Fluctuations In Plasma Concentrations Research Articles

Revolutionizing Nitrofurantoin Delivery: Unraveling Challenges and Pioneering Solutions for Enhanced Efficacy in UTI Treatment

Abstract: Nitrofurantoin is an antimicrobial drug, highly effective in the treatment of critical or chronic bacterial infections of the urinary tract, and hence, it is the first line choice of drug for the treatment of urinary tract infections (UTI). Although the molecule is legacy in nature, there are many challenges in terms of drug product formulation and efficacy thereof. The authors are main-ly focused in this literature review on, but not limited to, understanding the molecule in terms of physico-chemical properties of the drug, pharmacokinetics and pharmacodynamics, approved and withdrawn formulations, challenges concerning drug formulation, the cause of drug shortage in the market, improvement areas in terms of formulation and its therapeutic effectiveness. The au-thors found during their widespread review that the major challenge in the existing conventional drug delivery system of nitrofurantoin is the fluctuation of plasma concentration owing to its var-iability in drug absorption. Further, they understood that the variability in absorption is due to in-herent variability in particle size distribution. Based on the findings, authors also explored the possibilities to deliver the drug in novel drug delivery systems such as nano self-emulsifying emulsions, nanoemulsions and multiple emulsions where the drug can be presented in soluble form and hence the variability in absorption and fluctuation in plasma concentration of drug can be avoided and described briefly the salient features of each drug delivery in this review.

Advancements and challenges in pharmacokinetic and pharmacodynamic research on the traditional Chinese medicine saponins: a comprehensive review.

Recent research on traditional Chinese medicine (TCM) saponin pharmacokinetics has revealed transformative breakthroughs and challenges. The multicomponent nature of TCM makes it difficult to select representative indicators for pharmacokinetic studies. The clinical application of saponins is limited by their low bioavailability and short half-life, resulting in fluctuating plasma concentrations. Future directions should focus on novel saponin compounds utilizing colon-specific delivery and osmotic pump systems to enhance oral bioavailability. Optimizing drug combinations, such as ginsenosides with aspirin, shows therapeutic potential. Rigorous clinical validation is essential for practical applications. This review emphasizes a transformative era in saponin research, highlighting the need for clinical validation. TCM saponin pharmacokinetics, guided by traditional principles, are in development, utilizing multidisciplinary approaches for a comprehensive understanding. This research provides a theoretical basis for new clinical drugs and supports rational clinical medication.

Intraoperative methadone for day-case gynaecological laparoscopy: A double-blind, randomised controlled trial.

Optimal pain relief in day-case surgery is imperative to patient comfort and timely discharge from hospital. Short-acting opioids are commonly used for analgesia in modern anaesthesia, allowing rapid recovery after surgery. Plasma concentration fluctuations from repeated dosing of short-acting opioids can cause patients to oscillate between analgesia with potential adverse effects, and inadequate analgesia requiring rescue dosing. Methadone's unique pharmacology may offer effective and sustained analgesia with less opioid consumption, potentially reducing adverse effects. Using a double-blind, randomised controlled trial, we compared post-anaesthesia care unit opioid consumption between day-case gynaecological laparoscopy patients who received either intravenous methadone (10 mg), or short-acting opioids intraoperatively. The primary outcome was post-anaesthesia care unit opioid consumption in oral morphine equivalents. Secondary outcomes included total opioid consumption, discharge opioid consumption, pain scores (0-10) until discharge, adverse effects (respiratory depression, postoperative nausea and vomiting, excess sedation), and rate of admission. Seventy patients were randomly assigned. Patients who received methadone consumed on average 9.44 mg fewer oral morphine equivalents in the post-anaesthesia care unit than the short-acting group (18.02 mg vs 27.46 mg, respectively, 95% confidence interval 0.003 to 18.88, P = 0.050) and experienced lower postoperative pain scores at every time point, although absolute differences were small. There was no evidence of lower hospital or discharge opioid consumption. No significant differences between the methadone and short-acting groups in other outcomes were identified: respiratory depression 41.2% versus 31.4%, Padjusted >0.99; postoperative nausea and vomiting 29.4% versus 42.9%, Padjusted >0.99; overnight admission 17.7% versus 11.4%, Padjusted >0.99; excess sedation 8.82% versus 8.57%, Padjusted >0.99. This study provides evidence that, although modestly, methadone can reduce post-anaesthesia care unit opioid consumption and postoperative pain scores after day-case gynaecological laparoscopy. There were no significant differences in any secondary outcomes.

