Ocular Inserts Research Articles

Methods for Evaluation of Ocular Insert with Classification and Uses in Various Eye Diseases-A Review

Methods for Evaluation of Ocular Insert with Classification and Uses in Various Eye Diseases-A Review

Design and evaluation of soluble ocular insert for controlled release of chloramphenicol

Design and evaluation of soluble ocular insert for controlled release of chloramphenicol

IN VIVO STUDY OF PROMISING FORMULATED OCULAR BIO-ADHESIVE INSERTS OF CIPROFLOXACIN HYDROCHLORIDE COMBINATION WITH XANTHAN GUM AND CARBOPOL

<p class="Default"><strong>Objective: </strong>To study the <em>in vivo</em> behaviour and irritant properties of different ocular bio-adhesive inserts of ciprofloxacin hydrochloride (CFX-HCl) prepared using a spray dried (SD2) matrix system consisting of xanthan gum, carbopol, and propylene glycol.</p><p class="Default"><strong>Methods: </strong>CFX-HCl in aqueous humor samples was analysed using HPLC method. Applying a mobile phase of 0.01M sodium acetate: methanol (70:30 v/v) with pH around 3.00, and using Purosphere star 100RP-18 column (125 mm × 4.6 mm × 5 µm). The <em>in vivo</em> behaviour and irritant properties of ocular inserts was studied on rabbits. Twelve rabbits were used for the study and were divided into four groups. After placing the insert in the eye 100 µl of the aqueous humor was withdrawn at different time intervals in order to measure the concentration profile of CFX-HCl. The tested formulae R, F1, F2, and F3 were all containing 6.25 mg of CFX-HCl.</p><p class="Default"><strong>Results: </strong>The method was well validated according to linearity, recovery, and precision. Where the calibration curve was linear over a concentration range of (2.500–7.826) µg/ml, with an average recovery of 99.76%. The presence of the matrix system enhances the absorption of CFX-HCl and sustains its release up to four days leading to increasing its bioavailability. Also, the ocular inserts of F2 and F3 have better biocompatibility compared with R and F1.</p><strong>Conclusion: </strong>The analysis method was found sensitive, accurate and precise and could be used to assess the <em>in vivo</em>behaviour of CFX-HCl. The ratio of the free drug to the matrix system controlled the rate of drug release.<p class="Default"> </p><p> </p>

DESIGN AND EVALUATION OF CONTROLLED-RELEASE OCULAR INSERTS OF BRIMONIDINE-TARTRATE AND TIMOLOL MALEATE

<p><strong>Objective: </strong>The current work was attempted to formulate and evaluate a controlled-release matrix-type ocular inserts containing a combination of brimonidine tartrate and timolol maleate, with a view to sustain the drug release in the cul-de-sac of the eye.<strong></strong></p><p><strong>Methods: </strong>Initially, the infrared studies were done to determine the drug–polymer interactions. Sodium alginate-loaded ocuserts were prepared by solvent casting technique. Varying the concentrations of polymer—sodium alginate, plasticizer—glycerine, and cross-linking agent—calcium chloride by keeping the drug concentration constant, made a total of nine formulations. These formulations were evaluated for its appearance, drug content, weight uniformity, thickness uniformity, percentage moisture loss, percentage moisture absorption, and <em>in vitro </em>release profile of the ocuserts. Finally, accelerated stability studies and the release kinetics were performed on the optimised formulation.<strong></strong></p><p><strong>Results: </strong>It was perceived that polymer, plasticizer, and calcium chloride had a significant influence on the drug release. The data obtained from the formulations showed that formulation—F9 was the optimised formulation, which exhibited better drug release. The release data of the optimised formulation tested on the kinetic models revealed that it exhibited first-order release kinetics. <strong></strong></p><p><strong>Conclusion: </strong>It can be concluded that a natural bioadhesive hydrophilic polymer such as sodium alginate can be used as a film former to load water soluble and hydrophilic drugs like brimonidine tartrate and timolol maleate. Among all formulations, F9 with 400 mg sodium alginate, 2% calcium chloride and 60 mg glycerin were found to be the most suitable insert in terms of appearance, ease of handling, thickness, <em>in vitro</em> drug release and stability.</p>

