Premix Formulations Research Articles

Bio-effectivenessvis-a-visnon-target toxicity of pre-mix formulation, fenobucarb 20% ec + buprofezin 5% sc against sucking pests of rice under Gangetic alluvial plain of west bengal

Field evaluation of the bio-efficacy of pre mix insecticides fenobucarb 20% EC + buprofezin 5% SC along with traditional insecticides as foliar spray against brown plant hopper Nilaparvata lugens, white-backed plant hopper Sogatella furcifera and green leaf hopper Nephotettix nigropictus was undertaken in a progressive farmer's field at Nabagram (Burdwan), West Bengal under rainfed conditions with a HYV rice cultivar “Swarnamasuri”. the treatments at higher dosages (1500, 2000 and 3000 ml ha−1) were superior over standard check treatments buprofezin 25% sc and fenobucarb 50% ec. the highest yield (32.88–37.32 q ha−1) was obtained in case of higher dosages. the percent reduction of hopper population was maximum in treatments with high dosages with a mean ranging from 50.75–90.75%. the pre-mixed formulation was relatively soft to important natural enemies like Cyrtorhinus lividipennis and spiders and found suitable for economic rice pest management.

Practical Guidance on the Use of Premix Insulin Analogs in Initiating, Intensifying, or Switching Insulin Regimens in Type 2 Diabetes.

IntroductionPremix insulin analogs are a well-established treatment for type 2 diabetes (T2D). However, there is a lack of simple, clear guidance on some aspects of their use. These include choosing a regimen for insulin initiation, recognizing when patients need intensification of therapy, and switching from basal–bolus to a premix insulin analog when appropriate.MethodsAn independent expert panel formulated recommendations on the use in T2D of the premix insulin analog formulations widely available in Australasia, based on the available evidence and their own experience.ResultsResults from trials in both initiation and intensification of insulin show that no single insulin or regimen is best on all endpoints, and that improved glycemic control can be expected regardless of which regimen is used. Thus, individual patient factors and preferences become more important. Guidance is presented to help the clinician choose between a premix insulin analog or basal analog for insulin initiation, and to intensify insulin therapy using premix insulin analogs. Recommendations are made on dosing, titration, the concomitant use of non-insulin glucose-lowering drugs, and other practical issues, and on the special case of switching from basal–bolus to premix insulin analog therapy.ConclusionThis guidance is intended to help both general and specialist practitioners make informed choices and provide optimal care for patients with T2D. It emphasizes the importance of taking into account individual patient factors and preferences so that the choice of insulin regimen is individualized to the patient in the same way that glycemic targets are now individualized.FundingNovo Nordisk Region IO A/S.Electronic supplementary materialThe online version of this article (doi:10.1007/s13300-015-0116-0) contains supplementary material, which is available to authorized users.

Determination of EDTA in feed and premix formulations by HPLC-DAD

A simple analytical method for the quantitative determination of ethylenediaminetetraacetic acid (EDTA) in feed and premix formulations was developed and validated. The method involves an extraction with an acidic ferric chloride solution, to quantitatively convert EDTA species in the samples into the Fe(III)–EDTA complex, and its subsequent detection by Ion-Pair-Reversed Phase-High Performance Liquid Chromatography-Diode Array Detection (IP-RP-HPLC-DAD). A robust validation procedure was performed according to the Decision 2002/657/EC at concentrations ranging from 25 to 100mgkg−1 on sample. Good recoveries (85.6–92.8%) were obtained; repeatability of the method was in the range of 1.3–8.0%, with an intermediate precision ranging from 6.0% to 8.6%, both of them expressed as relative standard deviation (RSD). No interfering species hindered the straightforward detection of EDTA. Hence, the proposed method can be adopted for an effective and rapid routine analysis of products for livestock.

Evidence-based clinical use of insulin premixtures.

