Eye Drop Formulation Research Articles

Review of the latest solutions in the use of contact lenses as controlled release systems for ophthalmic drugs.

In recent years, there has been a great interest in the potential use of contact lenses as eye drug delivery systems. Static (individual layers of the cornea, sclera and retina) as well as dynamic barriers (blood flow) pose a serious challenge to the effective delivery of the drug substance to the eyeball. The current ophthalmic systems are not optimal for patients, especially in the form of eye drops, where almost 95% of the drug contained in them is lost through the process of absorption through the conjunctiva or tear drainage. This article describes in vitro experiments that examined the use of contact lenses in the context of drug treatment in infectious, inflammatory, allergic, and glaucomatous diseases. Various techniques used to modify the materials as well as their impact on drug release kinetics were discussed. It has also been demonstrated that these methods can be used in practice during in vivo research, both in animal models as well as in sick and healthy people. The advantages of using controlled-release drug systems in the form of contact lenses are the drug dosing regimen, bioavailability and the prolonged residence time of drugs in the eyeball.

Does Diabetes Influence Adherence in Glaucoma Patients?

With chronic diseases, patient adherence plays a crucial role in delaying disease progression and in determining the success of therapy. Problems arise not only from low medication adherence, but also non-adherence to recommended follow-up examinations. Obtaining an accurate estimate of adherence is difficult, especially in glaucoma patients, due to the fact that most antihypertensive drugs are administered in the form of eye drops. There is great variability in the published adherence values for glaucoma patients. Most studies report an average medication adherence of approximately 70%, with around 50% of patients having good adherence (at least 80% of medication administered as planned). Furthermore, 6.8 - 31.4% of the eye drops do not end up in the patient's eye, which means there is even less active ingredient to achieve a therapeutic effect. Glaucoma patients also show low persistence and adherence to follow-up appointments. Since diabetes increases the risk for POAG and secondary glaucoma and given that diabetics have particularly low adherence, the question arose whether a diabetes diagnosis is associated with reduced adherence in glaucoma patients. Previous studies found no significant association between diabetes and reduced adherence in glaucoma patients, although a significant impact of elevated HbA1c on adherence in glaucoma patients was found in one study. However, this connection still needs to be examined more closely in studies with larger samples.

Stability indicating HPLC method for the simultaneous analysis of Gatifloxacin and Loteprednol in eyedrop formulation using design of experiment approach

Design of experiment (DOE) assisted simple, rapid, precise and accurate stability indicating HPLC method has been developed for simultaneous estimation of Gatifloxacin (GTF) and Loteprednol (LOT) along with their forced degradation products. The developed method has been optimized and developed by using central composite design (CCD) in response surface methodology (RSM). Trails have been undertaken and ratio of phosphate buffer in mobile phase, pH of buffer and flow rate are selected as factors. Resolution, tailing factor (GTF) and tailing factor (LOTE) are selected for determining the system response in the process of method optimization. The responses have been optimized using the Derringer’s desirability function. The effective separation is achieved on Phenomenex EVO-C18 column (250 mm x 4.6 mm i.d, 5 μm particle size) with mobile composed of 10 mM phosphate buffer, pH 3.5 and organic phase composed of mixture of acetonitrile and methanol 60:40 % v/v, the flow rate was 1.0 mL/min, the signals were detected at 267 nm. The developed method was validated for linearity, accuracy, precision, and robustness. The method was applied successfully for stability samples.

Synthetic Strategies for Improving Solubility: Optimization of Novel Pyrazolo[1,5-a]pyrimidine CFTR Activator That Ameliorates Dry Eye Disease.

Dry eye disease (DED) is one of the most prevalent ocular diseases but has limited treatment options. Cystic fibrosis transmembrane conductance regulator (CFTR), a major chloride channel that stimulates fluid secretion in the ocular surface, may pave the way for new therapeutic strategies for DED. Herein, we report the optimization of Cact-3, a potent CFTR activator with poor solubility, to 16d, a potent CFTR activator with suitable solubility for eye drop formulation. Notably, 16d was well distributed in target tissues including cornea and conjunctiva with minimal systemic exposure in rabbit. Topical ocular instillation of 16d significantly enhanced tear secretion and improved corneal erosion in a mouse model of DED. In addition, 16d significantly reduced mRNA expression of pro-inflammatory cytokines including IL-1β, IL-17, and TNF-α and MMP2 in cornea and conjunctiva of DED mice.

