In-situ forming biodegradable implants for sustained Fluocinolone acetonide release to the posterior eye: In-vitro and in-vivo investigations in rabbits.

Delivering medication to the posterior segment of the eye presents a significant challenge. Intravitreal injection has emerged as the preferred method for drug delivery to this area. However, current injectable non-biodegradable implants for fluocinolone acetonide (FA) require surgical removal after prolonged drug release, potentially affecting patient compliance. This study aimed to develop an in-situ forming biodegradable implant (ISFBI) optimal formulation containing PLGA504H and PLGA756S (50:50 w/w%) with the additive NMP solvent. The goal was to achieve slow and controlled release of FA over a two-month period with lower burst release, following a single intravitreal injection. Through morphology, rheology, stability and in-vitro release evaluations, the optimal formulation demonstrated low viscosity (0.12-1.25 Pa. s) and sustained release of FA at a rate of 0.36 µg/day from the third day up to two months. Furthermore, histopathology and in-vivo studies were conducted after intravitreal injection of the optimal formulation in rabbits' eye. Pharmacokinetic analysis demonstrated mean residence time (MRT) of 20.02 ± 0.6 days, half-life (t1/2) of 18.80 ± 0.4 days, and clearance (Cl) of 0.29 ± 0.03 ml/h for FA in the vitreous humor, indicating sustained and slow absorption of FA by the targeted retinal tissue from vitrea over the two-month period and eliminating through the anterior section of the eye, as revealed by its presence in the aqueous humor. Additionally, FA exhibited no detection in the blood and no evidence of systemic side effects or damage on the retinal layer and other organs. Based on these findings, it can be concluded that in-situ forming injectable biodegradable PLGA implants can show promise as a long-acting and controlled-release system for intraocular drug delivery.

Preliminary evaluation of YUTIQ™ (fluocinolone acetonide intravitreal implant 0.18 mg) in posterior uveitis.

Uveitis is a major cause of ocular morbidity, potentially leading to significant visual impairment. The recent adoption of alternative drug delivery options has led to the development of new sustained-delivery corticosteroid systems, able to manage successfully chronic noninfectious posterior uveitis. The treatment goal is to target the site of inflammation with low dose of corticosteroids, delivered over an extended period of time, to minimize the cumulative damage resulting from repeated recurrences, reducing both injections frequency and ocular side effects. This article will review the pharmacology and preliminary clinical data of the 0.18 mg fluocinolone acetonide intravitreal implant (YUTIQ™), to show its efficacy and safety in the treatment of noninfectious posterior uveitis.

Cow ghee fortified ocular topical microemulsion; in vitro, ex vivo, and in vivo evaluation.

Aim: Utility of cow ghee (CG) as permeation enhancer in development of topical ocular microemulsion (ME) for delivery of fluocinolone acetonide (FA) to posterior eye. Methods: For ME preparation, oil, surfactant and cosurfactant were screened based on solubility of FA. Pseudoternary phase diagrams were constructed to determine their ratios. The developed MEs were characterised for their physicochemical properties like size, polydispersity index, zeta potential, and stability etc. They were evaluated for ex vivo permeation and irritation. In vivo pharmacokinetic studies were performed on Sprague dawley rats. Results: Lauroglycol as oil, labrasol as surfactant and Transcutol as cosurfactant were selected. The optimised ratio of oil:surfactant:cosurfactant:water was 4:23:23:50. The developed FA loaded ME fortified with CG was characterised. Ex vivo study revealed higher permeation and non-irritancy. In vivo pharmacokinetic study showed retention of CG fortified ME in posterior rat eye. Conclusion: Present investigation established CG as permeation enhancer for ocular topical formulation.

Development of Nanofibrous Ocular Insert for Retinal Delivery of Fluocinolone Acetonide.

