Formulation and evaluation of sustained release ocular inserts of betaxolol hydrochloride using arabinoxylan from Plantago ovata.

The purpose of the current studies was to develop ocular insert of betaxolol hydrochloride (BXH), using arabinoxylan (AX) as a film former. The inserts were prepared by sandwiching I mg of BXH between two films of AX. Six different formulations of ocular inserts were prepared in such a way that first three formulations contained varying concentrations of AX along with glycerol as plasticizer, whereas, rest of the formulations were added with 0.5mg of sodium alginate, sandwiched between two films of AX along with 1mg of BXH. Chemical compatibilities of the ingredients were assessed by using FTIR. Prepared ocular inserts were subjected to various physicochemical characterizations. The dissolution studies showed that ocular inserts containing sodium alginate with the AX showed sustained release effect better than the formulations with AX alone. Addition of sodium alginate resulted in inhibition of sudden release in initial phase and further sustained the release of drug from ocular inserts. Ocular inserts were pH compatible to the eyes as well as there was no interaction among the drug and excipients, suggesting that the selected excipients were suitable for the development of sustained release ocular inserts of BXH.

Wettability and contact angle affect precorneal retention and pharmacodynamic behavior of microspheres.

In the present study, we describe the development of betaxolol hydrochloride and montmorillonite with ion exchange in a single formulation to create a novel micro-interactive dual-functioning sustained-release delivery system (MIDFDS) for the treatment of glaucoma. Betaxolol hydrochloride molecule was loaded onto the montmorillonite by ion exchange and MIDFDS formation was confirmed by XPS data. MIDFDS showed similar physicochemical properties to those of Betoptic, such as particle size, pH, osmotic pressure, and rheological properties. Nevertheless, the microdialysis and intraocular pressure test revealed better in vivo performance of MIDFDS, such as pharmacokinetics and pharmacodynamics. With regards to wettability, MIDFDS had a larger contact angle (54.66 ± 5.35°) than Betoptic (36.68 ± 1.77°), enabling the MIDFDS (2.93 s) to spread slower on the cornea than Betoptic (2.50 s). Moderate spreading behavior and oppositely charged electrostatic micro-interactions had a comprehensive influence on micro-interactions with the tear film residue, resulting in a longer precorneal retention time. Furthermore, MIDFDS had a significant sustained-release effect, with complete release near the cornea. The dual-functioning sustained-release carrier together with prolonged pre-corneal retention time (80 min) provided sufficiently high drug concentrations in the aqueous humor to achieve a more stable and long-term IOP reduction for 10 h. In addition, cytotoxicity and hemolysis tests showed that MIDFDS had better biocompatibility than Betoptic. The dual-functioning microspheres presented in this study provide the possibility for improved compliance due to low cytotoxicity and hemolysis, which suggests promising clinical implications.

Ocular pharmacokinetics of atenolol, timolol and betaxolol cocktail: Tissue exposures in the rabbit eye.

Quantitative understanding of pharmacokinetics of topically applied ocular drugs requires more research to further understanding and to eventually allow predictive in silico models to be developed. To this end, a topical cocktail of betaxolol, timolol and atenolol was instilled on albino rabbit eyes. Tear fluid, corneal epithelium, corneal stroma with endothelium, bulbar conjunctiva, anterior sclera, iris-ciliary body, lens and vitreous samples were collected and analysed using LC-MS/MS. Iris-ciliary body was also analysed after intracameral cocktail injection. Non-compartmental analysis was utilized to estimate the pharmacokinetics parameters. The most lipophilic drug, betaxolol, presented the highest exposure in all tissues except for tear fluid after topical administration, followed by timolol and atenolol. For all drugs, iris-ciliary body concentrations were higher than that of the aqueous humor. After topical instillation the most hydrophilic drug, atenolol, had 3.7 times higher AUCiris-ciliary body than AUCaqueous humor, whereas the difference was 1.4 and 1.6 times for timolol and betaxolol, respectively. This suggests that the non-corneal route (conjunctival-scleral) was dominating the absorption of atenolol, while the corneal route was more important for timolol and betaxolol. The presented data increase understanding of ocular pharmacokinetics of a cocktail of drugs and provide data that can be used for quantitative modeling and simulation.