Eye drops for retinal disease

AbstractUsing topical application to deliver drugs to the posterior segment of the eye remains a challenge. Posterior segment diseases are currently treated by intravitreal injection or implant. Eye drop formulations based on γ‐cyclodextrin (γCD)‐based nanoparticle aggregates were developed and deliver therapeutic concentrations of drugs (dorzolamide and dexamethasone) to both anterior and posterior segments of the eye in animal models and clinical studies. An early study in humans showed dorzolamide/γCD eye drops could achieve comparable intraocular pressure decreases to commercial dorzolamide eye drops, but with less frequent application. Pilot studies with dexamethasone/γCD eye drops showed clinical effect in a range of human conditions, including diabetic macular oedema, cystoid macular oedema and vitritis secondary to uveitis, inflammation after cataract surgery and postoperative treatment in trabeculectomy. A multicentre, double‐masked, parallel‐group, randomized, Phase 2 study was performed to evaluate topical dexamethasone ophthalmic suspension in diabetic macular edema (DME). One hundred and forty four patients aged 18–85 years with DME of <3 years duration, ETDRS central subfield thickness ≥ 310 μm by SD‐OCT and ETDRS letter score ≤ 73 and ≥ 24 in the study eye were randomized 2:1 to OCS‐01 or matching vehicle, 1 drop 3 times/day for 12 weeks. Efficacy was evaluated as change from baseline to Week 12 of ETDRS letter score and central macular thickness (CMT). Mean CMT showed a greater decrease from baseline with OCS‐01 (N = 99) than vehicle (N = 45) at Week 12 (−53.6 vs −16.8 μm, p = 0.0115). Mean change in ETDRS letter score from baseline to Week 12 met the p was +2.6 letters with topical OCS‐01 and 1 letter with vehicle (p = 0.125). In a post‐hoc analysis, there was a greater difference in patients with baseline BCVA ≤65 letters, the OCS‐01 group improved 3.8 letters compared with 0.9 letters with vehicle. OCS‐01 was well‐tolerated, and increased intraocular pressure was the most common adverse event. Cyclodextrin nanoparticle eye drops deliver drugs to the retina in therapeutically relevant concentrations and promise a non‐invasive alternative in drug treatment of retinal diseases.

Langmuir Trough Study of the Interactions of Tear Mimetic Eyedrop Formulation with Human Meibum Films

Meibomian gland disease is associated with quantitative or qualitative deficiencies of meibum (MGS) that result in tear film instability. Thus, there is great demand for ophthalmic nanoemulsions that can replenish MGS and recover its performance at the air/tear surface. Rohto Dry Aid (RDA) utilizes TEARSHIELD TECHNOLOGYTM implementing a complex oil phase of non-polar and polar lipid-like molecules. Therefore, the interactions of RDA with MGS surface films deserve further study as they may provide valuable insights (i) into the mechanisms behind the nanoemulsion therapeutic action and (ii) for the design of novel ophthalmic formulations. Pseudobinary meibum/RDA films were formed at the air–water surface of the Langmuir trough. Surface pressure-area isocycles and stress relaxations were employed to probe the layer (i) reorganization upon cycling and (ii) dilatational elasticity, respectively. Film morphology was accessed by Brewster angle microscopy and the spreading properties of RDA-supplemented meibum were also probed. The diverse ingredients of the nanoemulsion oil phase complemented the non-polar and polar lipid constituents of the meibomian layers, which resulted in enhanced continuity of the MGS duplex film structure and facilitated the MGS spread and viscoelasticity. Nanoemulsions deserve further study as a potent tool for MGS-oriented therapy for dry eyes.

