Impact of co-administered stabilizers on the biopharmaceutical performance of regorafenib amorphous solid dispersions.

Poor solubility of drug candidates is a well-known and thoroughly studied challenge in the development of oral dosage forms. One important approach to tackle this challenge is the formulation as an amorphous solid dispersion (ASD). To reach the desired biopharmaceutical improvement a high supersaturation has to be reached quickly and then be conserved long enough for absorption to take place. In the presented study, various formulations of regorafenib have been produced and characterized in biorelevant in-vitro experiments. Povidone-based formulations, which are equivalent to the marketed product Stivarga®, showed a fast drug release but limited stability and robustness after that. In contrast, HPMCAS-based formulations exhibited excellent stability of the supersaturated solution, but unacceptably slow drug release. The attempt to combine the desired attributes of both formulations by producing a ternary ASD failed. Only co-administration of HPMCAS as an external stabilizer to the rapidly releasing Povidone-based ASDs led to the desired dissolution profile and high robustness. This optimized formulation was tested in a pharmacokinetic animal model using Wistar rats. Despite the promising in-vitro results, the new formulation did not perform better in the animal model. No differences in AUC could be detected when compared to the conventional (marketed) formulation. These data represent to first in-vivo study of the new concept of external stabilization of ASDs. Subsequent in-vitro studies revealed that temporary exposure of the ASD to gastric medium had a significant and long-lasting effect on the dissolution performance and externally administered stabilizer could not prevent this sufficiently. By applying the co-administered HPMCAS as an enteric coating onto Stivarga tablets, a new bi-functional approach was realized. This approach achieved the desired tailoring of the dissolution profile and high robustness against gastric medium as well as against seeding.

Preparation and Characterization of a Lutein Solid Dispersion to Improve Its Solubility and Stability.

Lutein has been used as a dietary supplement for the treatment of eye diseases, especially age-related macular degeneration. For oral formulations, we investigated lutein stability in artificial set-ups mimicking different physiological conditions and found that lutein was degraded over time under acidic conditions. To enhance the stability of lutein upon oral intake, we developed enteric-coated lutein solid dispersions (SD) by applying a polymer, hydroxypropyl methylcellulose acetate succinate (HPMCAS-LF), through a solvent-controlled precipitation method. The SD were characterized in crystallinity, morphology, and drug entrapment. In the dissolution profile of lutein SD, a F80 formulation showed resistance toward the acidic environment under simulated gastric conditions while exhibiting a bursting drug release under simulated intestinal conditions. Our results highlight the potential use of HPMCAS-LF as an effective matrix to enhance lutein bioavailability during oral delivery and to provide novel insights into the eye-care supplement industry, with direct benefits for the health of patients.

Biopharmaceutical characterization of a novel sustained-release formulation of allopurinol with reduced nephrotoxicity.

The present study was aimed to develop a novel sustained-release formulation for allopurinol (ALP/SR) with the use of a pH-sensitive polymer, hydroxypropyl methylcellulose acetate succinate, to reduce nephrotoxicity. ALP/SR was evaluated in terms of crystallinity, the dissolution profile, pharmacokinetic behavior, and nephrotoxicity in a rat model of nephropathy. Under acidic conditions (pH1.2), sustained release behavior was seen for ALP/SR, although both crystalline ALP and ALP/SR exhibited rapid dissolution at neutral condition. After multiple oral administrations of ALP samples (10 mg-ALP/kg) for 4 days in a rat model of nephropathy, ALP/SR led to a low and sustained plasma concentration of ALP, as evidenced by half the maximum concentration of ALP and a 2.5-fold increase in the half-life of ALP compared with crystalline ALP, possibly due to suppressed dissolution behavior under acidic conditions. Repeated-dosing of ALP/SR resulted in significant reductions in plasma creatinine and blood urea nitrogen levels by 73% and 69%, respectively, in comparison with crystalline ALP, suggesting the low nephrotoxic risk of ALP/SR. From these findings, a strategic SR formulation approach might be an efficacious dosage option for ALP to avoid severe nephrotoxicity in patients with nephropathy.

