Glibenclamide Tablets Research Articles

English

The objectives of this research were to formulate and evaluate PEGylated mucin matrix tablets containing Vernonia amygdalina leaf water extract. PEGylated mucin matrices formulated with PEG 8000 and mucin from the African land snail Archachatina marginata at ratios 1:1, 0:1, 1:0, 3:1 and 1:3 were used to prepare V. amygdalina tablets by dry granulation and direct compression. Characterization based on surface morphology, weight uniformity, friability, hardness/crushing strength and absolute drug content were carried out on the tablets. The in vitro release studies were performed in phosphate buffer saline (PBS, pH 7.4), while the in vivo release studies were conducted using alloxan-induced diabetic rats. The results obtained showed that the tablets were smooth and circular in shape, maintained a percentage deviation of 3 to 5% in the weight uniformity test, had percentage average resistances (friability) less than 1% and crushing strengths less than 5 kgf, and thus conformed to compendial requirements for acceptance. In vitro release studies indicated sustained release potentials of the tablet formulations. Further kinetic analysis of drug release showed predominance of the Higuchi square root model and Fickian diffusion release mechanism. In vivo antidiabetic study revealed mucin-dependent glucose lowering potentials of the tablets which were significantly (p < 0.05) greater than those of commercial glibenclamide tablets. The method of prepartion of PEGylated mucin tablets needs to be carefully selected to ensure the production of tablets with adequate bond strength to withstand the rigours of handling and at the same time release the active compound(s) for biological action. Key words: Vernonia amygdalina, PEGylated-mucin, hyperglycaemic, tablet.

Galenic approaches in troubleshooting of glibenclamide tablet adhesion in compression machine punches

This study aimed to examine the adhesion of glibenclamide 5mg tablets to the tools of compression machines. This problem is not commonly reported in the literature, since it is considered as tacit knowledge. The starting point was the implementation of three technical alternatives: changing the parameters of compression, evaluating the humidity of the powder blend and the manufacturer of the lubricant magnesium stearate. The adhesion was directly related to the characteristics of magnesium stearate from different manufacturers, and the feasibility of evaluating powder flow characteristics by different techniques that are not routinely followed in various pharmaceutical companies. In vitro dissolution tests showed that the magnesium stearate manufacturer can influence on the dissolution profile of glibenclamide tablets. This study presented various aspects of tablet adhesion to compression machine punches. Troubleshooting approaches can be, most of times, conducted based on previous experience, or an experimental research needs to be implemented in order to have confident results.

English

The pharmaceutical quality of five generics of glibenclamide that are available in the Jordanian market was assessed according to the British Pharmacopoeia (BP) monograph (2009). Similarly, the originator glibenclamide (Daonil®) which was obtained from the Saudi market was subjected to analysis and used as a reference product. All products were found satisfactory in terms of identification and related substances as per the BP requirements. However, the assay results showed that only two products, in addition to the reference (Daonil®) satisfied the BP specifications which required glibenclamide content to be within the range: 95 to 105% of the labeled content. All products, in spite of marginal deviations for two of them, were found to pass the United States Pharmacopoeia (USP) assay specifications (90 to 110%). Significant differences in dissolution behavior were observed between the different generics and the originator (Daonil®). Daonil® exhibited the lowest dissolution profile while some products showed dissolution profiles that were almost twice that of Daonil®. Key words: Glibenclamide tablets, pharmaceutical equivalency, dissolution testing, quality control.

PDB65 - Adherence To Therapy Among Diabetes Patients In A Niger Delta Referral Center