Brazil is expected to have 19.6 million patients with diabetes by the year 2030. A key concept in the treatment of type 2 diabetes mellitus (T2DM) is establishing individualized glycemic goals based on each patient’s clinical characteristics, which impact the choice of antihyperglycemic therapy. Targets for glycemic control, including fasting blood glucose, postprandial blood glucose, and glycated hemoglobin (A1C), are often not reached solely with antihyperglycemic therapy, and insulin therapy is often required. Basal insulin is considered an initial strategy; however, premixed insulins are convenient and are equally or more effective, especially for patients who require both basal and prandial control but desire a more simplified strategy involving fewer daily injections than a basal-bolus regimen. Most physicians are reluctant to transition patients to insulin treatment due to inappropriate assumptions and insufficient information. We conducted a nonsystematic review in PubMed and identified the most relevant and recently published articles that compared the use of premixed insulin versus basal insulin analogues used alone or in combination with rapid-acting insulin analogues before meals in patients with T2DM. These studies suggest that premixed insulin analogues are equally or more effective in reducing A1C compared to basal insulin analogues alone in spite of the small increase in the risk of nonsevere hypoglycemic events and nonclinically significant weight gain. Premixed insulin analogues can be used in insulin-naïve patients, in patients already on basal insulin therapy, and those using basal-bolus therapy who are noncompliant with blood glucose self-monitoring and titration of multiple insulin doses. We additionally provide practical aspects related to titration for the specific premixed insulin analogue formulations commercially available in Brazil.

Sustained release solid lipid matrices processed by hot-melt extrusion (HME)

The aim of this work was to develop sustained release solid lipid matrices of diclofenac sodium (Df-Na) processed by hot melt extrusion (HME) and subsequent compression into tablets. Different extrusion processing approaches such as “cold”, “hot” and pre-mixed formulations were used to develop the Compritol® 888 ATO lipid matrices by altering the extrusion temperatures, drug loading and formulation composition. The extrudates were characterized via a range of techniques such as differential scanning calorimetry (DSC), hot stage microscopy (HSM) and X-ray powder diffraction (XRPD) to identify the drug state within the lipid matrix. Df-Na was found to be either in crystalline or amorphous state depending on the processing conditions. Energy dispersive X-ray (EDX) microanalysis demonstrated excellent drug distribution of Df-Na on the surface of the compressed tablets. The lipid matrices developed by HME provided sustained release of pre-mixed formulations for 12h mainly controlled by diffusion.

Fortification of Staple Cereal Flours with Iron and other Micronutrients: Cost Implications of following World Health Organization—Endorsed Recommendations

Wheat and maize flours are widely used delivery vehicles for mass fortification. In lower-income countries, most, if not all, national-level cereal flour fortification programs routinely fortify with iron; however, cofortification with other micronutrients is common. Little information is available on the cost implications programs face when considering current fortification practices versus what the World Health Organization (WHO) interim consensus statement recommends. The objectives of the present paper are to provide information on the costs of adding different chemical forms of iron and/or other micronutrients to premix formulations, and to discuss some of the issues that should be considered regarding which micronutrients to include in the premix. Nine countries in Latin America, Africa, and Asia (three countries per region) that currently cofortify with multiple micronutrients including iron were selected based on low (< 75 g/day), medium (75 to 149 g/day), and high (> or = 150 g/day) mean population flour consumption levels. Premix costs per metric ton of flour produced were estimated for improving iron formulations and for following WHO recommendations for other micronutrients. For the selected programs to maintain current premix formulations and improve iron compounds, premix costs would increase by between 155% and 343% when the iron compound was switched from electrolytic iron to sodium iron ethylenediaminetetraacetate (NaFeEDTA), by 6% to 50% when it was switched from electrolytic iron to ferrous sulfate, and by 4% to 13 when iron addition rates were adjusted without switching the compound. To meet WHO recommendations for other micronutrients, premix costs would increase the most when the amounts of vitamins B12 and A were increased. For programs that currently cofortify with iron and additional micronutrients, the quality of the iron fortificant should not be overlooked simply to be able to afford to add more micronutrients to the premix. Micronutrients should be selected according to population needs, costs, and potential beneficial synergistic reactions the added micronutrients may have.

