the eyeball curvature. Moreover, homogenates of the choroid/retinal pigment epithelium (RPE) as well as the retina exhibited fluorescence during 4 weeks after implantation, confirming that the drug could be delivered to the retina by using the device. This developed sheet-type device offers the possibility of achieving minimally invasive transplantation into diseased tissues and organs, and could provide improved therapeutic modalities as well as reduce possible side effects.
Successful treatment of age-related macular diseases requires an effective controlled drug release system with less invasive route of administration in the eye to reduce the burden of frequent intravitreal injections for patients. In this study, we developed an episcleral implantable device for sustained release of ranibizumab, and evaluated its efficacy on suppression of laser-induced choroidal neovascularization (CNV) in rats. We tested both biodegradable and non-biodegradable sheet-type devices consisting of crosslinked gelatin/chitosan (Gel/CS) and photopolymerized poly(ethyleneglycol) dimethacrylate that incorporated collagen microparticles (PEGDM/COL). In vitro release studies of FITC-labeled albumin showed a constant release from PEGDM/COL sheets compared to Gel/CS sheets. The Gel/CS sheets gradually biodegraded in the sclera during the 24-week implantation; however, the PEGDM/COL sheets did not degrade. FITC-albumin was detected in the retina during 18 weeks implantation in the PEGDM/COL sheet-treated group, and was detected in the Gel/CS sheet-treated group during 6 weeks implantation. CNV was suppressed 18 weeks after application of ranibizumab-loaded PEGDM/COL sheets compared to a placebo PEGDM/COL sheet-treated group, and to the intravitreal ranibizumab-injected group. In conclusion, the PEGDM/COL sheet device suppressed CNV via a transscleral administration route for 18 weeks, indicating that prolonged sustained ranibizumab release could reduce the burden of repeated intravitreal injections.
To determine the in vitro permeability of human sclera to compounds varying in molecular weight. To evaluate the effects of age, cryotherapy, transscleral diode laser, and surgical thinning on scleral permeability.
Scleral tissue from 97 human eye bank eyes was tested individually in a two-chamber Ussing apparatus with the following hydrophilic radiolabeled compounds on one side of the chamber: 5-fluorouracil, sucrose, dexamethasone, methotrexate, inulin, and three separate dextran polymers (MWt = 10,000, 40,000, and 70,000). Scleral hydration levels were obtained on 20 more scleral specimens. Additional groups of scleral specimens were treated with either a cryotherapy probe, a transscleral diode laser retinopexy probe, or partial thickness lamellar dissection, and specimens were mounted in the Ussing chambers for testing. Scleral tissue was digested to measure the amount of radioactivity present. Scleral sections were examined with electron microscopy.
Scleral hydration was maintained during the perfusion. The mean scleral permeability (cm/second x 10(-6) +/- SD) was established for each of the above compounds. Age, cryotherapy, or diode laser treatment did not alter permeability or ultrastructure of the sclera. Surgical thinning significantly increased the scleral permeability to dexamethasone (P = 0.011) and methotrexate (P = 0.037).
This study establishes baseline human scleral permeability to a series of hydrophilic compounds with various molecular weights. Age, cryotherapy, and diode laser treatment do not alter the permeability or ultrastructure of the sclera, whereas surgical thinning significantly increases permeability.
To determine the dexamethasone concentration in aqueous, vitreous, and serum of patients after a subconjunctival injection with dexamethasone disodium phosphate and to compare the effectiveness of a subconjunctival injection as a method of delivering dexamethasone into the vitreous with that of two previously tested routes: peribulbar injection and oral administration.
In a prospective study, 50 phakic patients who underwent a pars plana vitrectomy received a single subconjunctival injection with 2.5 mg of dexamethasone disodium phosphate, aqueous solution (after topical anesthesia and a subconjunctival injection with lidocaine) at varied intervals before surgery. An aqueous and a vitreous sample were taken from each patient, and serum samples were collected at multiple time points from nine of 50 patients. Dexamethasone concentrations were measured by radioimmunoassay.