A novel nanoparticles impregnated ocular insert for enhanced bioavailability to posterior segment of eye: In vitro, in vivo and stability studies

The present investigation was carried out to demonstrate with the help of in vitro and in vivo studies that nanoparticles impregnated ocular inserts effectively delivers significant concentration of drug to the posterior segment of eye after topical administration for treatment of glaucoma. Drug loaded Nanoparticles and their ocular insert have been reported to reduce side effects of orally administered Acetazolamide. Eudragit NPs were prepared by the solvent diffusion nanoprecipitation technique. The prepared NPs were evaluated for various parameters such as particle size, zeta potential, % entrapment efficiency, % drug loading, DSC, FTIR, TEM and stability studies. Ocular inserts of NPs were prepared by solvent casting method. The prepared ocular inserts were evaluated for thickness, content uniformity, folding endurance, disintegration time, morphology and stability study. The NPs and ocular inserts were evaluated for in-vitro drug diffusion study, ex-vivo trans-corneal permeability study, in-vivo ocular tolerability and intra ocular pressure (IOP) reduction study. The optimized batch was stable for a period of 3months in lyophilized form. The optimized formulations had size range of 367nm±8nm, zeta potential around +7mV±1.3mV and 51.61%±3.84% entrapment efficiency with 19%±1.40% drug loading. The ex-vivo trans-corneal study showed higher cumulative corneal permeation, flux across corneal tissue (2.460±0.028μg/ml) and apparent corneal permeability (3.926×10−6cm2/s & 3.863×10−6cm2/s) from drug loaded Eudragit NPs and Ocular inserts as compared to drug solution (0.671±0.020μg/ml & 3.166×10−6cm2/s). In-vivo study showed the Eudragit NPs and ocular insert produced significant (P<0.001) lowering in intra ocular pressure compared with the solution of free drug after 3h of topical ocular administration. Plain Eudragit NPs caused no inflammation and/or discomfort in rabbit eyes and neither affected the intra ocular pressure establishing their safety and non irritancy.

Six-Month Intraocular Pressure Reduction with a Topical Bimatoprost Ocular Insert: Results of a Phase II Randomized Controlled Study

Improving adherence to manage elevated intraocular pressure (IOP) remains an unmet need. A topical bimatoprost ocular insert was compared with twice-daily timolol eye drops in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT) treated for 6 months. Parallel-arm, multicenter, double-masked, randomized, controlled trial. One hundred thirty adult OAG or OHT patients. Eligible patients were randomized 1:1 to receive a bimatoprost insert plus artificial tears twice daily or a placebo insert plus timolol (0.5% solution) twice daily for 6 months after a screening washout period. Diurnal IOP measurements (at 0, 2, and 8 hours) were obtained at baseline; weeks 2, 6, and 12; and months 4, 5, and 6. Key eligibility included washout IOP of 23 mmHg or more at time 0, IOP of 20 mmHg or more at 2 and 8 hours, and IOP of 34 mmHg or less at all time points; no prior incisional surgery for OAG or OHT; and no known nonresponders to prostaglandins. The primary efficacy end point examined the difference in mean change from baseline in diurnal IOPs (point estimate, 95% confidence interval) across 9 coprimary end points at weeks 2, 6, and 12 comparing the bimatoprost arm with the timolol arm using a noninferiority margin of 1.5 mmHg. Secondary end points were diurnal IOP measurements at months 4, 5, and 6 and adverse events (AEs). A mean reduction from baseline IOP of-3.2 to-6.4 mmHg was observed for the bimatoprost group compared with-4.2 to-6.4 mmHg for the timolol group over 6 months. The study met the noninferiority definition at 2 of 9 time points but was underpowered for the observed treatment effect. Adverse events were consistent with bimatoprost or timolol exposure; no unexpected ocular AEs were observed. Primary retention rate of the insert was 88.5% of patients at 6 months. Clinically relevant reduction in mean IOP was observed over 6 months with a bimatoprost ocular insert and seems to be safe and well tolerated. The topically applied bimatoprost insert may provide an alternative to daily eye drops to improve adherence, consistency of delivery, and reduction of elevated IOP.