Design of circular-ring film embedded contact lens for improved compatibility and sustained ocular drug delivery.

Contact lenses are ideal medical devices to sustain the release of ophthalmic drugs. However, the incorporation of drug loaded system can cause visual obstruction and poor oxygen/light permeability which restrict the application of contact lens for long-term wearing. Inspired by the physiological structure of our human eyes, we assume a circular-ring type inner layer embedded CLs might be a good solution to address the above-mentioned problems. In this study, taking betaxolol hydrochloride (BH) as a model drug, its complex with ion exchange resin was used as a carrier for adjusting drug loading amount, which is being dispersed into circular-ring shape Eudragit® S100 film as an inner layer, silicone-based hydrogel as the outer layer. Influence of resin particle size and drug/S100 ratio on drug release profiles was investigated. It was demonstrated that using resin as a carrier can not only increase drug loading amount but also sustain drug release, with the drug release rate well-tuned by either changing particle size of the resin or S100 ratio. Meanwhile S100 can well function as a pH-triggered drug release matrix, with limited drug leakage in the storage medium. Light transmittance of over 97% was achieved in the novel circular-ring layer-embedded CLs. Oxygen permeability coefficient (Dk) of the circular-ring film embedded CLs was 31.1 ± 3.7 barrer, similar to that of pure CLs. The sustained drug release behavior of this circular-ring embedded CLs was also well demonstrated in vivo. A level A IVIVC between in vitro drug release and in vivo drug concentration in tear fluid of the circular-ring embedded CLs was established. In conclusion, this circular-ring embedded contact lens is very promising for ophthalmic drug delivery with enhanced compatibility, sustained and pH triggered drug release characteristics.

Incorporation of ion exchange functionalized-montmorillonite into solid lipid nanoparticles with low irritation enhances drug bioavailability for glaucoma treatment.

Montmorillonite-loaded solid lipid nanoparticles with good biocompatibility, using Betaxolol hydrochloride as model drug, were prepared by the melt-emulsion sonication and low temperature-solidification methods and drug bioavailability was significantly improved in this paper for the first time to application to the eye. The appropriate physical characteristics were showed, such as the mean particle size, Zeta potential, osmotic pressure, pH values, entrapping efficiency (EE%) and drug content (DC%), all showed well suited for possible ocular application. In vitro release experiment indicated that this novel system could continuously release 57.83% drugs within 12 h owing to the dual drug controlled-release effect that was achieved by ion-exchange feature of montmorillonite and structure of solid lipid nanoparticles. Low irritability and good compatibility of nanoparticles were proved by both CAM-TBS test and cytotoxicity experiment. We first discovered from the results of Rose Bengal experiment that the hydrophilicity of the drug-loaded nanoparticles surface was increased during the loading and releasing of the hydrophilic drug, which could contribute to prolong the ocular surface retention time of drug in the biological interface membrane of tear-film/cornea. The results of in vivo pharmacokinetic and pharmacodynamics studies further confirmed that increased hydrophilicity of nanoparticles surface help to improve the bioavailability of the drug and reduce intraocular pressure during administration. The results suggested this novel drug delivery system could be potentially used as an in situ drug controlled-release system for ophthalmic delivery to enhance the bioavailability and efficacy.

Ocular Intracameral Pharmacokinetics for a Cocktail of Timolol, Betaxolol, and Atenolol in Rabbits.

