Preparation of levofloxacin loaded in situ gel for sustained ocular delivery: in vitro and ex vivo evaluations.

The major drawback of the eye drops is rapid elimination of drug from the precorneal region, thus ensuing poor bioavailability as well as therapeutic efficacy. To conquer these limitations, a pH triggered in situ gel was developed for sustained delivery of levofloxacin. Two polymers namely hydroxypropyl methylcellulose (HPMC) and sodium alginate along with the boric acid buffer were used to formulate the in situ gel. Based on the various physicochemical evaluation parameters like pH, clarity and gelling capacity placebo formulations were selected and further characterized for viscosity, in vitro release, ex vivo corneal permeation, and histopathological studies. The optimized in situ gel (F28) showed sustained release of 93 ± 4.23% for 24 h and cumulative drug permeation of 71.81 ± 4.7% for 72 h. Additionally, ocular irritation study and histopathology of the formulation treated cornea confirm the non-irritancy of the optimized formulation. Based on all the above performed studies, it can be concluded that the in situ gel would present a fruitful alternative for the ocular infections.

In Situ Gelling Systems Using Pluronic F127 Enhance Corneal Permeability of Indomethacin Nanocrystals.

We previously designed an ophthalmic dispersion containing indomethacin nanocrystals (IMC-NCs), showing that multiple energy-dependent endocytoses led to the enhanced absorption of drugs from ocular dosage forms. In this study, we attempted to prepare Pluronic F-127 (PLF-127)-based in situ gel (ISG) incorporating IMC-NCs, and we investigated whether the instillation of the newly developed ISG incorporating IMC-NCs prolonged the precorneal resident time of the drug and improved ocular bioavailability. The IMC-NC-incorporating ISG was prepared using the bead-mill method and PLF-127, which yielded a mean particle size of 50-150 nm. The viscosity of the IMC-NC-incorporating ISG was higher at 37 °C than at 10 °C, and the diffusion and release of IMC-NCs in the IMC-NC-incorporating ISG were decreased by PLF-127 at 37 °C. In experiments using rabbits, the retention time of IMC levels in the lacrimal fluid was enhanced with PLF-127 in the IMC-NC-incorporating ISG, whereby the IMC-NC-incorporating ISG with 5% and 10% PLF-127 increased the transcorneal penetration of the IMCs. In contrast to the results with optimal PLF-127 (5% and 10%), excessive PLF-127 (15%) decreased the uptake of IMC-NCs after instillation. In conclusion, we found that IMC-NC-incorporating ISG with an optimal amount of PLF-127 (5-10%) resulted in higher IMC corneal permeation after instillation than that with excessive PLF-127, probably because of the balance between higher residence time and faster diffusion of IMC-NCs on the ocular surface. These findings provide significant information for developing ophthalmic nanomedicines.

Chitosan-Based Thermogelling System for Nose-to-Brain Donepezil Delivery: Optimising Formulation Properties and Nasal Deposition Profile.

Donepezil nasal delivery strategies are being continuously investigated for advancing therapy in Alzheimer's disease. The aim of this study was to develop a chitosan-based, donepezil-loaded thermogelling formulation tailored to meet all the requirements for efficient nose-to-brain delivery. A statistical design of the experiments was implemented for the optimisation of the formulation and/or administration parameters, with regard to formulation viscosity, gelling and spray properties, as well as its targeted nasal deposition within the 3D-printed nasal cavity model. The optimised formulation was further characterised in terms of stability, in vitro release, in vitro biocompatibility and permeability (using Calu-3 cells), ex vivo mucoadhesion (using porcine nasal mucosa), and in vivo irritability (using slug mucosal irritation assay). The applied research design resulted in the development of a sprayable donepezil delivery platform characterised by instant gelation at 34 °C and olfactory deposition reaching a remarkably high 71.8% of the applied dose. The optimised formulation showed prolonged drug release (t1/2 about 90 min), mucoadhesive behaviour, and reversible permeation enhancement, with a 20-fold increase in adhesion and a 1.5-fold increase in the apparent permeability coefficient in relation to the corresponding donepezil solution. The slug mucosal irritation assay demonstrated an acceptable irritability profile, indicating its potential for safe nasal delivery. It can be concluded that the developed thermogelling formulation showed great promise as an efficient donepezil brain-targeted delivery system. Furthermore, the formulation is worth investigating in vivo for final feasibility confirmation.

