Development and characterization of novel ambroxol sustained-release oral suspensions based on drug-polymeric complexation and polymeric raft formation.

The aim was to develop sustained-release aqueous suspensions of ambroxol utilizing drug-polymer complexation and raft-forming formulations. Ambroxol-carrageenan (ABX-CRG) complexation was studied for the optimum binding capacity, which was used to prepare the complex by kneading and coprecipitation. The prepared complex was characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry and powder X-ray diffractometry. The complex was formulated as suspensions in aqueous raft-forming vehicle of sodium alginate (NA) and calcium carbonate (CC). The suspensions differed in the molecular weight and concentration of NA, in addition to CC level and inclusion of CRG in excess of drug-polymer complexation. In 0.1 M HCl as simulated gastric fluid, the suspensions were observed for their ability to form rafts and studied for drug-release. The optimum sustained-release, raft forming and pourable formulation using high molecular weight NA, NA concentration of 18 mg/ml and CC concentration of 9 mg/ml was reached. Another optimum suspension was obtained by replacement of CC with excess CRG. However, pH dissolution profiles of the optimum suspensions revealed less pH sensitivity of the release consequent to this replacement as well as more stable ABX release upon aging. Relative to Gaviscon liquid, the optimum suspensions formed rafts of similar strength and higher resilience.

Liposomal Form of the Echinochrome-Carrageenan Complex.

Inclusion of drugs in liposomes offers the potential for localized and sustained delivery to mucosal surfaces. The inclusion of the carrageenan matrix with echinochrome A ((Ech)-the active substance of the drug Histochrome) in liposomes was studied. According to the spectral characteristics, Ech was not oxidized and retained stability after encapsulation in the liposomes and the lyophilization process. Loading the liposomes with negatively charged polysaccharide results in the increase in the zeta potential to more negative values (from -14.6 to -24.4 mV), that together with an increasing in the sizes of liposomes (from 125.6 ± 2.5 nm to 159.3 ± 5.8 nm) propose of the formation of the polymer coating on liposomes. The interactions of liposomes with porcine stomach mucin was determined by the DLS and SEM methods. The changes in the zeta-potential and size of the mucin particles were observed as the result of the interaction of liposomes with mucin. To evaluate the mucoadhesive properties of liposomes and the penetration of Ech in the mucosa, a fresh-frozen inner surface of the small intestine of a pig as a model of mucous tissue was used. Polysaccharide-coated liposomes exhibit very good mucoadhesive properties -50% of Ech remains on the mucosa.

Self-assembled carbohydrate hydrogels for prolonged pain management.

CONTEXT: Nanoparticulate systems are new tools that promise a revolution in the field of drug delivery. Among their numerous benefits, polyelectrolyte complexes (PECs) have shown to provide a barrier to drug release. OBJECTIVE: In this study, PECs, in the form of self-assembled polymeric nanogels, have been studied as potential drug carriers of the freely soluble drug tramadol HCL trying to achieve a prolonged percutaneous permeation. METHODOLOGY: The hydrogels were subjected to swelling, rheology, release and permeation studies and were characterized by FTIR spectroscopy and scanning electron microscopy. RESULTS: P2 hydrogel composed of chitosan-carrageenan (1-1) PEC attained the most compromised rheological shear-thinning thixotropic behavior, good bioadhesive properties, the most retarded release and permeation with an f2 value <50 compared to chitosan hydrogel, altogether with non-irritancy to the skin. SEM photographs showed that P2 has spherical nanosized particles structure. CONCLUSION: This approach can provide us promising results for an around-the-clock analgesia with better safety and tolerability profile.

Synthesis and comparative assessment of antiradical activity, toxicity, and biodistribution of κ-carrageenan-capped selenium nanoparticles of different size: in vivo and in vitro study.