Clinical Outcomes After Insulin Initiation in Patients with Type 2 Diabetes: 24-Month Results from INSTIGATE

IntroductionTo examine changes in insulin regimens and glycemic control during the 24 months after initiation of insulin in patients with type 2 diabetes mellitus.MethodsData were collected over a 24-month period from patients requiring insulin initiation as part of usual care, in a prospective, observational study. Changes in insulin regimens and hemoglobin A1c (HbA1c) were examined within countries (Germany, Greece, Spain) and overall.ResultsPrandial insulin only was most commonly initiated in Germany, while basal or premixed formulations were initiated in Greece and Spain. In Germany, compared with Greece or Spain, the patients were slightly younger and had a shorter diabetes duration when initiating insulin. For patients overall, 76.1% did not change their insulin regimen between initiation and 24 months. The most obvious change was a shift from prandial to basal/bolus in Germany, with almost doubling of mean daily insulin dose; in Greece and Spain, more patients stopped using insulin and the trend to more complex regimens was not seen. Overall, mean (SD) HbA1c decreased from baseline (9.4 [1.7]%) to 6 months (7.2 [1.0]%), but with little further change through 24 months (7.2 [1.1]%). HbA1c change with basal/bolus insulin (−2.6 [2.0]%, baseline 10.1%) was greater than with basal only (−2.0 [1.8]%, baseline 9.3%). Mean HbA1c less than 7% was achieved and maintained over 24 months in Germany, but was not achieved at any time in Greece or Spain.ConclusionsWithin 24 months of insulin initiation, the majority of patients with type 2 diabetes remained on the same insulin regimen initially instigated, despite the well-established progressive loss of prandial and basal endogenous insulin secretion. Adequate glycemic control was best achieved where insulin dosage adjustments and insulin intensification took place.

Optimisation of polymer coating process for microencapsulating ferrous fumarate for salt double fortification with iodine and iron

An extrusion-based encapsulation process has been developed for making salt grain-sized iron premix for salt fortification. The first step of extrusion agglomeration process has been studied and reported previously. The focus of this study is on the optimisation of the colour-masking and polymer coating steps. Several colour-masking techniques and polymer encapsulants were investigated at various encapsulation levels. Salt samples prepared by blending the resulting iron premixes with iodised salt retained more than 90% of the original iodine and more than 93% of the ferrous iron after 3 months storage at 35°C and 60% relative humidity (RH). Hydrophilic coatings such as hydroxypropyl methyl cellulose (HPMC) offered more protection at the 10% encapsulation level compared to other coating materials studied. All iron premix formulations exhibited high particle density, good bioavailability and acceptable organoleptic properties. The process using the most effective formulations and optimised operation parameters is ready for pilot scale testing and field studies.

Persistence of insecticides in ready-mix formulations and their efficacy against Lipaphis erysimi (Kalt) in cauliflower

Persistence of cypermethrin, deltamethrin, profenofos, and triazophos in cauliflower curd was studied, following application of two premix formulations viz: Roket 44EC (profenofos 40% + cypermethrin 4%) and Anaconda Plus 36EC (triazophos 35% + deltamethrin 1%) at recommended (1.0L ha(-1)) and double doses (2.0L ha(-1)). In the case of Roket 44EC, residues of cypermethrin dissipated with the half-life values of 1.5-2.1days, whereas residues of profenofos dissipated with the half-life of 2.9-3.3days on cauliflower curd. In the case of Anaconda, residues of triazophos and deltamethrin dissipated from curd with the half-life values of 2.6-3.0 and 2.2-2.6days, respectively. Both the combination mix significantly reduced the aphid population up to 14days after spray and increased the yield by 155-160% over control. Anaconda (2.0L ha(-1)) treated plots yielded the highest number of marketable curds. Based on risk assessment analysis, safe waiting period of 3 and 5days has been suggested for Roket 44EC and Anaconda Plus 36EC, respectively, in cauliflower at recommended dose of application.

Intensifying Insulin Therapy with Insulin Analog Premixes: Transitioning from Basal Insulin in Type 2 Diabetes

Because of the progressive nature of type 2 diabetes, basal insulin alone may not be able to provide sufficient glycemic control over the long term, and thus insulin regimens will typically need to be intensified--especially for controlling postprandial glucose excursions. In patients with type 2 diabetes requiring more intensive intervention, insulin analog premix formulations can offer a simple, effective, and convenient option for tighter management of hyperglycemia in lieu of a traditional basal-bolus regimen.