Ocular inserts based on chitosan and brimonidine tartrate: Development, characterization and biocompatibility

The glaucoma is an ocular pathology characterized by the increase of intraocular pressure and possibility of retinal degeneration. The treatment is based on the administration of eye drops. However, they do not induce the permanence of drug in the eye, compromising its bioavailability. In this study, inserts based on chitosan and brimonidine tartrate were developed to treat the glaucoma by improving the drug bioavailability. Inserts were characterized using different analytical techniques FTIR, SEM, DSC and WAXS. The in vitro release profile of drug from inserts was evaluated. The in vitro biocompatibility against ARPE-19 and MIO-M1 cells was investigated. The in vivo biocompatibility using the chorioallantoic membrane was also demonstrated. Analytical techniques demonstrated that the amorphous drug was physically dispersed into the polymeric chains without chemical interactions. However, a portion of drug crystals was on the surface of systems. Inserts provided the controlled release of drug for 30 days without a burst effect. Inserts did not induce a deleterious effect to ocular cells, indicating their biocompatibility. They were also well tolerated in vivo, suggesting the absence of toxicity. These inserts could be potential delivery systems to reduce the intraocular pressure and to induce neuroprotective effects in glaucomatous patients.

Novel in situ gelling ocular inserts for voriconazole-loaded niosomes: design, in vitro characterisation and in vivo evaluation of the ocular irritation and drug pharmacokinetics

This work aimed to develop voriconazole in situ gelling ocular inserts loaded with niosomal suspension. Niosomes and mixed niosomes were prepared using span 40 and span 60 with pluronic L64 and pluronic F127. The entrapment efficiency percentages (EE%), mean vesicle size, polydispersity index (PI), zeta potential and in vitro drug release of these niosomes were evaluated. F3-mixed niosomes prepared with span 60 and pluronic L64 was selected, due to its highest EE; optimum vesicle size with smallest PdI and suitable release pattern of the drug (63% after 8 h). In situ ocular inserts were prepared using sodium carboxymethylcellulose (CMC Na) and sodium alginate (ALG) and characterised for surface morphology, surface pH, water uptake, mucoadhesion and in vitro release. ALG in situ ocular insert (S2) was selected for further in vivo evaluation of the ocular irritation and drug pharmacokinetics in the aqueous humour of rabbit's eyes. S2 in situ gelling ocular insert was non-irritant and showed significantly (p < 0.01) higher Cmax, delayed Tmax and increased bioavailability.

A Summary of Recent Advances in Ocular Inserts and Implants

With the physiological and anatomical constraints put forth by the eye it is a significant challenge to the pharmaceutical scientists to target drugs to the posterior segment of the eye. Severe ocular complications such as glaucoma, uveitis, cytomegalovirus retinitis, cataracts, age related macular degeneration, diabetic retinopathy, and retinitis pigmentosa pose urgency for the treatment of ocular diseases. Hence novel drug delivery strategies and formulations are to be developed and explored to overcome and treat these posterior ocular disorders. At present the topical and intravitreal routes are widely used to deliver therapeutic entities to retinal tissue. Various controlled delivery systems, such as ocular inserts and implants are in the progress of development and may improve drug delivery drastically in the years to come. In this review, we discuss the recent developments in ocular delivery using ocular implants and inserts.

Evaluation Study of Sustained Release Ocular Insert of Brimonidine Tartrate and Timolol

The present work showed that incorporation of hydrophilic polymer into hydrophobic matrix system can be successfully done in order to model ocular inserts of Brimonidine Tartrate and Timolol providing promising controlled release delivery system. The control of IOP, systemic absorption and hence possible side effects using inserts was found to be better than conventional eye drops. Thus, on the basis of in-vivo anti-glaucoma activity, ocular safety test and stability studies, it can be concluded that this ocular insert can be a promising once-a-day controlled release formulation after due considerations of human in vivo studies.

Formulation development and evaluation of opthalmic ocusert containing aciclovir

The aim of formulating aciclovir occusert was to prolong the drug residence time after ocular administration to achieve the controlled release of drug. Aciclovir is a antiviral agent and its use in the treatment of viral infections like herpes simplex infections. Ocular inserts were prepared by solvent casting method. Drug reservoir and rate controlling membrane were prepared using different hydrophilic and hydrophobic polymers respectively with polyethylene glycol 400 as the plasticizer.DSC and IR spectral studies were performed to confirm the interaction of drug and polymers in formulation. The ocusert were evaluated for their physical and chemical and in vitro – release characteristics. The developed formulation was stable sterile and non irritant. The final formulation F2 was subjected to UV irritation for sterilization. In the present work it was concluded that the F2 formulation shows 99.16% controlled release upto 8 hrs when compared to other formulations.