Erythromycin-loaded polymeric micelles: In situ gel development, in vitro and ex vivo ocular investigations.

Our present series of experiments was to create a value-added formulation that has the potential to exert a powerful and long-lasting antibacterial effect for use in ophthalmology. Erythromycin-loaded polymeric micelles were formulated with a micelle size of 87.14 nm in a monodisperse distribution with 86.94 % encapsulation efficiency. To decrease the polymeric micelle-like burst effect of these nanoparticles, the formulation was dispersed in a Carbopol 934P gel base to prolong the drug release and permeation profile of erythromycin. With successful incorporation, a short gelling time with proper sol to gel transition was experienced in the form of transparent gels. The optimized formulation has high mucoadhesion which is a critical factor for prolonging residence time. With the initial burst, the drug release was saturated with more than 75 % of the drug released in simulated tear fluid. Corneal permeability investigations revealed that the gel formulation provides the value-added properties of polymeric micelles, with elevated permeability through into the aqueous humour across the cornea. While retaining its antimicrobial activity, the formulation may be capable to be utilized as an innovative ophthalmic formulation for treating bacterial infections of the eye.

Development of Thermoresponsive-Gel-Matrix-Embedded Amoxicillin Trihydrate-Loaded Bovine Serum Albumin Nanoparticles for Local Intranasal Therapy.

A high dose of amoxicillin is recommended as the first-line therapy for acute bacterial rhinosinusitis (ABR). However, oral administration of amoxicillin is connected to many adverse reactions coupled with moderate bioavailability (~60%). Therefore, this study aimed to develop a topical nasal preparation of amoxicillin, employing a thermoresponsive nanogel system to increase nasal residence time and prolong drug release. Rheological investigations revealed that formulations containing 21−23% w/w Poloxamer 407 (P407) were in accordance with the requirement of nasal administration (gelling temperature ~35 °C). The average hydrodynamic diameter (<200 nm), pH (6.7−6.9), and hypertonic osmolality (611−663 mOsmol/L) of the in situ gelling nasal nanogel appeared as suitable characteristics for local rhinosinusitis treatment. Moreover, taking into account the mucoadhesive strength and drug release studies, the 21% w/w P407 could be considered as an optimized concentration for effective nasal delivery. Antibacterial activity studies showed that the ability of amoxicillin-loaded in situ gelling nasal nanogel to inhibit bacterial growth (five common ABR pathogens) preserved its effectiveness in comparison to 1 mg/mL amoxicillin aqueous solution as a positive control. Altogether, the developed amoxicillin-loaded in situ gelling thermoresponsive nasal nanogel can be a potential candidate for local antibiotic therapy in the nasal cavity.

Development and Characterization of Oral Raft Forming In Situ Gelling System of Neratinib Anticancer Drug Using 32 Factorial Design.

Neratinib (NTB) is an irreversible inhibitor of pan-human epidermal growth factor receptor (HER-2) tyrosine kinase and is used in the treatment of breast cancer. It is a poorly aqueous soluble drug and exhibits extremely low oral bioavailability at higher pH, leading to a diminishing of the therapeutic effects in the GIT. The main objective of the research was to formulate an oral raft-forming in situ gelling system of NTB to improve gastric retention and drug release in a controlled manner and remain floating in the stomach for a prolonged time. In this study, NTB solubility was enhanced by polyethylene glycol (PEG)-based solid dispersions (SDs), and an in situ gelling system was developed and optimized by a two-factor at three-level (32) factorial design. It was analyzed to study the impact of two independent variables viz sodium alginate [A] and HPMC K4M [B] on the responses, such as floating lag time, percentage (%) water uptake at 2 h, and % drug release at 6 h and 12 h. Among various SDs prepared using PEG 6000, formulation 1:3 showed the highest drug solubility. FT-IR spectra revealed no interactions between the drug and the polymer. The percentage of drug content in NTB SDs ranged from 96.22 ± 1.67% to 97.70 ± 1.89%. The developed in situ gel formulations exhibited a pH value of approximately 7. An in vitro gelation study of the in situ gel formulation showed immediate gelation and was retained for a longer period. From the obtained results of 32 factorial designs, it was observed that all the selected factors had a significant effect on the chosen response, supporting the precision of design employed for optimization. Thus, the developed oral raft-forming in situ gelling system of NTB can be a promising and alternate approach to enhance retention in the stomach and to attain sustained release of drug by floating, thereby augmenting the therapeutic efficacy of NTB.