Information on adherence among diabetes patient is rare in Bayelsa State, Niger Delta. The objective of the study was to determine the rate of adherence to therapy among diabetes mellitus patients. It was a cross sectional survey with the use of an interviewer-administered questionnaire. A 4-item Morisky self-reported adherence scale in addition to other self-developed, validated and pretested questionnaires were used. This was administered to 263 patients receiving treatment at the Outpatient Department of the hospital after seeking and obtaining their consent between June and August 2012 on clinic days. Questions related to demographics, medication history, adherence rate, etc., were included. In addition, the respective case notes (263) of the same set of patients were examined, and relevant data extracted (such as blood glucose level). Data was appropriately analysed using SPSS. Descriptive statistics were used in presentation of results. Majority of the 210 patients (80.0%) were taking both metformin and glibenclamide tablets. About 60 percent, 156 (59.3%), of patients were adjudged adherent with prescribed medications on the 4-item Morisky scale of adherence with a score of 1.22±0.2, which differs significantly from the non-adherent group with a score of 3.34±0.87. (p< 0.0001). However, overall adherences to all aspects of diabetes management were poorer as only 80 (30.5%) had normal fasting blood glucose level of less than 6.1mmol/l after at least five visits to the hospital. Only 42 (16.0%) patients self monitor their glucose level. The most frequently reported factor affecting adherence is high cost of drug therapy, 118 (44.8%), and forgetfulness, 99 (37.6%). Most of the patients, 201 (76.4%), have developed one complication or the other such as hypertension and glaucoma. There is poor adherence to anti-diabetic therapy among the patients. Financial constraint was found to be the most important factor affecting optimal adherence to therapy.

Application of the combinative particle size reduction technology H 42 to produce fast dissolving glibenclamide tablets

Standard particle size reduction techniques such as high pressure homogenization or wet bead milling are frequently used in the production of nanosuspensions. The need for micronized starting material and long process times are their evident disadvantages. Combinative particle size reduction technologies have been developed to overcome the drawbacks of the standard techniques. The H 42 combinative technology consists of a drug pre-treatment by means of spray-drying followed by standard high pressure homogenization. In the present paper, spray-drying process parameters influencing the diminution effectiveness, such as drug and surfactant concentration, were systematically analyzed. Subsequently, the untreated and pre-treated drug powders were homogenized for 20 cycles at 1500bar. For untreated, micronized glibenclamide, the particle size analysis revealed a mean particle size of 772nm and volume-based size distribution values of 2.686μm (d50%) and 14.423μm (d90%). The use of pre-treated material (10:1 glibenclamide/docusate sodium salt ratio spray-dried as ethanolic solution) resulted in a mean particle size of 236nm and volume-based size distribution values of 0.131μm (d50%) and 0.285μm (d90%). These results were markedly improved compared to the standard process. The nanosuspensions were further transferred into tablet formulations. Wet granulation, freeze-drying and spray-drying were investigated as downstream methods to produce dry intermediates. Regarding the dissolution rate, the rank order of the downstream processes was as follows: Spray-drying>freeze-drying>wet granulation. The best drug release (90% within 10min) was obtained for tablets produced with spray-dried nanosuspension containing 2% mannitol as matrix former. In comparison, the tablets processed with micronized glibenclamide showed a drug release of only 26% after 10min. The H 42 combinative technology could be successfully applied in the production of small drug nanocrystals. A nanosuspension transfer to tablets that maintained the fast dissolution properties of the drug nanocrystals was successfully achieved.

Formulation and dissolution kinetics of fast-release glibenclamide tablets

Background: Glibenclamide is oral antidiabetic drug that belongs to a class of medications known as sulfonylureas. It is indicated for the treatment of Type II non-insulin-dependent diabetes. Aim: The purpose of this work was to improve the dissolution of glibenclamide by utilizing solid dispersion technology. Materials and Methods: Glibenclamide was dispersed in water-soluble polymers; polyethylene glycol (PEG) 6000, and polyvinylpyrrolidone (PVP) using fusion and solvent method, respectively. The solubility and dissolution kinetics of solid dispersions were studied. Results: The effect of various drug:polymer ratios on the equilibrium solubility of glibenclamide was evaluated. The solubility increased as the amount of polymers was increased. Glibenclamide-PVP solid dispersion showed a threefoldincrease in the solubility of glibenclamide as compared to glibenclamide-PEG solid dispersion. The dissolution of dispersed glibenclamide was diffusion-controlled. The hydrodynamic layer thickness is influenced by the stirring rate. The data indicated that increasing the stirring rate decreased the thickness of the hydrodynamic layer. Tablets with an improved dissolution profile as compared to commercial product Euglucon® tablets were prepared. Conclusions: The solubility and dissolution profiles of glibenclamide were improved by solid dispersion technology. This may lead to enhancement of the bioavailability and efficiency of the drug.