EFFECTS OF DIFFERENT NUTRIENT FORMULATIONS SUPPLIED AT DIFFERENT CROP GROWTH STAGES ON YIELD IN BELL PEPPER (CAPSICUM ANNUUM L.) PLANTS GROWN IN STONEWOOL

Effects of fertigation with different pre-mixed fertilizers on growth, yield, leaf chlorophyll content and photosynthesis of bell pepper (Capsicum annuum L.) cultivar ‘California Wonder’ plants grown hydroponically in stonewool were investigated. Three different pre-mixed fertilizer formulations (Scotts Peters Professional water soluble fertilizer) were used: 20-20-20; 20-10-20; and 21-07-21 to provide NPK concentrations of (F1) 126-55-106; (F2) 256-55-214; and (F3) 385-55-321 mg/L respectively. P concentration (55 mg/L) and the ratio of N:K concentrations (1.2:1.0) were kept constant whilst N and K concentration trebled from F1 to F3. Fertigation regimes were applied according to plant physiological stage: (S1) vegetative stage, (S2) flowering stage, and (S3) fruiting stage. The experiment comprised of seven treatments replicated three times in a completely randomised design. Water and fertilizer solution was supplied automatically to the roots with five irrigation schedules per day (8:00; 10:00; 12:00; 14:00 and 16:00 h) and given similar volumes of nutrient solutions per irrigation event in each stage (6 min (S1), 8 min (S2) and 10 min (S3) daily. This study showed that fertigation with N and K gradually increasing from 126-106 to 265-214 and finally 385-321 mg/L (treatment 1) increased fruit yield of bell pepper significantly by 8% over the control. Higher yield in treatment 1 was associated with the higher leaf area, total dry matter production, number of fruits per plant and higher fertilizer-use efficiency.

Insulin lispro protamine suspension in the treatment of patients with type 1 and type 2 diabetes mellitus: a systematic review of published data

Introduction: Insulin lispro protamine suspension (ILPS) is a protamine-based insulin lispro formulation that allows 24-h coverage while limiting the number of daily injections. ILPS was developed to be the basal insulin component of premixed biphasic formulations with insulin lispro, i.e., the lispro/ILPS 25/75 and 50/50 mixed compounds, but has recently also been marketed as a basal insulin analog formulation, with an indication for the therapy of diabetic patients.Areas covered: This article reviews the available literature on pharmacokinetics/pharmacodynamics (PK/PD), efficacy and safety of ILPS administered as basal insulin, or in premixed biphasic formulations, in patients with type 1 and type 2 diabetes mellitus.Expert opinion: The results of this review suggest that ILPS may be associated with a favorable time–action profile, basal and postprandial glycemic control, and efficacy in terms of rates of patients reaching glycosylated hemoglobin targets; an increased risk of hypoglycemic episodes, compared to other basal insulins, seems to be related to the percentage of patients upgrading from once- to twice-daily injections. This increased risk might be linked with the concomitant use of insulin secretagogues in patients on higher daily dosages and is generally not observed in patients using one injection of ILPS a day. Thus, ILPS can be considered a valid option both as basal insulin and as basal component of the actual premixed formulations of lispro for the therapy of diabetic patients.

Nutrition therapy cost analysis in the US: pre-mixed multi-chamber bag vs compounded parenteral nutrition.

BackgroundBloodstream infections (BSI) occur in up to 350 000 inpatient admissions each year in the US, with BSI rates among patients receiving parenteral nutrition (PN) varying from 1.3% to 39%. BSI-attributable costs were estimated to approximate $US12000 per episode in 2000. While previous studies have compared the cost of different PN preparation methods, this analysis evaluates both the direct costs of PN and the treatment costs for BSI associated with different PN delivery methods to determine whether compounded or manufactured pre-mixed PN has lower overall costs.ObjectiveThe purpose of this study was to compare costs in the US associated with compounded PN versus pre-mixed multi-chamber bag (MCB) PN based on underlying infection risk.MethodsUsing claims information from the Premier Perspective™ database, multivariate logistic regression was used to estimate the risk of infection. A total of 44 358 hospitalized patients aged ≥18 years who received PN between 1 January 2005 and 31 December 2007 were included in the analyses. A total of 3256 patients received MCB PN and 41 102 received compounded PN. The PN-associated costs and length of stay were analysed using multivariate ordinary least squares regression models constructed to measure the impact of infectious events on total hospital costs after controlling for baseline and clinical patient characteristics.ResultsThere were 7.3 additional hospital days attributable to BSI. After adjustment for baseline variables, the probability of developing a BSI was 30% higher in patients receiving compounded PN than in those receiving MCB PN (16.1% vs 11.3%; odds ratio= 1.56; 95% CI 1.37, 1.79; p<0.0001), demonstrating 2172 potentially avoidable infections. The observed daily mean PN acquisition cost for patients receiving MCB PN was $US164 (including all additives and fees) compared with $US239 for patients receiving compounded PN (all differences p < 0.001). With a mean cost attributable to BSI of $US16 141, the total per-patient savings (including avoided BSI and PN costs) was $US1545.ConclusionIn this analysis of real-world PN use, MCB PN is associated with lower costs than compounded PN with regards to both PN acquisition and potential avoidance of BSI. Our base case indicates that $US1545 per PN patient may be saved; even if as few as 50% of PN patients are candidates for standardized pre-mix formulations, a potential savings of $US773 per patient may be realized.

