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.

Comparison of thermosensitive in situ gels and drug-resin complex for ocular drug delivery: In vitro drug release and in vivo tissue distribution.

Conventional ophthalmic eye drops are limited by their rapid elimination rate and short time of action. Ion exchange resin has been used to achieve sustained ocular drug delivery but the high selectivity of drug molecules restricts its broad application. In situ gel system seems to be a good strategy to address these problems but the influence of in situ gel type on the sustained release behavior and tissue distribution after ocular application is unclear. Therefore, in this study, using betaxolol hydrochloride as a model drug, poloxamer 407 and methylcellulose as the carriers, two thermosensitive in situ gel systems were prepared and characterized. Influence of formulation composition type and concentration on in vitro drug release was studied. Tissue distribution after ocular delivery of two different thermosensitive in situ gels was studied and compared with commercial BH eye drop (Betoptic S®). In vitro studies demonstrated that addition of 4% HPMC 606W in 15% P407 solution and 5% PEG4000 in 2% MC solution obtained gels with appropriate gelation temperature and similar sustained drug release rate. In vivo tissue distribution study indicated that they presented similar drug concentration in cornea, iris-ciliary and aqueous humor irrespective of gel type, with higher drug concentration achieved after 4 h compared to the commercial resin suspension eye drops. The AUC and MRT of the two in situ gel eye drops were 2 times higher than that of the commercial resin suspension eye drops in cornea. In conclusion, the two thermosensitive in situ gels have prolonged drug release after ocular drug delivery compared with ion exchange resin eye drops, implying their potential applications in clinic with broad drug adoptability.

The solid-state structure of the ß-blocker metoprolol: a combined experimental and in silico investigation.

Metoprolol {systematic name: (RS)-1-isopropylamino-3-[4-(2-methoxyethyl)phenoxy]propan-2-ol}, C15H25NO3, is a cardioselective ß1-adrenergic blocking agent that shares part of its molecular skeleton with a large number of other ß-blockers. Results from its solid-state characterization by single-crystal and variable-temperature powder X-ray diffraction and differential scanning calorimetry are presented. Its molecular and crystal arrangements have been further investigated by molecular modelling, by a Cambridge Structural Database (CSD) survey and by Hirshfeld surface analysis. In the crystal, the side arm bearing the isopropyl group, which is common to other ß-blockers, adopts an all-trans conformation, which is the most stable arrangement from modelling data. The crystal packing of metoprolol is dominated by an O-H...N/N...H-O pair of hydrogen bonds (as also confirmed by a Hirshfeld surface analysis), which gives rise to chains containing alternating R and S metoprolol molecules extending along the b axis, supplemented by a weaker O...H-N/N-H...O pair of interactions. In addition, within the same stack of molecules, a C-H...O contact, partially oriented along the b and c axes, links homochiral molecules. Amongst the solid-state structures of molecules structurally related to metoprolol deposited in the CSD, the ß-blocker drug betaxolol shows the closest analogy in terms of three-dimensional arrangement and interactions. Notwithstanding their close similarity, the crystal lattices of the two drugs respond differently on increasing temperature: metoprolol expands anisotropically, while for betaxolol, an isotropic thermal expansion is observed.

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.

Box-Behnken response surface modeling assisted enantiomeric resolution of some racemic ß-blockers using HPTLC and ß-cyclodextrin as chiral mobile phase additive: Application to check the enantiomeric purity of betaxolol.

Stereospecific separation method of (±) betaxolol, (±) carvedilol, and (±) sotalol using High Performance Thin Layer Chromatography (HPTLC) and ß-cyclodextrin as chiral selector has been developed and validated. The Box-Behnken surface response design was selected for optimizing the operating variables based on 15 trials design. The optimized method involves separation on Fluka HPTLC silica gel plates 60 F254 (20 × 10 cm) using acetonitrile-methanol-acetic acid-water (3.4:3.6:0.18:1 v/v) as a mobile phase containing 0.57 mM ß-cyclodextrin. Densitometric measurements were made at 220 nm for betaxolol and sotalol or at 245 nm for carvedilol. Maximum separation of the enantiomers of the three drugs was obtained by optimizing concentration of chiral selector, the mobile phase composition including acetonitrile amount in the organic part of the mobile phase and the volume of acetic acid added. The proposed method enables estimation of (-) and (+) enantiomers of betaxolol in drug substance and in various pharmaceuticals. The detection limit of betaxolol was 0.15 and 0.13 µg band-1 for (-) and (+) enantiomers, respectively. The detection limits were found to be 0.2 and 0.3 µg band-1 for carvedilol and sotalol, respectively, as racemate. In addition, the proposed method was applied in checking the enantiomeric purity of (-) BET in the presence of (+) BET at 1% level where the inactive (+) enantiomer was quantified with good accuracy and precision at 1% level in the active (-) enantiomer.