PURPOSE: Topical formulations are less effective in treating retinal inflammatory diseases due to poor avaliability of drug at target tissues. Nanofibers due to their unique structural features show great promise for drug delivery to retinal segment following topical application. AIM: The aim of the present study was to design preservative free controlled release ocular drug delivery system for improved drug availability at the target site with higher patient compliance. MATERIALS AND METHODS: The fluocinolone acetonide-loaded PCL nanofibers were prepared by electrospinning technique. Optimized formulation was chosen on the basis of outcome of inclusive in-vitro characterization, SEM, FTIR, XRD, in-vitro release, isotonicity, sterility, and biodegradibility. The relative efficacy of optimized formulation was investigated in rabbits against its marketed counter part. RESULTS: The prepared fibers were sterile, smooth, non-woven and they showed extended drug release behavior. Ocular and plasma kinetics showed therapeutic levels at the target site while minimizing systemic distribution. CONCLUSIONS: Preclinical results established that PCL nanofibers serve as a promising drug carrier for retinal segment.

Intravitreal fluocinolone acetonide implant (ILUVIEN®) for diabetic macular oedema: a literature review.

Diabetic macular oedema (DMO) is a common complication of diabetic retinopathy and may lead to severe visual loss. In this review, we describe the pathophysiology of DMO and review current therapeutic options such as macular laser photocoagulation, anti-vascular endothelial growth factor agents, and steroid implants with a focus on the new fluocinolone acetonide implant, ILUVIEN®. The results of the Fluocinolone Acetonide in Diabetic Macular Edema (FAME) studies are also presented together with the results of real-world studies to support the clinical use of ILUVIEN® in achieving efficient resolution of DMO and improving vision and macular anatomy in this challenging group of patients.

ILUVIEN® technology in the treatment of center-involving diabetic macular edema: a review of the literature.

Diabetic macular edema (DME) is one of the major causes of blindness, caused primarily by hyperglycemia and results from multiple pathological processes mostly secondary to increased levels of VEGF and other inflammatory cytokines. DME management includes control of systemic risk factors together with laser photocoagulation, frequent intraocular injections of anti-VEGF agents and steroids implants. Recent adoption of novel alternative drug delivery options has led to the development of sustained release ocular implants with longer duration of action with less injection frequency. This article will review the pharmacology and clinical data in terms of efficacy, safety and benefits of the sustained release steroid implants in treatment of DME with special emphasis on the fluocinolone acetonide ILUVIEN® implant.

INTRAVITREAL CORTICOSTEROIDS IN DIABETIC MACULAR EDEMA: PHARMACOKINETIC CONSIDERATIONS.

PURPOSE: To review the relationship between kinetics, efficacy, and safety of several corticosteroid formulations for the treatment of diabetic macular edema. METHODS: Reports of corticosteroid use for the treatment of diabetic macular edema were identified by a literature search, which focused on the pharmacokinetics, efficacy, and safety of these agents in preclinical animal models and clinical trials. RESULTS: Available corticosteroids for diabetic macular edema treatment include intravitreal triamcinolone acetonide, dexamethasone, and fluocinolone acetonide. Because of differences in solubility and bioavailability, various delivery mechanisms are used. Bioerodible delivery systems achieve higher maximum concentrations than nonbioerodible formulations. There is a relationship between visual gains and drug persistence in the intravitreal compartment. Safety effects were more complex; level of intravitreal triamcinolone acetonide exposure is related to development of elevated intraocular pressure and cataract; this does not seem to be the case for dexamethasone, where two different doses showed similar mean intraocular pressure and incidence of cataract surgery. With fluocinolone acetonide, rates of intraocular pressure elevations requiring surgery seem to be dose related; rates of cataract extraction were similar regardless of dose. CONCLUSION: Available corticosteroids for diabetic macular edema exhibit different pharmacokinetic profiles that impact efficacy and adverse events and should be taken into account when developing individualized treatment plans.

Sustained-release fluocinolone acetonide intravitreal insert for macular edema: clinical pharmacology and safety evaluation.