The estimated maximum dexamethasone concentration in the aqueous was 858 ng per ml at 2.5 hours after injection, and in the vitreous, 72.5 ng per ml at 3 hours. In serum, a mean maximum concentration of 32.4 ng per ml was measured at approximately 30 minutes after injection.
Subconjunctival injection of 2.5 mg of dexamethasone disodium phosphate resulted in an estimated vitreous dexamethasone peak concentration three and 12 times higher, respectively, than after a peribulbar injection of 5 mg of dexamethasone disodium phosphate and an oral dose of 7.5 mg of dexamethasone. Thus, a subconjunctival injection is the most effective method of delivering dexamethasone into both the anterior and posterior segments of the eye. Systemic drug absorption is considerable and is of the same order of magnitude as after peribulbar injection.
Within the last few decades, in response to the advent of potent and versatile therapeutic agents, the diversity of conventional ophthalmic formulations has gradually evolved, extending well beyond simple solutions, and now includes a variety of types of drug administration. In most recent publications, authors have broadened the notion of conventional ophthalmic delivery systems to encompass more than simple solutions and suspensions [1]. While not strictly ‘conventional’, the ready availability of several commonly used drug vehicles suggests they have achieved acceptance, have been elevated to the category of conventional, and will be considered in this comparison.In this article, I have summarized the types of commonly used ophthalmic formulations, indicated the generality of their applicability and acceptance, differentiated their characteristics and utility, and projected anticipated use and development in the decade to come. This should also serve to put into perspective the discussions of more sophisticated components and elaborations described in this issue.
Drug delivery to the eye for treatment of a number of important diseases involves non-steady-state transport across the sclera. Although the literature contains steady-state measurements of permeability, the transient transport properties of sclera have not been determined experimentally or described theoretically. In this study, carboxyfluorescein flux across human sclera is shown experimentally to approach a quasi-steady state with a lag time of 0.37 h. Because drug-sclera contact times in the body are often shorter than this, the use of steady-state permeability models will overpredict the amount of drug delivered to the eye. A theoretical model is also developed to describe the observed transient flux by accounting for both diffusion and solute binding within the sclera.
A model derived from fiber matrix theory to predict the permeability of the eye's fibrous tissues, namely the sclera and corneal stroma, to water and solutes ranging from low molecular-weight drugs to macromolecules was developed. The model is based upon the ultrastructure of the cornea and the sclera; all parameters correspond to the geometrical and physicochemical characteristics of the eye and solutes, and are estimated from independent literature data. Comparison of our predictions with a large set of experimental data shows good agreement. The model suggests that important factors controlling diffusion rates across the sclera and stroma are tissue hydration, tissue thickness, and the size and volume fraction of proteoglycans present in these tissues. Applications to ocular drug delivery and treatment of glaucoma are discussed.
Fibrin glue (FG) has been successfully used in a wide range of surgical fields such as skin graft fixation, nerve repair, cartilage reattachment and microvascular anastomoses. The sustained release of antibiotics from FG for a longer period is desirable to avoid bacterial infection after application. Ampicillin sodium (AMP-Na) was selected as a model antibiotic and incorporated into FG. The incorporation of AMP-Na was attempted in two different ways. One was incorporation of AMP-Na in a dispersed state with the modification of the preparation method of FG. The other was incorporation of bovine serum albumin microspheres (BSA-MS) containing AMP-Na. The in vitro release of AMP-Na from various FGs and BSA MS was examined. The modifications of FG were found not to be appropriate methods to achieve sustained release of AMP-Na. The incorporation of crosslinked BSA-MS containing AMP-Na into FG was found to reduce the initial rapid release of AMP-Na and retarded release of AMP-Na.