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.

An in vitro approach to investigate ocular metabolism of a topical, selective ß1-adrenergic blocking agent, betaxolol.

1. Topical glaucoma treatments have often been limited by poor absorption and bioavailability. Betaxolol, a selective ß1-blocker, has been well studied for its pharmacokinetics and disposition. Limited ocular, betaxolol metabolism data is available despite a growing number of novel ocular treatments. 2. In vitro ocular fractions indicated the formation of an active metabolite, across rat, rabbit and human, which was only observed historically in the liver. 3. Ocular metabolic profiles of preclinical toxicology species, rat and rabbit, were not predictive of human in vitro ocular data. M1 was specific to human and only captured by the liver data. 4. Liver S9 over predicted the extent of ocular metabolism compared to ocular fractions. Rabbit liver S9 fractions demonstrated extensive glucuronidation and higher parent turn-over in 1 h as compared to other matrices. 5. This research assesses in vitro species and organ differences across preclinical species and human. The complex data set highlights the need for an in vitro ocular system to explore poorly documented ocular metabolism.

Long acting betaxolol ocular inserts based on polymer composite.

Poor bioavailability and therapeutic response of conventional therapy due to many pre-corneal constraints necessitate the development of novel controlled and sustained ocular drug delivery to become a standard one in modern pharmaceutical era. This investigation aimed to study the drug release kinetics of betaxolol hydrochloride from a hydrophobic matrix system of PMMA cast with incorporating different proportions of polyethylene oxide (PEO) and evaluate its ability to improve ocular bioavailability and duration of action for the drug. Matrix type ocular inserts were prepared by the film casting technique and characterized in vitro by drug release studies using a flow through apparatus that simulated the eye conditions. All the formulations were subjected to physicochemical evaluation. Rabbit model with steroid induced glaucoma was used to establish in vivo efficacy of inserts. Polymer composition and concentration significantly affected the drug release based on change in diffusional path length and formation of gelaneous pores by polymer erosion. Formulations released the drug by non-fickian diffusion including anomalous transport (0.51). It was also observed that increasing the proportion of PEO in to PMMA does not affect the blend miscibility. IVIVC suggested no significant difference (P< 0.001) between in vitro and in vivo release of drug from inserts. In vivo IOP lowering activity was better for optimized insert F8 (for 24 h) as compared to eye drops (10 h). This ocular insert could be a promising once-a-day sustained release formulation for treating glaucoma.

Pulsed electromembrane method for simultaneous extraction of drugs with different properties.

In the current work, a new setup including two cathodes and one anode was designed and employed for the first time for pulsed electromembrane extraction (PEME) of atenolol (ATE) and betaxolol (BET) from water, urine, and plasma samples. Because these analytes have different lipophilicities, the composition of supported liquid membrane (SLM) should be optimized for each drug and it is impossible to extract them simultaneously using common electromembrane setups. The SLMs employed for the extraction of BET and ATE were pure 2-nitrophenyl octyl ether (NPOE) and a mixture of 90% NPOE and 10% di-(2-ethylhexyl) phosphate (DEHP), respectively, which were immobilized in the pores of two different hollow fibers. An electric field of 100V was applied to transfer the analytes from the sample solution across the SLMs into acidic acceptor solutions with pH 1.0 that were located inside the lumens of hollow fibers. Preconcentration factors in the range of 69 to 363 and satisfactory repeatabilities (2.2 < relative standard deviation [RSD] < 7.4) were obtained in different matrices. The method offered a good linearity with correlations of determination (R2) higher than 0.9944 and was applied for determination and quantification of the analytes in some real samples. Finally, satisfactory results were obtained.

Betaxolol hydrochloride loaded chitosan nanoparticles for ocular delivery and their anti-glaucoma efficacy.

