Effect of drug-ion exchange resin complex in betahistine hydrochloride orodispersible film on sustained release, taste masking and hygroscopicity reduction.

Orodispersible film (ODF) is a widely used oral solid dosage form. However, it's not suitable for drugs with short half-life, bitterness and strong hygroscopicity. The present study aims to develop a sustained release and stable betahistine hydrochloride ODF without bitterness. Drug-resin complex (IRDC) was prepared using batch method. In vitro dissolution experiment, e-Tongue and hygroscopicity experiment were conducted to compare the differences between ODF containing IRDC and ODF containing betahistine hydrochloride. Drug release kinetics showed that the diffusion of drug in IRDC was the rate-limiting step of drug release. DSC and FT-IR were conducted to explore the molecular mechanism of taste masking and hygroscopicity reduction. It turned out that taste masking was attributed to the ionic interaction between drug and resin and the slow dissolution of drug from IRDC. The site where drug form hydrogen bonds with water molecular was occupied by drug-resin interaction leading to hygroscopicity reduction. In summary, in this study we not only developed a betahistine hydrochloride ODF with good properties but also explored the effect of drug-resin interaction on sustained release, taste masking and hygroscopicity reduction.

Betahistine dihydrochloride transdermal delivery via optimized thermosensitive gels: percutaneous absorption evaluation using rat growth as a biomarker.

The aim of this study was to develop and optimize a betahistine dihydrochloride (BH) thermoreversible bioadhesive gel intended for transdermal delivery. The gels were obtained via cold method. A full factorial design was employed to investigate the joint effect of Poloxamer 407 concentration (18 and 20%), adhesive polymer type (Polyvinyl pyrolidone, Hydroxypropyl methylcellulose, and Carbopol 934), and adhesive polymer concentration (0.5 and 1.5%) on gelling temperature, viscosity at 37 °C, and adhesion strength. Data collected were analyzed using multiple linear regression. A desirability index approach with relative importance weight was used to choose the most desirable formulation. F4 (20% Poloxamer+1.5% Carbopol) was selected for further characterization. F4 released 96.97% drug in 12 h across hairless rat skin. F4 gelation temperature and time were 36 ± 0.35 °C, and 6 ± 0.7 min, respectively. F4 adhesive force was 8835.68 dyne/cm2. F4 was tested for its appetite suppressing effect in a rat model and it was evaluated histopathologically. Rats' chow intake and weight gain was significantly decreased with no signs of inflammation or lipolysis when the optimized BH gel formulation, F4, was compared with untreated animals and animals treated with BH free gel. The results suggest that BH is percutaneously absorbed from the gel base and that the BH gel is tolerable. The desirability index approach with relative importance weight of responses was effective in determination of the optimum formulation. BH is systemically effective and well-tolerated when applied topically in hydrogel-based systems. The Carbopol-Poloxamer gel is a promising modality for transdermal delivery of BH.

Transbuccal delivery of betahistine dihydrochloride from mucoadhesive tablets with a unidirectional drug flow: in vitro, ex vivo and in vivo evaluation.

OBJECTIVE: Betahistine dihydrochloride (BH.2HCl), an anti-vertigo histamine analog used in the treatment of Ménière's disease, undergoes extensive first-pass metabolism and suffers from short biological half-life. The aim of the present work was to develop and estimate controlled release mucoadhesive buccal tablets of BH.2HCl with a unidirectional drug flow to overcome this encumbrance. METHODS: A direct compression method was adopted for preparation of the tablets using mucoadhesive polymers like guar gum, hydroxypropyl methyl cellulose K4M, sodium carboxymethyl cellulose and their combinations. The tablets were coated from all surfaces except one surface with a solution of 5% (w/v) cellulose acetate and 1% (w/v) dibutyl phthalate. Different permeation enhancers like 2% sodium deoxycholate, 2% sodium cholate hydrate (SCH) and 5% menthol were tested. Swelling index, ex vivo residence time, mucoadhesion strength, in vivo testing of mucoadhesion time, in vitro dissolution and ex vivo permeation were carried out. Furthermore, compatibility and accelerated stability studies were performed for the drug excipients. Finally, drug bioavailability of the BH.2HCl-optimized buccal mucoadhesive formulation was compared with that of the orally administered Betaserc® 24 mg tablet in six healthy male volunteers. RESULTS: Formulation F10, which contained a combination of 35% guar gum and 5% sodium carboxymethyl cellulose, exhibited long adhesion time, high adhesion strength and diminished irritation to volunteers and showed zero-order release kinetics. SCH produced a significant enhancement in permeation of BH.2HCl across buccal mucosa. BH.2HCl-optimized buccal mucoadhesive formulation showed percentage relative bioavailability of 177%. CONCLUSION: The developed mucoadhesive tablets represent a promising alternative for the buccal delivery of BH.2HCl.