Many investigators have suggested that the acidic glycosaminoglycan component of proteoglycans may control the size and organization of collagen fibres. It was decided that the transition zone between central cornea and sclera is an ideal model for the study of the relationships between specific proteoglycans and the organization of collagen fibres. The number and size of collage fibres were correlated with the concentration and composition of acidic glycosaminoglycans at discrete intervals from mid-cornea to sclera. The concentration of acidic glycosaminoglycans is highest in the central cornea; keratan sulfate accounts for most of the acidic glycosaminoglycan and the remainder is chondroitin. The peripheral cornea has 24% less acidic glycosaminoglycan than central cornea. The proportion of keratan sulfate is decreased and chondroitin is replaced by chondroitin sulfate. Uniformity of fibre diameters and their arrangement decreases distally from the central cornea. The sharpest area of transition lies between the corneolimbus and the sclerolimbus where the rapid increase in fibre size and decrease in organization is accompanied by a rapid decrease in the concentration of acidic glycosaminoglycans (primarily a loss of keratan sulfate), and the presence of detectable quantities of dermatan sulfate. A direct relationship between degree of fibre organization and acidic glycosaminoglycan content was found. We conclude that the precisely ordered spacing of collagen fibres in the cornea is determined by specific molecular constraints imposed by the conformation of keratan sulfate proteoglycan. This study proviess further evidence that the organization of collagen fibres is controlled by proteoglycans.
We compared the ocular penetration of labeled with radioactive carbon gentamicin in squirrel monkeys after subconjunctival and retrobulbar administration. In both normal and infected (Staphylococcus aureus endophthalmitis) eyes, high concentrations of drug were achieved in the sclera and choroid-retina by both routes, while corneal levels were markedly higher after subconjunctival injection than after retrobulbar injection. Regional variations in concentration were evident in these tissues; the highest levels were clustered about the site of injection. Aqueous humor concentrations were lowest in the group with normal eyes treated by the retrobulbar route; vitreous humor levels were extremely low in normal eyes injected subconjunctivally. These data differ from those in rabbits, especially with regard to penetration of the vitreous humor of normal eyes. Interspecies differences were less marked in inflamed eyes. The two species were similar in demonstrating maximum access to the cornea and aqueous humor with subconjunctival injection, and equivalence of the two routes in penetrating the vitreous humor of the inflamed eyes.
Regions of beef sclera free from perforations were mounted between two chambers and the movement of substances from one side to the other determined. All dyestuffs tested were virtually impermeant except for fluorescein and acid fuchsin. A variety of ions and solutes up to the size of serum albumin were also tested and were found to diffuse across about three times more slowly than they do in the rabbit corneal stroma. This rate of diffusion would slow the passage of locally applied drugs through the selera to an extent compatible with the delay in their action on the pupil.
We compared the penetration of radioactive carbon (14C) labeled-gentamicin into ocular tissues and fluids of albino rabbit eyes after subconjunctival (anterior subtenon's) and retrobulbar (posterior subtenon's) injections. In both normal and infected (Staphylococcus aureus endophthalmitis) eyes, higher levels of drug were produced with subconjunctival rather than with retrobullar admininistration in cornea, sclera, choroid and retina (as a unit), and iris; levels in the aqueous and vitreous humors of infected eyes were similar with the two routes of injection. Marked regional variations in the concentrations of gentamicin were noted in cornea, sclera, and choroid-retina after subconjunctival therapy. The pattern of these variations suggests that subconjunctival antibiotic penetrates the eye by direct diffusion. The low levels of drug after retrobulblar injection may be due to systemic absorption through the highly vascular orbital plexus of the rabbit.
Corneal penetration of sulfonamide carbonic anhydrase inhibitors for topical treatment of glaucoma has been tested in human eye bank and rabbit tissue. Paired corneas, with the epithelia intact or removed, and excised sclera were perfused in vitro. Corneal permeability (Kp) to methazolamide and ethoxzolamide was similar in both species, but for benzolamide and bromacetazolamide the Kp was greater in humans. Human corneas without epithelium had Kp the same as scleral Kp. Topical methazolamide (6 mmol/L) was studied in vivo in rabbits and in ten humans before cataract surgery. The mean (+/- SE) concentration in the rabbit aqueous was 3.2 +/- 1.4 mumol/L at eight minutes and 1.2 +/- 0.16 mumol/L at one hour. In humans, less than 0.2 mumol/L was detected at eight minutes; at one hour none was detected in three cases, and 0.4 +/- 0.08 mumol/L was detected in four cases. Lower permeability in humans than rabbits may result from a fourfold greater blinking rate, a twofold greater tear turnover, and a twofold lower corneal/conjunctival area.