Design and Characterization of Hallow Porous Floating Microspheres of Favipiravir

The present investigation deals with the design and characterization of favipiravir floating microspheres for gastro retentive drug delivery system by employing 3² factorial design and also to investigate the main effects of different independent variables on microspheres that float. The emulsion solvent diffusion method was used to manufacture floating microspheres with Eudragit S 100 as the polymer. These microspheres will extend the release of the medicine, reducing the frequency of administration and the harmful effects caused by fluctuations in plasma concentration with conventional dosage forms. The main effect of independent variables like polymer Eudragit S 100 concentrations (50, 100, 150 mg) and stirring time (1, 2 and 3 hours) on the performance of microspheres. Formulated microspheres were characterized for responses including drug release, particle size, and entrapment efficiency and floating time. Based on the results of the responses, the optimized composition was arrived using the response surface method graphical and numerical optimization method using design of experiments (DoE) software. Then, the optimized formulation (OFES) was prepared and evaluated for the four responses compared with predicted values to find the validity of the selected model. The optimized formulation was further analyzed for drug-excipient compatibility by fourier-transform infrared (FTIR), differential scanning calorimetry (DSC), and also analyzed by X-ray diffraction (XRD), scanning electron microscope (SEM) analysis. Further zeta potential and micrometric properties were also observed. The results for the formulation FES 1 to 9 found were, that particles size ranged from 0.192 to 0.277 μm, entrapment efficiency ranged from 68.65 ± 1.9 to 76.25 ± 3.2%, percentage drug release range was from 89.25 ± 0.24 to 93.68 ± 0 .25%, and floating time range was from 12 to 23 hours. As per the design, OFES an optimized formulation fitted with the concentration of Eudragit S 100 of 139.1 mg and stirring time of 1-hour. Regarding the kinetic release, the responses were best fitted with Higuchi model of R² value of 0.9795 with kinetic mechanism of non-fickian diffusion with R² value of 0.9499, indicating good linearity. The combination of different variables and their effects on responses were investigated well using factorial design, and an optimized formulation was developed for favipiravir.

Association Between Clozapine Plasma Concentrations and Treatment Response: A Systematic Review, Meta-analysis and Individual Participant Data Meta-analysis.

Although therapeutic drug monitoring of clozapine is recommended, its optimisation is often adjusted only on the basis of dosage. The aim of this study was to assess the link between clozapine plasma concentrations and clinical response by a meta-analysis of published studies and by an individual participant data meta-analysis. We conducted a computerised search of bibliographic databases (EMBASE, PubMed, Clinical Trials, and Web of Science) to identify studies that assessed the relationship between clozapine serum or plasma concentrations and clinical efficacy. Using pooled data, we investigated the association between improvement of clinical outcome and clozapine or norclozapine plasma concentrations, the sum of clozapine and norclozapine plasma concentrations, and the coefficient of variation of clozapine plasma concentrations. Using available individual data, we assessed the relationship between clozapine plasma concentrations and clinical response (changes in the Brief Psychiatric Rating Scale score) and identified a threshold level for a favourable clinical response. Fifteen studies satisfied inclusion criteria. Our meta-analysis showed that responders had clozapine plasma concentrations that were, on average, 117 ng/mL higher than non-responders. The patients with plasma clozapine concentrations above the thresholds identified in each study had a higher likelihood of responding (odds ratio = 2.94, p < 0.001). Norclozapine plasma concentrations were not associated with a clinical response. The meta-analysis of individual data supported this result and confirmed the link between clozapine concentrations and a change in the Brief Psychiatric Rating Scale score and/or the probability of clinical response. Finally, with the analysis of the coefficient of variation of clozapine plasma concentrations, we found that a greater inter-individual fluctuation in plasma concentrations was associated with a loss of clinical response. Our work confirmed that, in contrast to clozapine doses, clozapine plasma concentrations were related to a favourable clinical response, with a mean difference between responders and non-responders of 117 ng/mL. A threshold for a treatment response of 407 ng/mL was determined, with a high discriminatory capacity,and a sensitivity and specificity of 71% and 89.1%, respectively.