Balance of Drug Residence and Diffusion in Lacrimal Fluid Determine Ocular Bioavailability in In Situ Gels Incorporating Tranilast Nanoparticles.

We previously designed ophthalmic formulations (nTRA) containing tranilast nanoparticles (Tra-NPs) with high uptake into ocular tissues. In this study, we used in situ gel (ISG) bases comprising combinations of pluronic F127 (F127) and methylcellulose (MC/F127), pluronic F68 (F68/F127), and Carbopol (Car/F127), and we developed in situ gels incorporating Tra-NPs (Tra-NP-incorporated ISNGs) such as nTRA-F127, nTRA-MC/F127, nTRA-F68/F127, and nTRA-Car/F127. Moreover, we demonstrated the therapeutic effect on conjunctival inflammation using lipopolysaccharide-induced rats. Each Tra-NP-incorporated ISNG was prepared by the bead mill method, the particle size was 40-190 nm, and the tranilast release and diffusion from formulation were nTRA > nTRA-F127 > nTRA-F68/F127 > nTRA-Car/F127 > nTRA-MC/F127. In the Tra-NP-incorporated ISNGs, the tranilast residence time in the lacrimal fluid, cornea, and conjunctiva was prolonged, although the Cmax was attenuated in comparison with nTRA. On the other hand, no significant difference in conjunctival inflammation between non- and nTRA-F127-instilled rats was found; however, the nTRA-F68/F127, nTRA-Car/F127, and nTRA-MC/F127 (combination-ISG) attenuated the vessel leakage, nitric oxide, and tumor necrosis factor-α expression. In particular, nTRA-F68/F127 was significant in preventing the conjunctival inflammation. In conclusion, we found that the combination-ISG base prolonged the residence time of Tra-NPs; however, Tra-NP release from the formulation was attenuated, and the Tmax was delayed longer than that in nTRA. The balance of drug residence and diffusion in lacrimal fluid may be important in providing high ocular bioavailability in formulations containing solid nanoparticles.

An in situ Gelling System Based on Methylcellulose and Tranilast Solid Nanoparticles Enhances Ocular Residence Time and Drug Absorption Into the Cornea and Conjunctiva.

We previously developed ophthalmic formulations containing tranilast nanopartaicles (ophthalmic TL-NPs formulations), and found them to show high uptake into ocular tissues. In this study, we aimed to design an in situ gel incorporating TL-NPs with 0.5-3% methylcellulose (MC, type SM-4) to ensure long residence time of the drug at the ocular surface. The ophthalmic TL-NPs formulations were prepared by the bead mill method, which yielded a mean particle size of ~93 nm with or without MC (0.5-3%). Although the dispersibility of TL particles in ophthalmic formulations increased with the MC content, the diffusion behavior of TL particles in the dispersion medium decreased with MC content. In an in vivo study using rats, the TL content in the lacrimal fluid was enhanced with MC content in the ophthalmic TL-NPs formulations, and the optimum amount of MC (0.5-1.5%) enhanced the TL content in the cornea and conjunctiva, and an anti-inflammatory effect of TL in rats instilled with ophthalmic TL-NPs formulations was observed. On the other hand, excessive MC (3%) prevented the corneal uptake of TL-NPs after instillation, and the anti-inflammation effect of TL was lower than that of ophthalmic TL-NPs formulations with optimum MC (0.5-1.5%). In conclusion, we found that gel formulations of TL-NPs with 0.5 and 1.5% MC provided a prolonged pre-corneal and pre-conjunctival contact time of TL, and resulted in higher TL contents in the cornea and conjunctiva following instillation in comparison with TL-NPs with or without 3% MC. This is probably due to the balance between the higher residence time and faster diffusion of TL-NPs on the ocular surface. These findings provide significant information that can be used to design further studies aimed at developing ophthalmic nanomedicines.