Formulation and In Vitro-In Vivo Correlation of Timolol Maleate Ocular Insert

The concept of in-vitro and in-vivo correlation studies was used in pharmaceutical research because a simple in-vitro release study on a drug product will be insufficient to predict its therapeutic efficiency. Therefore, correlation between in-vitro release behavior of a drug and its in-vivo absorption in rabbits must be demonstrated experimentally to reproduce therapeutic response. Aim of the study was to study the in vitro and in vivo evaluation and correlation of timolol maleate ocular insert. Timolol maleate ocular inserts were prepared by solvent casting method using guar gum in different proportions (0.25% w/v, 0.50% w/v, 0.75 % w/v, and 1.0% w/v). In vitro transcorneal permeation study was performed on goat cornea using modified Franz diffusion cell. The in vivo study was done using New Zeland albino rabbits and the in vitro invivo correlation (IVIVC) was determined by plotting a graph of in vivo drug release was plotted against in vitro release to determine the correlation. The cumulative % drug releases from the formulation ranged from 50.22±1.41 to 97.72±0.67over a period of 24 h. In vivo release of the timolol maleate from the optimized ocular inserts F2, through conjunctival cul-de-sac of rabbits was 76.03±1.43 at the end of 24 h. A high value of correlation coefficient (r2=0.9965) suggested good correlation between the in vitro-in vivo data of the timolol maleate ocular insert. Keywords: Guar gum, IVIVC, in vitro transcorneal permeation study, ocular insert, timolol maleate Formulasi dan Korelasi In vitro-In vivo pada Timolol Maleat dengan Penyisipan Okular Konsep studi korelasi in-vitro dan in-vivo telah digunakan dalam penelitian farmasi karena studi invitro yang sederhana pada produk obat tidak cukup untuk memprediksi efisiensi terapi. Oleh karena itu, korelasi antara pelepasan in vitro obat dan penyerapan secara in vivo pada kelinci harus dapat didemonstrasikan secara eksperimental untuk menghasilkan respons terapi. Tujuan penelitian ini adalah mengevaluasi formulasi dan korelasi in vitro dan invivo pada timolol maleat dengan penyisipan okular. Penyisipan okular timolol maleat disiapkan dengan metode pemilihan pelarut menggunakan guar gum pada proporsi berbeda (0,25% w/v, 0,50% w/v, 0,75 % w/v, dan 1,0% w/v). Permeasi transkorneal in vitro dilakukan pada kornea kambing menggunakan modifikasi difusi sel Franz. Studi in vivo dilakukan pada kelinci albino New Zeland dan korelasi invitro invivo (IVIVC) ditentukan dengan pelepasan in vivo obat yang diplot pada grafik yang dihubungkan dengan pelepasan in vitro untuk menentukan korelasi. Pelepasan kumulatif obat (%) dari formulasi memiliki rentang antara 50,22±1,41 sampai 97,72±0,67 pada lebih dari periode 24 jam. Pelepasan in vivo timolol maleat dari penyisipan okular teroptimasi F2, melalui konjungsi kul-de-sak pada kelinci yaitu 76,03±1,43 pada akhir periode 24 jam. Nilai yang tinggi dari koefisien korelasi (r2=0,9965) menunjukkan korelasi yang baik antara invitro dan invivo data penyisipan okular pada timolol maleat. Kata kunci: Guar gum, IVIVC, penyisipan okular, studi permeasi transkorneal in vitro, timolol maleat

Pharmaceutical Development and Evaluation of Reservoirtype Ciprofloxacin Ocular Insert

Ocular inserts of ciprofloxacin hydrochloride were prepared with the aim of achieving once a day administration. Drug reservoir was prepared using sodium CMC while rate controlling membrane was prepared using Eudragit RS100 and RL100. Ocular inserts were evaluated for their physicochemical parameters like thickness, weight uniformity, drug content, percent moisture loss, and percent moisture absorption. The in vitro drug release studies were carried out using Bi-chambered donor receiver compartment model. In vitro drug release kinetic data was treated according to Zero, First, and Higuchi kinetics to access the mechanism of drug release. At the end of 24th hr, in-vitro percentage drug release was obtained for the formulations RF1 was% 46.02 and for RF5 was 98.23%. The drug release from the formulation RF5 (Eudragit RS and RL 100 (1:1)) was 98.23 % at the end of 24th hour which was available as controlled and prolonged. In Kors Meyer Peppas, n value in optimized batch (RF5) was observed 1.399 which indicated super case II transport occurs. All physical parameters evaluated were satisfactory. So formulation RF5 was selected as the best formulation.