Non-destructive detection of adulterated tablets of glibenclamide using NIR and solid-phase fluorescence spectroscopy and chemometric methods

This study describes a method for non-destructive detection of adulterated glibenclamide tablets. This method uses near infrared spectroscopy (NIRS) and fluorescence spectroscopy along with chemometric tools such as Soft Independent Modeling of Class Analogy (SIMCA), Partial Least Squares-Discriminant Analysis (PLS-DA) and Unfolded Partial Least Squares with Discriminant Analysis (UPLS-DA). Both brand name (Daonil) and generic glibenclamide tablets were used for analysis. The levels of glibenclamide in each type of tablet were evaluated by derivative spectrophotometry in the ultraviolet region. The results obtained from the NIR and fluorescence spectroscopy along with those obtained from multivariate data classification show that this combined technique is an effective way to detect adulteration in drugs for the treatment of diabetes. In the future, this method may be extended to detect different types of counterfeit medications.

Stabilized amorphous glibenclamide nanoparticles by high-gravity technique

The stable amorphous glibenclamide nanoparticles was obtained via anti-solvent precipitation using the high-gravity technique in this study. The effects of operating variables on the particle size were investigated. The properties of glibenclamide nanoparticles were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC) and dissolution test. The prepared glibenclamide nanoparticles had a mean size of 220 nm within a narrow distribution. The dissolution rate of glibenclamide nanoparticles was obviously faster than that of the raw glibenclamide or the commercial glibenclamide tablet. It achieved 85% in 5 min, while those of the raw glibenclamide and the commercial glibenclamide tablet achieved 35% and 55% respectively during the same period. The physical stability of the nanoparticles was tested after storing for more than 70 days at room conditions. Their morphology, particle size, crystalline form and dissolution rate almost remained constant during storage.

Tooth Discoloration in Patients With Neonatal Diabetes After Transfer Onto Glibenclamide

OBJECTIVETo assess if tooth discoloration is a novel side effect of sulfonylurea therapy in patients with permanent neonatal diabetes due to mutations in KCNJ11.RESEARCH DESIGN AND METHODSA total of 67 patients with a known KCNJ11 mutation who had been successfully transferred from insulin injections onto oral sulfonylureas were contacted and asked about the development of tooth discoloration after transfer.RESULTSAltered tooth appearance was identified in 5 of the 67 patients. This was variable in severity, ranging from mild discoloration/staining (n = 4) to loss of enamel (n = 1) and was only seen in patients taking glibenclamide (glyburide).CONCLUSIONSThese previously unreported side effects may relate to the developing tooth and/or to the high local concentrations in the children who frequently chewed glibenclamide tablets or took it as a concentrated solution. Given the multiple benefits of sulfonylurea treatment for patients with activating KCNJ11 mutations, this association warrants further investigation but should not preclude such treatment.

Sulphonylurea therapy improves cognition in a patient with the V59M KCNJ11 mutation

KCNJ11 mutations are a common cause of diabetes diagnosed in the first 6 months of life, and approximately 25% of patients have neurological features. Sulphonylureas have been shown to improve glycaemic control and also motor function, but the impact on cognitive function has not been extensively addressed previously. The patient had a low birth weight and was found to have diabetes at the age of 2 days. The patient was treated with insulin from diagnosis. The child also had marked developmental delay so that his average functional age was 2.5 years when he was 12 years old. A V59M mutation in KCNJ11 was found on sequencing, resulting in a diagnosis of intermediate developmental delay, epilepsy, neonatal diabetes (DEND) syndrome. Identification of a Kir6.2 mutation allowed insulin injections to be replaced by glibenclamide tablets. This resulted not only in improved glycaemic control (HbA(1c) fell from 8.1 to 6.5%), but also an impressive improvement in many aspects of cognitive function, with the functional age increasing to 4 years within 6 months of treatment change. This is the first clear report of cognitive function improving in a patient with the neurological features associated with a K(ATP) channel mutation following transfer to sulphonylureas. The finding of cognitive improvement suggests that glibenclamide is likely to be acting directly on the brain and not just on nerve and muscle, improving muscle strength.

