Fig 7 - uploaded by Mariana Shoukry
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Histology of (A) normal rabbit corneal tissue (control negative), showing normal corneal epithelium, stroma with keratocytes. (B) Infected non-treated rabbit corneal tissue (control positive), showing desquamation of corneal epithelium, blood capillaries, edematous stroma with inflammatory cells. (C) Treated rabbits corneal tissue with G5 formula and (D) treated rabbits with PDT showing intact corneal epithelium and stroma with keratocytes. H&E, X: 100. (S) = stroma, (arrow) = corneal epithelium, (arrow head) = keratocytes, (thin arrow) = blood capillaries, (double arrow head) = inflammatory cells.
Source publication
In this study, six in situ gelling formulations based on Gelrite were prepared and evaluated for the retained ophthalmic delivery of Moxifloxacin (Mox). The effectiveness of the best developed formula G5 was compared with photodynamic therapy (PDT), the recent expanding approach for the treatment of ophthalmologic disorders after the assessment of...
Contexts in source publication
Context 1
... Also the histological examination revealed desquamation of the outermost superficial cells in corneal epithelium, stromal edema, prominent blood capillaries with numerous inflammatory cells (lymphocytes) aggregated in perivascular area in the stroma and reduced number of keratocytes in the stroma, compared with normal rabbit cornea as shown in Fig. 7. Treatment with formula G5 or PDT showed good response where, the signs of infection Table V. Effect of light fluence (0.9-9 J/cm 2 ) on the % reduction of bacterial species (mean ± S.D., n = 6) Bacterial ...
Context 2
... ± 2.09 25.1 ± 1.67 and inflammation were disappeared with no fluorescence detection. It is worthy noting that, group of animals treated with formula G5 showed remarkable improvement of stromal edema and increase in the number of keratocytes with faster epithelium healing after four days of G5 application compared to seven days of PDT treatment (Fig. ...
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Citations
... Mayol et al. noted the instability and poor mechanics associated with poloxamer systems, and found that the addition of hyaluronic acid into the polymer blend created improvement in the mucoadhesive and viscoelastic properties, and has potential to be used for sustained drug delivery systems in the future (MAYOL et al., 2008). Ion responsive gelling systems include Gellan gum (El-Laithy et al., 2011) and Alginate based systems (Liu et al., 2006), while pH responsive systems focus primarily on Carbopol (WU et al., 2007) and Chitosan (Gupta, 2010). ...
The eye is an isolated and complex organ, with multiple robust anatomical and physiological barriers on the ocular surface which protect it from noxious insults such as the blink reflex, tear film and corneoscleral tissue layers. However, these also make it difficult for drugs to reach their therapeutic target within the eye, resulting in very low bioavailability in most commercially available ophthalmic drugs. This review will detail the mechanisms present on the ocular surface which impede drug delivery and give an overview of traditional eye drop formulations, as well as methods of improving their bioavailability through viscosity and permeation enhancement. We also review the evidence for more novel technologies, such as nanoparticles, in-situ gels, blood products, and alternatives to eye drops such as drug loaded contact lenses and ocular inserts.
... It is used topically for treating various ocular infections including conjunctivitis, bacterial keratitis, and keratoconjunctivitis. This drug exists as unionized form at neutral pH of tears and thereby causing an enhanced corneal permeation and 2-3 folds higher concentration in the aqueous humour than other fluoroquinolones derivatives [14]. Few attempts have been made to enhance the ocular delivery of moxifloxacin using carriers including liposomes, microemulsions and nanoemulsions [15][16][17][18]. ...
In situ gels have been extensively explored as ocular drug delivery system to enhance bioavailability and efficacy. The objective of present study was to design, formulate and evaluate ion-activated in situ gel to enhance the ocular penetration and therapeutic performance of moxifloxacin in ophthalmic delivery. A simplex lattice design was utilized to examine the effect of various factors on experimental outcomes of the in situ gel system. The influence of polymers (independent variables) such as gellan gum (X 1 ), sodium alginate (X 2 ), and HPMC (X 3 ) on gel strength, adhesive force, viscosity and drug release after 10 h (Q 10 ) were assessed. Selected formulation (MH7) was studied for ex vivo permeation, in vivo irritation and pharmacokinetics in rabbits. Data revealed that increase in concentration of polymers led to higher gel strength, adhesive force and viscosity, however, decreases the drug release. MH7 exhibited all physicochemical properties within acceptable limits and was stable for 6 months. Release profile of moxifloxacin from MH7 was comparable to the check point batches and followed Korsmeyer-Peppas matrix diffusion-controlled mechanism. Ocular irritation study signifies that selected formulation is safe and non-irritant for ophthalmic administration. In vivo pharmacokinetics data indicates significant improvement of moxifloxacin bioavailability ( p < 0.0001) from MH7, as evidenced by higher C max (727 ± 56 ng/ml) and greater AUC (2881 ± 108 ng h/ml), when compared with commercial eye drops (C max ; 503 ± 85 ng/ml and AUC; 978 ± 86 ng h/ml). In conclusion, developed in situ gel system (MH7) could offers a more effective and extended ophthalmic therapy of moxifloxacin in ocular infections when compared to conventional eye drops.