Development of methylcellulose-based sustained-release dosage by semisolid extrusion additive manufacturing in drug delivery system.

The objective of this study is to fabricate customized dosage forms using extrusion-based 3D printing for the sustained delivery of theophylline. The therapeutic paste was prepared by combining various doses of theophylline (0, 75, 100, and 125 mg) with different concentrations of methylcellulose (MC) A4M (8, 10, and 12%). The paste was then 3D printed into semisolid tablets under optimized printing conditions. The rheological properties of printing pastes were related to the 3D printability. Our results indicated that to be 3D printed using the current platform, the storage modulus (G') of the printing paste should be higher than the loss modulus (G″) during the frequency sweep (0.1-600 rad/s), and the tan δ should fall in the range of 0.25-0.27 at 0.63 rad/s. The printed tablets formulated with 10% MC showed the highest overall quality, considering the aspects of resolution, texture, and shape retention regardless of the dosage. The scanning electron microscopy images indicated that the cross-linked structure of MC A4M formed the microscale porous microstructure, which has the potential to embed the theophylline, thus delayed the release through the barrier effect. The in vitro dissolution test revealed that the 3D printed tablets exhibited a sustained release during the first 12 hr. The findings in this study will support the development of customized, personalized medicine with improved efficacy.

An enhanced charge-driven intranasal delivery of nicardipine attenuates brain injury after intracerebral hemorrhage.

Intranasal drug delivery provided an alternative and effective approach for the intervention of an intracerebral hemorrhage (ICH). However, the short retention time at the absorption site and slow drug transport in intranasal gel influence the drug bioavailability and outcome of ICH. Herein, we fabricated a novel intranasal gel with oriented drug migration utilizing a charge-driven strategy to attenuate brain injury after ICH. Nicardipine hydrochloride (NCD) was entrapped in chitosan nanoparticles (CS NPs) and dispersed in an HAMC gel. Subsequently, one side of the gel was coated with a positively charged film. The oriented migration of CS NPs in the HAMC gel was determined, and the drug bioavailability was also enhanced. Furthermore, a blood-induced ICH rat model was established to evaluate the therapeutic effect of CS NPs + HAMC composites. Intranasal administration of the CS NPs + HAMC (+) composite showed a stronger neuroprotective effect in terms of brain edema reduction and neural apoptosis inhibition compared to the CS NPs + HAMC composite. These results suggested that the oriented and rapid drug transport from nose to brain can be achieved using the charge-driven strategy, and this intranasal drug delivery system has the potential to provide a new therapeutic strategy for the treatment of ICH.

Highly Soluble Drugs Directly Granulated by Water Dispersions of Insoluble Eudragit® Polymers as a Part of Hypromellose K100M Matrix Systems.

The aim of the present study was to investigate the suitability of insoluble Eudragit® water dispersions (NE, NM, RL, and RS) for direct high-shear granulation of very soluble levetiracetam in order to decrease its burst effect from HPMC K100M matrices. The process characteristics, ss-NMR analysis, in vitro dissolution behavior, drug release mechanism and kinetics, texture profile analysis of the gel layer, and PCA analysis were explored. An application of water dispersions directly on levetiracetam was feasible only in a multistep process. All prepared formulations exhibited a 12-hour sustained release profile characterized by a reduced burst effect in a concentration-dependent manner. No effect on swelling extent of HPMC K100M was observed in the presence of Eudragit®. Contrary, higher rigidity of formed gel layer was observed using combination of HPMC and Eudragit®. Not only the type and concentration of Eudragit®, but also the presence of the surfactant in water dispersions played a key role in the dissolution characteristics. The dissolution profile close to zero-order kinetic was achieved from the sample containing levetiracetam directly granulated by the water dispersion of Eudragit® NE (5% of solid polymer per tablet) with a relatively high amount of surfactant nonoxynol 100 (1.5%). The initial burst release of drug was reduced to 8.04% in 30 min (a 64.2% decrease) while the total amount of the released drug was retained (97.02%).

