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Hindustan Abdul Ahad et al., (2010)99: The main objective of the present study was to develop a matrix tablet of glimepiride with Hibiscus esculentus fruit mucilage and to study its functionality as a matrix forming agent for sustained release matrix tablet formulations. Physicochemical properties of dried powdered mucilage of Hibiscus esculentus mucilage were studied. Various formulations of glimepiride Hibiscus esculetus mucilage were prepared. They found to have better uniformity of weight and drug content with low SD values. The swelling behavior and release rate characteristics were studied. The dissolution study proved that the dried Hibiscus esculentus mucilage can be used as a matrix forming material for making sustained release matrix tablets.
Bhawandeep Gill, et.al100: Glimepiride (GMP) is poorly water soluble drug, so solubility is the main constraint for oral its bioavailability. An attempt has been made to increase the solubility of this model drug by formulating soild dispersion (SD) using Poloxamer 188 (PXM 188) as polymer and then formulating SDs tablets of the best formulation of SDs. Tablet formulations were prepared by direct compression technique using superdisintegrant croscarmellose sodium in different concentrations. SDs were evaluated for XRD, SEM, in ritro dissolution profiles, and dissolution efficiency, and developed tablet formulations were evaluated for various pharmaceutical characteristics viz. hardness, % friability, weight variation, drug content, disintegration time, in vitro dissolution profiles, and dissolution efficiency. Among different formulations of SDs, SD containing drug is to polymer ratio 1 : 4 gives best dissolution profile and dissolution efficiency and among tablet formulations, formulations containing 5% croscarmellose sodium gives best disintegration and dissolution profiles compared with other formulations. Results showed that poloxamer is a promising polymer for enhancing the solubility of GMP.
T. Kiran, Nalini Shastri, et.al101: Surface solid dispersions using water-insoluble carriers like crospovidone, croscarmellose sodium, sodium starch glycolate, pre-gelatinized starch, potato starch and Avicel PH 101 were investigated to enhance the dissolution rate of the glimepiride, a poorly water insoluble drug. The effect of various carriers on dissolution profile was studied using presence absence model. The surface solid dispersion on crospovidone with drug to carrier ratio of 1 : 19 showed highest dissolution rate with the dissolution efficiency of 81.89% in comparison to pure drug (22.88%) and physical mixture (35.96%). The surface solid dispersion on crospovidone was characterized by power X-ray diffractometry, differential scanning calorimetry, Fourier transform infrared spectroscopy, gas chromatography and scanning electron microscopy. The optimized dispersion was formulated into tablets by wet granulation method. These tablets, apart from fulfilling the official and other specifications, exhibited higher rates of dissolution and dissolution efficiency values.
H.O. Ammar, et.al102: Glimepiride is a third generation sulfonylurea antidiabetic drug. Its low aqueous solubility could lead to a lack of does-proportionality and high intra- and inter-subject variability. The rationale of this study was to improve the solubility and dissolution of this drug through complexation with dimethyl-Î²-cyclodextrin (DM- Î²-CD). An inclusion complex of glimepiride in DM- Î²-CD was prepared in a molar ration of 1 : 2 by the kneading method. The durg-CD complex was characterized by scanning electron microscopy, thermo gravimetric analysis and X-ray diffractometry. Ternary systems of the drug, cyclodextrin and a water soluble polymer ( HPMC, PVP, PEG4000 or PEG6000) were also prepared. The phase solubility diagram showed that the solubility of the drug increased following cyclodextrin addition, and an Ap type plot indicated high order complexation. Dissolution of the drug from the prepared ternary systems was highly dependent on the polymer type and concentration. Dissolution of the drug from the prepared ternary systems was highly dependent on the polymer type and concentration. Dissolution of the drug from ternary systems containing PEG4000 or PEG6000 seemed to generally higher than from systems containing HPMC or PVP. An optimum increase in the dissolution rate of the drug was observed at a polymer concentration of 5% for PEG4000 and PEG6000. The dissolution rate of the drug from the ternary system glimepiride- DM- Î²-CD-5% PEG6000 was higher than from other systems. The dissolution of glimepiride is markedly increased by complexation with DM- Î²-CD in the presence of PEG. This should help improve the biological performance of the drug.