... Gellan and xanthan gum are already used in clinic as in situ gels, such as TIMOLOL MALEATE EX® (Timolol 0.25%, Sandoz Inc., Switzerland), TIMOPTIC-XE® (Timolol 0.25%, Valeant Pharms LLC, USA), TIMOLOL L.P.® (Timolol 0.25% and 0.5%, Santen Oy, Japan) and MOXEZA® (Moxifloxacin 0.5%, Novartis Pharms Corp, Switzerland). On an in vivo rabbit model, gellan gum was used to deliver moxifloxacin [35] and brinzolamide [18]. It was shown that the gellan gum-based in situ gel could deliver a 6-fold higher concentration of moxifloxacin in the aqueous humor compared to VIGOMOX®, as control [35]. ...
... On an in vivo rabbit model, gellan gum was used to deliver moxifloxacin [35] and brinzolamide [18]. It was shown that the gellan gum-based in situ gel could deliver a 6-fold higher concentration of moxifloxacin in the aqueous humor compared to VIGOMOX®, as control [35]. Moreover, the delivery of brinzolamide by the developed in situ gel prolonged the IOP lowering effect compared to standard solutions [18]. ...
Topical instillation of eye drops remains the most common and for most the easiest route of ocular drug administration, representing the treatment of choice for many ocular diseases. Nevertheless, low ocular bioavailability of topically applied drug molecules can considerably limit their efficacy. Over the last several decades, numerous drug delivery systems (DDS) have been developed in order to improve drug bioavailability on the ocular surface. This review systematically covers the most recent advances of DDS applicable by topical instillation, that have shown better performance on in vivo models compared to standard eye drop formulations. These delivery systems are based on in situ forming gels, nanoparticles and combinations of both. Most of the DDS have been developed using natural or synthetic polymers. Polymers offer many advantageous properties for designing advanced DDS including biocompatibility, gelation properties and/or mucoadhesiveness. However, despite the high number of studies published over the last decade, there are several limitations for clinical translation of DDS. The potential challenges for commercialization of new DDS are also presented in this review.
... Herein, the RS release was dependent on two simultaneous rate processes: both swelling-controlled and diffusion-controlled release mechanisms. Water migration into the microspheres and drug diffusion throughout the continuously swelling spheres are the combined proposed mechanisms that governed the overall release profile (79,80). n values above 0.85 indicate case II transport which is related to polymer relaxation during swelling, while n values below 0.43 indicate that drug release follows Fickian diffusion through the polymer (15,22). ...
Risedronate sodium (RS) is a potent inhibitor of bone resorption, having an extreme poor permeability and limited oral bioavailability (0.62%). RS should be orally administered under fasting conditions while keeping in an upright posture for at least 30 min to diminish common gastroesophageal injuries. To surmount such limitations, novel risedronate–chitosan (RS–CS) crosslinker-free nebulizable microspheres were developed adopting the quality by design (QbD) approach and risk assessment (RA) thinking. RS:CS ratio, surfactant (Pluronic® F127) concentration, homogenization duration, speed, and temperature were identified using Ishikawa diagrams as the highest formulation and process risk factors affecting the critical quality attributes (CQAs), average particle size (PS), and entrapment efficiency (EE%). The risk factors were screened using the Plackett–Burman design, and the levels of the most significant factors were optimized using a multilevel factorial design to explore the optimized system with the least PS, maximum EE%, and a prolonged drug release profile. The optimized system (B6) was developed at a RS:CS ratio of 1:7, a surfactant concentration of 2% (w/v), and a homogenization speed of 14,000 rpm. It revealed good correlation with QbD theoretical prediction, where positively charged (47.9 ± 3.39 mV) discrete, spherical microspheres (3.47 ± 0.16 μm) having a high EE% (94.58 ± 0.19%) and prolonged RS release over 12 h (Q12 h, 89.70 ± 0.64%) were achieved. In vivo lung deposition after intratracheal instillation of B6 confirmed the delivery of high RS percentage to rat lung tissues (87 ± 3.54%) and its persistence for 24 h. This investigation demonstrated the effectiveness of QbD philosophy in developing RS–CS crosslinker-free nebulizable microspheres.
... A modified dissolution test was used for evaluating the in vitro release profile [17]. A glass cylinder (2.3×8 cm in dimensions), open at both ends, was used for the purpose of the study. ...