Influence of Polymers on the Physical and Chemical Stability of Spray-dried Amorphous Solid Dispersion: Dipyridamole Degradation Induced by Enteric Polymers.

Amorphous solid dispersions (ASDs) are inherently unstable because of high internal energy. Evaluating physical and chemical stability during the process and storage is essential. Numerous researches have demonstrated how polymers influence the drug precipitation and physical stability of ASDs, while the influence of polymers on the chemical stability of ASDs is often overlooked. Therefore, this study aimed to investigate the effect of polymers on the physical and chemical stability of spray-dried ASDs using dipyridamole (DP) as a model drug. Proper polymers were selected by assessing their abilities to inhibit drug recrystallization in supersaturated solutions. HPMC E5, Soluplus®, HPMCP-55, and HPMCAS-LP were shown to be effective stabilizers. The optimized formulations were further stored at a high temperature (60 °C) and high humidity (40 °C, 75% RH) for 2 months, and their physical and chemical stability was evaluated using polarizing optical microscopy, FTIR, HPLC, and mass spectrometry (MS). In general, crystallization was observed in all samples, which indicated the physical instability under stressed storage conditions. Also, it was noted that the polymers in ASDs rather than physical mixtures, induced a dramatic drug degradation after being exposed to a high temperature (HPMCP-55 > 80% and HPMCAS-LP > 50%) and high humidity (HPMCP-55 > 40% and HPMCAS-LP > 10%). The MS analysis further confirmed the degradation products, which might be generated from the reaction between dipyridamole and phthalic anhydride decomposed from HPMCP-55 and HPMCAS-LP. Overall, the exposure of ASDs to stressed conditions resulted in recrystallization and even the chemical degradation induced by polymers.

Correlation between the viscoelastic properties of the gel layer of swollen HPMC matrix tablets and their in vitro drug release.

Drug release from hydroxypropyl methylcellulose (HPMC) hydrophilic matrix tablets is controlled by drug diffusion through the gel layer of the matrix-forming polymer upon hydration, matrix erosion or combination of diffusion and erosion mechanisms. In this study, the relationship between viscoelastic properties of the gel layer of swollen intact matrix tablets and drug release was investigated. Two sets of quetiapine fumarate (QF) matrix tablets were prepared using the high viscosity grade HPMC K4M at low (70 mg/tablet) and high (170 mg/tablet) polymer concentrations. Viscoelastic studies using a controlled stress rheometer were performed on swollen matrices following hydration in the dissolution medium for predetermined time intervals. The gel layer of swollen tablets exhibited predominantly elastic behavior. Results from the in vitro release study showed that drug release was strongly influenced by the viscoelastic properties of the gel layer of K4M tablets, which was further corroborated by results from water uptake studies conducted on intact tablets. The results provide evidence that the viscoelastic properties of the gel layer can be exploited to guide the selection of an appropriate matrix-forming polymer, to better understand the rate of drug release from matrix tablets in vitro and to develop hydrophilic controlled-release formulations.

Formulation of bi-layer matrix tablets of tramadol hydrochloride: Comparison of rate retarding ability of the incorporated hydrophilic polymers.