H.O. Ammar, et.al103: The effect complexation of glimepiride, a poorly water-soluble antidiabetic drug, with Î²-cyclodextrin and its derivatives (HP- Î²-CyD and SBE- Î²-CyD) in presence of different concentrations of water-soluble polymers (HPMC, PVP, PGE 4000 and PEG 6000) on the dissolution rate of the drug has been investigated. The results revealed that the dissolution rate of the drug from these ternary systems is highly dependent on polymer type and concentration. The dissolution rate of the drug from ternary systems containing PEG 4000 or PEG 6000 seems to be generally higher than from systems containing HPMC or PVP. An optimum increase in the dissolution rate of the drug was observed at a polymer concentration of 5% for PEG 4000 or PEG 6000 and at 20% concentration of HPMC or PVP. The dissolution rate of the drug from the ternary system glimepiride-HP- Î²-CyD-5% PEG 4000 was high compared to the other systems. Tablets containing the drug or its equivalent amount of this ternary system were prepared and subjected to accelerated stability testing at 40°C/75% R.H. to investigate the effect of storage on the chemical stability as well as therapeutic efficacy of the tablets. The results revealed stability of the tablets and consistent therapeutic efficacy on storage.
Kouichi Inukai, et.al104: We investigated the efficacy of glimepiride, a third-generation sulfonylurea (SU), in Japanese type 2 diabetic patients in whom glycemic control had been inadequate with a conventional SU, gliclazide or glibenclamide. A total of 172 Japanese type 2 diabetic patients (HbA1Câ‰¥7.0%), maintained on a conventional SU, were randomly assigned to the 3rd SU group (SU treatements switched to glimepiride) or the 2nd SU group (treatments not changed). The conventional SU was switched to the indicated dosed of glimepiride (gliclazide 40 mg = glimepiride 1 mg, glibenclamide 2.5 mg = glimepiride 2 mg). After 6months, glycemic control (HbA1C and fasting plasma glucose) had not changed significantly in either the 2nd or the 3rd SU group. The homeostasis assessment model of insulin resistance (HOMA-IR) in the 3rd SU group was decreased by more than 10% (p=0.015), whereas no change was observed in the 2nd SU group. The triglyceride level was decreased by approximately 10% in the 3rd SU group, not a significant change (p=0.080). Patients who had been treated with only SU, or treated with SU for a short time (less than 5 years), and who were also obese (BMI â‰¥ 25) or had a high HOMA-IR (HOMA-IR â‰¥ 3), showed significantly reduced insulin resistance. According to logistic regression analysis, high BMI (â‰¥25) was the only variable predicting that glimepiride would more effectively improve HBa1C than conventional SU treatment. In conclusion, switching conventional SUs toj glimepiride reduced insulin resistance without improving glycemic control. A notable finding of this study is that glimepiride was more beneficial in obese than in non-obese Japanese type 2 diabetic patients.
R. RoBkamp, et.al105: Glimepiride is a new sulphonylurea being prudently characterized in more than 2000 NIDDM patients. It has a short onset of action and a long duration of action. The same pharmacodynamic effect as with traditional sulphonylureas is achieved with secretion of less insulin, suggesting a possible extrapancreatic action. Glimepiride is given once daly in doses from 1-8mg/day. 100% absolute bioavailability and the absence of a food interaction guarantee highly reproducible pharmacokinetics. Glimepiride is a remarkably safe drug especially in NIDDM patients at high risk e.g. the renally impaired, elderly or physically very active person. Hypoglycemia is less frequent in the first weeks of treatment than with glibenclamide. Ongoing studies are investigating the possible beneficial clinical effect of its different behavior to the potassium channel, especially in the heart.