INTRODUCTION: Inflammation plays a key role in the pathological processes leading to macular edema. Sustained release, low-dose intraocular corticosteroid delivery devices provide long-term anti-inflammatory therapy. Recently, a novel fluocinolone acetonide intravitreal insert (FAi, Iluvien), has been introduced with promising long-term results in the treatment of macular edema. AREAS COVERED: An extensive review of the literature in the English language was performed to provide comprehensive information on the pharmacological properties of FAi and its safety and efficacy data from various multi-center randomized clinical trials. EXPERT OPINION: The FAc, Retisert is a sustained-release device that is surgically implanted in the vitreous and has been approved by the US FDA for the treatment of non-infectious intermediate, posterior or panuveitis. FAi was developed after FAc and is an intravitreal corticosteroid delivery system that allows controlled release of therapeutic levels of fluocinolone acetonide (FA). Initial efficacy and safety data suggest that this delivery system maintains clinical effectiveness for up to 3 years after a single delivery of the device. This second-generation fluocinolone delivery device has shown superior safety results in clinical trials compared to the previous version of the higher dose FAc (0.59 mg). Sustained delivery preparations may help to reduce the treatment burden and its associated risks by decreasing the frequency of intravitreal injections. However, much needs to be learnt from additional clinical trials, post-marketing surveillance and results of extension studies. Concerns of intravitreal corticosteroids, such as cataract and increase in intraocular pressure, remain major challenges for this therapeutic strategy.

Ocular pharmacokinetics of fluocinolone acetonide following Iluvien implantation in the vitreous humor of rabbits.

PURPOSE: The purpose of this study was to evaluate the systemic and ocular pharmacokinetics (PK) of fluocinolone acetonide (FAc) following administration of Iluvien(®) intravitreal implants. METHODS: The FAc intravitreal implant was administered to rabbits in 3 doses (0.2, 0.5, and 1.0 µg/day). The concentration of FAc was measured by a validated liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) method in plasma and ocular tissues at various time points through month 24. RESULTS: Following administration of the 0.2 µg/day implant, FAc levels peaked in most tissues at day 2 or 8, reached approximate steady state levels by month 3 and very gradually decreased over the duration of the study. The FAc level in the aqueous humor was not measurable at most time points in the rabbit. FAc was still present in most ocular tissues at 2 years. The 0.5 and 1.0 µg/day dose groups followed the same pattern through month 9. The elimination half lives in the tissues for which it was measurable were greater than 83 days. Exposure to FAc was highest in the choroid/retinal pigment epithelium for all doses, followed by lens and retina. CONCLUSIONS: The results of this study demonstrate sustained delivery of FAc from the Iluvien intravitreal implant in the ocular tissue of rabbits. Retina and lens FAc levels with the Iluvien implant were approximately 1/10 those reported with the Retisert(®) implant. FAc levels in the aqueous were not measureable with Iluvien where they were measured for 12 months with Retisert.

Development characterization and skin permeating potential of lipid based novel delivery system for topical treatment of psoriasis.

The aim of this study was to develop, optimize and evaluate the potential of solid lipid nanoparticles (SLNs) as a topical delivery system for targeted and prolonged release of Fluocinolone acetonide (FA). FA loaded SLNs were successfully developed by an emulsification-ultrasonication method and optimized using 17-run, 3-factor, 3-level Box-Behnken design of Design Expert software. SLNs were evaluated for particle size, polydispersity index, zeta potential, drug encapsulation efficiency and drug loading. Shape and surface morphology of the SLNs confirmed spherical shape of nanoparticles when investigated under a transmission electron microscope. Complete encapsulation of drug in the nanoparticles was confirmed by powder X-ray diffraction and differential scanning calorimetry. The drug release study confirmed prolonged release from the SLNs following Higuchi release kinetics with R(2) value of 0.995 where as pure drug suspension exhibited faster drug release following zero order release kinetics with R(2) value of 0.992. Stability study confirmed that SLNs were stable for 3 months at 4 °C. Furthermore, in vitro skin distribution studies showed presence of significant amount of FA on the epidermal layer of skin when treated with FA loaded SLNs suspension while plain FA suspension showed minimum amount of FA in the epidermis and dermis. Moreover, selective accumulation of FA in the epidermis might eliminate adverse side effects associated with systemic exposure. Results demonstrated that FA loaded SLNs could be a promising modality for psoriasis treatment but to establish clinical utility of the present system further studies are required in clinically relevant models.