Bi-layer tablets of tramadol hydrochloride were prepared by direct compression technique. Each tablet contains an instant release layer with a sustained release layer. The instant release layer was found to release the initial dose immediately within minutes. The instant release layer was combined with sustained release matrix made of varying quantity of Methocel K4M, Methocel K15MCR and Carbomer 974P. Bi-layer tablets were evaluated for various physical tests including weight variation, thickness and diameter, hardness and percent friability. Drug release from bi-layer tablet was studied in acidic medium and buffer medium for two and six hours respectively. Sustained release of tramadol hydrochloride was observed with a controlled fashion that was characteristic to the type and extent of polymer used. % Drug release from eight-hour dissolution study was fitted with several kinetic models. Mean dissolution time (MDT) and fractional dissolution values (T25%, T50% and T80%) were also calculated as well, to compare the retarding ability of the polymers. Methocel K15MCR was found to be the most effective in rate retardation of freely water-soluble tramadol hydrochloride compared to Methocel K4M and Capbomer 974P, when incorporated at equal ratio in the formulation.

Effect of Eye Drops Containing Disulfiram and Low-Substituted Methylcellulose in Reducing Intraocular Pressure in Rabbit Models.

PURPOSE: We attempted to develop anti-glaucoma eye drops using 0.5% disulfiram (DSF), 5% 2-hydroxypropyl-ß-cyclodextrin, 0.1% hydroxypropylmethylcellulose, and 2% methylcellulose (MC) (DSF eye drops with MC), and tested the ability of a DSF eye drops with MC to reduce intraocular pressure (IOP) in rabbit models. METHODS: Elevated IOP was induced by the rapid infusion of 5% glucose solution (15 ml/kg of body weight) through the marginal ear vein or by keeping rabbits in the dark for 5 h. IOP and the nitric oxide (NO) level in the aqueous humor were measured with an electronic tonometer and by a microdialysis method, respectively. ΔIOP and ΔNO values were analyzed as the differences in IOP and NO in rabbits instilled with saline or eye drops, respectively. RESULTS: Increased IOP in rabbit models was reduced by the instillation of DSF eye drops with or without MC, and a close relationship was observed between IOP and NO levels in rabbit receiving a rapid infusion of isotonic glucose. We present kinetic parameters [secondary AUC (prolonged drug effect) and secondary MRT (prolonged effective time)] analyzed as the area under the curve (AUC) of ΔIOP or ΔNO versus time using rabbits instilled with eye drops 10, 50, or 90 min prior to the infusion of the isotonic glucose solution. The elevations in IOP and NO level were reduced by the instillation of DSF eye drops with or without MC; the addition of MC increased the secondary AUC and MRT of DSF eye drops. CONCLUSIONS: The present study demonstrates that 0.5% DSF eye drops suppress increased IOP in rabbit models, probably by inhibiting the elevation in NO levels. In addition, we propose a kinetic analysis method to predict drug effects and effective time. These findings suggest that a low-substituted MC-based drug delivery system promotes drug effectiveness and effective time.

The effect of HPMC particle size on the drug release rate and the percolation threshold in extended-release mini-tablets.

The particle size of HPMC is a critical factor that can influence drug release rate from hydrophilic matrix systems. Percolation theory is a statistical tool which is used to study the disorder of particles in a lattice of a sample. The percolation threshold is the point at which a component is dominant in a cluster resulting in significant changes in drug release rates. Mini-tablets are compact dosage forms of 1.5-4 mm diameter, which have potential benefits in the delivery of drug to some patient groups such as pediatrics. In this study, the effect of HPMC particle size on hydrocortisone release and its associated percolation threshold for mini-tablets and tablets was assessed. For both mini-tablets and tablets, large polymer particles reduced tensile strength, but increased the drug release rate and the percolation threshold. Upon hydration, compacts with 45-125 µm HPMC particles formed a strong gel layer with low porosity, reducing hydrocortisone release rates. In comparison, faster drug release rates were obtained when 125-355 µm HPMC particles were used, due to the greater pore sizes that resulted in the formation of a weaker gel. Using 125-355 µm HPMC particles increased the percolation threshold for tablets and to a greater extent for mini-tablets. This work has demonstrated the importance of HPMC particle size in ER matrices, the effects of which are even more obvious for mini-tablets.

Study the effect of formulation variables on drug release from hydrophilic matrix tablets of milnacipran and prediction of in-vivo plasma profile.