Objective: This work aims to formulate and evaluate an ophthalmic in-situ gel of ciprofloxacin hydrochloride (HCl) using poloxamer 407 (P407) as a gelling agent and hydroxypropyl methylcellulose (HPMC) as a viscosity modifier. The objective of this work was to prolong the contact time as the in-situ gel will be converted into a gel upon contact with the cul-de-sac. Methods: Ciprofloxacin HCl ophthalmic in-situ gel was prepared by utilizing (P407) as a temperature-dependent polymer while hydroxypropyl methylcellulose was used as a viscosity modifier. The system was evaluated for physical appearance, pH, drug content, sterility, irritancy and stability. In addition, gelation temperature and a viscosity at different shear rates and different temperatures were studied. The compatibility of the polymer with ciprofloxacin was studied by using fourier transform infrared spectroscopy (FTIR). The in vitro release of the drug was also evaluated and supported by a preliminary in vivo test.Results: The results showed that the prepared formulas were clear, with acceptable pH and the drug contents were within the acceptable limits. FTIR results detected no incompatibility between poloxamer 407 and ciprofloxacin HCl. Notably, the viscosity of the system showed a pseudoplastic behaviour where a reduction in viscosity upon increasing the shear rate was observed. The in vitro release study confirmed the prolongation of the release of the optimized formula (F6) up to 8 h. Upon application of F6 into eyes of rabbits there was no irritancy. In addition, in vivo elimination study showed a prolonged contact for the in-situ gel in comparison with the rapid clearance of eye drop. Stability study indicated the stability of the optimized formula (F6). Conclusion: The prepared optimized formula (F6) represents a successful, safe, stable and prolonged release in-situ gel formula of ciprofloxacin.
... Upon administration, the lower eye-lid was slightly pulled downward and away from the eye to allow the formulations or the control solution to accumulate over the surface of the cornea in the lower cul-de-sac, and then the lower lid was lifted again to mix the prepared formulations with the lacrimal fluids of the eye (Law et al., 2000). The rabbits were anaesthetized systemically using ketamine hydrochloride (intramuscular injection, 50 mg/kg) in addition to xylazine as a muscle relaxant (intramuscular injection, 10 mg/kg) (El-Laithy et al., 2011). The loading of the formulations was carefully achieved by two instillations (of 50 μl each) using a micropipette, while avoiding touching and damaging the eye (Sun et al., 2007). ...
... They concluded that compared to the eye drop, higher amount of moxifloxacin was retained in the aqueous humor. Against the bacterial corneal inflammation, they had a major improvement after four days compared to seven days for the conventional eye drops [135]. ...
The last fifty years, ophthalmic drug delivery research has made much progress, challenging scientists about the advantages and limitations of this drug delivery approach. Topical eye drops are the most commonly used formulation in ocular drug delivery. Despite the good tolerance for patients, this topical administration is only focus on the anterior ocular diseases and had a high precorneal loss of drugs due to the tears production and ocular barriers. Antibiotics are popularly used in solution or in ointment for the ophthalmic route. However, their local bioavailability needs to be improved in order to decrease the frequency of administrations and the side effects and to increase their therapeutic efficiency. For this purpose, sustained release forms for ophthalmic delivery of antibiotics were developed. This review briefly describes the ocular administration with the ocular barriers and the currently topical forms. It focuses on experimental results to bypass the limitations of ocular antibiotic delivery with new ocular technology as colloidal and in situ gelling systems or with the improvement of existing forms as implants and contact lenses. Nanotechnology is presently a promising drug delivery way to provide protection of antibiotics and improve pathway through ocular barriers and deliver drugs to specific target sites.
... However, they did not assess the impact of PDI as a single treatment. In the same year, El-Laithy et al. 40 treated Staphylococcus aureus keratitis in rabbits with the photosensitizer hematoporphyrin and red light (λ = 630 nm). However, they failed to detect a statistically significant impact of this therapy regimen. ...
Following corneal epithelium scratches, mouse corneas were infected with the multidrug resistant (MDR) P. aeruginosa strain PA54. 24 hours later, 0% (for control group), 0.01%, 0.05% or 0.1% Chlorin e6 (Ce6), a second generation photosensitizer derived from chlorophyll, was combined with red light, for photodynamic inactivation (PDI). 1 hour or 2 days later, entire mouse eyes were enucleated and homogenized for counting colony forming units (CFU) of P. aeruginosa. For comparison, 0.1% Ce6 mediated PDI was started at 12 hours post infection, and 0.005% methylene blue mediated PDI 24 hours post infection. Clinical scores of corneal manifestation were recorded daily. Compared to the control, CFU 1 hour after PDI started 24 hours post infection in the 0.01% Ce6 and 0.05% Ce6 groups were significantly lower (more than one log10 reduction), the CFU 2 days post PDI higher in the 0.1% Ce6 group, clinical score lower in the 0.1% Ce6 group at 1 day post PDI. These findings suggest that PDI with Ce6 and red light has a transient efficacy in killing MDR-PA in vivo, and repetitive PDI treatments are required to fully resolve the infection. Before its clinical application, the paradoxical bacterial regrowth post PDI has to be further studied.