Flunisolide for the treatment of asthma.

Inhaled corticosteroids (ICSs) are recommended for treatment of persistent asthma. Several ICSs are available and delivered by a variety of devices. After the banning of chlorofluorocarbon (CFC), a formulation of hydrofluoroalkane (HFA)-flunisolide marketed with an in-built spacer has been developed, complying with the request of efficacy and safety for children and adults. It delivers an aerosol with mass median aerodynamic diameter smaller than that of the CFC-formulation (1.2 vs 3.8 m). The extrafine aerosol and the add-on spacer are peculiarities of HFA-flunisolide with respect to the traditional ICSs, assuring larger lung deposition, lower oro-pharyngeal dose and targeting small airways. HFA-flunisolide with the spacer is effective at one-third the dose of CFC-flunisolide delivered without spacer. HFA-flunisolide may be considered an effective alternative to currently available ICSs for asthma management of adult and pediatric patients 6 years of age and older.

Inhaled corticosteroid use in HIV-positive individuals taking protease inhibitors: a review of pharmacokinetics, case reports and clinical management.

As a consequence of inhibition of the hepatic cytochrome P450 3A4 isozyme, treatment with HIV protease inhibitors can result in significant drug-drug interactions. One noteworthy interaction is between protease inhibitors and inhaled or intranasal corticosteroids. This interaction can result in adrenal insufficiency and iatrogenic Cushing's syndrome (with symptoms such as rapid weight gain, obesity, facial hirsutism and swelling), as well as hypertension, osteoporosis and decreased CD4 cell count. In this paper, we review and unite pharmacokinetic data, case reports and current research regarding this drug-drug interaction in order to suggest options for the clinical management of HIV-positive patients requiring treatment with protease inhibitors and inhaled or intranasal corticosteroids.

Late spontaneous dissociation of a fluocinolone acetonide implant (Retisert).

PURPOSE: To describe a case of spontaneous dissociation of a fluocinolone acetonide implant (Retisert) 5 years following implantation. DESIGN: Case report. METHODS: A patient with chronic uveitis underwent placement of a fluocinolone acetonide implant in the right eye in 2006. The patient's inflammation was well controlled and did not recur, so the device was not replaced. RESULTS: Five years after implantation, the patient presented with a new complaint of a shadow in his vision. The drug pellet was found to have separated spontaneously from the anchoring strut and was floating in the vitreous. Pars plana vitrectomy was performed with removal of the drug pellet, and the anchoring strut was left in place. CONCLUSIONS: Spontaneous intraocular dissociation of a fluocinolone acetonide implant (Retisert) can occur years after placement, in the absence of trauma or other risk factors. Surgeons and patients must be aware of this potential complication as the implants age.

Aqueous levels of fluocinolone acetonide after administration of fluocinolone acetonide inserts or fluocinolone acetonide implants.