The mechanisms of drug clearance from the aqueous humor are poorly defined. In this study, a cocktail approach was used to simultaneously determine the pharmacokinetics of three ß-blocker agents after intracameral (ic) injection into the rabbit eyes. Aqueous humor samples were collected and analyzed using LC-MS/MS to determine drug concentrations. Pharmacokinetic parameters were obtained using a compartmental fitting approach, and the estimated clearance, volume of distribution, and half-life values were the following: atenolol (6.44 µL/min, 687 µL, and 73.87 min), timolol (19.30 µL/min, 937 µL, and 33.64 min), and betaxolol (32.20 µL/min, 1421 µL, and 30.58 min). Increased compound lipophilicity (atenolol < timolol < betaxolol) resulted in higher clearance and volume of distributions in the aqueous humor. Clearance of timolol and betaxolol is about 10 times higher than the aqueous humor outflow, demonstrating the importance of other elimination routes (e.g., uptake to iris and ciliary body and subsequent elimination via blood flow).

Inner layer-embedded contact lenses for ion-triggered controlled drug delivery.

Drug leakage during manufacturing and storage process is the main obstacle hindering the application of contact lenses as the carrier for extended ocular drug delivery. In this study, we have designed a novel inner layer-embedded contact lens capable of ion-triggered drug release for extended ocular drug delivery. Using betaxolol hydrochloride as a drug model, drug-ion exchange resin complex dispersed polymer film was used as an inner layer, and silicone hydrogel was used as an outer layer to fabricate inner layer-embedded contact lens. Influence of composition of the inner film and crosslinking degree of the outer hydrogel on drug release profile was studied and optimized for weekly use. The ion-triggered drug eluting property enables the inner layer-embedded contact lens being stable when stored in distilled water at 5 °C for at least 30 days with ignorable drug loss and negligible changes in drug release kinetics. In vivo pharmacokinetic study in rabbits showed sustained drug release for over 168 h in tear fluid, indicating significant improvement in drug corneal residence time. A level A IVIVC was established between in vitro drug release and in vivo drug concentration in tear fluid. In conclusion, this inner layer embedded contact lens design could be used as a platform for extended ocular drug delivery with translational potential for both anterior and posterior ocular disease therapy.

Montmorillonite/chitosan nanoparticles as a novel controlled-release topical ophthalmic delivery system for the treatment of glaucoma.

BACKGROUND: To date, the rapid clearance from ocular surface has been a huge obstacle for using eye drops to treat glaucoma, since it has led to the short preocular residence time and low bioavailability. METHODS: The novel nanoparticles (NPs) were designed for topical ophthalmic controlled drug delivery system through intercalating the BH into the interlayer gallery of Na-montmorillonite (Na+Mt) and then further enchasing chitosan nanoparticles. The resulting nanoparticles had a positive charge (+29±0.18 mV) with an average diameter of 460±0.6 nm. RESULTS: In vitro study of drug release profiles suggested controlled release pattern. The irritation experiment analysis on both human immortalized cornea epithelial cell (iHCEC) and chorioallantoic membrane-trypan blue staining (CAM-TBS) showed good tolerance for ocular tissues. It was interestingly found that the nanoparticles could enter into iHCEC from the result of cellular uptake experiment measured by confocal layer scan microscopy (CLSM). Meanwhile, multilayered iHCEC was used to simulate the barrier of corneal epithelial cells for in vivo preocular retention capacity study, which suggested that BH-Mt/CS NPs could prolong the retention time in comparison with BH solution. The ocular pharmacokinetics studied by microdialysis sampling technique showed that AUC0-t and MRT0-t of BH-Mt/CS NPs were 1.99-fold and 1.75-fold higher than those of BH solution, indicating higher bioavailability. Moreover, the study of blood drug concentration, few researchers have reported, showed that low level drug could enter into blood, suggesting lower systematic side effect. Importantly, pharmacodynamics studies suggested that BH-Mt/CS NPs could make a significant decreased intraocular pressure on glaucomatous rabbits. CONCLUSION: Inspired by these advance of montmorillonite/chitosan nanoparticles, we envision that the BH-Mt/CS NPs will be a potential carrier for BH, opening up the possible applications in glaucoma therapy.

Sustained ophthalmic delivery of highly soluble drug using pH-triggered inner layer-embedded contact lens.