Transcorneal permeation has traditionally been the mechanism by which topically applied ophthalmic drugs are believed to gain access to the internal ocular structures. Relatively little attention has been given to alternate routes by which drugs may enter the eye. A system has been developed which allowed the investigation in vivo of the contribution of noncorneal absorption to intraocular drug levels after topical dosing. Using timolol and inulin as probe drugs, it was shown that the noncorneal absorption route may contribute significantly to drug penetration into intraocular tissues. Furthermore, results demonstrated that drugs absorbed by the noncorneal route appeared to enter certain intraocular tissues by a mechanism which bypasses the anterior chamber. These studies suggested that intraocular penetration via noncorneal routes involves penetration of drug across the conjunctiva/sclera. Neither reentry from the general circulation after drug absorption into the blood or drug delivery by the local vasculature accounted for the observed results. In terms of topical ophthalmic drug delivery, the noncorneal absorption route may be important for drugs that are poorly absorbed across the cornea due to their physical-chemical properties. We have demonstrated this using inulin as a model for a poorly absorbed, high molecular weight substance.
Pluronic F-127 (a polyoxyethylene-polyoxypropylene surface-active block copolymer) was evaluated as a vehicle substance for topical administration of anticancer agents. 5-Fluorouracil and adriamycin were used in this evaluation. The effects of the concentration of Pluronic F-127, temperature, and the drug concentration on the release were studied by means of an in vitro release method using a cellulose membrane. With increasing concentration of Pluronic F-127 in the vehicle a corresponding decrease in the apparent release rate of the anticancer agents occurred. The apparent release rate increased with increasing temperature from 30 to 44°C. Increase in drug concentration increased the drug release rate. The Pluronic F-127 gels appeared to have good potential for use in topical drug delivery systems since they exhibit reverse thermal gelation behavior and have good drug release characteristics and low toxicity.
To study the dexamethasone level reached in human vitreous after a peribulbar injection of 5 mg of dexamethasone disodium phosphate and to assess its systemic uptake.
In a prospective study, 61 eyes of 61 patients scheduled for vitrectomy received a single peribulbar injection of 5 mg of dexamethasone disodium phosphate at varied intervals before surgery. At the start of vitrectomy, an undiluted vitreous sample was taken. In 22 patients, multiple serum samples were collected. Dexamethasone concentrations were measured by radioimmunoassay. The physiologic cortisol concentration was determined in the vitreous of 12 eyes of 12 patients who did not receive dexamethasone.
An average dexamethasone peak concentration of approximately 13 ng/ml was reached in vitreous 6 to 7 hours after peribulbar injection. In serum the average peak concentration was approximately 60 ng/ml 20 to 30 minutes after peribulbar injection. The average physiologic cortisol concentration in vitreous was 5.1 ng/ml.
After a peribulbar injection of 5 mg of dexamethasone disodium phosphate, an average intravitreal dexamethasone concentration is reached with a 75 times greater anti-inflammatory potency than physiologically present cortisol. Dexamethasone concentration in serum, however, is several times higher. Peribulbar injection is not just a local treatment but results in serum levels comparable to those achieved by a high oral dose.
To assess the mean thickness and surface area of human sclera.
Fifty-five formalin-fixed eye bank eyes were hemisected from anterior to posterior. Cross-sectional slides were taken to include a millimeter scale ruler in each photograph. Slide photographs were projected and the scleral silhouette sketched. Mean scleral thickness measurements with standard deviation were obtained. Twenty-five human eye bank eyes were used to determine total scleral surface area by either a computerized tracing method (17 globes) or volumetric calculations (eight globes) using fluid displacement.
