[Applicability of a natural swelling matrix as the propellant of osmotic pump tablets].

The purpose of this study is to investigate the applicability of a natural swelling matrix derived from boat-fruited sterculia seed (SMS) as the propellant of osmotic pump tablets. The sugar components, static swelling, water uptake and viscosity of SMS were determined and compared with that of polythylene oxide (WSR-N10 and WSR-303). Both ribavirin and glipizide were used as water-soluble and water-insoluble model drugs. Then, the monolayer osmotic pump tablets of ribavirin and the bilayer osmotic pump tablets of glipizide were prepared using SMS as the osmotically active substance and propellant. SMS was mainly composed of rhamnose, arabinose, xylose and galactose and exhibited relatively high swelling ability. The area of the disintegrated matrix tablet was 20.1 times as that at initial after swelling for 600 s. SMS swelled rapidly and was fully swelled (0.5%) in aqueous solution with relative low viscosity (3.66 +/- 0.03) mPa x s at 25 degrees C. The monolayer osmotic pump tablets of ribavirin and the bilayer osmotic pump tablets of glipizide using SMS as propellant exhibited typical drug release features of osmotic pumps. In conclusion, the swelling matrix derived from boat-fruited sterculia seed, with low viscosity and high swelling, is a potential propellant in the application of osmotic pump tablets.

Polypharmacy (herbal and synthetic drug combination): a novel approach in the treatment of type-2 diabetes and its complications in rats.

The aim of present study was to evaluate the effect of aqueous leaf extract of Annona squamosa with Glipizide in a high fat diet and streptozocin-induced type-2 diabetes. Nine groups (n = 6) of male Sprague-Dawley rats were used for the study, with. Basal blood glucose, urine volume, and body weights were measured and the rate were kept on a high fat diet. After 15 days, streptozocin in sub-diabetic dose (35 mg/kg) was administered to the animals to induce diabetes. With 1 week of consistent hyperglycemia, treatment was initiated. Aqueous extract of Annona squamosa was administered orally at 350 mg/kg body weight alone and in combination with reduced and reducing dose combinations of Glipizide. Blood glucose, body weight, urine volume were measured every 10th day. The elevated blood-glucose level in diabetic rats was controlled better with combination therapy compared with the synthetic drug alone or the herbal stand-alone drug. All the results were statistically significant (P < 0.001). A combination of Annona squamosa along with Glipizide may be helpful in dose reduction of Glipizide up to 50%, reducing the risk of the onset of insulin therapy.

Glipizide controlled-release tablets, with or without acarbose, improve glycaemic variability in newly diagnosed Type 2 diabetes.

1. The aim of the present study was to compare the effects of glipizide controlled-release (CR) tablets monotherapy with that of glipizide CR tablets plus acarbose on glycaemic variability in newly diagnosed Type 2 diabetes (T2DM) patients using a continuous glucose-monitoring system (CGMS). 2. Forty newly diagnosed T2DM patients whose glycated haemoglobin A1c (HbA1c) levels ranged from 7.0% to 9.8% were randomized to either monotherapy or combination therapy. Overall glycaemic control and blood glucose variability were evaluated by CGMS parameters. 3. After 8 weeks treatment, fasting and postprandial blood glucose, HbA1c, glycated albumin (GA), mean blood glucose (MBG), mean amplitude of glycaemic excursions (MAGE), postprandial incremental area under the curve (AUC(pp)) and homeostasis model assessment of insulin resistance decreased significantly in both groups (P < 0.01). There was also a significant decrease in the mean of daily differences (MODD) in the combination therapy group. Mean changes in MBG, MAGE, MODD and AUC(pp) were significantly greater in the combination therapy group than in the monotherapy group (all P < 0.01), whereas no significant differences were found in the mean changes of HbA1c and GA. Multivariate regression analysis showed that the decrement in AUC(pp) was significantly associated with decreases in MAGE. 4. In conclusion, glipizide CR tablets alone or in combination with acarbose can improve overall blood glucose levels and glycaemic variability. Combination therapy using glipizide CR tablets and acarbose was more effective in reducing intraday and day-to-day glycaemic variability than glipizide CR tablet monotherapy.

