Hyaluronan-Cholesterol Nanogels for the Enhancement of the Ocular Delivery of Therapeutics

The anatomy and physiology of the eye strongly limit the bioavailability of locally administered drugs. The entrapment of therapeutics into nanocarriers represents an effective strategy for the topical treatment of several ocular disorders, as they may protect the embedded molecules, enabling drug residence on the ocular surface and/or its penetration into different ocular compartments. The present work shows the activity of hyaluronan-cholesterol nanogels (NHs) as ocular permeation enhancers. Thanks to their bioadhesive properties, NHs firmly interact with the superficial corneal epithelium, without penetrating the stroma, thus modifying the transcorneal penetration of loaded therapeutics. Ex vivo transcorneal permeation experiments show that the permeation of hydrophilic drugs (i.e., tobramycin and diclofenac sodium salt), loaded in NHs, is significantly enhanced when compared to the free drug solutions. On the other side, the permeation of hydrophobic drugs (i.e., dexamethasone and piroxicam) is strongly dependent on the water solubility of the entrapped molecules. The obtained results suggest that NHs formulations can improve the ocular bioavailability of the instilled drugs by increasing their preocular retention time (hydrophobic drugs) or facilitating their permeation (hydrophilic drugs), thus opening the route for the application of HA-based NHs in the treatment of both anterior and posterior eye segment diseases.

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.

Hyaluronan-Cholesterol Nanogels for the Enhancement of the Ocular Delivery of Therapeutics

The anatomy and physiology of the eye strongly limit the bioavailability of locally administered drugs. The entrapment of therapeutics into nanocarriers represents an effective strategy to topically treat some ocular disorders, as they may protect the entrapped molecules, facilitating drug residence on the ocular surface and/or its penetration into different ocular compartments. The present work shows the activity of hyaluronan-cholesterol nanogels (NHs) as ocular permeation enhancers. Thanks to their bioadhesive properties, NHs firmly interact with the superficial corneal epithelium, without penetrating the stroma, modifying the transcorneal penetration of loaded therapeutics. Ex-vivo transcorneal permeation experiments showed that the permeation of hydrophilic drugs (i.e. tobramycin and diclofenac sodium salt), loaded in NHs, is significantly enhanced when compared to the free drug solutions. On the other side the permeation of hydrophobic drugs (i.e. dexamethasone and piroxicam) is strongly dependent on the water solubility of the entrapped molecules. The obtained results suggest that NHs formulations can improve the ocular bioavailability of the instilled drugs by increasing their preocular retention time (hydrophobic drugs) or facilitating their permeation (hydrophilic drugs), thus opening the route for the application of HA-based NHs in the treatment of both anterior and posterior eye segment diseases.

In-Situ Forming Polymeric Drug Delivery Systems for Ophthalmic Use: An Overview

Delivery of drug into the ocular region is hindered by the protective layers that encapsulate the eyes, it has always been a major problem to get an effective bioavailability of the active drug in the ocular region due to the low precorneal resident time of most of the ocular delivery systems specifically convention once such as ointment, solution and suspension, as a result, most of the delivery systems are not capable of effectively treating ocular diseases. Several works have and are being carried out to overcome this problem one of which is using in-situ forming polymeric systems. Ocular In-situ gelling systems are a novel class of ocular drug delivery systems that are initially in a solution form but instantaneously gets converted into a viscous gel upon introduction or installation in the ocular cavity from which the active drugs get released in a sustained manner. This sol-to-gel phase transition depends upon various factors like change in pH, ion presence and change in temperature. Gel formed after the transformation has preferred viscosity along with bio-adhesive property, which increases the gel’s resident time in the ocular area and also releases the drug in a prolonged and sustained manner unlike conventional eye drops and ointments. This review emphasizes various ocular in-situ systems namely, pH triggered, Ion activated, and Temperature triggered systems which have prolonged residence time in the cul-de-sac area of the eye, hence increasing the ocular bioavailability. Keywords: In-situ gel, Ocular Drug delivery, Ocular Bioavailability, Polymer

A REVIEW ON POLOXAMER AND HYDROXY PROPYL METHYL CELLULOSE COMBINATION AS THERMORESPONSIVE POLYMERS IN NOVEL OPHTHALMIC IN SITU GEL FORMULATION AND THEIR CHARACTERIZATION