In the present work the feasibility of using inner layer-embedded contact lenses (CLs) to achieve sustained release of highly water soluble drug, betaxolol hydrochloride (BH) on the ocular surface was investigated. Blend film of cellulose acetate and Eudragit S100 was selected as the inner layer, while silicone hydrogel was used as outer layer to construct inner layer-embedded contact lenses. Influence of polymer ratio in the blend film on in vitro drug release behavior in phosphate buffered solution or simulated tear fluid was studied and drug-polymer interaction, erosion and swelling of the blend film were characterized to better understand drug-release mechanism. Storage stability of the inner layer-embedded contact lenses in phosphate buffer solution was also conducted, with ignorable drug loss and negligible change in drug release pattern within 30 days. In vivo pharmacokinetic study in rabbits showed sustained drug release for over 240 h in tear fluid, indicating prolonged drug precorneal residence time. In conclusion, cellulose acetate/Eudragit S100 inner layer-embedded contact lenses are quite promising as controlled-release carrier of highly water soluble drug for ophthalmic delivery.

Preparation, pharmacokinetics and pharmacodynamics of ophthalmic thermosensitive in situ hydrogel of betaxolol hydrochloride.

Conventional ophthalmic formulations often eliminate rapidly after administration and cannot provide and maintain an adequate concentration of the drug in the precorneal area. To solve those problems, a thermosensitive in situ gelling and mucoadhesive ophthalmic drug delivery system was prepared and evaluated, the system was composed of poloxamer analogs and polycarbophil (PCP) and betaxolol hydrochloride (BH) was selected as model drug. The concentrations of poloxamer 407 (P407) (22% (w/v)) and poloxamer 188 (P188) (3.5% (w/v)) were identified through central composite design-response surface methodology (CCD-RSM). The BH in situ hydrogel (BH-HG) was liquid solution at low temperature and turned to semisolid at eye temperature. BH-HG showed good stability and biocompatibility, which fulfilled the requirements of ocular application. In vitro studies indicated that addition of PCP enhanced the viscosity of BH-HG and the release results of BH from BH-HG demonstrated a sustained release behavior of BH because of the gel dissolution. In vivo pharmacokinetics and pharmacodynamics studies indicated that the BH-HG formulation resulted in an improved bioavailability and a significantly lower intraocular pressure (IOP). The results suggested BH-HG could be potentially used as an in situ gelling system for ophthalmic delivery to enhance the bioavailability and efficacy.

Evaluation of skin permeation of ß-blockers for topical drug delivery.

PURPOSE: ß-Blockers have recently become the main form of treatment of infantile hemangiomas. Due to the potential systemic adverse effects of ß-blockers, topical skin treatment of the drugs is preferred. However, the effect and mechanism of dosage form pH upon skin permeation of these weak bases is not well understood. To develop an effective topical skin delivery system for the ß-blockers, the present study evaluated skin permeation of ß-blockers propranolol, betaxolol, timolol, and atenolol. METHODS: Experiments were performed in side-by-side diffusion cells with human epidermal membrane (HEM) in vitro to determine the effect of donor solution pH upon the permeation of the ß-blockers across HEM. RESULTS: The apparent permeability coefficients of HEM for the ß-blockers increased with their lipophilicity, suggesting the HEM lipoidal pathway as the main permeation mechanism of the ß-blockers. The pH in the donor solution was a major factor influencing HEM permeation for the ß-blockers with a 2- to 4-fold increase in the permeability coefficient per pH unit increase. This permeability versus pH relationship was found to deviate from theoretical predictions, possibly due to the effective stratum corneum pH being different from the pH in the donor solution. CONCLUSIONS: The present results suggest the possibility of topical treatment of hemangioma using ß-blockers.

Penetration of betaxolol HCL ionic suspension 0.25% and betaxolol HCL solution 0.50% into the aqueous humor.