Host-guest complexation of cucurbit[7]uril and cucurbit[8]uril with the antimuscarinic drugs tropicamide and atropine

Cucurbiturils are useful excipients in eye drop formulations: they can increase the water solubility of the drug, enhance drug absorption into the eye, improve aqueous stability and reduce local irritation. Effective and safe drug delivery is, however, a challenge and the information on the host (CBs)/guest (tropicamide and atropine) interactions can help improving the existing treatments and develop novel therapies not limited only to eye diseases/conditions. Since this carrier system can easily modify the properties of the drug and ensure its delivery at the targeted ocular tissue, further insight into the intimate mechanism of the host-guest recognition is crucial. The present DFT/SMD study focuses on the role of numerous factors governing this process, namely the specific position of the guest molecule in the cavity of the cucurbituril, the ionization form (non/protonated) of the antimuscarinic drug, the dielectric constant of the medium, and the size of the cavitant pore. The obtained results are in line with experimental observations and shed light on the mechanism, at atomic resolution, of recognition between the CBs and the two parasympatholytic drugs.

Development of an ophthalmic formulation with a postbiotic of Lactiplantibacillus plantarum CRL 759.

The term postbiotics has acquired great interest in recent years. Numerous studies have shown a potential beneficial effect of its use in many inflammatory pathologies. However, it has not been much explored in ocular inflammatory diseases. The aims of this study were to develop and characterise an ophthalmic formulation with a postbiotic of Lactiplantibacillus plantarum CRL 759, and to evaluate its anti-inflammatory actions on murine macrophage stimulated with lipopolysaccharides (LPS) in vitro. First, we evaluated the ability of L. plantarum CRL 759 to generate a supernatant with anti-inflammatory property using different buffers. Then, we studied the stability at different temperatures and storage times of the generated postbiotic. In vitro assays showed that incubation of L. plantarum CRL 759 in modified phosphate buffer according to Sorensen (called POF-759), generated a supernatant that significantly reduced the production of interleukin-6, tumour necrosis factor-α, and nitric oxide by RAW 264.7 cells stimulated with LPS. Furthermore, POF-759 maintained its anti-inflammatory activity at room temperature, 4 and -20 °C, up to 30 days of storage. From the studies reported here, a postbiotic product with anti-inflammatory properties and optimal characteristics for the formulation of eye drops was obtained.

Aqueous Prostaglandin Eye Drop Formulations.

Glaucoma is one of the leading causes of irreversible blindness worldwide. It is characterized by progressive optic neuropathy in association with damage to the optic nerve head and, subsequently, visual loss if it is left untreated. Among the drug classes used for the long-term treatment of open-angle glaucoma, prostaglandin analogues (PGAs) are the first-line treatment and are available as marketed eye drop formulations for intraocular pressure (IOP) reduction by increasing the trabecular and uveoscleral outflow. PGAs have low aqueous solubility and are very unstable (i.e., hydrolysis) in aqueous solutions, which may hamper their ocular bioavailability and decrease their chemical stability. Additionally, treatment with PGA in conventional eye drops is associated with adverse effects, such as conjunctival hyperemia and trichiasis. It has been a very challenging for formulation scientists to develop stable aqueous eye drop formulations that increase the PGAs’ solubility and enhance their therapeutic efficacy while simultaneously lowering their ocular side effects. Here the physiochemical properties and chemical stabilities of the commercially available PGAs are reviewed, and the compositions of their eye drop formulations are discussed. Furthermore, the novel PGA formulations for glaucoma treatment are reviewed.

Pitavastatin loaded nanoparticles: A suitable ophthalmic treatment for Acanthamoeba Keratitis inducing cell death and autophagy in Acanthamoeba polyphaga

Statins are effective sterol lowering agents with high amoebicidal activity. Nevertheless, due to their poor aqueous solubility, they remain underused especially in eye drop formulation. The aim of the present study is to develop Pitavastatin loaded nanoparticles suitable for ophthalmic administration and designed for the management of Acanthamoeba Keratitis. These nanocarriers are aimed to solve both the ophthalmic route-associated problems and the limited aqueous drug solubility issues of Pitavastatin. Nanoparticles were obtained by a nanoprecipitation-solvent displacement method and their amoebicidal activity was evaluated against four strains of Acanthamoeba: A. castellanii Neff, A. polyphaga, A. griffini and A. quina. In Acanthamoeba polyphaga, the effect of the present nanoparticles was investigated with respect to the microtubule distribution and several programmed cell death features. Nanoparticles were able to eliminate all the tested strains and Acanthamoeba polyphaga was determined to be the most resistance strain. Nanoparticles induced chromatin condensation, autophagic vacuoles and mitochondria dysfunction.