Effect of loading dose and formulation on safety and efficacy of conivaptan in treatment of euvolemic and hypervolemic hyponatremia

The effect of loading dose and formulation on the safety and efficacy of conivaptan in the treatment of euvolemic and hypervolemic hyponatremia was studied. This parallel-group study randomized 121 hospitalized patients with euvolemic or hypervolemic hyponatremia to one of four treatment regimens: placebo loading dose followed by conivaptan continuous i.v. infusion using the ampul formulation (regimen 1), conivaptan loading dose followed by continuous i.v. infusion using the ampul formulation (regimen 2), placebo loading dose followed by conivaptan continuous i.v. infusion using the premixed formulation (regimen 3), or conivaptan loading dose followed by continuous i.v. infusion using the premixed formulation (regimen 4). The primary variable was the incidence and severity of injection-site reactions (ISRs), as evaluated using the ISR modified 5-point scale (ISRMS). Secondary outcomes included effects on serum sodium concentration (SSC), duration of effect, and safety and tolerability. All four dosing regimens were efficacious, safe, and well tolerated. No significant differences in ISRMS scores or differences in changes from baseline SSC or in the duration of effects on SSC were observed between the regimens. Overly rapid SSC increases occurred in 7%, 7%, 3%, and 21% of patients treated with regimens 1, 2, 3, and 4, respectively. Overall, adverse events related to general disorders and ISRs occurred in 39%, 43%, 53%, and 55% of patients receiving regimens 1, 2, 3, and 4, respectively. Intravenous conivaptan regimens with or without a loading dose, whether using the ampul or a premixed formulation, had similar safety, tolerability, and efficacy in patients with euvolemic or hypervolemic hyponatremia. The pre-mixed formulation used with a loading dose may be associated with an increased frequency of overly rapid increase in SSC compared with the other regimens studied.

Clinical outcomes after insulin initiation in patients with type 2 diabetes: 6-month data from the INSTIGATE observational study in five European countries

Objectives:To examine insulin regimens and factors that affect glycaemic control at 6 months after initiation of insulin therapy in patients with type 2 diabetes mellitus.Research design and methods:Information on patients requiring insulin initiation as part of usual care was collected in a prospective, observational, open-label study in five European countries. Univariate and multiple regression analyses were used to investigate factors associated with HbA1c achieved at 6 months.Results:Mean HbA1c for all patients at baseline was 9.6 ± 1.8%. Long/intermediate-acting insulin only was most commonly initiated in France and Spain, while long/intermediate or pre-mixed formulations were initiated in Greece and UK. This was consistent with guidelines used in those countries and there was little change in insulin regimen at 6 months in these countries. In Germany, short-acting insulin only was favoured at baseline and there was a shift towards basal/bolus regimens at 6 months, which reflected the local guidelines for insulin initiation in Germany. Mean HbA1c reduction was greatest in Germany (−2.3%), which was the only country to achieve a mean of <7% at 6 months. In all countries, HbA1c achieved at 6 months was associated with baseline HbA1c. Differences between countries were seen for influence of factors such as BMI, duration of diabetes, insulin regimen, insulin dose and number of oral anti-diabetes drugs on HbA1c achieved. Explained variability for the factors ranged from 5.6% to 22.9%.Conclusions:Differences in insulin regimen were observed between countries, and appeared to reflect the guidelines and treatment regimens used.