H.O. Ammar, et.al106: Glimepiride is one of third generation sulfonylureas used for treatment of type 2 diabetes. Poor aqueous solubility and slow dissolution rate of the drug lead to irreproducible clinical response or therapeutic failure in some cases dure to subtherapeutic plasma drug levels. Consequently, the rationale of this study was to improve the biological performance of this drug through enhancing its solubility and dissolution rate. Inclusion complexes of glimepiride in Î²-cyclodextrin (Î²-CyD), hydroxypropyl- Î²-cyclodextrin (HP- Î²-CyD) and sulfobutylether- Î²-cyclodextrin (SBE- Î²-CyD), with or without water soluble polymers were prepared by the kneading method. Binary systems were characterized by thermo gravimetric analysis, IR spectroscopy and X-ray diffractometry. Phase solubility diagrams revealed increase in solubility of the drug upon cyclodextrin addition, showing Ap type plot indicating high order complexation. All the ternary systems containing Î²-CyD or HP- Î²-CyD showed higher dissolution efficiency compared to the corresponding binary systems. The hypoglycemic effect of the most rapidly dissolving ternary system of glimepiride-HP- Î²-CyD-PEG 4000 was evaluated after oral administration in diabetic rats by measuring blood glucose levels. The results indicated that this ternary system improves significantly the therapeutic efficacy of the drug. In conclusion, the association of water soluble polymers with glimepiride-CyD systems leads to great enhancement in dissolution rate, increased duration of action and improvement of therapeutic efficacy of the drug.
O.P. Bliar Singh, S. Biswal, et.al107: The aim of this study was to investigate the physicochemical properties of glimepiride in SDs with PEG 20000. The phase solubility behavior of Glimepiride in presence of various concentrations of PEG 20000 in pH 7.4 buffer was obtained at 37°C. The solubility of glimepiride increased with increasing amount of PEG 20000 in Ph 7.4 buffer. Gibbs free energy (Î” G°tr) values were all negative, indicating the spontaneous nature of glimepiride solubilization and Î” G°tr decreased with increase in the PEG 20000 concentration, demonstrating that the reaction conditions became more favorable as the concentration of PEG 20000 increased. The SDs of glimepiride with PEG 20000 were prepared at 1:1, 1:3 and 1:5 (glimepiride: PEG 20000) ratio by melting method. Evaluation of the properties of the SDs was performed by using dissolution, Fourier-transform infrared (FTIR) spectroscopy and X-ray diffraction (XRD) studies. The SDs of glimepiride with PEG 20000 exhibited enhanced dissolution rate of glimepiride, and the rate increased with increasing concentration of PEG 20000 in SDs. Mean dissolution time (MDT) of glimepiride decreased significantly after preparation of SDs and physical mixture with PEG 20000. The FTIR spectroscopic studies showed the stability of glimepiride and absence of well-defined glimepiride-PEG 20000 interaction. The XRD studies indicated the amorphous state of glimepiride in SDs glimepiride with PEG 20000.
Ema zagar, et.al108: The aim of this work was to study the feasibility of using hyper branched polymers with highly branched structure and a large number of functional groups as solubilization enhancers for poorly water-soluble drugs. Antidiabetic drug glimepiride was used as a model drug and commercially available hyper branched poly (ester amide)s as drug carriers. The results of in vitro dissolution studies showed significantly enhanced aqueous-solubility of glimepiride in the form of solid dispersions with hyper branched poly (ester amide)s as compared to pure Glimepiride in crystalline or amorphous form. The results of IR spectroscopic measurements revealed that improved solubility is a consequence of a complex formation between glimepiride and hyper branched polymer. HB poly(ester amide)s with carbonyls of ester (O)-C=O and amide (N)-C=O groups serve mainly as a source of proton acceptor groups to which NH groups of glimepiride establish hydrogen bonds. Due to complex formation, glimepiride is within solid dispersion with HB polymers amorphous up to concentration of 5% (w/w) as revealed by X-ray powder diffraction measurements. Above this limit, glimepiride crystallizes as a separate phase during solvent evaporation.