In the present study, water-soluble hybrid selenium-containing nanocomposites have been synthesised via soft oxidation of selenide-anions, preliminarily generated from elemental bulk-selenium in the base-reduction system 'N2H4-NaOH'. The nanocomposites obtained consist of Se0NPs (4.6-24.5 nm) stabilised by κ-carrageenan biocompatible polysaccharide. The structure of these composite nanomaterials has been proven using complementary physical-chemical methods: X-ray diffraction analysis, transmission electron microscopy, optical spectroscopy, and dynamic light scattering. Optical ranges of 'emission/excitation' of aqueous solutions of nanocomposites with Se0NPs of different sizes are established and the most important parameters of their luminescence are determined. For the obtained nanocomposites, the expressed antiradical activity against free radicals 2,2-diphenyl-1-picrylhydrazyl and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid has been found, the value of which depends on the size of selenium nanoparticles. It is experimentally revealed that all obtained nanocomposites are low toxic (LD50 >2000 mg/kg). It is also found that small selenium nanoparticles (6.8 nm), in contrast to larger nanoparticles (24.5 nm), are accumulated in organisms to significantly increase the level of selenium in the liver, kidneys, and brain (in lesser amounts) of rats.

Poly(hydroxybutyrate-co-hydroxyvalerate) microparticles embedded in κ-carrageenan/locust bean gum hydrogel as a dual drug delivery carrier.

A novel composite hydrogel was prepared as a dual drug delivery carrier. Poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV) microparticles were prepared to encapsulate simultaneously ketoprofen and mupirocin, as hydrophobic drug models. These microparticles were embedded in a physically crosslinked hydrogel of κ-carrageenan/locust bean gum. This composite hydrogel showed for both drugs a slower release than the obtained release from microparticles and hydrogel separately. The release of both drugs was observed during a period of 7 days at 37 °C. Different kinetic models were analyzed and the results indicated the best fitting to a Higuchi model suggesting that the release was mostly controlled by diffusion. Also, the drug loaded microparticles were spherical with average mean particle size of 1.0 µm, mesoporous, and distributed homogeneously in the hydrogel. The composite hydrogel showed a thermosensitive swelling behavior reaching 183% of swelling ratio at 37 °C. The composite hydrogel showed the elastic component to be higher than the viscous component, indicating characteristics of a strong hydrogel. The biocompatibility was evaluated with in vitro cytotoxicity assays and the results indicated that this composite hydrogel could be considered as a potential biomaterial for dual drug delivery, mainly for wound healing applications.

Polyelectrolyte-drug complexes of lambda carrageenan and basic drugs: relevance of particle size and moisture content on compaction and drug release behavior.

The interaction between polyelectrolytes (PE) and oppositely charged drugs (D) results in complexes (PE-D) that can be exploited in controlled release drug delivery systems. The aim of this work is to better understand the relevance of some preparative parameters such as moisture content and particle size on the performance of two PE-D complexes to be used in oral controlled release tablets. PE-D complexes containing diltiazem HCL (DTZ) or metoprolol tartrate (MTP) and lambda carrageenan were obtained at two particle size levels (<45 microm and 75-105 microm), maintained at different values of relative humidity (RH) (11, 52, 75, and 93%), and compressed. The tablets were characterized for porosity, hardness, moisture content, and contact angle. Drug release profiles were fitted to the Weibull equation, and a factorial design was used to understand the relevance of particle size and RH% on release rate as a function of medium pH. The results indicated that the hydrophobic character of the complex between PE and D depended on the drug and in the present case was more pronounced for DTZ than for MTP. This in turn affected the possible release mechanism and therefore the importance of particle size and RH%.

Relation between structural and release properties in a polysaccharide gel system.

The potential utility of kappa-carrageenan gels for preparing drug release devices is here shown. Structural properties of kappa-carrageenan gels prepared with different salt composition and containing Ketoprofen sodium salt, as model drug, have been evaluated with static light scattering and rheological measurements. These properties have been correlated with release profiles in vitro at pH 5.5. Release properties from gelled matrices have been compared with those obtained by two commercial products containing the same drug. Results show that: i) in this system it is possible to easily control the gel texture by using different cationic concentration; ii) the kinetics of drug release by kappa-carrageenan gels are dependent on the structural properties of matrices; iii) in the typical interval time used in classical local applications, all gel samples release the loaded drug almost completely, at difference with the commercial products. All these findings can provide useful suggestions for the realization of classical topical release systems.