Oil-free eye drops containing Cyclosporine A/cyclodextrin/PVA supramolecular complex as a treatment modality for dry eye disease

According to the global mapping of dry eye disease (DED), nearly 5 to 50 % of people suffer from DED, and this number is on the rise. The drug of choice Cyclosporine A (CsA) exhibits poor ocular bioavailability due to high molecular weight and lipophilicity. Moreover, formulations of CsA currently available are in the form of oil-based emulsions that are known to cause ocular irritation and pain. In this study, sulfobutylether-β-cyclodextrin (SBE-β-CD) based binary and ternary supramolecular complexes of CsA were developed as completely oil-free, and particle-free eye drops to treat DED. The physicochemical characterizations were supplemented with relevant in silico studies, to ascertain the findings. Further, the efficacy of the complexes was evaluated in the scopolamine-induced mouse model of DED. The complexation improved the CsA solubility by ~21-fold, with ~4-fold improvement in dissolution and transcorneal permeation. The non-irritancy and non-toxicity were confirmed by hen's egg chorioallantoic membrane assay and cytotoxicity assay using human corneal epithelial cells, respectively. The in vivo treatment with the ternary CD complex demonstrated better management of the dry eye supported by the tear volume assessment, corneal fluorescein staining, and histopathological studies of the cornea, lacrimal gland, and harderian gland. The study demonstrates the potential of the supramolecular complex as an alternative to the oil-based formulation of eye drops for drugs that show low solubility and poor corneal permeation.

Ocular biodistribution of cysteamine delivered by a sustained release microsphere/thermoresponsive gel eyedrop

The objective of the investigation was to determine the ocular biodistribution of cysteamine, a reducing agent used for treatment of cystine crystals in cystinosis, following topical administration of a sustained release formulation and traditional eyedrop formulation. To the right eye only, rabbits received a 50 µL drop of 0.44% cysteamine eyedrops at one drop per waking hour for 2, 6, 12, and 24 h. A second group received one 100 µL drop of a sustained release formulation containing encapsulated cysteamine microspheres suspended in a thermoresponsive gel. Upon serial sacrifice, ocular tissues from both eyes and plasma were obtained and quantified for cysteamine using LC-MS/MS. Cysteamine was detected in the cornea, aqueous humor and vitreous humor. Systemic plasma concentrations of cysteamine from treatment groups were below the limit of detection. As expected, 0.44% cysteamine eyedrops when administered hourly maintained drug concentrations within the cornea at a magnitude 5 times higher than a single dose of the sustained release formulation over 12 h. The sustained release formulation maintained cysteamine presentation across 12 h from a single drop. These studies demonstrate distribution of cysteamine to the eye following topical administration, including high drug uptake to the cornea and low systemic distribution.

Penetrating-peptide-mediated non-invasive Axitinib delivery for anti-neovascularisation.

The unique physiological makeup of the eye limits the use of small-molecule drugs for treating the posterior segment of the eye. Nevertheless, transmembrane-peptide-mediated non-invasive drug delivery can serve as an ideal treatment strategy, as it is capable of delivering small-molecule drugs across the membrane in the form of eye drops, thereby achieving the effective treatment of neovascularisation in the posterior cavity. In this study, we screened and compared the posterior segment distribution of two poly(ethylene glycol)-distearoylphosphatidylethanolamine carriers modified using targeting-peptides. Thereafter, a transmembrane peptide (i.e., PENE) with a greater ability of transmembrane delivery was selected for delivering the anti-vascular drug (i.e., Axitinib) to the posterior segment of the eye. Using two different mouse models with fundus neovascular diseases, the complete non-invasive delivery of Axitinib to the posterior segment of the eye was confirmed using the targeted system; the designed eye drops (i.e., PENE-nanoparticles) could achieve drug distribution to the retina and veins of the eye as well as good drug permeability for renewal. Moreover, using the eye-drop treatment, neovascularisation was substantially reduced, demonstrating the high efficacy of this drug delivery system. This study, which combines nanodrug-loading technology and the transmembrane delivery of penetrating-peptides to achieve the goal of the non-invasive delivery of small-molecule drugs through the dense blood vessels of the sclera, shows wide applicability and considerably expands the use of ocular drugs. Thus, this study is expected to help develop a more acceptable drug administration strategy for the drug treatment of the posterior segment of the eye.