87 Awardee Talk: Frequency of Energy Supplementation Modulates Growth, Reproduction, Immune Function, and Fetal Programming in Beef Cattle

Abstract Fluctuations in nutrient intake and metabolism can be detrimental to beef cattle performance. Multiple studies evaluated the impacts of reducing the frequency of energy supplementation from daily (7X) to once (1X) or 3 times (3X) weekly during heifer development, calf preconditioning, and late gestation of beef cows on growth, reproduction, immune function, and progeny performance. Reducing the supplementation frequency from 7X to 3X weekly: (1) did not impact average daily gain (ADG; P = 0.52) but hastened (P ≤ 0.05) puberty and pregnancy attainment of beef heifers; and (2) reduced ADG (P = 0.02), increased (P ≤ 0.03) plasma indicators of physiological stress (cortisol and haptoblogin), and decreased (P ≤ 0.05) humoral immune response against pathogens associated with bovine respiratory disease (BRD) in preconditioning beef steers. Reducing the supplementation frequency from 7X to either 3X or 1X weekly during late gestation did not (P ≥ 0.21) impact cow prepartum body condition score and reproduction, but linearly decreased (P = 0.05) calf preweaning growth. The negative effects of infrequent energy supplementation may be attributed to greater fluctuations in plasma concentrations of insulin growth factor-1, glucose, insulin, and urea nitrogen compared to frequent energy supplementation. Later attempts to offset such negative effects of infrequent supplementation observed that neither increasing the supplementation amount (P ≥ 0.21) nor altering the timing of vaccination relative to weaning (P ≥ 0.12) prevented performance reductions in beef cattle supplemented infrequently. Only a gradual reduction in supplementation frequency for preconditioning calves prevented a reduction on growth and improved (P ≤ 0.05) the immune response against BRD pathogens. Combined, these results revealed that frequent energy supplementation during preconditioning of beef steers, development of replacement beef heifers, and late gestation of beef cows was required to optimize their growth, immunity, and reproduction, and the growth performance of their progeny.

Applying pharmacokinetic/pharmacodynamic measurements for linezolid in critically ill patients: optimizing efficacy and reducing resistance occurrence

PurposeLinezolid (LZD) levels are frequently insufficient in intensive care unit (ICU) patients receiving standard dose, which is predictive of a poor prognosis. Alternative dosing regimens are suggested to address these insufficient levels, which are substantial factors contributing to the emergence of multidrug-resistant bacteria, resulting in increased morbidity and mortality among people who are critically ill.MethodsForty-eight patients admitted to the intensive care unit were enrolled in an open-label, prospective, randomized study and assigned to one of three LZD administration modes: intermittent groupI (GpI) (600 mg/12 h), continuous infusion groupII (GpII) (1200 mg/24 h) or continuous infusion with loading dose groupIII (GpIII) (on Day 1, 300 mg intravenously plus 900 mg continuous infusion, followed by 1200 mg/24 h on Day 2). We evaluated serum levels of LZD using a validated ultra-performance liquid chromatography (UPLC) technique.ResultsTime spent with a drug concentration more than 85% over the minimum inhibitory concentration (T > MIC) was substantially more common in GpII and III than in GpI (P < 0.01). AUC/MIC values greater than 80 were obtained more frequently with continuous infusion GpIII and GpII than with intermittent infusion GpI, at 62.5%, 37.5% and 25%, respectively (P < 0.01). In GpI, the mortality rate was significantly higher than in the other groups.ConclusionIn critically ill patients, continuous infusion with a loading dose (GpIII) is obviously superior to continuous infusion without a loading dose (GpII) or intermittent infusion (GpI) for infection therapy. Additionally, it might limit fluctuations in plasma concentrations, which may help overcome LZD resistance.