Positron Emission Tomography for the Development and Characterization of Corneal Permanence of Ophthalmic Pharmaceutical Formulations.

Purpose: This work is aimed at describing the utility of positron emission tomography/computed tomography (PET/CT) as a noninvasive tool for pharmacokinetic studies of biopermanence of topical ocular formulations. Methods: The corneal biopermanence of a topical ophthalmic formulation containing gellan gum and kappa carragenan (0.82% wt/vol) labeled with 18Fluorine (18F) radiotracers (18F-FDG and 18F-NaF) was evaluated by using a dedicated small-animal PET/CT, and compared with the biopermanence of an aqueous solution labeled with the same compounds. Regions of interest (ROIs) were manually drawn on the reconstructed PET images for quantifying the radioactivity concentration in the eye. The biopermanence of the formulations was determined by measuring the radioactivity concentration at different times after topical application. Additionally, cellular and ex vivo safety assays were performed to assess the safety of the performed procedures. Results: Differences were observed in the ocular pharmacokinetics of the two formulations. After 1.5 hours of contact, 90% of the hydrogel remained in the ocular surface, while only 69% of the control solution remained. Furthermore, it was observed that flickering had a very important role in the approach of the trial. The application of 18F-FDG in the eye was neither irritating nor cytotoxic for human corneal epithelial cells. Conclusions: The use of small-animal PET and 18F radiotracers in ocular pharmacokinetics of ophthalmic formulations is feasible and could be a safe method for future ocular pharmacokinetic studies in humans.

Digestive fate of dietary carrageenan: Evidence of interference with digestive proteolysis and disruption of gut epithelial function.

SCOPE: The objective of this study was to interrogate two mechanisms by which commercial Carrageenans (E407) (CGN) may adversely affect human health: (i) Through modification of gastric proteolysis and (ii) Through affecting gut epithelial structure and function. METHODS AND RESULTS: Three commercial CGN samples with distinct zeta-potentials (stable at the pH range of 3-7 and varied with physiological levels of CaCl2 ) were mixed with milk, soy or egg protein isolates, then subjected to a semi-dynamic in vitro digestion model and analyzed by SDS-PAGE. This revealed varying levels of interference with gastric digestive proteolysis and a significant decrease in pepsin activity. Further, a Caco-2 cell model was used to explore various effects of physiologically digested CGN (pdCGN) on various epithelial cell functions and characteristics. Samples of pdCGN (0.005-0.5 mg/mL) affected the epithelial barrier function, including redistribution of the tight-junction protein Zonula Occludens (Zo)-1, changes in cellular F-actin architecture and increased monolayer permeability to the transfer of macromolecules. Moreover, pdCGN induced elevation in the levels of the pro-inflammatory IL-8 receptor CXCR1. CONCLUSION: This work raises the possibility that CGN may reduce protein and peptide bioaccessibility, disrupt normal epithelial function, promote intestinal inflammation, and consequently compromise consumer health.

First-in-Human Trial of MIV-150 and Zinc Acetate Coformulated in a Carrageenan Gel: Safety, Pharmacokinetics, Acceptability, Adherence, and Pharmacodynamics.