Dissolution test for glibenclamide tablets

The aim of this work is to develop and validate a dissolution test for glibenclamide tablets. Optimal conditions to carry out the dissolution test are 500 mL of phosphate buffer at pH 8.0, paddles at 75 rpm stirring speed, time test set to 60 min and using equipment with six vessels. The derivative UV spectrophotometric method for determination of glibenclamide released was developed, validated and compared with the HPLC method. The UVDS method presents linearity (r² = 0.9999) in the concentration range of 5-14 µg/mL. Precision and recoveries were 0.42% and 100.25%, respectively. The method was applied to three products commercially available on the Brazilian market.

Determinação da glibenclamida por espectrofotometria derivada no ultravioleta para avaliação do teste ou perfil de dissolução de comprimidos

A glibenclamida (GLIB) ou gliburida, agente hipoglicemiante oral de segunda geracao, da classe das sulfonilureias, e usada sob a forma de comprimidos para controle do diabetes mellitus. Possui baixa solubilidade aquosa, podendo proporcionar baixa liberacao no teste de dissolucao de comprimidos e acarretar variabilidades no tratamento. A solucao metanolica de GLIB apresenta maximos de absorcao em lambda 210 nm, 227,5 nm e 300 nm na regiao ultravioleta (UV). Apos liberacao de comprimidos, a sua determinacao espectrofotometrica na regiao UV e dificultada devido a baixa concentracao proporcionada apos o teste de dissolucao (comprimidos GLIB 5 mg, volume de meio 900 mL, 0,56 mg%) e a baixa absortividade em comprimento de onda caracteristico, lambda 300 nm. Por estas razoes, ate hoje, nao existe um metodo de analise proposto para o teste de dissolucao em farmacopeias nacional ou estrangeiras para monografia de glibenclamida comprimidos. A falta de uniformidade nestes procedimentos onera a execucao de testes de dissolucao para verificacao da equivalencia farmaceutica de especialidades candidatas a genericos. Este trabalho propoe a determinacao espectrofotometrica de GLIB por derivada de primeira e segunda ordens (maximos lambda 238 nm e 218 nm, respectivamente, em tampao fosfato 0,1 mol L-1), utilizando comprimidos referencia e teste contendo 5 mg de farmaco por dose unitaria.

Glibenclamide plus metformin combination tablets are effective, convenient and well tolerated in the treatment of type 2 diabetes mellitus

Combination therapy with an insulin-stimulating agent (i.e. glibenclamide [glyburide]) and an insulin-sensitising agent (i.e. metformin) is an optimal and rational therapeutic first- and second-line treatment in patients with type 2 diabetes mellitus. Single-tablet glibenclamide/metformin achieves better glycaemic control than monotherapy with either agent. The improved convenience of fixed-dose glibenclamide/metformin may improve patient compliance with treatment, thereby improving glycaemic control.

Multivariate Chemometric Approach to Fiber-Optic Dissolution Testing

The use of fiber optics in in vitro dissolution testing opens up new possibilities for more powerful data evaluation since an entire UV-Vis spectrum can be collected at each measuring point. This paper illustrates a multivariate chemometric approach to the solution of problems of interfering absorbance of excipients in in vitro dissolution testing. Two different chemometric approaches are tested: multivariate calibration using partial least squares (PLS) regression and curve resolution using multivariate curve resolution alternating least squares (MCR-ALS), generalized rank annihilation (GRAM), and parallel factor analysis (PARAFAC). Multivariate calibration (PLS) can, following the construction of a calibration model from a calibration sample set, give selective and accurate determinations of the active ingredient in dissolution testing despite the presence of interfering absorbance from excipients. Curve resolution (MCR-ALS, GRAM, or PARAFAC) can be applied to dissolution testing data in order to determine the dissolution rate profiles and spectra for the interfering excipients as well as for the active ingredient without any precalibration. The concept of the application of these chemometric methods to fiber-optic dissolution testing data is exemplified by analysis of glibenclamide tablets enclosed in hard gelatin capsules. The results show that, despite highly overlapping spectra and unresolved raw data, it is possible with PLS to obtain an accurate dissolution rate profile of glibenclamide. Applying curve resolution makes it possible to obtain accurate estimates of both dissolution rate profiles and spectra of both the gelatin capsule and the glibenclamide. The application of multivariate chemometric methods to fiber-optic dissolution testing brings a fresh scope for a deeper understanding of in vitro dissolution testing, solving the problem of interfering absorbance of excipients and making it possible to obtain dissolution rate profiles and spectra of these. Obtaining dissolution rate profiles of multiple active pharmaceutical ingredients in tablets consisting of several active compounds is another possibility.