Dissipation of cypermethrin, chlorpyriphos, and profenofos in tomato fruits and soil following application of pre-mix formulations

Persistence of cypermethrin, chlorpyriphos, and profenofos in tomato and soil were studied following application of two pre-mix formulations of insecticides viz. Roket 44EC (profenofos 40% + cypermethrin 5%) and Action-505EC (chlorpyriphos 50% + cypermethrin 5%) at recommended (0.8-1.0 L ha(-1)) and double dosage (1.6-2.0 L ha(-1)). In all the treatments residues persisted beyond 7 days in tomato fruits. Half-life values were calculated from first-order dissipation kinetics. In the case of Roket 44EC, residues of cypermethrin on fruits dissipated with half-life of 2.0-3.6 days, whereas residues of profenophos dissipated with the half-life of 2.2-5.4 days. In the case of Action-505EC, residues of chlorpyriphos and cypermethrin dissipated from fruits with the half-life values of 2.9-3.3 and 2.5-4.8 days, respectively. In soil, residues of profenofos persisted for 7-15 days, whereas residues of chlorpyrophos and cypermethrin persisted for 0-7 days only.

Mid‐ and high‐ratio premix insulin analogues: potential treatment options for patients with type 2 diabetes in need of greater postprandial blood glucose control

Some patients with type 2 diabetes continue to have high postprandial blood glucose levels on twice-daily regimens of 'low-ratio' premix insulin formulations (up to 30% rapid-acting, with 70% protracted insulin). These patients require intensified insulin therapy, which can be provided by a twice- or thrice-daily regimen of mid-ratio (50% rapid-acting and 50% protaminated intermediate-acting insulin - human or analogue) or high-ratio (70% rapid-acting and 30% protaminated insulin - analogue only) premix insulin. Alternatively, a third daily injection of low-ratio premix insulin can be added to the regimen, with the option of incorporating one or more injections of mid- or high-ratio premix as required, and as an alternative to basal-bolus therapy. How these mid- and high-ratio formulations differ from the low-ratio premix insulins is reviewed here, with the aim of identifying the role of these formulations in diabetes management. Glucose clamp studies have shown that premix analogues give serum insulin levels proportional to their percentage of rapid-acting uncomplexed insulin: the higher the proportion, the greater the maximum level reached. Other pharmacokinetic parameters were not always significantly different between the mid- and high-ratio formulations. In clinical trials, postprandial plasma glucose and glycated haemoglobin A1c (HbA(1c)) levels were significantly reduced with thrice-daily mid- /high-ratio premix analogue when compared with twice-daily low-ratio biphasic human insulin (BHI) 30/70 or once-daily insulin glargine. Moreover, glycaemic control with mid-/high-ratio premix analogue was found to be similar to that with a basal-bolus therapy. Mid- and high-ratio premix regimens are generally well tolerated. The frequency of minor hypoglycaemia was reportedly higher with mid- /high-ratio premix analogues than with BHI 30, but nocturnal hypoglycaemia was less frequent. Although there is little evidence that clinical outcomes with mid-ratio premix analogues are different from those with high-ratio, they are useful additions to the low-ratio formulations for the management of diabetes, and addressing postprandial hyperglycaemia in particular.

High-mix analogue insulins: do they have a therapeutic role?

It is estimated that 39% of diabetic patients worldwide that use insulin therapy are prescribed premixed insulin formulations, largely because of the practical advantages of addressing both prandial and basal insulin needs with a single product. High-mix insulin analogues are a relatively little used therapy and this paper explores their role in the management of diabetes. There is a paucity of research on their clinical efficacy and safety with regards to hypoglycaemia and we conclude that in certain patients they can be helpful for difficult-to-control postprandial hyperglycaemia, but there are no long-term outcome studies to assess whether this has an impact on cardiovascular outcomes and the current gold standard of insulin therapy still remains a basal bolus regimen. Br J Diabetes Vasc Dis 2009;9:166—170

Frozen delivery of brushite calcium phosphate cements

Calcium phosphate cements typically harden following the combination of a calcium phosphate powder component with an aqueous solution to form a matrix consisting of hydroxyapatite or brushite. The mixing process can be very important to the mechanical properties exhibited by cement materials and consequently when used clinically, since they are usually hand-mixed their mechanical properties are prone to operator-induced variability. It is possible to reduce this variability by pre-mixing the cement, e.g. by replacing the aqueous liquid component with non-reactive glycerol. Here, for the first time, we report the formation of three different pre-mixed brushite cement formulations formed by freezing the cement pastes following combination of the powder and liquid components. When frozen and stored at −80 °C or less, significant degradation in compression strength did not occur for the duration of the study (28 days). Interestingly, in the case of the brushite cement formed from the combination of β-tricalcium phosphate with 2 M orthophosphoric acid solution, freezing the cement paste had the effect of increasing mean compressive strength fivefold (from 4 to 20 MPa). The increase in compression strength was accompanied by a reduction in the setting rate of the cement. As no differences in porosity or degree of reaction were observed, strength improvement was attributed to a modification of crystal morphology and a reduction in damage caused to the cement matrix during manipulation.