Improvement of PnPP-19 peptide bioavailability for glaucoma therapy: Design and application of nanowafers based on PVA

PurposeThis study proposed the development and characterization of a system of drug nano-reservoirs, the nanowafers, containing PnPP-19, a synthetic peptide designed from a toxin present in the venom of the spider Phoneutria nigriventer, that showed hypotensive effect for rat's eye by the topical ocular use. MethodsA silicon base with circular wells were produced by electron beam lithography which was initially coated with a photoresist material. Then molds based on polydimethylsiloxane were made and, subsequently, poly (vinyl alcohol) nanowafers. The systems obtained were characterized by: i) morphological analysis using scanning and optical electron microscopy, ii) verification of the device's surface pH and its degree of swelling, iii) evaluation of the in vivo release profile of the nanowafer containing a marker (fluorescein) and comparison with the administration of the marker in the form of eye drops, iv) study of the effectiveness of this device with PnPP-19 concerning eye drops containing the same dose. ResultsPoly (vinyl alcohol) nanowafers were produced, characterized and presented satisfactory values of pH and swelling. The nanowafer was able to prolong the delivery of the peptide to the eye surface compared to eye drops. This effect was observed due to an increase in the fluorescence of the ocular surface when the nanowafer filled with fluorescein was used and by the improvement of the hypotensive effect of PnPP-19, transmitted through the device. ConclusionsIt was possible to evidence the safety and potential therapeutic effect of the nanowafer system with PnPP-19 for the treatment of diseases of the retina, such as glaucoma.

Chitosan/sulfobutylether-β-cyclodextrin based nanoparticles coated with thiolated hyaluronic acid for indomethacin ophthalmic delivery

Indomethacin (IND) is topically administered for the treatment of the anterior segment diseases such as conjunctivitis, uveitis, and inflammation prevention for post-cataract surgery, as well as posterior segment diseases as macular edema. Currently IND is available as 0.1% w/v hydroxypropyl-β-cyclodextrin-based eye drop formulation and its bioavailability is limited by several drawbacks such as the nasolacrimal duct draining, the reflex blinking and the low volume of the conjunctival sac. In this study, chitosan (CS)/sulfobutylether-β-cyclodextrin (SBE-β-CD) based nanoparticles (NPs) with a mean diameter of 340 (±7) nm, a ζ-potential value of +18.3 (±0.5) mV and coated with thiolated low molecular weight hyaluronic acid were formulated to improve both the solubility and the residential time in the conjunctival sac of the loaded drug IND. The NPs were prepared through the ionotropic gelation technique, exploiting the interaction between the positively charged amino group of CS and the negatively charged sulfonic group of SBE-β-CD. The mucoadhesive properties of the NPs were evaluated on chicken trachea and esophagus tissues using a texture analyser. The irritability effects of NPs were disclaimed with Hecam test. The developed coated NPs showed increased residential time in the conjunctival sac, displayed no irritancy or toxicity for local administration, making them an optimal and innovative drug delivery system for the treatment of anterior segment inflammation diseases. On the other hand, the uncoated NPs displayed better permeating properties since they are smaller and could be further exploited for the treatment of posterior segment diseases.

A Water-Free Omega-3 Fatty Acid Eye Drop Formulation for the Treatment of Evaporative Dry Eye Disease: A Prospective, Multicenter Noninterventional Study.