Mean scleral thickness +/- SD was 0.53 +/- 0.14 mm at the corneoscleral limbus, significantly decreasing to 0.39 +/- 0.17 mm near the equator, and increasing to 0.9 to 1.0 mm near the optic nerve. The mean total scleral surface area by surface area computerized tracings was 16.3 +/- 1.8 cm2 and, by the volume displacement method, was 17.0 +/- 1.5 cm2.
Scleral thickness and surface area measurements from cadaver eyes are important for ophthalmic surgeons and have implications for transscleral diffusion.
To determine the dexamethasone concentration in vitreous and serum of patients after oral administration of dexamethasone and to compare the results with the concentrations in vitreous and serum found in a previous study with peribulbar injection of 5 mg dexamethasone disodiumphosphate.
In a prospective study, 54 patients who were scheduled for vitrectomy received 7.5 mg dexamethasone orally at varied time intervals before surgery. A vitreous sample was taken from each patient and serum samples were collected at multiple time points from 32 out of 54 patients. Dexamethasone concentrations were measured by radioimmunoassay.
Dexamethasone concentrations in serum ranged from 2.5 to 98.1 ng/ml (median, 61.6 ng/ml) between 1 and 3 hours after oral administration of 7.5 mg dexamethasone. Serum concentrations after peribulbar injection of 5 mg dexamethasone disodiumphosphate (containing 3.75 mg dexamethasone) were lower by a factor of 1.5. Concentrations in vitreous ranged from 1.7 to 23.4 ng/ml (median, 5.2 ng/ml) between 4 and 10 hours after oral administration. After peribulbar injection of 5 mg dexamethasone disodiumphosphate, the intravitreal concentrations were 3.9 times higher.
An oral dose of 7.5 mg dexamethasone resulted in an intravitreal corticosteroid concentration with an anti-inflammatory potency that is clearly above physiological level. This concentration, however, is several times lower than is the intravitreal concentration after a peribulbar injection of 5 mg dexamethasone disodiumphosphate, although the two routes of administration resulted in nearly equal dexamethasone concentrations in serum. The higher intravitreal concentration after peribulbar injection is probably caused by diffusion from the serum and additional transscleral diffusion.
The objective of this study was to collect a comprehensive database of ocular tissue permeability measurements found in a review of the literature to guide models for drug transport in the eye. Well over 300 permeability measurements of cornea, sclera, and conjunctiva, as well as corneal epithelium, stroma, and endothelium, were obtained for almost 150 different compounds from more than 40 different studies. In agreement with previous work, the corneal epithelium was shown generally to control transcorneal transport, where corneal stroma and endothelium contribute significantly only to the barrier for small, lipophilic compounds. In addition, other quantitative comparisons between ocular tissues are presented. This study provides an extensive database of ocular tissue permeabilities, which should be useful for future development and validation of models to predict rates of drug delivery to the eye.
The purpose of this study was to evaluate the effects of intraocular pressure on the permeability of human and rabbit sclera to water, dexamethasone, and carboxyfluorescein.
Scleral sections excised from moist-chamber-stored human globes or eyes obtained from euthanatized New Zealand White rabbits were mounted in a perfusion chamber that can create a transscleral pressure that simulates an intraocular pressure. A small depot of drug (100 microl) was added to the episcleral surface while perfusing an irrigating solution slowly across the choroidal side. The perfusate was collected and scleral permeability calculated. Experiments were performed at 0, 15, 30, and 60 mm Hg for each compound in human and rabbit tissue.
Analysis of variance showed a significant effect of intraocular pressure on both human and rabbit scleral permeability. Human scleral permeability was decreased by as much as a factor of two for water (P = 0.0004), dexamethasone (P<0.0001), and carboxyfluorescein (P = 0.0064) at elevated intraocular pressures. Rabbit scleral permeability was similarly affected by elevated intraocular pressure for water (P = 0.0039), dexamethasone (P = 0.0001), and carboxyfluorescein (P = 0.0016).