Terminalia arjuna gum/alginate in situ gel system with prolonged retention time for ophthalmic drug delivery.

Poor availability is the major barrier to accept the new smart gel system as a preferred ophthalmic solution for various eye problems. Smart gel system especially derived from natural source allows the rapid transition of ocular solution into gel form upon contact to tear solution. The present experimental scheme was intended to prepare and characterize a pH triggered in situ gelling system using moxifloxacin HCl (MOX-HCl). Gum was extracted from Terminalia arjuna bark resin and used as gelling agent in blend with sodium alginate. Sterilized formulations were developed and characterized for their physicochemical attributes. These were further investigated for microbiological testing and eye irritation studies. Drug loaded in situ gel was appeared as clear sol that converted into gel phase in presence of tear solution. Optimized formulation was stable, therapeutically efficacious, non-irritant and has a sustained release of the drug for twelve hours period. Instillation of MOX-HCl loaded in situ gel did not cause any type of irritation symptoms like redness, inflammation and excessive tear production in rabbits as compared to control. MOX-HCl loaded in situ gel can be appraised as a substitute for conventional eye drops for extended precorneal retention, improved corneal permeability along with better ocular bioavailability.

In vivo biocompatibility and efficacy of dexamethasone-loaded PLGA-PEG-PLGA thermogel in an alkali-burn induced corneal neovascularization disease model.

Challenges of ophthalmic drug delivery arise not only from the limited solubility of hydrophobic therapeutics, but also the restricted permeability and fast clearance of drugs due to the complex anatomy and physiology of eyes. Excellent biocompatibility of a thermosensitive polymer, PLGA-PEG-PLGA (1800-1500-1800, LA:GA ratio = 3:1), as an ophthalmic delivery system was demonstrated in our previous work. In this study, delivery of dexamethasone using this thermogel via a single subconjunctival injection for prolonged treatment was evaluated with corneal neovascularization using an alkali-burn diseased model in rat. Solubility of dexamethasone in the polymeric solution was increased by 5.2-fold and the resulting drug-loaded solution formed in situ rigid gel at body temperature. Prolonged in vitro release of dexamethasone from the gel structure was noted. Dexamethasone gel formulation was demonstrated to be more effective in reducing the burn stimulus and neovascularization in the rat diseased model. The findings suggest the PLGA-PEG-PLGA in situ gelling system can be applied for ophthalmic drug delivery to achieve sustained drug release and improved efficacy.

Thermosensitive glycol chitosan-based hydrogel as a topical ocular drug delivery system for enhanced ocular bioavailability.

In the present study, we developed and evaluated an in situ gelling system based on hexanoyl glycol chitosan (H-GCS) for enhanced ocular bioavailability. An aqueous solution of H-GCS exhibited a typical sol-gel transition at 32 °C. The formed H-GCS hydrogel was characterized by rheology and scanning electron microscopy (SEM). H-GCS had minimal in vitro cytotoxicity against L-929 and HCEC cells over a concentration range of 0-0.8 mg/mL. Additionally, the H-GCS hydrogel exhibited good ocular tolerance and biocompatibility after a single instillation. Moreover, H-GCS hydrogel significantly prolonged the precorneal retention of fluorescein sodium compared with its aqueous solution. An in vivo pharmacokinetic study demonstrated that the levofloxacin-loaded H-GCS hydrogel could provide a significantly higher Cmax and AUC0-12h compared with the levofloxacin aqueous solution, thus increasing ocular bioavailability. Overall, the proposed H-GCS hydrogel acts as an in situ gelling system that might represent a promising vehicle for topical ocular drug delivery.

In Situ Gelling Scaffolds Loaded with Platelet Growth Factors to Improve Cardiomyocyte Survival after Ischemia.