PURPOSE: To determine the intraocular penetration of topical drops of betaxolol HCl 0.25% suspension and betaxolol HCl 0.50% solution into the aqueous humor. METHODS: Fifteen patients were randomly assigned to receive topical betaxolol HCl 0.25% suspension (n=7) or topical betaxolol HCl 0.50% solution (n=8) the day before cataract surgery. Aqueous samples were collected 2 hours after the administration of the morning dose during cataract surgery. Drug concentrations were determined by high-performance liquid chromatography with fluorescence detection. RESULTS: The mean aqueous humor concentration of topical betaxolol HCl 0.25% suspension was 275.1+/-168.8 micro g/mL (range 570-70 micro g/mL) and the mean aqueous humor concentration of topical betaxolol HCl 0.50% solution was 195.4+/-102.4 micro g/mL (range 334-50 micro g/mL) (p=0.281). CONCLUSIONS: The mean aqueous humor concentration of betaxolol 0.25% suspension was higher than betaxolol 0.50% solution; however, the difference was not statistically significant. With twofold reduced concentration and similar anterior chamber penetration, betaxolol 0.25% suspension could be first choice for Beta 1 selective blocker therapy when considered for patients with glaucoma.

Concentrations of betaxolol in ocular tissues of patients with glaucoma and normal monkeys after 1 month of topical ocular administration.

PURPOSE: To measure the concentration of betaxolol in tissues of humans with glaucoma and normal monkeys after topical administration. METHODS: Enucleated eyes (n = 7) of patients with glaucoma (age range, 27-79 years), without apparent anatomic disruption that would be likely to influence betaxolol absorption and intraocular distribution (exceptions: one pseudophakic, one aphakic) or other disease, were analyzed for betaxolol concentrations after self-administration of 0.25% betaxolol twice daily for 28 days or longer. The last instillation was made within 6 hours of surgery. Cynomolgus monkeys (n = 3) received 0.25% betaxolol twice daily unilaterally for 30 days. Betaxolol was measured by HPLC and tandem mass spectrometry (MS/MS) in plasma and ocular tissues. RESULTS: In humans, mean betaxolol concentrations (excluding the aphakic patient) were 71.4 +/- 41.8 ng/g in the retina, 31.2 +/- 14.8 ng/g in the optic nerve head, and 1290 +/- 1170 ng/g in the choroid. Mean concentrations in the iris and ciliary body were 73,200 +/- 89,600 and 4,250 +/- 3,020 ng/g, respectively. Betaxolol concentration was higher in all ocular tissues than in the plasma (0.59 +/- 0.32 ng/mL). In the monkeys the concentrations in the posterior tissues of the treated eyes were higher than in the untreated eyes, with mean differences in the retina and optic nerve head of 121 and 130 ng/g, respectively. CONCLUSIONS: Topically applied betaxolol was bioavailable to posterior ocular tissues, including the retina and optic nerve head, of patients with glaucoma and of normal cynomolgus monkeys. The higher betaxolol levels in the treated versus untreated monkey eyes are consistent with betaxolol's reaching posterior tissues by local absorption and distribution.

Betaxolol-induced deterioration of asthma and a pharmacodynamic analysis based on beta-receptor occupancy.

OBJECTIVE: To report a case of deterioration of asthma associated with continuous use of oral betaxolol, a beta1-selective beta-blocking agent. We also analyzed the pharmacokinetics in this case by applying a receptor occupancy model. CASE SUMMARY: A 68-year-old woman taking 5 mg of betaxolol for hypertension occasionally experienced asthmatic coughing after upper respiratory tract infection. Two years after the start of betaxolol, her asthma gradually worsened. Although pharmacotherapy for asthma was introduced, betaxolol was continued. Finally, she was admitted to hospital with bronchospasm. When she was discharged after 2 months, betaxolol was discontinued and losartan potassium (25 mg/d) was initiated instead for her hypertension. Since then, she has been free from bronchospasm. METHOD: We calculated the mean receptor occupancy (phiSS) of the beta1- and beta2-receptors after the usual oral dose of betaxolol by using pharmacokinetic-pharmacodynamic parameters obtained from the literature. We estimated the decrease in the exercise pulse rate or the forced expiratory volume in 1 second (FEV1) by applying the phiSS values to the model previously reported by us. RESULTS: Betaxolol seems less likely than other beta1-blocking agents to cause pulmonary adverse effects. However, the estimated decrease in FEV1 after oral administration of betaxolol (5 mg) was close to that after oral bisoprolol (5 mg), which has been reported to induce asthma. CONCLUSIONS: Oral betaxolol may induce bronchospasm, although betaxolol is considered to be highly cardioselective and seems less likely than other beta1-selective blocking agents to cause pulmonary adverse effects. Betaxolol should be administered with caution to patients with asthma or chronic pulmonary disease.