Formulation and performance evaluation of betahistine dihydrochloride microspheres as sustained release systems.

UNLABELLED: Betahistine dihydrochloride is a histamine-like drug widely used in relieving the symptoms associated with Ménière's syndrome. Pharmacokinetic studies of betahistine have demonstrated that it has a short plasma half-life of 3-4 hours. In such cases frequent administration of the drug is required in order to keep plasma concentration within the therapeutic range. However, this may lead to noncompliance and aggravate patients' comfort. An advanced approach for achieving sustained release of drugs is their incorporation in microparticulate carriers. AIM: To design a sustained release microsphere formulation of betahistine providing reduced dose frequency and lower risk of side effects occurrence. MATERIALS AND METHODS: Betahistine-loaded chitosan microspheres were obtained via W/O emulsion solvent evaporation technique and were characterized for particle size, drug loading and entrapment efficiency. Drug release into phosphate buffer saline pH 7.4 was performed and dissolution profiles of the formulations were obtained. To study the mechanism of drug release from the microspheres the dissolution data was fitted to various mathematic models. RESULTS: Betahistine-loaded microspheres were produced with a high drug loading and entrapment efficiency. The microcarriers were spherical in shape with mean particle size of 3.82 µm to 7.69 µm. Betahistine release studies from the microspheres showed similar and slightly increasing dissolution profiles. The drug release proceeded in a controlled manner following Fickian diffusion. CONCLUSION: The obtained results suggest that betahistine-loaded chitosan microspheres prepared by solvent evaporation method are capable of sustained release of drugs and therefore can be used as drug delivery systems in the treatment of Ménière's syndrome.

Transdermal delivery of betahistine hydrochloride using microemulsions: physical characterization, biophysical assessment, confocal imaging and permeation studies.

Transdermal delivery of betahistine hydrochloride encapsulated in various ethyl oleate, Capryol 90(®), Transcutol(®) and water microemulsion formulations was studied. Two different kinds of phase diagrams were constructed for the investigated microemulsion system. Pseudoplastic flow that is preferable for skin delivery was recorded for the investigated microemulsions. A balanced and bicontinuous microemulsion formulation was suggested and showed the highest permeation flux (0.50±0.030mgcm(-2)h(-1)). The effect of the investigated microemulsions on the skin electrical resistance was used to explain the high permeation fluxes obtained. Confocal laser scanning microscopy was used to confirm the permeation enhancement and to reveal the penetration pathways. The results obtained suggest that the proposed microemulsion system highlighted in the current work can serve as a promising alternative delivery means for betahistine hydrochloride.

Development and optimization of a multiple-unit controlled release formulation of a freely water soluble drug for once-daily administration.