Many effective anti-glaucoma drugs available for the treatment of ocular hypertension and open angle glaucoma are associated with rapid and extensive precorneal loss caused by the drainage and high tear fluid turnover. The present study involved design of mucoadhesive nanoparticulate carrier system containing betaxolol hydrochloride for ocular delivery to improve its corneal permeability and precorneal residence time. Nanoparticles were prepared by spontaneous emulsification method and had a particle size of 168-260 nm with zeta potential of 25.2-26.4 mV. The in vitro release studies in simulated tear fluid exhibited biphasic release pattern with an initial burst followed by sustained release upto 12 h. The sterility tests confirmed that formulation was free from viable microorganisms and suitable for ocular delivery. The ocular tolerance of nanoparticles was evaluated using Hen Egg-Chorion Allantoic Membrane (HE-CAM) method and was found to be non-irritant. Stability studies of nanoparticles revealed that there was no significant change in particle size and drug content after storage at 25 ± 2°C/60 ± 5% RH over a period of 3 months. In vivo pharmacodynamic studies were carried out in dexamethasone induced glaucoma model in rabbits. The developed nanoparticles showed significant decrease in intraocular pressure (IOP) compared to marketed formulation. Optimized formulation of BN3 showed gradual reduction of IOP reaching peak value of 9.9 ± 0.5mm Hg, equivalent to 36.39 ± 1.84% reduction in IOP compared to control at the end of 5 h which was significant (p < 0.05) compared to marketed formulation. Thus, our studies demonstrate that developed nanoparticles offer a promising delivery system for the management of glaucoma.

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.

The structure of betaxolol studied by infrared spectroscopy and natural bond orbital theory.

Betaxolol is a selective beta(1) receptor blocker used in the treatment of hypertension and glaucoma. A study of the betaxolol structure based on infrared spectroscopy and natural bond orbital (NBO) theory is the main aim of the present research. FTIR spectra of the solid betaxolol were recorded in the region from 4000 to 400cm(-1), in the temperature range between 25 and -170 degrees C. For spectral interpretation, spectrum of the deuterated betaxolol and the theoretical vibrational spectra of the conformer present in the solid obtained at the B3LYP/6-31G* level of theory, were used. Further insight into the structure was provided by natural bond orbital theory. NBO analysis of the conformer, before and after optimization, was carried out at the same level of theory referred above. Vibrational modes involved in hydrogen bond in the stretching and bending region were used in the estimation of the enthalpy using empirical correlations between enthalpy and the frequency shift that occurs as a result of the establishment of intermolecular hydrogen bonds. A detailed study of the structure of betaxolol and of its intermolecular interactions was obtained from the combination spectroscopy and NBO theory.

Microcalorimetric and spectrographic studies on the interaction of DNA with betaxolol.

The interaction of calf thymus deoxyribonucleic acid (ct-DNA) with betaxolol (BET) in aqueous buffer solution (pH 7.40) has been investigated using isothermal titration calorimetry (ITC), ultraviolet absorption (UV), fluorescence spectroscopy (FS) and circular dichroism (CD). Thermodynamic parameters, i.e., equilibrium constants, standard changes of enthalpy (DeltaH degrees ), Gibbs free energy (DeltaG degrees) and entropy (DeltaS degrees ), for the binding process of the drug to the bio-macromolecules have been derived from the calorimetric data. Analysis of the thermodynamic data indicates that there are two classes of binding sites on the DNA molecules being able to coordinate with BET molecules. One class of binding takes place at the sites formed by base pairs, which is synergistically driven by enthalpy and entropy, while the other one takes place on phosphate groups and shown as an entropy driven process. The thermodynamic behavior of the DNA-drug supramolecular system has been discussed in the light of the important weak interactions, hydrophobic force, hydrogen bond and electrostatic force, according to the UV, FS and CD spectra.

Application of kinetic resolution using HCS as chiral auxiliary: novel synthesis of beta-blockers (S)-betaxolol and (S)-metoprolol.

Optically pure (S)-betaxolol and (S)-metoprolol were prepared with an extremely facile and practical method using kinetic resolution of beta-amino alcohols employing HCS as chiral auxiliary. High enantiomeric purity (ee > 99%) was achieved and the synthetic strategy is amenable to industrial scale-up.

[In vitro microstructural analysis of commercial ophthalmic suspensions by HRT II Rostock Cornea Module]. / In-vitro-Untersuchung der Mikrostruktur von handelsüblichen ophthalmologischen Suspensionen mittels HRT-II Rostock Cornea Modul.

BACKGROUND: To investigate the particles of commercially used ophthalmic suspensions with the HRT II Rostock Cornea Module and to compare them with particle parameters given in the literature. METHODS: Software-aided analysis was carried out for the suspensions brinzolamide 1%, betaxolol HCl 0.25%, dexamethasone phosphate 0.1% and prednisolone acetate 0.5%, including measurements of length, area and circumference and calculation of ellipticity and shape factor (SF). RESULTS: Particle characteristics (SF and ellipticity) of different suspensions demonstrated that the particles are not spherical. Significant aggregation affinity of prednisolone acetate particles was observed. CONCLUSION: Exact and reproducible in vitro microstructural examination of ophthalmic suspensions was possible due to the high resolution of the HRT II Rostock Cornea Module.