Myocardial infarction is caused by prolonged ischemia and it is one of the main cause that leads to heart failures. The aim of the present work was the development of in situ gelling systems, based on poloxamer 407 (P407) or sodium alginate (Alg), loaded with platelet lysate (PL) to enhance cardiomyocyte survival after ischemia. Chondroitin sulfate (CS), a negatively charged glycosaminoglycan able to interact with different positively charged bioactive molecules, such as growth factors, was also investigated with both the systems. The gelation properties of both systems (viscosity, viscoelasticity, consistency by means of penetrometry, and injectability) were characterized in a physiological environment. In vitro evaluation of biocompatibility using fetal cardiac cells (cardiomyocytes and cardiac fibroblasts) demonstrated that the PL loaded alginate/chondroitin sulfate system retained the highest number of viable cells with equal distribution of the populations of cardiomyocytes and fibroblasts. Furthermore, the ability of the systems to improve cardiomyocyte survival after ischemia was also assessed. PL allowed for the highest degree of survival of cardiomyocytes after oxidative damage (simulating ischemic conditions due to MI) and both the Alg + CS PL and, to a greater extent, the PL alone demonstrated a considerable increase in survival of cardiomyocytes. In conclusion, an in situ gelling alginate-chondroitin sulfate system, loaded with platelet lysate, was able to improve the survival of cardiomyocytes after oxidative damage resulting in a promising system to improve cardiac cell viability after ischemia.

Innovative pharmaceutical approaches for the management of inner ear disorders.

The sense of hearing is essential for permitting human beings to interact with the environment, and its dysfunctions can strongly impact on the quality of life. In this context, the cochlea plays a fundamental role in the transformation of the airborne sound waves into electrical signals, which can be processed by the brain. However, several diseases and external stimuli (e.g., noise, drugs) can damage the sensorineural structures of cochlea, inducing progressive hearing dysfunctions until deafness. In clinical practice, the current pharmacological approaches to treat cochlear diseases are based on the almost exclusive use of systemic steroids. In the last decades, the efficacy of novel therapeutic molecules has been proven, taking advantage from a better comprehension of the pathological mechanisms underlying many cochlear diseases. In addition, the feasibility of intratympanic administration of drugs also permitted to overcome the pharmacokinetic limitations of the systemic drug administration, opening new frontiers in drug delivery to cochlea. Several innovative drug delivery systems, such as in situ gelling systems or nanocarriers, were designed, and their efficacy has been proven in vitro and in vivo in cochlear models. The current review aims to describe the art of state in the cochlear drug delivery, highlighting lights and shadows and discussing the most critical aspects still pending in the field.

Non-invasive strategies for targeting the posterior segment of eye.

The safe and effective treatment of eye diseases has been remained a global myth. Several advancements have been done and various drug delivery and treatment techniques have been suggested. The Posterior segment disorders are the leading cause of visual impairments and blindness. Targeting the therapeutic agents to the anterior and posterior segments of the eye has attracted extensive attention from the scientific community. Significant key factors in the success of ocular therapy are the development of safe, effective, economic and non-invasive novel drug delivery systems. These specialized non-invasive ocular drug delivery systems revolutionized the drug delivery strategies by overcoming the limitations, provided targeted delivery to the ocular tissues by avoiding larger doses, and reducing the toxicity encountered by the conventional approaches. These non-invasive systems are fabricated by ingredients encompassing biodegradability, biocompatibility, mucoadhesion, solubility and permeability enhancement and stimuli responsiveness. The variety of routes are utilized to provide minimally invasive drug delivery to the patients without any discomfort and pain. This review is focused on the brief introduction, types, significance, preparation techniques, components and mechanism of drug release of non-invasive systems, including in situ gelling systems, microspheres, iontophoresis, nanoparticles, nanosuspensions and specialized novel emulsions.

Thermosensitive PEG-PCL-PEG (PECE) hydrogel as an in situ gelling system for ocular drug delivery of diclofenac sodium.