Y.S.R. Krishnaiah, et.al109: The aim of the present investigation was to improve the dissolution properties of glimepiride. The oral Antidiabetic drug, glimepiride, was chosen as a model drug because of its low does and poor solubility. One possible way to overcome this problem is to prepare solid dispersions of the drug with inert carriers in an attempt to improve the dissolution of poorly soluble glimepiride. The solid dispersions were prepared by the solvent evaporation method using different proportions of water soluble inert carriers such as PEG4000, HPC or lactose in the ration of 1:9. Physical mixtures of glimepiride and PEG4000, HPC or lactose were also prepared in the same ratio of 1:9. Both the prepared solid dispersion systems and physical mixtures were evaluated for solubility and dissolution studies. In vitro drug release of the solid dispersions was studies in USP XXIII dissolution apparatus (apparatus 2, 50 rpm) using 900 ml of phosphate buffer pH 7.4 at 37± 0.5°C. The dissolution rate of glimepiride was increased by 3 to 4-fold with PEG4000 or lactose as carrier when compared to drug alone. Both the physical mixture and solid dispersions of glimepiride, with PEG4000 as carrier, were characterized by Differential Scanning Calorimetry and X-ray powder diffraction. The diffraction spectrum of pure glimepiride showed that drug was crystalline in amorphous. The X-ray diffraction pattern of the physical mixture (1:9 of drug and PEG4000) presented slightly crystalline form whereas the solid dispersion (1:9 drug and PEG4000) was absolutely amorphous. The DSC studies showed no possibility of glimepiride interaction with the carriers used in the study.
J. Lee, et.al110: Comminution has evolved into an effective method to prepare drug nanoparticles. Although nano-comminution has advantages, such as cost-effectiveness and easy scale-up, the processing is significantly sensitive to the selection of a polymeric stabilizer, which suffers from a lack of systematic understanding in this field. Herein, the combinations of various water-insoluble drugs and pharmaceutical polymers were systematically compared to assess the general relationships between the properties of the drugs and polymers. As a rule of thumb, drugs of high molecular weight, low solubility, high melting points, and a surface energy similar to that of the polymers, can be successfully processed into nanoparticles of unimodal particle size distribution. The addition of small molecular weight surfactants results in an additional size reduction in certain polymer/drug pairs, generally by reducing the size of large particles. Both anionic and cationic surfactants produce similar size reductions in a polymer/drug pair indicating that the charge-charge interaction between polymer and surfactant is not important.
Waheed A. Badawy, et.al111: Quantitative determination of rosiglitazone, pioglitazone, glimepiride and Glyburide as Antidiabetic drugs for type 2 diabetic patients was performed conveniently and economically using cyclic voltammetry (CV) and differential pulse voltammetry (DPV). Carbon paste (CPE) and glassy carbon (GCE) electrodes were successfully used as sensors for these drugs in Nriton-Robinson (B-R) as buffer solution. The preparation of CPE and the GCE as ion selective electrodes is based on the construction of 10%standared drug ion pair with reineckate or tungstophosphate imbedded as electro active material. Working standards were freshly prepared just before the assay by dilution from a 10-2 mol L-1 drug stock solution. At a scan rate of 100 mVs-1 the cyclic voltammograms showed a well defined anodic peak with high selectivity. The DVP gave a reproducible well defined diffusion controlled peak for each drug at a scan rate of 10m mVs-1. The oxidation peaks were used to determine the tested drug concentrations. The quantitative determination of the four drugs in their pharmaceutical preparations by the proposed electrochemical technique was found to be identical with the values obtained by the standard HPLC method. A mean % recovery of 100± 1 was obtained and the % relative standard repeatability. The proposed electronalytical technique using either the CPE or the GCE is economic, selective and can be applied for both the qualitative and quantitative determination of the drugs in their pharmaceutical preparations, without special drug separation.
Stephen N. Davis, et.al112: Type 2 diabetes mellitus, a disorder of insulin secretion and insulin resistance, has reached epidemic proportions. The effective management of Type 2 diabetes is of vital concern to clinicians. The identification of high-risk individuals and lifestyle management can help control diabetes; however, most patients require pharmacologic intervention. The goals of pharmacologic therapy are to achieve adequate glycemic control while avoiding hypoglycemia and weight gain and to minimize the risk of future micro- and macro vascular complications. There are a number of available glucose-lowering agents from which to choose. This review focuses on the sulfonylureas, the first oral agents introduced for the management of Type 2 diabetes, which are effective, well-tolerated, and well-established drugs, Second-generation sulfonylureas are now widely used in the management of Type 2 diabetes. The most recent addition, glimepiride, can be used in combination with Metformin, the Thiazolidinediones, Î±-glucosidase inhibitors, and insulin. The unique properties of glimepiride may provide advantages over other currently available insulin secretagogues.