Comparison of the pharmacokinetic and pharmacodynamic profiles of biphasic insulin aspart 50 and 30 in patients with type 2 diabetes mellitus: A single-center, randomized, double-blind, two-period, crossover trial in Japan

Background:To overcome the complicated mixing procedures required in the use of insulin formulations, premixed formulations consisting of rapid-acting and intermediate-type insulin in various mixing proportions have been developed. Biphasic insulin aspart 50 (BIAsp50) and 30 (BlAsp30) are 2 premixed formulations containing the active ingredient insulin aspart (IAsp) and consisting of a rapid-acting component soluble IAsp) and intermediate-acting component (protamine-crystallized protracted IAsp) in ratios of 50/50 and 30/70, respectively. These formulations are provided with the expectation that BIAsp30 and BIAsp50 will be beneficial for patients needing to improve their postprandial blood glucose control without changing their dietary habits and lifestyles. BIAsp30 has been widely used in medical practice, whereas BIAsp50 is being investigated in clinical trials. Objective:The aim of this study was to compare the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of BIAsp50 (test) and BIAsp30 (reference) after single-dose SC injection in patients with type 2 diabetes mellitus. Methods:This single-center, randomized, doubleblind, 2-period, crossover trial was conducted at the H.E.C. Science Clinic, Yokohama, Japan. Male and female patients aged ≥20 years with a ≥ 1-year history of type 2 diabetes were eligible. Patients were randomly assigned to 1 of 2 treatment sequences: group A received BIAsp30 in period 1 and BIAsp50 in period 2; group B received BIAsp50 in period 1 and BIAsp30 in period 2. All treatments were administered as an SC injection of a single dose (0.3 U/kg). The study periods were separated by a washout period of 4 to 21 days. For PK analysis of IAsp (maximum serum IAsp concentration [Cmax,IAsp; primary end point], AUC of serum IAsp 0 to 120, 240, and 480 minutes after administration [AUC0–120 min,IAspl, AUC0–240 min,IAsp, and AUC0–480 min,IAsp5 respectively], and time to Cmax,IAsp [Tmax,IAsp] ), blood samples were drawn immediately before (baseline) and at prespecified time points over 480 minutes after administration. The PD profiles of BIAsp50 and BIAsp30 were also examined by comparing the time course of the glucose infusion rate (GIR) using the euglycemic clamp technique. The PD end points were AUC of GIR 0 to 120 minutes after administration (AUC0–120 min,GIR), maximum GIR (GIRmax), and time to GIRmax (Tmax,GIR). Tolerability was assessed using physical examination, including vital sign measurement, electrocardiography, body weight, adverse events (AEs), and clinical laboratory analysis (hematology and serum biochemistry). Results:Six men and 4 women were enrolled in the study (mean age, 62.4 years; mean body weight, 58.3 kg; mean body mass index, 22.22 kg/m2; mean duration of diabetes, 9.53 years; and mean glycosylated hemoglobin concentration, 6.07%). MeanCmax,IAsp with BIAsp50 was 63% higher than that for BIAsp30 (P < 0.002). The BIAsp50/BIAsp30 ratio with AUC0–120 min,IAsp was 1.68 (95% CI, 1.31–2.14). The BIAsp50/BIAsp30 ratiofor AUC0–120 min,GIR was 1.31 (95% CI, 1.02–1.68). A total of 9 AEs were reported in 5 patients, but none of the AEs were considered related to the study drug. Conclusion:In this small PK/PD study in adults with type 2 diabetes in Japan, mean Cmax,IAsp was significantly higher with BIAsp50 than with BIAsp30, and AUC0–120 min,IAsp and AUC0–120 min,GIR were higher with BIAsp50 than with BIAsp30.