Poor bioavailability is one of the most significant problems in the delivery of the ocular drug system. Ophthalmic ointments, solutions and suspensions are the most frequently used dosage forms to treat ocular disease, and their effectiveness as a drug are compromised by several limitations that lead to poor ocular bioavailability. In situ gel is one of the most promising strategy and solutions to improve the ocular bioavailability of drugs. The purpose of this review is to discuss the formulation and characterization of in situ gel. This review is written based on the data or information obtained by using several search engines and several scientific journals, focused on Poloxamer 407 and Hydroxy Propyl Methyl Cellulose (HPMC) bases combination. Active ingredients to treat ocular disease such as Ciprofloxacin, Fluconazole and Ofloxacin can be formulated with the combination of Poloxamer 407 as polymer gelling agent and HPMC as viscosity enhancer to produce good quality in situ gel dosage forms. The in situ gel dosage forms can be a promising alternate solution for the ophthalmic delivery system.

Formulation and Evaluation of Brimonidine Maleate Nanolipid in Situ Gel

The main objective of present research work was aimed to formulate and evaluate the nano lipid-based drug delivery system by incorporating a brimonidine maleate drug for ocular therapy. The patient can be improved by preparing nano lipid in situ gel as a vehicle by reducing the frequency of administration and increasing the ocular bioavailability. Nanolipids were prepared by film hydration technique and then prepared nanolipids were incorporated into insitu gel by using various polymers like Carbopol 940 and HPMC K15M with different concentration. The various formulations prepared showed excellent and effective results for visual appearance, pH, and gellation study. It was further observed that formulations had entrapment efficiency within the range of 67.20% to 97.3% for brimonidine maleate loaded insitu gel formulations. F1 entrapment efficiency was found to be 97.3% and shown maximum when compared with other formulations. From the drug release data, it was found that F1 (99.0%) shows maximum drug release compare to other formulations.

Biopharmaceutical Assessment of Dexamethasone Acetate-Based Hydrogels Combining Hydroxypropyl Cyclodextrins and Polysaccharides for Ocular Delivery

We previously developed two optimized formulations of dexamethasone acetate (DXMa) hydrogels by means of special cubic mixture designs for topical ocular administration. These gels were elaborated with hydroxypropyl-β-CD (HPβCD) and hydroxypropyl-γ-CD (HPγCD) and commercial hydrogels in order to enhance DXMa water solubility and finally DXMa’s ocular bioavailability and transcorneal penetration. The main objective of this study was to characterize them and to evaluate in vitro, ex vivo, and in vivo their safety, biopermanence, and transcorneal permeation. Gels A and B are Newtonian fluids and display a viscosity of 13.2 mPa.s and 18.6 mPa.s, respectively, which increases their ocular retention, according to the in vivo biopermanence study by PET/CT. These hydrogels could act as corneal absorption promoters as they allow a higher transcorneal permeation of DXMa through porcine excised cornea, compared to DEXAFREE® and MAXIDEX®. Cytotoxicity assays showed no cytotoxic effects on human primary corneal epithelial cells (HCE). Furthermore, Gel B is clearly safe for the eye, but the effect of Gel A on the human eye cannot be predicted. Both gels were also stable 12 months at 25 °C after sterilization by filtration. These results demonstrate that the developed formulations present a high potential for the topical ocular administration of dexamethasone acetate.

Micelles of Progesterone for Topical Eye Administration: Interspecies and Intertissues Differences in Ex Vivo Ocular Permeability

Progesterone (PG) may provide protection to the retina during retinitis pigmentosa, but its topical ocular supply is hampered by PG poor aqueous solubility and low ocular bioavailability. The development of efficient topical ocular forms must face up to two relevant challenges: Protective barriers of the eyes and lack of validated ex vivo tests to predict drug permeability. The aims of this study were: (i) To design micelles using Pluronic F68 and Soluplus copolymers to overcome PG solubility and permeability; and (ii) to compare drug diffusion through the cornea and sclera of three animal species (rabbit, porcine, and bovine) to investigate interspecies differences. Micelles of Pluronic F68 (3–4 nm) and Soluplus (52–59 nm) increased PG solubility by one and two orders of magnitude, respectively and exhibited nearly a 100% encapsulation efficiency. Soluplus systems showed in situ gelling capability in contrast to the low viscosity Pluronic F68 micelles. The formulations successfully passed the hen’s egg-chorioallantoic membrane test (HET-CAM) test. PG penetration through rabbit cornea and sclera was faster than through porcine or bovine cornea, although the differences were also formulation-dependent. Porcine tissues showed intermediate permeability between rabbit and bovine. Soluplus micelles allowed greater PG accumulation in cornea and sclera whereas Pluronic F68 promoted a faster penetration of lower PG doses.