Ocular drug delivery using 20-kHz ultrasound.

The cornea is a major pathway for drug delivery to diseased eye structures. We have investigated the application of 1-s bursts of 20-kHz ultrasound, at I(SAPA) of 14 W/cm(2) (I(SATA) of 2 W/cm(2)), for enhancement of corneal permeability to glaucoma drugs of different lipophilicity (atenolol, carteolol, timolol and betaxolol). The permeability of rabbit cornea increased by 2.6 times for atenolol, 2.8 for carteolol, 1.9 for timolol and 4.4 times for betaxolol (all p-values < 0.05), after 60 min of ultrasound (US) exposure in vitro. The differences between the treatment and control experiments were statistically significant after 10 to 30 min of US exposure for all four drugs. US application appeared to produce epithelial disorganization and structural changes in the corneal stroma. Further studies are needed to determine the optimal US parameters for a safe and effective treatment.

Determination of betaxolol in human aqueous humour by high-performance liquid chromatography with fluorescence detection.

A reversed-phase high-performance liquid chromatographic method is described for the determination of betaxolol in human aqueous humour. Betaxolol and the internal standard metoprolol were extracted with cyclohexane and separated on a reversed-phase column (Luna C(18), 250 x 4.6 mm, 5 microm) with a mobile phase containing acetonitrile-phosphate buffer (40:60, v/v) at a flow-rate of 0.8 ml/min. The column effluent was monitored with a fluorescence detector at 227 nm (excitation) and 301 nm (emission). The retention times for metoprolol and betaxolol were 3.55 and 5.63 min, respectively. The recovery from aqueous humour was found to be 71.6% for betaxolol at 1.25 microg/ml. The within-day and day-to-day accuracy values were in the range of 96.17-105.2% for betaxolol at 0.1, 4 and 12 microg/ml (n=6), within-day and day-to-day precision values were less than 10% for betaxolol at the concentrations given above. The detection limit corresponding to the signal-to-noise ratio of 3:1 was 15 ng/ml. The presented method was suitable for measuring betaxolol levels in human aqueous humour samples obtained from patients after topical administration.

Plasma concentration of topically applied betaxolol in elderly glaucoma patients.

Our aim was to study the concentration of betaxolol in plasma after its topical ocular use during the normal 12 hr dosing interval. Twenty microliters of betaxolol 0.5% solution were applied into both eyes of nine glaucoma patients, and the plasma concentrations of the drug were measured 12 hr thereafter using a radioreceptor assay. The same amount of betaxolol was then applied ocularly, and its concentration in plasma was measured at 5, 10, 15, 30 min and 1, 2, 4 and 8 hr thereafter. The mean (SD) concentration of betaxolol in plasma twelve hr after the first dose was 0.4 (0.2) ng/ml. After the second dose, the patients showed a biphasic concentration vs. time curve, the first peak occurring at 8 (4) min, and the second peak at 210 (132) min; the mean (SD) peak concentrations being 1.1 (0.3) and 2.0 (1.1) ng/ml, respectively. The area under the concentration vs. time curve showed a 4-fold variation among our patients. Topically applied betaxolol was rapidly absorbed into systemic circulation, and concentrations were detectable even at 12 hr. The interindividual variation in the systemic absorption of betaxolol was large.