OBJECTIVE: To evaluate the safety and pharmacokinetics of MIV-150 and zinc acetate in a carrageenan gel (PC-1005). Acceptability, adherence, and pharmacodynamics were also explored. DESIGN: A 3-day open-label safety run-in (n = 5) preceded a placebo-controlled, double-blind trial in healthy, HIV-negative, abstinent women randomized (4:1) to vaginally apply 4 mL of PC-1005 or placebo once daily for 14 days. METHODS: Assessments included physical examinations, safety labs, colposcopy, biopsies, cervicovaginal lavages (CVLs), and behavioral questionnaires. MIV-150 (plasma, CVL, tissue), zinc (plasma, CVL), and carrageenan (CVL) concentrations were determined with LC-MS/MS, ICP-MS, and ELISA, respectively. CVL antiviral activity was measured using cell-based assays. Safety, acceptability, and adherence were analyzed descriptively. Pharmacokinetic parameters were calculated using noncompartmental techniques and actual sampling times. CVL antiviral EC50 values were calculated using a dose-response inhibition analysis. RESULTS: Participants (n = 20) ranged from 19-44 years old; 52% were black or African American. Among those completing the trial (13/17, PC-1005; 3/3, placebo), 11/17 reported liking the gel overall; 7 recommended reducing the volume. Adverse events, which were primarily mild and/or unrelated, were comparable between groups. Low systemic MIV-150 levels were observed, without accumulation. Plasma zinc levels were unchanged from baseline. Seven of seven CVLs collected 4-hour postdose demonstrated antiviral (HIV, human papillomavirus) activity. High baseline CVL anti-herpes-simplex virus type-2 (HSV-2) activity precluded assessment of postdose activity. CONCLUSIONS: PC-1005 used vaginally for 14 days was well tolerated. Low systemic levels of MIV-150 were observed. Plasma zinc levels were unchanged. Postdose CVLs had anti-HIV and anti-human papillomavirus activity. These data warrant further development of PC-1005 for HIV and sexually transmitted infection prevention.

Carrageenans can regulate the pulmonary absorption of antiasthmatic drugs and their retention in the rat lung tissues without any membrane damage.

Effects of various viscous vehicles on pulmonary absorption of antiasthmatic drugs were examined by an in situ pulmonary absorption experiment. Theophylline and fluticasone propionate were used as antiasthmatic drugs. The serum concentration-time profile of theophylline without viscous vehicles was similar to that following the intravenous injection, indicating that pulmonary absorption of theophylline was rapid and absolute. The serum concentration of theophylline was not controlled in the presence of 5% gelatin or 2% sodium alginate. However, 1% iota-carrageenan could control and regulate the serum concentration of theophylline. In the pharmacokinetic analysis, the C(max) values of theophylline significantly decreased, and its T(max) values increased in the presence of 1% and 2% iota-carrageenan, 1% kappa-carrageenan, and 2% sodium alginate compared with the control. The MRT and MAT values of theophylline with 1% iota-carrageenan were significantly higher than those without viscous vehicles. The local concentration of theophylline in the lung at 1h after intratracheal administration increased five-fold with 1% iota-carrageenan compared with the control. On the other hand, the pulmonary absorption of fluticasone propionate was controlled and regulated in the presence of 0.5% kappa-carrageenan. Additionally, the pulmonary inflammation after the exposure of carrageenans administered to the lung was evaluated in rats. Iota- and kappa-carrageenans did not cause local serious damage and inflammation to the pulmonary tissue. Therefore, these findings indicated that the carrageenans were effective to regulate the absorption rate of antiasthmatic drugs including theophylline and fluticasone propionate.

An infant formula toxicity and toxicokinetic feeding study on carrageenan in preweaning piglets with special attention to the immune system and gastrointestinal tract.