THE USE OF GENERIC DRUGS IN PHARMACY IN THE MUNICIPALITY OF YOGYAKARTA DURING MONETARY CRISIS (OBSERVATION ON MARCH 1997 - MARCH 1998)

Monetary crisis that strike Indonesia had also impacts on health services either private or public services, including pharmaceutical industries. The industries had difficulty to find raw materials for production which in turn resulting in scarce and the rise of drug price. The situation could urged the patients to shift of using the patented medicines into generic ones which are relatively cheaper. The present study has therefore aimed to observe the usage of generic products before (March 1997 - August 1997) and during (September 1997 - March 1998) the monetary crisis periods in five pharmacies of Yogyakarta Municipality. The data were taken from the stocks units and from doctor’s prescriptions, which were then analyzed by ANAVA (p=0,5). Other data were also collected and analyzed descriptively from questionnaires requested to the a hundred of pharmacy’s visitors at the same periods as above. The results have shown that the number of generic product usage was not different between the two periods, except amoxycillin 500 mg, antalgin, dextrometorphan, captopril 25 mg, and glibenclamide tablets. The respondents have revealed that they have information on generic products (91%) from mostly mass media (44%). As many as 39 % of them assume that the generic products are cheaper than of patented products and it has the same effect. Key words : monetary crisis, generic product, pharmacies

Screening and Quantitative Analysis for Sulfonylurea-Type Oral Antidiabetic Agents in Adulterated Health Food Using Thin-Layer Chromatography and High-Performance Liquid Chromatography

Screening and quantitative analysis for six sulfonylurea-type oral antidiabetic agents (SU-OADs), tolbutamide (TOL), acetohexamide (ACE), chlorpropamide (CHL), gliclazide (GLC), glibenclamide (GLB), and glimepiride (GLM), in adulterated health food has been developed. The SU-OADs were extracted with acetone and then the extract was subjected to thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC). In the TLC analysis, good separation was achieved with a mixture of n-butyl acetate containing 0.4% formic acid as a solvent. Ultraviolet irradiation at 254 nm was used to detect the SU-OADs. Specificity was obtained with Dragendorff's test solution, 10% phosphomolybdic acid methanol solution, and 30% sulfuric acid methanol solution. On the other hand, with a gradient reverse-phase HPLC system equipped with a photodiode array detector, we were able to detect the SU-OADs within 15 min using an ODS column and acetonitrile-ammonium acetate buffer as a mobile phase. Quantitative analysis based on HPLC was also performed with the absolute calibration curve method. Recoveries were 90.7-105.2% for the drugs tested. The intra- and interassay relative standard deviations were 0.2-8.1 and 0.6-7.2%, respectively. When the methods were applied to prescription glibenclamide tablets, health food, and spiked samples, good selectivity, separation, recovery, and precision were obtained.

Optimization of glibenclamide tablet composition through the combined use of differential scanning calorimetry and d-optimal mixture experimental design

A systematic analysis of the influence of different proportions of excipients on the stability of a solid dosage form was carried out. In particular, a d-optimal mixture experimental design was applied for the evaluation of glibenclamide compatibility in tablet formulations, consisting of four classic excipients (natrosol as binding agent, stearic acid as lubricant, sorbitol as diluent and cross-linked polyvinylpyrrolidone as disintegrant). The goal was to find the mixture component proportions which correspond to the optimal drug melting parameters, i.e. its maximum stability, using differential scanning calorimetry (DSC) to quickly obtain information about possible interactions among the formulation components. The absolute value of the difference between the melting peak temperature of pure drug endotherm and that in each analysed mixture and the absolute value of the difference between the enthalpy of the pure glibenclamide melting peak and that of its melting peak in the different analyzed mixtures, were chosen as indexes of the drug–excipient interaction degree.