The objective of this study was to design oral controlled release (CR) matrix tablets of Milnacipran using hydroxypropyl methylcellulose (HPMC) as the retardant polymer and to study the effect of various formulation factors such as polymer proportion, polymer viscosity, compression force and also the pH of dissolution medium on the in-vitro release of drug. Two viscosity grade of HPMC (15 K and 100 K) were used in the proportion of 50, 100, 150 and 200 mg per CR tablet. In-vitro release rate was characterized using various model dependent approaches and model independent dissolution parameters [T50% and T80% dissolution time, mean dissolution time (MDT), mean residence time (MRT), dissolution efficiency (DE)]. The statistical analysis was performed on all the model independent approaches using student t test and ANOVA. Results were found that as polymer concentration (50 mg to 200 mg) and viscosity (15 K to 100 K) increases, the MDT, MRT, T50% and T80% extended significantly. Drug release rate was found to be significantly different at different hardness. In-vivo human plasma concentration--time profile was predicted from in-vitro release data using convolution method. Predicted human pharmacokinetic parameters shows that the design CR formulation has capability to sustained the plasma drug level of milnacipran.

Pharmacokinetic study of hydroxypropylmethylcellulose microparticles loaded with cimetidine.

OBJECTIVES: The objective of this study was to assess the pharmacokinetic behavior of floating hydroxypropylmethylcellulose microparticles loaded with cimetidine (FMC) prepared using the non-solvent addition coacervation technique. MATERIAL AND METHODS: Based on the physico-chemical characteristics of three formulations (FMC1, FMC2 and FMC3), FMC2 having a 1:3 ratio of cimetidine:HPMC was found optimum. For in vivo analysis, a new HPLC analytical method was developed and validated. The optimized formulations were subjected to in vivo studies to calculate the various pharmacokinetic parameters for developed optimized microparticulate formulation FMC3. The developed floating microparticles of cimetidine were further evaluated by in vivo experimentation. RESULTS: The bioavailability parameters were found as: Cmax 1508.79 ± 37.95 ng/ml, Tmax 3.67 ± 0.17 h and AUC 14366.19 ± 377.64 ng h /mL. CONCLUSIONS: For prolonged drug release in the stomach, developed floating microparticles of cimetidine (FMC3) may be used, thereby improving the bioavailability and patient compliance.

Trivalent ion cross-linked pH sensitive alginate-methyl cellulose blend hydrogel beads from aqueous template.

pH sensitive alginate-methyl cellulose blend hydrogel beads were prepared by single water-in-water (w/w) emulsion gelation method in a complete aqueous environment. The influence of different variables like total polymer concentration, gelation time and crosslinker content on in vitro physico-chemical characteristics and drug release rate in different medium were investigated. Drug loaded beads were evaluated through Fourier Transform Infra-red (FTIR), X-ray diffraction (XRD) and Differential Scanning Calorimetry (DSC) analysis. Scanning electron microscopy (SEM) picture of the dried beads suggested the formation of hemispherical particles. FTIR analysis indicated the stable nature of the drug in the blend hydrogel beads. DSC and XRD analysis revealed amorphous state of drug after encapsulation. The drug release profile in acidic medium was considerably less in compared in alkaline media. Formulations showed non-Fickian type transport mechanism. This trivalent ion crosslinked beads not only improves drug encapsulation efficiency but also enhances drug release in alkaline media.

Comparison of two encapsulated curcumin particular systems contained in different formulations with regard to in vitro skin penetration.