Purpose: NovaTears®+Omega-3 is a water-free eye drop solution with non-animal-derived omega-3 fatty acids. It allows to supplement omega-3 fatty acids directly in the tear film of patients with dry eye disease (DED). This post-market clinical follow-up (PMCF) study evaluated for the first time the effects on clinical signs and patient symptoms of DED, and safety and tolerability of NovaTears+Omega-3 (0.2%) eye drops, when used in accordance with its approved label. Methods: A prospective, multicenter, single-arm, uncontrolled, open-label observational cohort study was performed in patients suffering from symptoms of evaporative DED. Patients were treated 4 times daily bilaterally according to the instructions for use for 8 weeks, and standard of care clinical end points were assessed at baseline and follow-up. The trial was conducted at 2 investigational sites in Germany, Europe. Results: Thirty-six patients were included and 33 completed the study. NovaTears+Omega-3 (0.2%) showed clinically and statistically significant improvements in various clinical signs, such as total corneal staining, tear film break-up time, and Meibomian gland dysfunction (MGD) score, as well as in symptoms measured by Ocular Surface Disease Index (OSDI©) and visual analog scales over the 8-week treatment period with change from baseline P values all <0.0001. No worsening of any safety parameter (intraocular pressure, slit-lamp examination, visual acuity) was observed, and no adverse event was reported throughout the study. Conclusions: In this observational PMCF study, NovaTears+Omega-3 was safe and well tolerated. Treatment over an 8-week period resulted in significantly improved clinical signs and subjective symptoms in patients with evaporative dry eye. The study was registered at www.clinicaltrials.gov (NCT04521465).

Enzyme-instructed self-assembly of peptide-drug conjugates in tear fluids for ocular drug delivery

In vivo self-assembly of small molecules offers an excellent opportunity for targeted and long-term accumulation of a therapeutic agent at the lesion site. Here we demonstrate the strategy of enzyme-instructed self-assembly (EISA) by designing a phosphorylated peptide-drug (IBF-HYD-GFFpY) precursor through the ester bond to release active drugs at the target site. Meanwhile, the in vivo assembly can be achieved by the catalysis of alkaline phosphatase (ALP) in the tear fluid for ocular drug delivery efficiently. The in vitro enzymatic experiments indicate that the dephosphorylation of IBF-HYD-GFFpY occurs firstly with the yield of IBF-HYD-GFFY which subsequently self-assembles into the supramolecular hydrogel to afford sustained drug release over 96 h. In the treatment of lipopolysaccharide (LPS)-activated Raw 264.7 macrophages, IBF-HYD-GFFpY exerts the more potent anti-inflammatory efficacy than that of free ibuprofen (IBF) at the concentration of 200 μM. Moreover, the aqueous solution of IBF-HYD-GFFpY via topical instillation hardly causes ocular irritation, and displays longer precorneal retention compared to the conventional eye drop formulation. In addition, in the in vivo study, a rabbit model of endotoxin-induced uveitis (EIU) evidences the comparable therapeutic efficacy of IBF-HYD-GFFpY eye drops with that of clinically used 0.1 wt% diclofenac (DIC) sodium eye drops by the reduction of macrophage and leukocyte influx. This work, in situ EISA in the tear microenvironment directing in vivo self-assembly of small molecules, may guide a powerful approach for developing enzymatic self-assembled molecules as an efficient delivery system of ocular drugs.

Imaging Methods for the Assessment of a Complex Hydrogel as an Ocular Drug Delivery System for Glaucoma Treatment: Opportunities and Challenges in Preclinical Evaluation.

Glaucoma is one of the leading causes of loss of vision. The problems associated with the marketed formulations of anti-glaucoma drugs are low bioavailability, unwanted side effects, and low patient compliance. Hydrogels are an important class of soft materials that play a crucial role in developing an ocular drug delivery system. They assume a special significance in addressing the problems associated with the marketed formulations of eyedrops. An appropriate design of the hydrogel system capable of encapsulating single or multiple drugs for glaucoma has emerged in recent times to overcome such challenges. Although various modes of imaging play critical roles in assessing the efficacy of these formulations, evaluating hydrogels for drug permeation and retention remains challenging. Especially, the assessment of dual drugs in the hydrogel system is not straightforward due to the complexity in measuring drug penetration and retention for in vivo or ex vivo systems. There is a need to develop tools for the fabrication and validation of hydrogel-based systems that give insight into precorneal retention, biocompatibility, cellular uptake, and cell permeation. The current review highlights some of the complexities in formulating hydrogel and benchmarking technologies, including confocal laser scanning microscopy, fluorescent microscopy, slit-lamp biomicroscopy, and camera-based imaging. This review also summarizes recent evaluations of various hydrogel formulations using in vitro and in vivo models. Further the article will help researchers from various disciplines, including formulation scientists and biologists, set up preclinical protocols for evaluating polymeric hydrogels.