A toxicity/toxicokinetic swine-adapted infant formula feeding study was conducted in Domestic Yorkshire Crossbred Swine from lactation day 3 for 28 consecutive days during the preweaning period at carrageenan concentrations of 0, 300, 1000 and 2250 ppm under GLP guidelines. This study extends the observations in newborn baboons (McGill et al., 1977) to piglets and evaluates additional parameters: organ weights, clinical chemistry, special gastrointestinal tract stains (toluidine blue, Periodic Acid-Schiff), plasma levels of carrageenan; and evaluation of potential immune system effects. Using validated methods, immunophenotyping of blood cell types (lymphocytes, monocytes, B cells, helper T cells, cytotoxic T cells, mature T cells), sandwich immunoassays for blood cytokine evaluations (IL-6, IL-8, IL1ß, TNF-α), and immunohistochemical staining of the gut for IL-8 and TNF-α were conducted. No treatment-related adverse effects at any carrageenan concentration were found on any parameter. Glucosuria in a few animals was not considered treatment-related. The high dose in this study, equivalent to ~430 mg/kg/day, provides an adequate margin of exposure for human infants, as affirmed by JECFA and supports the safe use of carrageenan for infants ages 0-12 weeks and older and infants with special medical needs.

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.

A novel intravaginal ring to prevent HIV-1, HSV-2, HPV, and unintended pregnancy.

Women urgently need a self-initiated, multipurpose prevention technology (MPT) that simultaneously reduces their risk of acquiring HIV-1, HSV-2, and HPV (latter two associated with increased risk of HIV-1 acquisition) and prevents unintended pregnancy. Here, we describe a novel core-matrix intravaginal ring (IVR), the MZCL IVR, which effectively delivered the MZC combination microbicide and a contraceptive. The MZCL IVR contains four active pharmaceutical ingredients (APIs): MIV-150 (targets HIV-1), zinc acetate (ZA; targets HIV-1 and HSV-2), carrageenan (CG; targets HPV and HSV-2), and levonorgestrel (LNG; targets unintended pregnancy). The elastomeric IVR body (matrix) was produced by hot melt extrusion of the non-water swellable elastomer, ethylene vinyl acetate (EVA-28), containing the hydrophobic small molecules, MIV-150 and LNG. The solid hydrophilic core, embedded within the IVR by compression, contained the small molecule ZA and the macromolecule CG. Hydrated ZA/CG from the core was released by diffusion via a pore on the IVR while the MIV-150/LNG diffused from the matrix continuously for 94 days (d) in vitro and up to 28 d (study period) in macaques. The APIs released in vitro and in vivo were active against HIV-1ADA-M, HSV-2, and HPV16 PsV in cell-based assays. Serum LNG was at levels associated with local contraceptive effects. The results demonstrate proof-of-concept of a novel core-matrix IVR for sustained and simultaneous delivery of diverse molecules for the prevention of HIV, HSV-2 and HPV acquisition, as well as unintended pregnancy.

Carrageenan-gelatin mucoadhesive systems for ion-exchange based ophthalmic delivery: in vitro and preliminary in vivo studies.

Lambda-carrageenan is an anionic polymer able to ionically interact with alkaline drugs. This results in a complex that releases the drug slowly, due to displacement by the counterions of the release medium. The aim of this work was to assess the possible ophthalmic employment of such a complex. As a model drug, an alkaline anti-glaucoma drug, timolol maleate, was chosen. Systems in which lambda-carrageenan interacted both with the drug and a mucoadhesive polymer such as gelatin were studied. The combination of carrageenan and gelatin in different ratios proved to be useful in modulating the drug release profiles, the rheological properties of the hydrated formulations and their mucoadhesive properties. Both films and microspheres were prepared and tested in vitro. A microsphere formulation was also tested in vivo in albino rabbits. The drug concentration and bioavailability in the aqueous humour were significantly high in comparison with commercial formulations.

Intestinal transport of some macromolecules in food.

This review focuses on the intestinal transport of macromolecules in food. Although it is known that neonates have the ability to absorb proteins from the intestine as a means of passive immunization, it has generally been assumed that adults do not retain this capability. A number of studies have shown that the adult mammalian small intestine is capable of transporting a variety of macromolecules in food to a very limited extent. The evidence demonstrating the transport of test substances in the micron-size range across the adult intestinal epithelial barrier is examined for a number of food substances and environmental contaminants. It will be shown that macromolecules can be transported across this barrier by endocytosis; by uptake into the gut-associated lymphoid tissue, and possibly by uptake into the goblet cells. It is considered highly unlikely that large micron-sized particles pass between intestinal cells due to the integrity of the tight junctions between cells that exclude particles in this size range. Quantitative estimates for macromolecular uptake are included along with a discussion of the physiological parameters influencing macromolecular transport.

