New Preservative-Free Formulation for the Enhanced Ocular Bioavailability of Prostaglandin Analogues in Glaucoma.

Glaucoma is a wide-spread eye disease caused by elevated intraocular pressure. Uncontrolled, this pressure may lead to damages to the optic nerve. Prostaglandin analogues, such as latanoprost and travoprost (which are water-insoluble active substances), are the most used class of active pharmaceutical ingredient. To administer them as eye drops, preservatives, such as benzalkonium chloride, are used as solubilizers. The latter is known to cause a local inflammation when used chronically and is not recommended for patients with ocular surface disorders. In this work, we sought to use polysorbate 80 (PS80) as a solubilizing agent simultaneously with sodium hyaluronate (NaHA) as a thickener and cytoprotective agent for the corneal surface. The first part of this study assessed the compatibility of the excipients with the active substance, using physicochemical methods such as spectra fluorescence and differential scanning calorimetry (DSC), as well as the solubilization mechanism of PS80 regarding prostaglandin analogues using nuclear magnetic resonance (NMR). The second part evaluated the stability of a formula candidate, its viscosity upon instillation, and its pharmacokinetic profile in rabbits as compared to the commercially approved medicine Travatan®. The results show that sodium hyaluronate is inert with respect to travoprost, while PS80 successfully solubilizes it, meaning that benzalkonium chloride is no longer required. Moreover, the pharmacokinetic profiles of the rabbits showed that the original formula described in the present study enhanced the ocular bioavailability of the drug, making it a promising product to control intraocular pressure with a potential reduced dosage of travoprost, therefore minimizing its related side effects.

In Situ Gelling Ophthalmic Drug Delivery System for the Optimization of Diagnostic and Preoperative Mydriasis: In Vitro Drug Release, Cytotoxicity and Mydriasis Pharmacodynamics.

Mydriasis is required prior to many eye examinations and ophthalmic surgeries. Nowadays, phenylephrine hydrochloride (PHE) and tropicamide (TPC) are extensively used to induce mydriasis. Several pharmaceutic dosage forms of these two active ingredients have been described. However, no optimal therapeutic strategy has reached the market. The present work focuses on the formulation and evaluation of a mucoadhesive ion-activated in situ gelling delivery system based on gellan gum and hydroxyethylcellulose (HEC) for the delivery of phenylephrine and tropicamide. First, in vitro drug release was studied to assess appropriate sustained drug delivery on the ocular surface region. Drug release mechanisms were explored and explained using mathematical modeling. Then, in situ gelling delivery systems were visualized using scanning electron microscopy illustrating the drug release phenomena involved. Afterward, cytotoxicity of the developed formulations was studied and compared with those of commercially available eye drops. Human epithelial corneal cells were used. Finally, mydriasis intensity and kinetic was investigated in vivo. Mydriasis pharmacodynamics was studied by non-invasive optical imaging on vigilant rabbits, allowing eye blinking and nasolacrimal drainage to occur physiologically. In situ gelling delivery systems mydriasis profiles exhibited a significant increase of intensity and duration compared with those of conventional eye drops. Efficient mydriasis was achieved following the administration of a single drop of in situ gel reducing the required amount of administered active ingredients by four- to eight-fold compared with classic eye drop regimen.

Novel in situ gelling ophthalmic drug delivery system based on gellan gum and hydroxyethylcellulose: Innovative rheological characterization, in vitro and in vivo evidence of a sustained precorneal retention time.

Achieving drug delivery at the ocular level encounters many challenges and obstacles. In situ gelling delivery systems are now widely used for topical ocular administration and recognized as a promising strategy to improve the treatment of a wide range of ocular diseases. The present work describes the formulation and evaluation of a mucoadhesive and ion-activated in situ gelling delivery system based on gellan gum and hydroxyethylcellulose for the delivery of phenylephrine and tropicamide. First, physico-chemical characteristics were assessed to ensure suitable properties regarding ocular administration. Then, rheological properties such as viscosity and gelation capacity were determined. Gelation capacity of the formulations and the effect of hydroxyethylcellulose on viscosity were demonstrated. A new rheological method was developed to assess the gel resistance under simulated eye blinking. Afterward, mucoadhesion was evaluated using tensile strength test and rheological synergism method in both rotational and oscillatory mode allowing mucoadhesive properties of hydroxyethylcellulose to be point out. Finally, residence time on the ocular surface was investigated in vivo, using cyanine 5.5 dye as a fluorescent marker entrapped in the in situ gelling delivery systems. Residence performance was studied by non-invasive optical imaging on vigilant rabbits, allowing eye blinking and nasolacrimal drainage to occur physiologically. Fluorescence intensity profiles pointed out a prolonged residence time on the ocular surface region for the developed formulations compared to conventional eye drops, suggesting in vitro / in vivo correlations between rheological properties and in vivo residence performances.

Cyanine derivative as a suitable marker for thermosensitive in situ gelling delivery systems: In vitro and in vivo validation of a sustained buccal drug delivery.

Buccal administration route is a promising way for a large number of drugs exhibiting a low oral bioavailability. The present work describes the formulation and evaluation of a mucoadhesive and thermosensitive in situ gelling delivery system based on poloxamer 407, poloxamer 188 and xanthan gum for buccal drug delivery. First, the mucoadhesion properties were evaluated using a tensile test. The effect of xanthan gum on the mucoadhesion force was demonstrated. Then, to assess the buccal residence time which reflects the mucoadhesion properties, the validation of a fluorescence probe for in vivo optical imaging experiment was conducted. Methyl-Cyanine 5 derivative (Me-Cy5) was used to label the hydrogels, dissolution tests and permeation studies through buccal epithelium cells showed that Me-Cy5 release from hydrogels was mainly due to an erosion mechanism and presented a limited penetration across epithelium cells. These results suggest that, Me-Cy5 is a suitable marker for thermosensitive in situ gelling delivery systems as the probe mostly stays entrapped in the hydrogel and do not cross the epithelial barrier. Buccal residence performance of the hydrogel was evaluated for the first time by non-invasive optical imaging after administration to mice. This technique is an interesting alternative compared to visual observations and sacrifice involved experiments, which could also be exploited to various administration routes.