This study shows that simulated intraocular pressure ranging from 15 to 60 mm Hg can decrease scleral permeability to small molecules by one half when compared with the sclera with no pressure applied.
To investigate the feasibility of transscleral drug delivery to the choroid and retina.
An osmotic pump was used to deliver IgG across the sclera of pigmented rabbits, and levels were measured in the choroid, retina, vitreous humor, aqueous humor, orbit, and plasma over 28 days. This method was then used to deliver an anti-intercellular adhesion molecule-1 (ICAM-1) monoclonal antibody (mAb), and its effect on inhibiting vascular endothelial growth factor (VEGF)-induced leukostasis in the choroid and retina was determined by measuring tissue myeloperoxidase (MPO) activity.
Levels of retinal and choroidal IgG were significantly higher than baseline at all points up to 28 days (P < or = 0.01). IgG levels in the orbit, vitreous humor, aqueous humor, and plasma were negligible (P > 0.05). MPO activity in the choroid of eyes treated with anti-ICAM-1 mAb was 80% less (P = 0.01) than in eyes receiving an equal rate of delivery of an isotype control antibody. Inhibition of MPO activity in the retina was 70% (P = 0.01). The plasma concentration of anti-ICAM-1 mAb was 31,000-fold less than the concentration in the osmotic pump.
Minimally invasive transscleral delivery can be used to deliver therapeutic levels of bioactive drugs to the choroid and retina with negligible systemic absorption. This method of ocular drug delivery may be used in the treatment of a variety of chorioretinal disorders.
To determine the in vitro permeability of the sclera to high molecular weight compounds and the relationship between scleral permeability and molecular size.
Fresh rabbit sclera was mounted in a two-chamber diffusion apparatus, and its permeability to sodium fluorescein, fluorescein isothiocyanate (FITC)-conjugated bovine serum albumin, FITC-IgG, and FITC dextrans ranging in molecular weight from 4 to 150 kDa was determined by fluorescence spectrophotometry. Electron microscopy was used to assess the impact of the experimental design on scleral ultrastructural integrity. The effect of the diffusion apparatus on scleral hydration was examined. Rabbit scleral permeability was compared with previously reported data for human and bovine sclera.
Scleral permeability decreased with increasing molecular weight and molecular radius, consistent with previous human and bovine data. Molecular radius was a better predictor of scleral permeability than molecular weight. The sclera was more permeable to globular proteins than to linear dextrans of similar molecular weight. The experimental apparatus did not alter scleral ultrastructure. Permeability of rabbit sclera was similar to human sclera but greater than bovine sclera.
Large molecules, such as IgG, diffuse across sclera in a manner consistent with porous diffusion through a fiber matrix. Transscleral delivery of immunoglobulins and other large compounds to the choroid and retina may be feasible.
To determine dexamethasone concentrations in the subretinal fluid of patients after a peribulbar injection, a subconjunctival injection, or an oral dose of dexamethasone and to compare the results with those of previous similar studies of dexamethasone concentrations in the vitreous.
Prospective, nonrandomized, comparative trial.
One hundred forty-eight patients with a rhegmatogenous retinal detachment.
Fifty patients received a peribulbar injection of 5 mg dexamethasone disodium phosphate, 49 received a subconjunctival injection of 2.5 mg dexamethasone disodium phosphate, and 49 received an oral dose of 7. 5 mg dexamethasone at various time intervals before surgery. At the time of surgery, a subretinal fluid sample was taken from each patient.
The dexamethasone concentration in the subretinal fluid measured by radioimmunoassay.
The estimated maximum dexamethasone concentrations in the subretinal fluid after the peribulbar injection, the subconjunctival injection, and the oral dose were, respectively, 82.2 ng/ml (standard error, 17. 6), 359 ng/ml (standard error, 80.2), and 12.3 ng/ml (standard error, 1.61). Corrected for dose, the maximum dexamethasone concentrations after subconjunctival injection and peribulbar injection were, respectively, 120 (95% confidence interval, 54/180) and 13 (95% confidence interval, 6.8/20) times greater than after oral administration.