PURPOSE: To compare aqueous levels of fluocinolone acetonide (FAc) after administration of FAc inserts or FAc implants (Retisert; Bausch & Lomb, Rochester, NY). DESIGN: Comparison of pharmacokinetics from 2 prospective, interventional, clinical trials. PARTICIPANTS: Thirty-seven patients with diabetic macular edema (DME) (Fluocinolone Acetonide in Human Aqueous [FAMOUS] Study, C-01-06-002) and 7 patients with uveitis (NA-00019318). METHODS: Aqueous FAc was measured after administration of FAc implants or 0.2 µg/day (low dose, ILUVIEN; Alimera Sciences Inc., Alpharetta, GA) or 0.5 µg/day (high dose) FAc inserts. MAIN OUTCOME MEASURES: The primary end point was aqueous levels of FAc. RESULTS: At 1 month after administration for subjects who received 1 treatment, mean aqueous FAc levels were 2.17 (low dose) and 3.03 ng/ml (high dose) for FAc inserts and 6.12 ng/ml for FAc implants with maximum levels of 3.83, 6.66, and 13.50 ng/ml, respectively. At 3 months, mean FAc levels were 1.76, 2.15, and 6.12 ng/ml, respectively. Between 6 and 36 months after low-dose inserts, aqueous levels of FAc were remarkably stable, ranging from 1.18 to 0.45 ng/ml. After high-dose inserts, mean FAc levels were stable between 6 and 24 months, ranging from 1.50 to 0.84 ng/ml and then decreasing to 0.35 ng/ml at 30 months and 0.15 ng/ml at 36 months. In implant-containing eyes, mean FAc levels remained >6 ng/ml through 15 months, the last time point with measurements from at least 6 eyes. CONCLUSIONS: Low- and high-dose FAc inserts both provide stable long-term release of FAc with comparable peak levels in the aqueous: slightly >2 ng/ml for approximately 3 months followed by steady-state levels between 1.0 and 0.5 ng/ml through 36 months for low-dose inserts versus levels between 1.5 and 1.1 ng/ml through 24 months for high-dose inserts. Steady-state aqueous levels after FAc implants were >6 ng/ml. These results provide new insights that aid in the interpretation of efficacy trials and indicate that there is a dose effect for steroid-induced ocular hypertension. In susceptible patients, prolonged aqueous levels of FAc >1 ng/ml moderately increased the risk of glaucoma and levels >6 ng/ml posed a markedly increase risk.

Sustained ocular delivery of fluocinolone acetonide by an intravitreal insert.

PURPOSE: To compare Iluvien intravitreal inserts that release 0.2 or 0.5 microg/day of fluocinolone acetonide (FA) in patients with diabetic macular edema (DME). DESIGN: Prospective, randomized, interventional, multicenter clinical trial. PARTICIPANTS: We included 37 patients with DME. METHODS: Subjects with persistent DME despite > or = 1 focal/grid laser therapy were randomized 1:1 to receive an intravitreal insertion of a 0.2- or a 0.5-microg/day insert. MAIN OUTCOME MEASURES: The primary end point was aqueous levels of FA throughout the study with an important secondary outcome of the change from baseline in best-corrected visual acuity (BCVA) at month 12. RESULTS: The mean aqueous level of FA peaked at 3.8 ng/ml at 1 week and 1 month after administration of a 0.5-microg/day insert and was 3.4 and 2.7 ng/ml 1 week and 1 month after administration of a 0.2-microg/day insert. For both inserts, FA levels decreased slowly thereafter and were approximately 1.5 ng/ml for each at month 12. The mean change from baseline in BCVA was 7.5, 6.9, and 5.7 letters at months 3, 6, and 12, respectively, after administration of a 0.5 microg/day-insert and was 5.1, 2.7, and 1.3 letters at months 3, 6, and 12, respectively, after administration of a 0.2-microg/day insert. There was a mild increase in mean intraocular pressure after administration of 0.5-microg/day inserts, but not after administration of 0.2-microg/day inserts. CONCLUSIONS: The FA intravitreal inserts provide excellent sustained intraocular release of FA for > or = 1 year. Although the number of patients in this trial was small, the data suggest that the inserts provide reduction of edema and improvement in BCVA in patients with DME with mild effects on intraocular pressure over the span of 1 year. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

A reappraisal of the clinical efficacy of nebulized flunisolide in pediatric asthma: the Italian experience.