Simvastatin loaded composite polyspheres of gellan gum and carrageenan: in vitro and in vivo evaluation.

We investigated the lipid lowering ability of simvastatin loaded gellan gum-carrageenan composite polyspheres, which were prepared by ionotropic gelation/covalent crosslinking method. The surface morphology revealed that the polyspheres have rough and dense surface. The drug entrapment efficiency of the polyspheres prepared by ionic crosslinking was higher than those prepared by dual crosslinking. The in vitro drug release study indicated that the ionically crosslinked polyspheres discharged the drug quickly whereas, dual crosslinked polyspheres extended the drug release for longer period. The hypolipidemic activity performed on Wistar rats indicated that the polyspheres have effectively reduced the elevated total serum cholesterol and triglycerides.

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.

The influence of AT1002 on the nasal absorption of molecular weight markers and therapeutic agents when co-administered with bioadhesive polymers and an AT1002 antagonist, AT1001.

OBJECTIVES: The purpose of this study was to demonstrate the effects of the tight junction permeation enhancer, AT1002, on the nasal absorption of molecular weight markers and low bioavailable therapeutic agents co-administered with bioadhesive polymers or zonulin antagonist. METHODS: The bioadhesive polymers, carrageenan and Na-CMC, were prepared with AT1002 to examine the permeation-enhancing effect of AT1002 on the nasal absorption of inulin, calcitonin and saquinavir after nasal administration to Sprague-Dawley rats. Blood samples were collected over a 6-hour period from a jugular cannula. In addition, we determined whether AT1002 exerts a permeation-enhancing effect via activation of PAR-2 specific binding to a putative receptor of zonulin. To examine this zonulin antagonist, AT1001, was administered 30 min prior to dosing with an AT1002/inulin solution and blood samples were collected over a 6-hour period. KEY FINDINGS: The bioadhesive polymers did not directly increase the absorption of inulin, calcitonin and saquinavir, but promoted the permeation-enhancing effect of AT1002 when delivered nasally, thereby significantly increasing the absorption of each drug. Pre-treatment with AT1001 antagonized the zonulin receptor and significantly minimized the permeation-enhancing effect of AT1002. CONCLUSION: These findings will assist in understanding the permeation-enhancing capability of and the receptor binding of AT1002. Further, combining AT1002 with carrageenan supports the development of the mucosal delivery of therapeutic agents that have low bioavailability even with bioadhesive agents.

Comparison of ion-activated in situ gelling systems for ocular drug delivery. Part 2: Precorneal retention and in vivo pharmacodynamic study.

In situ gelling systems are viscous polymer-based solutions that exhibit a sol-to-gel phase transition upon change in a physicochemical parameter such as ionic strength, temperature or pH, therefore prolonging the formulations' residence time on the ocular surface. Ion-activated in situ gelling systems, that are able to crosslink with the cations in the tear fluid, have previously been evaluated in terms of their rheological, textural and in vitro release characteristics. The present study describes the ocular irritancy, precorneal retention time and in vivo release characteristics of the same formulations. It was shown that all tested polymer systems were non-irritant. Precorneal retention studies revealed a biphasic rapid release for the solution with less than 40% radioactivity left on the ocular surface after 15 min, while formulations based on gellan gum, xanthan gum and carrageenan seemed to drain at an almost constant rate with more than 80% radioactivity remaining. This was in agreement with the in vivo miotic studies, which demonstrated that the area under the curve and the miotic response at 120 min after administration for gellan gum, xanthan gum and carrageenan formulations of pilocarpine were increased by 2.5-fold compared to an aqueous solution, which demonstrates their potential use in ophthalmic formulations.