A subconjunctival injection of dexamethasone disodium phosphate is more effective in delivering dexamethasone into the subretinal fluid of patients with a rhegmatogenous retinal detachment compared with peribulbar injection or oral administration. The subretinal dexamethasone concentrations were higher than concentrations measured in the vitreous in previous studies with a similar setup after all three delivery methods.
Introduction
A previous paper3 reported that labeled albumin injected into the suprachoroid penetrates the sclera through the perivascular spaces and most probably also through other pathways and moves into the conjunctiva where it is then collected by conjunctival lymph vessels.In the present experiments the drainage of albumin from the suprachoroid was studied with an improved technique in animals with an intact anterior chamber and in animals with a low intraocular pressure due to chamber puncture. It was also determined to what extent albumin injected into the suprachoroid can pass into the blood after the cervical lymph vessels have been opened. The routes for colloid drainage through the sclera were studied using red dextran.Methods
Albino rabbits weighing 1.8 to 2.8 kg were used. Anesthesia was induced by I.V. administration of pentobarbital (30 mg/kg body weight). Additional doses were given if required for the suprachoroidal injection but after this
The purpose of this study was to determine whether trans-scleral pressure affects scleral solute permeability by altering scleral thickness or hydration, and to investigate the sustained release delivery of dexamethasone. Scleral sections from donor human globes were mounted for in vitro flux studies. Scleral thickness and hydration were measured as functions of trans-scleral pressure. For the sustained release studies, 3H-dexamethasone in pluronic F-127 gel or in fibrin sealant was added to the episcleral side of the tissue and flux studies were performed. While scleral thickness showed a tendency to decrease with increasing pressure, a significant decrease in thickness was measured only at a trans-scleral pressure of 60 mmHg. No significant changes in scleral hydration were measured over the range of trans-scleral pressures studied. The apparent permeability constants (Ktrans) of human sclera for 3H-dexamethasone in BSS plus, fibrin sealant and F-127 gel were 11.5 x 10(-6), 7.3 x 10(-6), and 1.5 x 10(-6) cm sec(-1), respectively. Human scleral permeability to dexamethasone differed significantly among the three vehicles (p < 0.0001). Cumulative delivery of dexamethasone from BSS plus, F-127 gel, and fibrin sealant were 85.0, 29.3, and 67.9% at 20 hr, respectively. Scleral hydration was unaffected by trans-scleral pressures. Scleral thinning was only observed at 60 mmHg. Trans-scleral pressures below 60 mmHg would not be expected to significantly affect the permeability of the tissue to solutes in the size range of conventional drugs. F-127 gel and fibrin sealant provided a slow, relatively uniform sustained release through a 24 hr period. These systems might be employed to achieve sustained therapeutic levels of drugs to the posterior segment of eye.
Proteoglycans and collagen fibre Miyamoto
- J Ambati
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A fiber matrix model of sclera therapeutic approaches for treating visually devastat-and corneal stroma for drug delivery to the eye ing diseases of the posterior segment of the eye
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- M R Prausnitz
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This research was funded in part by grants from Han, S.Y. Jeong, Development of a local antibiotic delivery The Foundation Fighting Blindness and from The system using fibrin glue
- B G Yu
- I C Kwon
- Y H Kim
- D K Han
- K D Park
B.G. Yu, I.C. Kwon, Y.H. Kim, D.K. Han, K.D. Park, K. This research was funded in part by grants from Han, S.Y. Jeong, Development of a local antibiotic delivery The Foundation Fighting Blindness and from The system using fibrin glue, J. Controlled Release 39 (1996) 65–70.
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Intraocular penetration of diseases and degenerations are developed, the trans-gentamicin after subconjunctival and retrobulbar injection, scleral route of drug delivery offers exciting promise
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Importance of the non-corneal absorption route in topical ophthalmic drug delivery
- Ahmed