Alleviation of dry eye syndrome with one dose of antioxidant, anti-inflammatory, and mucoadhesive lysine-carbonized nanogels

Most dry eye syndromes (DES) are caused by oxidative stress and an overactive inflammatory response, leading to tear deficiency and excessive tear evaporation. Conventional eye drops for DES treatment require high doses and frequent administration due to their insufficient precorneal residence time. To overcome these problems, in this study, we have developed carbonized nanogels (CNGs) via the straightforward pyrolysis of lysine hydrochloride (Lys) to provide a long-lasting eye drop formulation for topical DES therapy. This methodology thermally converts Lys-into nitrogen-doped crosslinked polymers with embedded nanographitic structures, which enable efficient free radical scavenging. The cationic and crosslinked polymeric features of the Lys-CNGs also prolong the precorneal retention time and improve ocular bioavailability. These Lys-CNGs exhibit high biocompatibility with corneal epithelial cells both in vitro and in vivo, indicating their safety as eye drops. In a DES rabbit model, a single dose of Lys-CNGs (50 µg mL−1) can effectively alleviate the signs of DES within 4 days, whereas multiple treatments of 10-fold higher concentration of cyclosporine A are needed to achieve similar therapeutic effects (one dose every 12 h; 500 µg mL−1). The topical administration of Lys-CNGs enable a reduced therapeutic dose and extended dosing interval, thereby demonstrating a superior therapeutic efficacy compared to the commercial cyclosporine A eye drops. These Lys-CNGs, which exhibit significant free radical scavenging, anti-inflammatory activity, high biocompatibility, and a remarkable ocular bioadhesive property, hold great potential as a long-lasting eye drop formulation for the treatment of dry eye disease. Statement of significanceMultifunctional nanobiomaterial-based eye drops can render an ideal pharmaceutical formulation for the treatment of a variety of ocular surface diseases. To our knowledge, this is the first report describing the development of carbonized nanogels as topically administered therapeutics for alleviating dry eye syndrome (DES). We present evidence that the thermal transformation of lysine hydrochloride into carbonized nanogels (Lys-CNGs) endows superior antioxidant, anti-inflammatory, and bioadhesive properties. While a single dose of Lys-CNGs (50 µg mL−1) is sufficient to relieve the symptoms of DES for 4 days, multiple treatments of 10-fold higher concentration of commercially available cyclosporine eye drops are needed to achieve similar therapeutic outcomes (one dose every 12 h; 500 µg mL−1), suggesting an effective and long-lasting ocular carbonized nanomedicine.

Lyophilized ophthalmologic patches as novel corneal drug formulations using a semi-solid extrusion 3D printer

3D printing technology is a novel and practical approach for producing unique and complex industrial and medical objects. In the pharmaceutical field, the approval of 3D printed tablets by the US Food and Drug Administration has led to other 3D printed drug formulations and dosage forms being proposed and investigated. Here, we report novel ophthalmologic patches for controlled drug release fabricated using a semi-solid material extrusion-type 3D printer. The patch-shaped objects were 3D printed using hydrogel-based printer inks composed of hypromellose (HPMC), sugar alcohols (mannitol, xylitol), and drugs, then freeze-dried. The viscous properties of the printer inks and patches were dependent on the HPMC and sugar alcohol concentrations. Then, the physical properties, surface structure, water uptake, antimicrobial activity, and drug release profile of lyophilized patches were characterized. Lyophilized ophthalmologic patches with different dosages and patterns were fabricated as models of personalized treatments prepared in hospitals. Then, ophthalmologic patches containing multiple drugs were fabricated using commercially available eye drop formulations. The current study indicates that 3D printing is applicable to producing novel dosage forms because its high flexibility allows the preparation of patient-tailored dosages in a clinical setting.