Infrared study of the acidic and basic forms of betaxolol.

Betaxolol and its respective hydrochloride salt were studied in solution by computational calculations and infrared spectroscopy. The solution molecular conformations were taken to be the same as those exhibited by the compounds in the solid state given by X-ray diffraction and calculated after full geometry optimization by ab initio Hartree-Fock methods using the 6-31G(d) basis set. Infrared spectra of carbon tetrachloride solutions provide valuable information on the structure of the compounds in non-polar solvents at different concentrations.

Insoluble ionic complexes of polyacrylic acid with a cationic drug for use as a mucoadhesive, ophthalmic drug delivery system.

We have developed a new mucoadhesive drug delivery formulation based on an ionic complex of partially neutralized poly(acrylic acid) (PAA) and a highly potent beta blocker drug, levobetaxolol x hydrochloride (LB x HCl), for use in the treatment of glaucoma. PAA was neutralized with sodium hydroxide to varying degrees of neutralization. Aqueous solutions containing concentrations of LB x HCl equivalent to the degree of PAA neutralization were added to the PAA solutions and formed insoluble complexes, which were isolated. The complex formation was followed by turbidimetric titration, and the complexes were characterized by IR and 1H NMR spectroscopy. Complexes were prepared with varying degrees of drug loading, such that the same PAA chain would have free -COOH groups for mucoadhesion along with ionic complexes of LB x H+ with COO- groups. Thin films of the complexes dissociated to release the drug by ion exchange with synthetic tear fluid. The films shrunk continuously during release of the drug and dissolved completely in 1 h. Solid inserts of these films could be useful as a mucoadhesive ophthalmic drug delivery system.

A novel approach to predicting P450 mediated drug metabolism. CYP2D6 catalyzed N-dealkylation reactions and qualitative metabolite predictions using a combined protein and pharmacophore model for CYP2D6.

A combined protein and pharmacophore model for cytochrome P450 2D6 (CYP2D6) has been extended with a second pharmacophore in order to explain CYP2D6 catalyzed N-dealkylation reactions. A group of 14 experimentally verified N-dealkylation reactions form the basis of this second pharmacophore. The combined model can now accommodate both the usual hydroxylation and O-demethylation reactions catalyzed by CYP2D6, as well as the less common N-dealkylation reactions. The combined model now contains 72 metabolic pathways catalyzed by CYP2D6 in 51 substrates. The model was then used to predict the involvement of CYP2D6 in the metabolism of a "test set" of seven compounds. Molecular orbital calculations were used to suggest energetically favorable sites of metabolism, which were then examined using modeling techniques. The combined model correctly predicted 6 of the 8 observed metabolites. For the well-established CYP2D6 metabolic routes, the predictive value of the current combined protein and pharmacophore model is good. Except for the highly unusual metabolism of procainamide and ritonavir, the known metabolites not included in the development of the model were all predicted by the current model. Two possible metabolites have been predicted by the current model, which have not been detected experimentally. In these cases, the model may be able to guide experiments. P450 models, like the one presented here, have wide applications in the drug design process which will contribute to the prediction and elimination of polymorphic metabolism and drug-drug interactions.

Betaxolol, a beta1-adrenoceptor antagonist, has an affinity for L-type Ca2+ channels.

The effect of betaxolol on the specific binding of [3H]diltiazem and [3H]nitrendipine to rat cortical membranes was examined. Betaxolol inhibited specific [3H]diltiazem and [3H]nitrendipine binding with IC50 values of 19.7 and 46.3 microM, respectively. The effect of betaxolol on L-type Ca2+ channels showed little stereospecificity, since similar inhibitions of radioligand binding were observed with both racemic betaxolol and L-betaxolol. The dissociation kinetics of [3H]diltiazem were unaffected by 30 microM betaxolol, whereas it increased the [3H]nitrendipine dissociation rate, thus suggesting that betaxolol directly interacts with the benzothiazepine binding site and allosterically modulates the dihydropyridine binding site. Carteolol, propranolol and timolol were also found to inhibit both specific [3H]diltiazem and [3H]nitrendipine binding to rat cortical membranes, but with less potency than betaxolol. The ability of betaxolol to interact with L-type Ca2+ channels may have a role in its therapeutic effects in the management of systemic hypertension and in reducing neuronal death as occurring in glaucoma.