Lack of pharmacokinetic interaction for ISIS 113715, a 2'-0-methoxyethyl modified antisense oligonucleotide targeting protein tyrosine phosphatase 1B messenger RNA, with oral antidiabetic compounds metformin, glipizide or rosiglitazone.

BACKGROUND: ISIS 113715 is a 20-mer phosphorothioate antisense oligonucleotide (ASO) that is complementary to the protein tyrosine phosphatase 1B (PTP-1B) messenger RNA and subsequently reduces translation of the PTP-1B protein, a negative regulator of insulin receptor. ISIS 113715 is currently being studied in early phase II clinical studies to determine its ability to improve or restore insulin receptor sensitivity in patients with type 2 diabetes mellitus. Future work will investigate the combination of ISIS 113715 with antidiabetic compounds. METHODS: In vitro ultrafiltration human plasma protein binding displacement studies and a phase I clinical study were used to characterise the potential for pharmacokinetic interaction of ISIS 113715 and three marketed oral antidiabetic agents. ISIS 113715 was co-incubated with glipizide and rosiglitazone in whole human plasma and tested for increased free drug concentrations. In a phase I clinical study, 23 healthy volunteers received a single oral dose of an antidiabetic compound (either metformin, glipizide or rosiglitazone) both alone and together with subcutaneous ISIS 113715 200 mg in a sequential crossover design. A comparative pharmacokinetic analysis was performed to determine if there were any effects that resulted from coadministration of ISIS 113715 with these antidiabetic compounds. RESULTS: In vitro human plasma protein binding displacement studies showed only minor effects on rosiglitazone and no effect on glipizide when co-incubated with ISIS 113715. The results of the phase I clinical study further indicate that there were no measurable changes in glipizide (5 mg), metformin (500 mg) or rosiglitazone (2 mg) exposure parameters, maximum plasma concentration and the area under the concentration-time curve, or pharmacokinetic parameter, elimination half-life when coadministered with ISIS 113715. Furthermore, there was no effect of ISIS 113715, administered in combination with metformin, on the urinary excretion of metformin. Conversely, there were no observed alterations in ISIS 113715 pharmacokinetics when administered in combination with any of the oral antidiabetic compounds. CONCLUSION: These data provide evidence that ISIS 113715 exhibits no clinically relevant pharmacokinetic interactions on the disposition and clearance of the oral antidiabetic drugs. The results of these studies support further study of ISIS 113715 in combination with antidiabetic compounds.

Pharmacological evaluation of membrane-moderated transdermal system of glipizide.

1. Membrane-moderated transdermal systems of glipizide were prepared using drug-containing carbopol gel (drug reservoir) and ethyl cellulose, as well as Eudragit RS-100, Eudragit RL-100 (Rohm Pharma, Darmstadt, Germany) and ethylene vinyl acetate (EVA; 2, 9 and 19% vinyl acetate content) rate-controlling membranes, and were subsequently evaluated in vitro (drug content and drug permeation studies) and in vivo (acute and long-term hypoglycaemic activity, effect on glucose tolerance, biochemical and histopathological studies, skin irritation test and pharmacokinetic studies in mice). 2. The drug content of the systems was found to be more than 99%. Variations in drug permeation patterns were observed among the formulations containing different rate-controlling membranes. 3. The system with the EVA (19% vinyl acetate) rate-controlling membrane was selected for in vivo experiments. This transdermal system produced better improvement with respect to hypoglycaemic activity, glucose tolerance and tested biochemical, histopathological and pharmacokinetic parameters all compared with oral administration and exhibited negligible skin irritation. 4. The transdermal system successfully prevented severe hypoglycaemia in the initial hours and it was also effective for chronic application.

Development and evaluation of osmotically controlled oral drug delivery system of glipizide.