Massimo Massi-Benedetti, MD, et.al113: Sulfonylureas (SUs) have been used for many years as first-line therapy for patients with type 2 diabetes mellitus whose blood glucose levels have not been effectively controlled by diet and exercise alone. Glimepiride is a once-daily SU that was introduced in 1995. Since then, a considerable body of evidence has been amassed regarding its use in type 2 diabetes. This review provides a comprehensive summary of available data on the pharmacology, pharmacokinetics, efficacy, and safety profile of glimepiride in the treatement of type 2 diabetes. It also examines the use of glimepiride to achieve and maintain good glycemic control in patients with type 2 diabetes in current clinical practice. Relevant articles were identified through a search of MEDLINE for English-language studies published from 1990 to 2002. The search terms used were glimepiride, sulfonylureas, and type 2 diabetes mellitus. The manufacturer of glimepiride provided additional information. Glimepiride differs from other SUs in a number of respects. In clinical studies, glimepiride was generally associated with a lower risk of hypoglycemia and less weight gain than other SUs. Results of other studies suggest that glimepiride can be used in older patients and those with renal compromise. There is evidence that glimepiride preserves myocardial preconditioning, a protective mechanism that limits damage in the even of an ischemic event. Glimepiride can be used in combination with other oral Antidiabetic agents or insulin to optimize glycemic control.
J. Lee, et.al114: Comminution has evolved into an effective method to prepare drug nanoparticles. Although nano-comminution has advantages, such as cost-effectiveness and easy scale-up, the processing is significantly sensitive to the selection of a polymeric stabilizer, which suffers from a lack of systematic understanding in this field. Herein, the combinations of various water-insoluble drugs and pharmaceutical polymers were systematically compared to assess the general relationships between the properties of the drugs and polymers. As a rule of thumb, drugs of high molecular weight, low solubility, high melting points, and a surface energy similar to that of the polymers, can be successfully processed into nanoparticles of unimodal particle size distribution. The addition of small molecular weight surfactants results in an additional size reduction in certain polymer/drug pairs, generally by reducing the size of larger particles. Both anionic and cationic surfactants produce similar size reductions in a polymer/drug pair indication that the charge-charge interaction between polymer and surfactant is not important.
I. Ilic, R.Dreu, et.al115: Drug-free micro particles were prepared using a spray congealing process with the intention of studying the influence of processing parameter. By varying the atomizing pressure and liquid feed rate, micro particles with median sizes (d(0.5)) from 58 to 278 µm were produced, with total process yields ranging from 81% to 96%. An increased liquid feed rate was found to increase micro particle size was achieved by pressures were found to decrease micro particle size. Greater change in micro particle size was achieved by varying atomizing pressure, which can be considered a dominant process parameter regarding micro particle size. In addition, microoparticles with glimepiride, amodel poorly water-soluble drug, were prepared by spray congealing using three different hydrophilic meltable carriers: Gelucire® 50/13, poloxamer 188, and PEG 6000. Spherical microoparticles with relatively smooth surfaces were obtained, with no drug crystals evident on the surfaces of drug-loaded microoparticles. XRPD showed no change in crystallinity of the drug due to the technological process of micro particle production. All glimepiride-loaded micro particles showed enhance solubility compared to pure drug: however, Gelucire® 50/13 as a carrier represents the most promising approach to the dissolution rate enhancement of glimepiride. The influence of storage (30 C/65% RH for 30 days) on the morphology of glimepiride/ Gelucire® 50/13 microoparticles was studied, and the formation of leaf-like structures was observed (a "blooming" effect).