... Prior intrastromal injection all rabbits were systemically anaesthetized with intramuscular injections of ketamine hydrochloride (50 mg/kg) in combination with a relaxing agent xylazine (10 mg/kg) [25]. They were locally anaesthetized with benoxinate HCl (0.4% w/v, 2 drops) applied to the rabbit eyes at post instillation, aqueous humor samples (0.15 ml ≈ 50-80 µl) were withdrawn at 1, 4, 8 and 12 hours by anterior chamber paracentesis using an insulin syringe (1.0 ml) fitted with a 29 gauge needle. ...
Background
Voriconazole (VCZ) is a lipophilic candidate, effective against fungal infections like ocular keratitis and endopthalmitis.
Objective
The purpose to develop, optimize and characterize voriconazole microemulsion as sustained medication for ophthalmic application.
Methods
The pseudo-ternary phase diagrams were developed using oleic acid, isopropyl myristate and isopropyl palmitate (oil phases), tween 80 (surfactant), propylene glycol (co-surfactant), distilled water (aqueous phase) and modified chitosan (Mod.CH) as mucoadhesive polymer. The optimum composition of oil, S mix and water was selected on the basis of phase diagrams and as mucoadhesive polymer Mod.CH was used in the formulations. All the formulations were evaluated for thermodynamic stability/dispersibility, physicochemical parameters (droplet size, polydispersity index, zeta potential, drug content, viscosity, pH and conductivity), in vitro , ex vivo and in vivo studies.
Results
All formulations showed droplet size below 250 nm, positive zeta potential and polydispersity index below 0.5. The in vitro drug release study performed on selected formulations showed maximum sustained release than marketed formulation. The in vitro transcorneal permeation experiment of formulations suggests that optimized formulations showed better permeation. The selected formulation of voriconazole microemulsion was able to produce maximum antifungal activity against Candida albicans when compared to marketed formulation. In vivo study performed on rabbit eyes, found more drug concentration in aqueous humor of optimized formulation; the AUC 0→ t of IPMVM-11 was approximately 6.84-fold higher than VOZOLE and efficiently enhanced the corneal bioavailability.
Conclusion
The modified chitosan based on voriconazole loaded microemulsion was promising novel carrier for sustained action in ophthalmic medication.
... The marketed formulation (0.5% w/v, 50 ml) and LE-loaded NE-ISG2 gel (0.5%, w/v) were instilled with micropipette into lower conjunctiva sac of the right eye of all rabbits, which were divided 5 in each group. Ketamine hydrochloride (50 mg/kg) in combination with a relaxing agent xylazine (10 mg/kg) was used intramuscularly to anesthetize the rabbits (El-Laithy et al., 2011). 0.1 ml of aqueous humor samples was withdrawn at the time interval of 0.25, 0.5, 1, 1.5, 4, 8 and 10 h post instillation after giving local anesthetics Benoxinate HCl (0.4%, w/v, 2 drops). ...
A novel cationic nanoemulsified in-situ ophthalmic gel of loteprednol etabonate (LE) was developed to improve the permeability and retention time of formulations for overall improvement of drug's ocular bioavability. Capryol 90 (oil phase), tween 80 (surfactant) and transcutol P (cosurfactant) was selected as formulation excipients to construct pseudoternary phase diagrams and nanoemulsion region was recognized from diagrams. Spontaneous emulsification method was used to manufacture LE nanoemulsion and it was optimized using 3(2) factorial design by considering the amount of oil and the ratio of surfactant to cosurfactant (Smix) as independent variables and evaluated for various physicochemical properties. Optimized NE was dispersed in Poloxamer 407 and 188 solution to form nanoemulsified sols that were predictable to transform into in-situ gels at corneal temperature. Drug pharmacokinetics of sterilized optimized in situ NE gel, NE-ISG2 [0.69% w/w Capryol 90, 0.99%w/w Smix (3:1), 13% Poloxamer 407, 4% w/w Poloxamer 188] and marketed formulation were assessed in rabbit aqueous humor. The in-situ gels were clear, shear thinning in nature and displayed zero-order drug release kinetics. NE-ISG2 showed the minimum ocular irritation potential and significantly (p < 0.01) higher Cmax and AUC(0-10 h), delayed Tmax, extended mean residence time and improved (2.54-fold times) bioavailability compared to marketed formulation.