Sterilization of Ocular Medical Inserts with Immobilized Proteins

The influence of sterilization of ocular medicinal inserts with human serum albumin (HSA), lysozyme, papain, and urea on the preservation of their physicochemical properties was studied. It was found that the physicochemical properties of inserts with HSA and lysozyme preserved totally their physicochemical properties after sterilization by γ-irradiation in doses of 10, 17, and 28 kGy. The influence of γ-irradiation on the proteolytic activity of ocular medicinal inserts with papain and urea was dose-dependent and reduced the activity by 85 and 93% and led to its complete loss. Adding antiseptics used in the production of ophthalmologic preparations (nipagin, sodium metabisulfite, benzyl alcohol, benzalkonium chloride, etc.) caused an activity loss of the ocular medicinal inserts with papain and urea and did not provide microbiological purity and sterility. UV irradiation of ocular medicinal inserts with papain and urea produced microbiologically pure inserts that preserved 63.8% of the proteolytic activity. Manufacturing of ocular medicinal inserts with papain and urea under aseptic conditions using sterilizing filtration (79.7% activity preservation) was recommended for sterilization.

Исследование стерилизации глазных лекарственных пленок с иммобилизованными белками

Исследовано влияние стерилизации глазных лекарственных пленок с сывороточным альбумином человека, лизоцимом, папаином и мочевиной на сохранение их физико-химических свойств. Установлено полное сохранение физико-химических свойств пленок с сывороточным альбумином человека и лизоцимом после стерилизации γ-облучением в дозах 10, 17, 28 кГр. Показано дозозависимое влияние γ-облучения на протеолитическую активность глазных лекарственных пленок с папаином и мочевиной, приводящее к снижению таковой на 85, 93 % и ее полной потере. Дополнительное введение антисептиков, используемых в производстве офтальмологических препаратов (нипагина, метабисульфита натрия, бензилового спирта, бензалкония хлорида и др.), приводит как к потере активности глазных лекарственных пленок с папаином и мочевиной, так и не обеспечивает микробиологическую чистоту и стерильность препарата. УФ-облучение глазных лекарственных пленок с папаином и мочевиной способствует получению микробиологически чистых препаратов с сохранением протеолитической активности 63,8 %. Для стерилизации глазных лекарственных пленок с папаином и мочевиной предложено их изготовление в асептических условиях с применением стерилизующей фильтрации (сохранение активности 79,7 %).

Advances in ophthalmic drug delivery.

Various strategies for ocular drug delivery are considered; from basic formulation techniques for improving availability of drugs; viscosity enhancers and mucoadhesives aid drug retention and penetration enhancers promote drug transport into the eye. The use of drug-loaded contact lenses and ocular inserts allows drugs to be better placed where they are needed for more direct delivery. Developments in ocular implants gives a means to overcome the physical barriers that traditionally prevented effective treatment. Implant technologies are under development allowing long-term drug delivery from a single procedure, these devices allow posterior chamber diseases to be effectively treated. Future developments could bring artificial corneas to eliminate the need for donor tissue and one-off implantable drug depots lasting the patient's lifetime.