BACKGROUND: Curcumin is known for its anti-inflammatory, antioxidative, and anticarcinogenic properties. However, the strong lipophilic compound is not easily applicable, neither in water, nor directly in o/w formulations. So far, loading of nano or micro scaled carriers has enabled only an uptake up to 30% of curcumin. METHOD: In the present article, curcumin was successfully encapsulated into two different safe and inexpensive polymers, ethyl cellulose and methyl cellulose blended ethyl cellulose with a loading capacity of ~ 46-48%. In addition, the in vitro skin penetration of the two curcumin encapsulated particular systems, which were applied each in three different formulations, an o/w, w/o lotion, and water suspension, was investigated on porcine ear skin using Laser scanning microscopy. RESULTS: It was found that in comparison to water suspensions, o/w and w/o lotions enhanced, especially the follicular penetration of the encapsulated curcumin particles into porcine skin, whereas the w/o enhanced the penetration better than the o/w lotion. Furthermore, the application of ethyl cellulose blended with methyl cellulose improved the penetration of curcumin in all formulations. CONCLUSION: High loaded encapsulated curcumin systems, prepared from a simple and highly efficient encapsulation system can be used to transport curcumin effectively into the skin.

Screening paediatric rectal forms of azithromycin as an alternative to oral or injectable treatment.

The aim of this study was to identify a candidate formulation for further development of a home or near-home administrable paediatric rectal form of a broad-spectrum antibiotic - specially intended for (emergency) use in tropical rural settings, in particular for children who cannot take medications orally and far from health facilities where injectable treatments can be given. Azithromycin, a broad-spectrum macrolide used orally or intravenously for the treatment of respiratory tract, skin and soft tissue infections, was selected because of its pharmacokinetic and therapeutic properties. Azithromycin in vitro solubility and stability in physiologically relevant conditions were studied. Various pharmaceutical forms, i.e. rectal suspension, two different rectal gels, polyethylene glycol (PEG) suppository and hard gelatin capsule (HGC) were assessed for in vitro dissolution and in vivo bioavailability in the rabbit. Azithromycin PEG suppository appears to be a promising candidate.

Decoupling the role of image size and calorie intake on gastric retention of swelling-based gastric retentive formulations: pre-screening in the dog model.

Gastric retention is postulated as an approach to improve bioavailability of compounds with narrow absorption windows. To elucidate the role of image size on gastric retention and pharmacokinetics, formulations with different image sizes and swelling kinetics but similar dissolution rates were designed and imaged in dogs. Diet had a clear effect, with increasing calorific intake prolonging retention in the dog model. In contrast to clinical observations, no obvious effect of image size on gastric retention was observed in the dog, with the larger gastric retentive (GR) and smaller controlled release (CR) formulations both demonstrating similar gastric emptying. Comparable pharmacokinetic profiles were observed for the two formulations, corroborating the imaging data and providing evidence of similar in vivo dissolution rates and dosage form integrity in the dog. Food, specifically meal composition, resulted in comparable enhancements in exposure in the dog and clinic due to prolonged gastric retention. However, differentiating retention based on image size in the dog was not feasible due to the smaller pyloric aperture compared to humans. This work illustrates that the dog is capable of determining the pharmacokinetic advantage of gastric retention relative to immediate release (IR) or CR formulations, however, has limited value in differentiating between CR and GR formulations.

Pharmacokinetic and pharmacodynamic evaluation of the anti-cataract effect of eye drops containing disulfiram and low-substituted methylcellulose using ICR/f rats as a hereditary cataract model.

We attempted to develop anti-cataract eye drops using disulfiram (DSF) and low-substituted methylcellulose (MC), and evaluated their anti-cataract effect in terms of the lens opacification vs. age-profile curves using a one-exponential equation. The eye drops were prepared using 0.5% DSF and 2% MC (DSF eye drops), and ICR/f rats, a recessive-type hereditary cataractous strain, were used as the experimental model. Gelation of DSF eye drops containing MC was first observed at about 35°C, close to body temperature. In in vivo transcorneal penetration experiments using rabbit corneas, only diethyldithiocarbamate (DDC) was detected in the aqueous humor, while DSF was not detected. The DDC penetration level of DSF eye drops containing MC was approximately 1.3-fold higher than that of DSF eye drops. The opacification rate constant (k) of ICR/f rat instilled with DSF eye drops with or without MC was lower, and the initial time of opacification (τ) was longer than those of ICR/f rats instilled with saline. Furthermore, the k of ICR/f rats instilled with DSF eye drops with MC was lower than that of ICR/f rats instilled with DSF eye drops without MC. In conclusion, the analysis of kinetic parameters including k and τ using a one-exponential equation provided useful information for clarifying the anti-cataract effect of eye drops. ICR/f rats instilled with DSF eye drops using a low-substituted MC-based drug delivery system demonstrated a delay in cataract development, probably resulting from an increase in the retention of DSF eye drops on the cornea.