Extended release formulation of glipizide based on osmotic technology was developed and evaluated. The effect of different formulation variables, namely, level of solubility modifier in the core, membrane weight gain, and level of pore former in the membrane, were studied. Drug release was found to be affected by the level of solubility modifier in the core formulation. Glipizide release was inversely proportional to the membrane weight but directly related to the initial level of pore former (PVP) in the membrane. Burst strength of the exhausted shells increased with the weight gain of the membrane. On the other hand, burst strength decreased with an increase in the level of pore former in the membrane. Drug release from the developed formulations was independent of pH and agitational intensity, but dependent on the osmotic pressure of the release media. Results of SEM studies showed the formation of pores in the membrane from where the drug release occurred. The numbers of pores were directly proportional to the initial level of pore former in the membrane. The manufacturing procedure was found to be reproducible and formulations were stable after 3 months of accelerated stability studies.

A short-term cost-of-treatment model for type 2 diabetes: comparison of glipizide gastrointestinal therapeutic system, metformin, and acarbose.

OBJECTIVE: To compare, from a managed care perspective, the 3-year costs of 3 first-line monotherapy strategies in type 2 diabetes patients: glipizide gastrointestinal therapeutic system (GITS), metformin, and acarbose. STUDY DESIGN: A Markov model, with a Monte Carlo simulation, was developed to compare the costs to achieve full glycemic control (hemoglobin A1c of < or = 7%) with each first-line strategy. PATIENTS AND METHODS: The patient population for the model was assumed to be all newly diagnosed type 2 diabetes patients eligible for monotherapy with an oral agent. Each monotherapy could be succeeded by add-on treatments. The model included the costs of routine medical care and supplies, medication, adverse events, and treatment failures. RESULTS: Using a Monte Carlo simulation, the mean 3-year cumulative costs per patient were $4971, $5273, and $5311 for glipizide GITS, metformin, and acarbose first-line strategies, respectively. The main cost drivers were drug prices. Mean 3-year cost savings for first-line glipizide GITS were $301 over metformin and $340 over acarbose. Between 83% and 85% of all simulations showed cost savings with glipizide GITS compared with the other agents. CONCLUSIONS: The model suggests first-line monotherapy with glipizide GITS should result in desirable short-term economic benefits for managed care. Because the model incorporates recommended glycemic goals and performed well in sensitivity analyses, it should be applicable to a variety of clinical practices and useful for economic assessments of new therapies. Results of this model should be verified prospectively in typical care settings.

The effects of gliclazide and other sulfonylureas on low-density lipoprotein oxidation in vitro.

Diabetes is associated with increased oxidant stress. This may contribute to the development of diabetic macrovascular complications through increased oxidation of low-density lipoprotein (LDL), which is thought to be a crucial step in the development of atherosclerosis. The sulfonylurea gliclazide has been shown to have free radical-scavenging activity in vitro, but its effects on LDL oxidation, and these effects of other sulfonylureas, are unknown. To investigate this we studied the effects of in vitro supplementation with gliclazide 1 mumol/L on copper-induced oxidation of LDL isolated from 20 control subjects and 22 type II diabetic patients. The effects of 1 mumol/L vitamin C, a known water-soluble antioxidant, were studied simultaneously. The resistance to oxidation, expressed as the lag time between the addition of copper and commencement of oxidation, was significantly increased by both gliclazide and vitamin C, and the effect was similar for LDL from diabetic and control subjects. The baseline oxidation lag time was 63.4 +/- 2.1 minutes, and increased to 108 +/- 4.4 minutes with gliclazide and 88.7 +/- 5.6 minutes with vitamin C (P = .0001, baseline v either treatment). The increase in lag time with gliclazide of 70% +/- 3% was greater than the 30% +/- 5% increase with vitamin C (P < .0005). In a separate experiment, LDL isolated from eight control and 10 diabetic subjects was supplemented with 1 mumol/L gliclazide, glibenclamide, glipizide, and tolbutamide. For each LDL sample, all drugs were studied simultaneously and the oxidation lag time was compared against that of untreated LDL. Gliclazide increased the lag time from 53.7 +/- 2.4 minutes to 108.4 +/- 4.5 minutes (P = .0001). None of the other sulfonylureas had any effect on lag time. These findings demonstrate that gliclazide is an effective inhibitor of in vitro LDL oxidation, and in this respect, it is more potent on a molar basis than vitamin C. This antioxidant property of gliclazide was not shared by the other sulfonylureas studied.