Development and Validation of a High Performance Liquid Chromatographic Method for Determination of Bimatoprost in Chitosan-Based Ocular Inserts

Glaucoma is one of the most prominent causes of blindness around the world. Conventional eye-drops, currently used in the treatment of the disease, must be taken every day and can cause severe systemic side effects. In order to address these problems, a solvent casting method was used to produce chitosan-based polymeric ocular inserts for controlled release of bimatoprost, a prostaglandin analog highly powerful in reducing intraocular pressure. The development and validation of quality control methods are an important concern in the field of pharmaceutical technology when dealing with new drug delivery systems. In this context, a rapid method using reverse phase high-performance liquid chromatography with ultraviolet detection was developed and validated for the determination of the pharmaceutical into the chitosan-based polymeric matrix. The method was linear (determination coefficient higher than 0.99) over the range of 3.00–15.00 µg/mL, precise (relative standard deviation lower than 5%), accurate (recovery of 104.09%), selective, and had limits of quantification and detection of 0.90 and 0.60 µg/mL, respectively. The validated method was successfully employed for assay and performance measurements of bimatoprost in the developed formulation.

Ocular Drug Delivery Systems for Treatment of Glaucoma

Glaucoma is a common eye disease that can cause irreversible blindness if left undiagnosed and untreated. Glaucoma is a prevalent neurodegenerative disorder of the eye. Glaucoma can be roughly divided into two main categories "open angle" and "closed angle" (or "angle closure") glaucoma. Every available treatment to prevent progressive glaucoma involves a certain amount of risk and financial expense. Conventional first-line treatment of glaucoma usually begins with the use of a topical selective or nonselective β-blockers or topical prostaglandin analogs. Second-line drugs of choice include α-agonists and topical carbonic anhydrase inhibitors. Parasympatho-mimetic agents, most commonly pilocarpine, are considered third-line treatment options. For patients who do not respond to antiglaucoma medications, laser trabeculoplasty and incisional surgery are further methods that can be used to lower intraocular pressure. Ocular drug delivery is hampered by the barriers protecting the eye. The bioavailability of the active drug substance is often the major hurdle to overcome. Conventional ocular dosage form, including eye drops, is no longer sufficient to combat ocular diseases. This article reviews the better understanding about glaucoma disease like prevention and diagnosis and explores various approaches like niosomes, liposomes, hydrogels, nanoparticles, nanosuspensions, microparticles, microemulsions, prodrugs and ocular inserts to improve the ocular bioavailability of drug and provide continuous and controlled release of the drug to the anterior and posterior chamber of the eye. In near future, a great deal of attention will be paid to develop a suitable and effective treatment for the vision threatening disorders like glaucoma.

Bimatoprost-loaded ocular inserts as sustained release drug delivery systems for glaucoma treatment: in vitro and in vivo evaluation.

The purpose of the present study was to develop and assess a novel sustained-release drug delivery system of Bimatoprost (BIM). Chitosan polymeric inserts were prepared using the solvent casting method and characterized by swelling studies, infrared spectroscopy, differential scanning calorimetry, drug content, scanning electron microscopy and in vitro drug release. Biodistribution of 99mTc-BIM eye drops and 99mTc-BIM-loaded inserts, after ocular administration in Wistar rats, was accessed by ex vivo radiation counting. The inserts were evaluated for their therapeutic efficacy in glaucomatous Wistar rats. Glaucoma was induced by weekly intracameral injection of hyaluronic acid. BIM-loaded inserts (equivalent to 9.0 µg BIM) were administered once into conjunctival sac, after ocular hypertension confirmation. BIM eye drop was topically instilled in a second group of glaucomatous rats for 15 days days, while placebo inserts were administered once in a third group. An untreated glaucomatous group was used as control. Intraocular pressure (IOP) was monitored for four consecutive weeks after treatment began. At the end of the experiment, retinal ganglion cells and optic nerve head cupping were evaluated in the histological eye sections. Characterization results revealed that the drug physically interacted, but did not chemically react with the polymeric matrix. Inserts sustainedly released BIM in vitro during 8 hours. Biodistribution studies showed that the amount of 99mTc-BIM that remained in the eye was significantly lower after eye drop instillation than after chitosan insert implantation. BIM-loaded inserts lowered IOP for 4 weeks, after one application, while IOP values remained significantly high for the placebo and untreated groups. Eye drops were only effective during the daily treatment period. IOP results were reflected in RGC counting and optic nerve head cupping damage. BIM-loaded inserts provided sustained release of BIM and seem to be a promising system for glaucoma management.

Erratum to: Formulation, in vitro and in vivo evaluation of lidocaine HCl ocular inserts for topical ocular anesthesia

Erratum to: Formulation, in vitro and in vivo evaluation of lidocaine HCl ocular inserts for topical ocular anesthesia