The disintegration behaviour of capsules in fed subjects: a comparison of hypromellose (carrageenan) capsules and standard gelatin capsules.

Two-piece hard shell capsules made from hypromellose (or hydroxypropyl methylcellulose, HPMC) containing carrageenan as a gelling agent have been proposed as an alternative to conventional gelatin capsules for oral drug delivery. We have previously compared the disintegration of hypromellose(carrageenan) (Quali-V(®)) and gelatin capsules (Qualicaps) in fasted human subjects using the technique of gamma scintigraphy. This second study used the same technique with both fasted and fed human subjects. Size 0 capsules were filled with powder plugs made from lactose and did not contain croscarmellose as in the original study. The capsules were separately radiolabelled with indium-111 and technetium-99m. Both capsules were administered simultaneously with 180ml water to eight healthy male subjects following an overnight fast. Each volunteer was positioned in front of the gamma camera and sequential 60s images were acquired in a continuous manner for 30min. The mean (±S.D.) disintegration time in the fasted state for the hypromellose(carrageenan) capsules was 8±2min and for gelatin 7±3min. These results were not statistically different from the data in the original study and show that the removal of the croscarmellose had no effect on the results. The mean (±S.D.) disintegration time in the fed state for the hypromellose(carrageenan) capsules was 16±5min and for the gelatin capsules was 12±4min. There was no statistical difference between the hypromellose(carrageenan) and gelatin capsules in either the fed or fasted state.

In-vitro and in-vivo evaluation of carrageenan/methylcellulose polymeric systems for transscleral delivery of macromolecules.

In this study, polymeric dispersions composed of methylcellulose (MC) and either kappa carrageenan (KC) or iota carrageenan (IC) were proposed as a platform for transscleral delivery of macromolecules. The additive effects of the two polymers were investigated using oscillatory rheometer and FT-IR spectroscopy. Mechanical spectra demonstrated a conformation dependent association of the two polymers at 37 °C in the presence of selected counter ions. The polymer association was also confirmed by the shifts in MC peaks at 1049.5, 1114 and 1132.9 cm(-1) in the presence of carrageenans, which corresponds to the stretching vibrations of C-O-C bonds of the polysaccharides. The MC-IC polymeric system displayed the highest bio-adhesion, owing to the relatively high negative charge. However, the MC-IC system did not affect the in-vitro scleral permeability of sodium fluorescein and 10 kDa FITC-dextran. Nonetheless, the formulation properties had a substantial impact on the results of the in-vivo studies. The efficacy of transscleral drug delivery was determined using rats with altered connexin 43 (Cx43) levels, a gap junction protein, in the choroid. Periocular injection of Cx43 antisense oligonucleotides (AsODN) incorporated in the MC-IC system lead to a significant reduction in the Cx43 levels in the choroid of rats at 24 h of treatment. AsODN incorporated in phosphate buffered saline (PBS) also demonstrated a trend towards reduced Cx43 levels; however this was not statistically significant owing to great variability between treated animals. Consequently the in-vivo data suggests the transscleral route to be of value in delivering therapeutics to the choroid. Moreover this study identified a new polymeric system based on MC and IC which provides aqueous loading of therapeutics and prolonged retention at the site of administration.