Flunisolide (FLU) is a synthetic corticosteroid with potent topical anti-inflammatory activity. Its oral bioavailability is poor (6.7%). After gastrointestinal and lung absorption, the drug undergoes rapid and extensive first-pass metabolism by the liver to an inactive 6beta-hydroxylated metabolite. Plasma half-life is estimated to be 3.9 to 4.6 hours. FLU has a low volume of distribution at steady state and a short terminal half-life after inhalation (96 L and 1.6 hour, respectively). FLU, like budesonide, has a short pulmonary residence time and it is hypothesized that it may undergo esterification in the cell due to the presence of a free hydroxyl group at C21. Nebulization may offer important advantages over other inhalation methods. Nebulizers allow drug delivery in very young children through passive inhalation, depending less on patient coordination and cooperation. Comparative studies indicate that FLU is nebulized to a better advantage than beclomethasone dipropionate and budesonide. This is attributed to its elevated water solubility. The aim of this article is to outline the factors that influence drug nebulization and the pharmacokinetics-pharmacodynamics of FLU compared to other inhaled corticosteroids. In addition, we report a series of clinical data regarding the efficacy of nebulized FLU with focus on the Italian experience. Overall, the physicochemical characteristics and pharmacokinetic profile of FLU favor its use for nebulization. Clinical data indicate that nebulized FLU is effective in asthma treatment in infants and children. Side effects were not reported at the commonly used doses.

Long-term release of fluocinolone acetonide using biodegradable fumarate-based polymers.

Intraocular drug delivery systems made from biodegradable polymers hold great potential to effectively treat chronic diseases of the posterior segment of the eye. This study is based on the hypothesis that crosslinked poly(propylene fumarate) (PPF)-based matrices are suitable long-term delivery devices for the sustained release of the anti-inflammatory drug fluocinolone acetonide (FA) due to their hydrophobicity and network density. FA-loaded rods of 10 mm length and 0.6 mm diameter were fabricated by photo-crosslinking PPF with N-vinyl pyrrolidone (NVP). The released amounts of FA and NVP were determined by HPLC analysis. The effects of drug loading and the ratio of PPF to NVP on the release kinetics were investigated using a 2(3-1) factorial design. Overall, FA release was sustained in vitro over almost 400 days by all tested formulations. Low burst release was followed by a dual modality release controlled by diffusion and bulk erosion with release rates up to 1.7 microg/day. The extent of the burst effect and the release kinetics were controlled by the drug loading and the matrix composition. Matrix water content and degradation were determined gravimetrically. Micro-computed tomography was used to image structural and dimensional changes of the devices. The results show that photo-crosslinked PPF-based matrices are promising long-term delivery devices for intraocular drug delivery.

Efficacy of low-release-rate fluocinolone acetonide intravitreal implants to treat experimental uveitis.

OBJECTIVE: To determine the efficacy of 0.5-mg and 0.1-mg sustained-release fluocinolone acetonide intravitreal implants to inhibit ocular inflammation in a rabbit model of severe uveitis. METHODS: The in vitro pharmacokinetic profile of both the 0.5-mg and 0.1-mg sustained-release fluocinolone intravitreal implants was determined during a 10-day period. A sustained-release fluocinolone acetonide intravitreal implant with a release rate of either 0.5 microg/d (n = 16) or 0.1 microg/d (n = 16) was implanted into the vitreous cavity of the right eye in albino rabbits after a subcutaneous injection of tuberculin antigen. Control animals (n = 14) received empty devices. Uveitis was induced with an intravitreal tuberculin antigen injection. A masked observer graded anterior chamber flare, anterior chamber cells, vitreous opacity, and inflammation on histologic sections. RESULTS: In vitro, the drug was released from both devices in a linear manner. In vivo, treated eyes were significantly less inflamed than untreated eyes (P< or =.02). Inflammation was suppressed to a greater degree with the 0.5-microg/d implant compared with the 0.1-microg/d implant. CONCLUSION: Sustained-release fluocinolone intravitreal implants suppress ocular inflammation in a rabbit model of severe uveitis. CLINICAL RELEVANCE: The efficacy demonstrated with the 0.1-microg/d implant provides the rationale for future human studies with lower-release-rate implants than are currently used in noninfectious uveitis clinical trials.

Retisert (Bausch & Lomb/Control Delivery Systems).

Retisert (Envision TD), a sustained release intraocular implant containing fluocinolone acetonide, has been developed and launched in the US by Bausch & Lomb and Control Delivery Systems for the treatment of chronic non-infectious uveitis affecting the posterior segment of the eye.