In vitro and in vivo evaluation of in situ gelling systems for sustained topical ophthalmic delivery: state of the art and beyond.

In situ gelling delivery systems for the ocular administration of drugs has been a major focus of research over the past two decades, improving the treatment of diseases of the anterior segment of the eye by simple, safe, and reproducible drug administration. This drug delivery strategy results in high ocular bioavailability by avoiding rapid precorneal clearance resulting from nasolacrimal drainage and eye blinking. However, the development of such unconventional forms requires many parameters to be mastered, such as gelation time, viscoelastic behavior, mucoadhesion, and sustained release. In this review, we describe and assess the in vitro and in vivo methods available for in situ gelling ophthalmic delivery systems, highlighting the advantages of existing methods and, in some cases, the need for more relevant assays.

Poloxamer bioadhesive hydrogel for buccal drug delivery: Cytotoxicity and trans-epithelial permeability evaluations using TR146 human buccal epithelial cell line.

A salbutamol sulfate (SS)-Poloxamer bioadhesive hydrogel specially developed for buccal administration was investigated by studying interactions with TR146 human buccal epithelium cells (i.e. cellular toxicity (i) and trans-epithelial SS diffusion (ii)). The assessment of cell viability (MTT, Alamar Blue), membrane integrity (Neutral Red), and apoptosis assay (Hoechst 33342), were performed and associated to Digital Holographic Microscopy analysis. After the treatment of 2h, SS solution induced drastic cellular alterations that were prevented by hydrogels in relation with the concentrations of poloxamer and xanthan gum. The formulation containing P407 19%/P188 1%/Satiaxane 0.1% showed the best tolerance after single and multiple administrations and significantly reduced the trans-epithelial permeability from 5.00±0.29 (×10(3)) (SS solution) to 1.83±0.22 cm/h. Digital Holographic Microscopy images in good agreement with the viability data confirmed the great interest of this direct technique. In conclusion, the proposed hydrogels represent a safe and efficient buccal drug delivery platform.

Buccal acetaminophen provides fast analgesia: two randomized clinical trials in healthy volunteers.

BACKGROUND: Acetaminophen (APAP) by oral or intravenous (iv) routes is used for mild to moderate pain but may take time to be effective. When fast relief is required and/or oral or iv routes are not available because of the patient's condition, the transmucosal route may be an alternative. METHODOLOGY: A new transmucosal/buccal (b) pharmaceutical form of APAP dissolved in 50% wt alcohol is compared with other routes of administration. Two consecutive randomized, crossover, double-blind clinical trials (CT1: NCT00982215 and CT2: NCT01206985) included 16 healthy volunteers. CT1 compared the pharmacology of 250 mg bAPAP with 1 g iv APAP. CT2 compared the pharmacodynamics of 125 mg bAPAP with 1 g iv and 125 mg sublingual (s) APAP. Mechanical pain thresholds are recorded in response to mechanical stimuli applied on the forearm several times during 120 minutes. The objective is to compare the time of onset of antinociception and the antinociception (area under the curve) between the routes of administration with analysis of variance (significance P<0.05). RESULTS: bAPAP has a faster time of antinociception onset (15 minutes, P<0.01) and greater antinociception at 50 minutes (P<0.01, CT1) and 30 minutes (P<0.01, CT2) than ivAPAP and sAPAP. All routes are similar after 50 minutes. CONCLUSION: bAPAP has a faster antinociceptive action in healthy volunteers. This attractive alternative to other routes would be useful in situations where oral or iv routes are not available. This finding must now be confirmed in patients suffering from acute pain of mild and moderate intensity.

Influence of additives on a thermosensitive hydrogel for buccal delivery of salbutamol: relation between micellization, gelation, mechanic and release properties.

Thermosensitive hydrogels developed for buccal delivery of salbutamol were prepared using poloxamer analogs (Kolliphor(®) P407/P188), xanthan gum (Satiaxane(®) UCX930) and NaCl. P188 increased gelation temperature (Tsol-gel) by 2.5-5°C, micellization temperature (<1°C) and gelation time by >3s. To obtain a suitable Tsol-gel at 28-34°C, P407 and P188 concentrations were set to 18-19% and 1%. NaCl reduced Tsol-gel (>2°C) out of the optimal range. Six formulations containing 0.05-0.1% Satiaxane(®) fulfilled the temperature criteria. Concerning the gel strength, 1% P188 had no significant effect, NaCl increased it at 20°C, and Satiaxane(®) enhanced it at 20°C and 37°C. The release study using membrane-less (to mimic oral cavity) and membrane (to mimic buccal mucosa side) methods allowed a complete investigation showing that erosion and diffusion both contributed to the drug release but differed according to the formulation. In the membraneless method, simple P407 formulations had weak ability to retain salbutamol (T80=35 min). P188 accelerated drug release. NaCl accelerated release in the membraneless method by 5-11 min but slightly reduced it in the membrane method. The hydrogels containing Satiaxane(®) exhibited the slowest release. In the membrane method, combination of P407/P188/Satiaxane(®) provided a sustained diffusion with a burst effect (T25=9.6 min, T80=97.8 min), which provides potential clinical interests.