Limitations when use chloramphenicol-bcyclodextrins complexes in ophtalmic solutions buffered with boric acid/borax system

Abstract

Chloramphenicol eye drops are commonly prescribed in concentrations of 0.5-1% in the treatment of infectious conjunctivitis. In terms of ophthalmic solution preparation, the major disadvantage of chloramphenicol consists in its low solubility in water. The solubility is increased by substances that form chloramphenicol-complexes, for example: boric acid/borax or cyclodextrins. Objective: Experimental studies aimed to evaluate the potential advantages of enhancing the solubility and stability of chloramphenicol (API) by molecular encapsulation in b-cyclodextrin (CD), in formulation of ophthalmic solutions buffered with boric acid/borax system. Methods and Results: We prepared four APIb-CD complexes, using two methods (kneading and co-precipitation) and two molar ratio of API/b-cyclodextrin (1:1 and 1:2). The formation of complexes was proved by differential scanning calorimetry (DSC) and the in vitro dissolution tests. Using these compounds, we prepared eight ophthalmic solutions, formulated in two variants of chloramphenicol concentrations (0.4% and 0.5%). Each solution was analyzed, by the official methods, at preparation and periodically during three months of storing in different temperature conditions (4°C, 20°C and 30°C). Conclusions: Inclusion of chloramphenicol in b-cyclodextrin only partially solves the difficulties due to the low solubility of chloramphenicol. The protection of chloramphenicol molecules is not completely ensured when the ophthalmic solutions are buffered with the boric acid/borax system. IntroductionChloramphenicol eye drops are commonly prescribed in concentrations of 0.5-1% in the treatment of infectious conjunctivitis, this antibiotic taking the advantage of a broad-spectrum coverage of most gram-positive, gram negative and anaerobic bateria [1,2].In terms of ophthalmic solution preparation, the major disadvantage of chloramphenicol as active pharmaceutical ingredient (API) consists in its low solubility in water (1:400) which allows the obtaining of solutions only up to 0.25% (pH = 4.5 to 7.5). In such solutions, chloramphenicol is stable in the pH 2 to 9 range. The solubility of chloramphenicol is increased by substances that form slightly soluble chloramphenicol-complexes, for example: boric acid/sodium tetraborate (borax) or cyclodextrin (CD). Such complexes make possible the achieving of solutions more concentrated in chloramphenicol (0.5-8%) [3,4].Classically, the eye drops containing 0.5-1% chloramphenicol are prepared using the method of dissolution by mild heating the API in buffer solutions containing boric acid/borax, thus forming chloramphenicol-boric acid/borax complex, in form of sodium salt. Solubility and stability of the resulted complex depend on the pH created in solution by the buffer system. As a consequence: 0.5% chloramphenicol in solution is obtained at pH= 6.8 to 7.2 (solution being stable 10-12 days, stored at room tem-

Chitosan Derivatives with Mucoadhesive and Antimicrobial Properties for Simultaneous Nanoencapsulation and Extended Ocular Release Formulations of Dexamethasone and Chloramphenicol Drugs

“…Its primary effect is to inhibit the synthesis of prokaryotic protein and it can be used in wound dressings [ 26 ], for the preparation of antimicrobial films with nano-engineered three-dimensional hierarchical surfaces by nanoimprint lithography [ 27 ], as a localised drug delivery system encapsulated in β-pyrophosphate for tissue engineering applications [ 28 ] and eye infections treatment. Due to its extremely low water solubility (1:400), it is not possible to prepare eye drop solutions with chloramphenicol concentrations higher than 0.5–1%, a fact that drastically reduces its bioavailability and thus its effectiveness [ 29 ]. This already low concentration is even further reduced in the conjunctival sac due to the lacrimal drainage system.…”

“…For the production of eye drop solutions, chloramphenicol is usually slightly heated in buffer solutions containing boric acid/borax in order to form sodium salt complexes, but that does not particularly increase its solubility [ 29 ]. Several other approaches can be found in literature, such as the treatment with cyclodextrins (CDs), where the aromatic part of chloramphenicol enters the cyclodextrin cavity, forming amorphous complexes with subsequently increased solubility [ 31 , 32 ].…”

“…Several other approaches can be found in literature, such as the treatment with cyclodextrins (CDs), where the aromatic part of chloramphenicol enters the cyclodextrin cavity, forming amorphous complexes with subsequently increased solubility [ 31 , 32 ]. Additional compounds, such as boric acid/borax (1:54 water-soluble) [ 29 ] or amino acids [ 33 ] can also be added to this system to further enhance its solubility. In all cases, drug release was completed after 5–60 min, depending on the type of the prepared complex.…”

Thermo‐Responsive Microemulsions Containing Deep Eutectic‐Based Antibiotic Formulations for Improved Treatment of Resistant Bacterial Ocular Infections

“…An aliquot of 500 μL (with ≈100 mg mL −1 of chloramphenicol) for each formulation was placed in the donor compartment. Then, 300 μL of the receptor medium was removed at designated time points (15,30,45,60,90,120,240,360, and 480 min) and immediately replaced with the same volume of fresh solution. Each collected sample was diluted to 1:3 in acetonitrile, filtered, and analyzed by HPLC-DAD following the former method described.…”

Chloramphenicol Loaded Sponges Based on PVA/Nanocellulose Nanocomposites for Topical Wound Delivery

“…CHL (Scheme 1) is a broad-spectrum antibiotic used extensively in topical treatment. The main drawback of chloramphenicol is its very low aqueous solubility, which limits its bioavailability and, thus, its therapeutic efficiency [32,33]. Rihawy et al studied the chemical crosslinking of PVA reinforced with carboxymethylcellulose (CMC) with 2-hydroxyethyl acrylate (HEA) using CHL as an antibacterial drug [34].…”