Gunter Muller, et.al116: The contribution of extra pancreatic effects of sulfonylureas to the blood glucose-decreasing activity was reevaluated in vivo and in vitro with several conventional sulfonylureas and with the new one glimepiride. In vivo, in dogs, after single approximately equipotent blood glucose-decreasing doses, the sulfonylureas wre tested for a ranking in the ratios of mean plasma insulin-increasing and blood glucose-decreasing activity. Studies were also performed in hyperglycemic hyperinsulinemix KK-Ay mice under once daily treatment for 8 weeks. IN vitro, glimepiride and Glibenclamide were tested for the ranking of their extra pancreatic activity with respect to the stimulation of glucose transport and glucose metabolizing processes in normal and insulin-resistant fat cells as well as in the isolated diaphragm. Furthermore, in vitro studies were performed, especially with glimepiride, in order to characterize the molecular mechanism for the extra pancreatic activity. The dog studies revealed a marked ranking in the ratios of plasma insulin-increasing and blood glucose-decreasing activity between the different sulfonylureas (Glimepiride < Glipizide < Glibenclamide). In the hyperglycemic hyperinsulinemix KK- Ay mice, glimepiride reduced blood glucose by 40%, plasma insulin by 50% and HBA1c by 33%, whereas Glibenclamide and Gliclazide had no effect on these parameters. In vitro, glimepiride and Glibenclamide had extra pancreatic effects within the lower µM range, with glimepiride exhibiting 2-3-fold lower ED50 values than Glibenclamide. In the absence of insulin, both stimulated glucose transport - up to 60% of the maximum insulin response in the rat diaphragm and up to 35% in 3T3 adipocytes. Glycogenesis was stimulated into a rat diaphragm - up to 55% of the maximum insulin effect; lipogenesis in 3T3 adipocytes - up to 40%. The studies on the molecular mechanism of extra pancreatic activity with rat adipocytes and diaphragm suggest that these direct insulin-mimetic effects rely on the induction of GLUT4 translocation from internal stores to the plasma membrane and on the activation of the key metabolic enzymes, glycogen synthase and glycerol-3-phosphate acyltransferase. These processes occur within the same drug concentration range and with the same ranking between glimepiride and Glibenclamide as observed for glucose utilization and transport. The direct effects of sulfonylureas may ultimately be regulated by a glycosyl-phosphatidylinositol-specific phospholipase C, shown to be activated by glimepiride in rat adipocytes. Lipolytic cleavage products thereby generated from glycolipidic structures may in turn stimulate specific protein phosphates which activate key regulatory proteins/enzymes of glucose and lipid metabolism. From the ranking of the sulfonylureas in the ratio of mean insulin-releasing and mean blood glucose decreasing-activity at single doses in vivo, it is deduced that Sulfonylureas have a variable degree of blood glucose decreasing-activity which is independent of their insulin secretion-stimulating activity. The different degree of this extra pancreatic activity in vivo is confirmed by a corresponding ranking in stimulation of glucose utilization in vitro. Dephoshorylation and activation of key enzymes of glucose transport and metabolism induced by a a glycosyl phosphatidylinositol-specific phospholipase C might be the molecular basis for the extra pancreatic activity of sulfonylureas.
Annke Frick, Helga Moller et al., (1998)117: The development of in vitro dissolution tests using the paddle and basket apparatus is described with respect to the qualification/validation of the testing procedure. Three examples of immediate release products containing phenoxymethylpenicillin potassium, glimepiride, and levofloxacin providing different solubility characteristics are evaluated. The solubility was high in the ease of phenoxymethylpenicillin potassium and levofloxacin and low for glimepiride according to the biopharmaceutics classification system. The permeability is studied using the human colorectal carcinoma cell line CaCo-2. The permeability (10-6cm/s) of phenoxymethylpenicillin potassium, glimepiride, and levofloxacin was high. The determined permeability data are confirmed by absorption data obtained by means of numerical deconvolution of plasma concentrations. Recommendations are given for the biopharmaceutical characterization of the three immediate release drug products, taking into account in vitro and in vivo comparison as well as the biopharmaceutics drug classification system. The evaluated acceptance criteria are the following: phenoxymethylpenicillin potassium (80% in 30 min), glimepiride (80% in 15 min) and levofloxacin (80% in 30 min). Typically, for immediate release formulations, one limit is specified for the dissolution to ensure the release of the active ingredient within the present time period. Since phenoxymethylpenicillin potassium and levofloxacin belong to Case 1, no in vitro/in vivo correlation is expected, absorption may be gastric emptying dependent. Glimepiride is categorized to Case 2. Nevertheless, a correlation with the in vivo dissolution profile does not exist, because of the pH-dependent low solubility of the drug. Finally, recommendations are made for the batch control of drug products in accordance with the four Cases.