A controlled release resinate beads of betahistine diHCl (BHCl), a short half-life freely water soluble drug, was developed to allow once-daily administration to improve patient compliance and eliminate the risk of intolerance of the drug. BHCl-resin complex was subsequently coated with Eudragit RS100. A 2(4) full factorial design was employed for optimization and to explore the effect of Eudragit RS100 concentration in the coating solution (X(1)), the coating percentage (X(2)), the speed of rotation (X(3)) and the concentration of plasticizer (PEG 400) (X(4)) on the release rate of the drug from the microcapsules. The extent of coating (Y(1)), and the percentage drug released at given times (Y(2), Y(3) and Y(4)) were selected as dependent variables. The optimization process was performed for X(1), X(2), X(3) and X(4) using target ranges of these responses determined based on target release model deduced form zero-order dissolution profile of BHCl for once-daily administration. The levels of X(1), X(2), X(3) and X(4) of optimized BHCl microcapsules are 14.42%, 50.63%, 1495rpm and 9.94%, respectively. The calculated value of f(2) for the optimized BHCl microcapsules filled into hard gelatin capsules was 67.03 indicating that the dissolution profiles of the optimized formulation is comparable to that of the target release model. It could be concluded that a promising once-daily extended-release microcapsules of the highly water soluble drug, BHCl, was successfully designed.

Stress degradation studies on betahistine and development of a validated stability-indicating assay method.

The purpose of this work was to study the stability of betahistine (BET) at different stress conditions and to develop a sensitive stability-indicating high-performance liquid chromatographic (HPLC) assay method. The stress conditions applied were including the effect of heat, moisture, acid-base, and ultra-violet (UV) light. Betahistine and its decomposition products were derivatized by reaction with dansyl chloride (Dan-Cl) and analyzed by HPLC equipped with fluorescence detector (FL) set at 336 and 531 nm as excitation and emission wavelengths, respectively. The drug was particularly labile at UV light and oxygen rich media. Two potential degradation products could be separated and identified by spectral methods. The chromatographic method involved Zorbax Eclipse XDB-C(18) column kept at 30+/-2 degrees C and a gradient elution with mobile phase composed of acetonitrile and 0.02 mol L(-1) sodium acetate. The response factor of dansylated BET monitored by fluorescence detection was 32 times more than its UV response. The calibration curve of BET in bulk form was linear from 0.005 to 4.2 ng microL(-1). Intraday and interday precision were less than 0.04% (CV), and accuracy was between 99.2% and 100.9% over 2.0 ng microL(-1). The limit of detection was 0.002 ng microL(-1). The method was also validated for sample stability during reaction, robustness and selectivity. The method was applied for purity testing of betahistine in tablet form.

Betahistine: what's new on the agenda?

BACKGROUND: Betahistine is an orally administered, centrally acting histamine H(1) receptor agonist with partial H(3) antagonistic activity and no H(2)-binding effects. In the past betahistine was clinically studied mainly as a vasodilator for conditions such as cluster headaches, vascular dementia and Meniere's disease, for which it is still used. In recent years, histamine was found to be a key neurotransmitter in the regulation of feeding behavior. OBJECTIVE: To provide a review of the developmental history and current research interests of betahistine. METHODS: All reports of betahistine use in animals and humans were retrieved and reviewed. RESULTS/CONCLUSION: The unique pharmacologic properties of betahistine point to its potential future use as an antiobesity agent.

Utilization of carbon disulphide for the analytical determination of betahistine hydrochloride and captopril in their pharmaceutical preparations.

Spectrophotometric, atomic absorption spectrometric and high performance liquid chromatographic (HPLC) procedures have been developed for the determination of betahistine hydrochloride and captopril. The three procedures are based on the reaction of the drugs with carbon disulphide in alkaline medium with the formation of the dithiocarbamate or the trithiocarbonate derivative of betahistine (BHT) and captopril (CAP), respectively, then subsequent chelation with divalent metals. The absorbance measurement of the formed chelates or of the metal moiety of chelates was used as the basis for the spectrophotometric and atomic absorption spectrometric determinations. The formed complexes have been used as pre-column derivatizing procedure for the HPLC determination of the two drugs. The different experimental conditions were optimized. The calibration graphs were linear over the applicable concentration ranges. The proposed procedures were applied successfully for the determination of the two investigated drugs in their tablets dosage form.