Typical variability and evaluation of sources of variability in drug dissolution testing

To investigate variability in dissolution testing an international collaborative study was performed by 29 laboratories. Glibenclamide (glyburide) tablets were used in the investigation in which multipoint dissolution profiles were established using USP paddle apparatus. In contrast to a previous report, the variability of the glibenclamide dissolution data was significantly lower. Total variances (s 2) were found to range from 18.34–44.18, Between Laboratory and Between Analyst variances (synthetic value) ranged from 12.9–38.7 and the Within Analyst variances ranged from 5.08–5.78. The dissolution profiles and corresponding variances obtained by laboratories with little or no experience in glibenclamide dissolution testing were similar to those obtained by more experienced laboratories, indicating that the test, especially when designed as multiple point dissolution testing, is sufficiently robust and capable of identifying differences in a manufacturing process or drug formulation. The smallest statistically detectable mean difference between two dissolution runs was calculated (95% CI) to be 7% for one analyst, or 5% if two analysts were to perform the dissolution tests.

Cause of high variability in drug dissolution testing and its impact on setting tolerances

Considering a variable mixing/stirring and flow pattern in a drug dissolution vessel as a likely source of high variability in results, experiments were conducted using USP paddle apparatus by placing (aligned to the walls) a metal strip (1.7 mm thick×6.4 mm wide) in a dissolution vessel. The metal strip forces the undisintegrated tablet to settle about 3 mm away from the centre, facilitates spread of disintegrated material and diminishes the cone formation at the bottom of the vessel. To assess the impact of this altered environment in the vessel, but still maintaining the vessel dimensions within required specifications, drug release characteristics were evaluated for products having different formulation/manufacturing attributes. Tests were conducted with calibrator tablets (USP prednisone and salicylic acid tablets and FDA proposed NCDA No. 2 prednisone tablets) and two commercially available products (250 mg amoxicillin capsules and 5 mg glibenclamide tablets). Except for the glibenclamide tablet product, all products gave significantly ( P<0.01) higher dissolution results with vessels containing metal strip than without. The extent of increased dissolution with the metal strip varied from product to product i.e. USP prednisone tablet was the smallest (14.4%) and NCDA No. 2 was the largest (88.4%). Based on the results obtained from this study, it is concluded that employing the current apparatuses, in many cases products will provide lower than anticipated results which may not be reflective of the product drug release characteristics. Test-to-test variability, within or between laboratories, can also be very high depending on the settling position of the product once dropped in the vessel and/or due to slight aberration in the walls of the vessel by altering the extent of spread of disintegrated material at the bottom of the vessel. Thus, dissolution testing will require wider tolerances to be useful for comparison of batch-to-batch or interlaboratory results.

Typical variability in drug dissolution testing: study with USP and FDA calibrator tablets and a marketed drug (glibenclamide) product

To evaluate variability in drug dissolution testing 28 laboratories analyzed USP calibrators, US FDA prednisone tablets and a marketed glibenclamide tablet product. The experiments were conducted using paddle and basket methods at 50 (calibrators) and 75 (glibenclamide) rpm. The media employed were deaerated by equilibrating at 37°C for 24 h and by the USP recommended method. The 95% CI values for percent drug release for the USP calibrator tablets were similar to the reported tolerances for the USP Acceptance Ranges; however, individual results from 15 of 28 laboratories suggest that the apparatus would not comply with the USP Apparatus Suitability Criteria. For FDA prednisone calibrator tablets, percent drug release using equilibrated medium was different ( P=0.003) than by the USP recommended method. For the glibenclamide tablet results, a CV of 14–37% was observed, depending upon the sampling time and the type of apparatus employed. The results indicate that failure to meet the USP Dissolution Apparatus Suitability Test may not truly mean that the apparatus is `out of compliance'. Due to the high variability in dissolution testing, in many cases the impact of formulation or manufacturing changes on drug release characteristics may not be observed, in particular with multi-point profiles.