Development of efficient ocular drug delivery systems was still a challenging task. The objective of this article was to develop a thermosensitive PEG-PCL-PEG (PECE) hydrogel and investigate its potential application for ocular drug delivery of diclofenac sodium (DIC). PECE block polymers were synthesized by coupling MPEG-PCL co-polymer using IPDI reagent, and then its sol-gel transition as a function with temperature was investigated by a rheometer. The results showed that 30% (w/v) PECE aqueous solution exhibited sol-gel transition at approximately 35 °C. In vitro release profiles showed the entrapped DIC was sustained release from PECE hydrogels up to 7 days and the initial drug loading greatly effect on release behavior of DIC from PECE hydrogels. MTT assay results indicated that no matter PECE or 0.1% (w/v) DIC-loaded PECE hydrogels were nontoxic to HCEC and L929 cells after 24 h culturing. In vivo eye irritation test showed that the instillation of either 30% (w/v) PECE hydrogels or 0.1% (w/v) DIC-loaded PECE hydrogels to rabbit eye did not result in eye irritation within 72 h. In vivo results showed that the AUC0-48 h of 0.1% (w/v) DIC-loaded PECE hydrogels exhibited 1.6-fold increment as compared with that of commercial 0.1% (w/v) DIC eye drops, suggesting the better ophthalmic bioavailability could be obtained by the instillation of 0.1% (w/v) DIC-loaded PECE hydrogels.

Injectable thermosensitive gelling delivery system for the sustained release of lidocaine.

BACKGROUND: Patients undergoing arthroplasty require appropriate postsurgical pain relief. Analgesia is typically achieved through bolus doses of short-acting local anesthetics and with oral analgesics such as opiates, which are associated with systemic side effects. By formulating an injectable thermosensitive gelling system containing lidocaine, sustained and local delivery can be achieved following a single administration. RESULTS: Poloxamer-based thermosensitive gelling formulations were prepared. Altering the weight ratios of poloxamers affected the sol-to-gel transition temperature, mechanical and rheological properties and in vitro drug release. Desirable formulations gelled between 28 and 33°C providing sustained release of lidocaine over 48 h. CONCLUSION: Thermosensitive gelling systems are promising for sustained drug release following patient administration and may be beneficial in addressing postoperative pain.

In vitro and in vivo ocular safety and eye surface permanence determination by direct and Magnetic Resonance Imaging of ion-sensitive hydrogels based on gellan gum and kappa-carrageenan.

Gellan gum, kappa-carrageenan and alginates are natural polysaccharides able to interact with different cations that can be used to elaborate ion-activated in situ gelling systems for different uses. The interaction between fluid solutions of these polysaccharides and cations presents into the tear made these biopolymers very interesting to elaborate ophthalmic drug delivery systems. The main purpose of this study is to evaluate the ability of mixtures of these polymers to obtain ion-activated ophthalmic in situ gelling systems with optimal properties for ocular use. To achieve this purpose different proportion of the biopolymers were analyzed using a mixture experimental design evaluating their transparency, mechanical properties and bioadhesion in the absence and presence of simulated tear fluid. Tear induces a rapid sol-to-gel phase transition in the mixtures forming a consistent hydrogel. The solution composed by 80% of gellan gum and 20% kappa-carrageenan showed the best mechanical and mucoadhesive properties. This mixture was evaluated for rheological behavior, microstructure, cytotoxicity, acute corneal irritancy, ex-vivo and in vivo ocular toxicity and in vivo corneal contact time using Magnetic Resonance Images (MRI) techniques. Result indicates that the system is safe at ophthalmic level and produces an extensive ocular permanence higher than 6h.

Development and in vitro/in vivo evaluation of thermo-sensitive in situ gelling systems for ocular allergy

Ocular allergy is one of the most common disorders of the eye surface. Following diagnosis this condition is typically treated with preparations containing antihistamines. However, anatomy of the eye and its natural protective mechanisms create challenges for ocular drug delivery. Rapid elimination of antihistamine substances due to short residency times following application can lead to insufficient treatment of ocular allergies. With this in mind, the aim of this study was to prepare a controlled ocular delivery system to extend the retention time of olopatadine hydrochloride (OLO) and in doing so to reduce the need for frequent application. We developed extended-release ocular in situ gelling systems for which in vivo retention times were determined in sheep following in vitro characterization and cytotoxicity studies. In vivo results were then compared to commercially available Patanol eye drops. the transparent gels formulated using appropriate amounts of polymers and having longer ocular retention times appear to be a viable alternative to commercially available eye drops.