A REVIEW ON MICROSPHERES AS A NOVEL CONTROLLED DRUG DELIVERY SYSTEM

Over the past three decades, controlled drug delivery systems have become more developed and play a key role in pharmaceuticals formulations. There are many shortcomings in Traditional or Conventional drug delivery systems like for maintaining desired therapeutic drug plasma concentration there is a need for frequent dosing for particular drugs having shorter half-lives. Furthermore, because of frequent dosing requirement, there is poor patient compliance which causes fluctuation in plasma concentration of the drug. The limitations of conventional drug delivery can be overcome by the development of novel drug delivery systems, of which the controlled drug delivery can maintain constant drug plasma concentration by slowly releasing the drug over an extended period. Developing controlled drug delivery systems can also improve the systemic bioavailability of the drug, thus enhancing the therapeutic efficacy of the drug and better patient compliance. There are many different approaches for such controlled delivery systems such as liposomes, niosomes, ethosomes, phytosomes, microemulsion, and microspheres. Among all the approaches microspheres are more convenient as the drug is slowly released from the polymeric matrix and the polymers used are mostly biodegradable and possess no side effects. Therefore, microspheres can be used in various medicinal departments such as oncology, gynecology, radiology, pulmonary, cardiology, diabetes, and vaccine therapy. This review article focuses on recent different types of microspheres along with their methods of preparation. The microspheres formulated can be later evaluated and characterized by different procedures.

Effect of a New Lithium Preparation on the Behavior of CBA/CaLac Mice in an Experimental Conflict Model.

The use of lithium drugs in clinical practice requires constant monitoring of lithium plasma concentration, because toxicity is sometimes observed at therapeutic concentrations of lithium. This is often associated with fluctuations of plasma concentration of lithium ions after intake of individual doses. Therefore, the use of a porous carrier providing a stable blood level of the drug is extremely promising and important for clinical practice. We studied activity of a new lithium drug (lithium complex) consisting of aluminum-silicon base and lithium citrate immobilized on its surface. Lithium carbonate served as the reference drug. It was shown that lithium carbonate and lithium complex exhibited no anxiolytic activity in the conflict model, but produced an antidepressant effect and improved exploratory behavior of animals.

Metabolomics Evaluation of Patients With Stage 5 Chronic Kidney Disease Before Dialysis, Maintenance Hemodialysis, and Peritoneal Dialysis.

ObjectiveCurrent treatment options for patients with stage 5 chronic kidney disease before dialysis (predialysis CKD-5) are determined by individual circumstances, economic factors, and the doctor’s advice. This study aimed to explore the plasma metabolic traits of patients with predialysis CKD-5 compared with maintenance hemodialysis (HD) and peritoneal dialysis (PD) patients, to learn more about the impact of the dialysis process on the blood environment.MethodsOur study enrolled 31 predialysis CKD-5 patients, 31 HD patients, and 30 PD patients. Metabolite profiling was performed using a targeted metabolomics platform by applying an ultra-high-performance liquid chromatography-tandem mass spectrometry method, and the subsequent comparisons among all three groups were made to explore metabolic alterations.ResultsCysteine metabolism was significantly altered between predialysis CKD-5 patients and both groups of dialysis patients. A disturbance in purine metabolism was the most extensively changed pathway identified between the HD and PD groups. A total of 20 discriminating metabolites with large fluctuations in plasma concentrations were screened from the group comparisons, including 2-keto-D-gluconic acid, kynurenic acid, s-adenosylhomocysteine, L-glutamine, adenosine, and nicotinamide.ConclusionOur study provided a comprehensive metabolomics evaluation among predialysis CKD-5, HD, and PD patients, which described the disturbance of metabolic pathways, discriminating metabolites and their possible biological significances. The identification of specific metabolites related to dialysis therapy might provide insights for the management of advanced CKD stages and inform shared decision-making.

Formulation and optimization of captopril-loaded microspheres based compressed tablets: in vitro evaluation

The core objective of this work was to formulate compressed tablets containing captopril-loaded microspheres for controlled delivery. Captopril is rapidly absorbed orally and has a bioavailability of ∼75%. The duration of action after a single oral dose is 6–8 h. Due to its relatively short half-life, a controlled released captopril formulation would bring benefits to patients, including reduction in frequency of administration, increased patient compliance and effectiveness of treatment, reduction in plasma concentration fluctuations, as well as a reduction in side effects. Double emulsification technique accompanied by solvent evaporation was employed for manufacturing captopril-loaded microspheres. Developed polymeric carriers were characterized for particle size analysis, entrapment efficiency, DSC, TGA, XRD, EDS, SEM, swelling index, and release studies. Microspheres have displayed spherical geometry and a size within micrometric range. They have shown high encapsulation efficiency (95%) at polymer to drug ratio (1:5:5). All the ingredients were compatible with each other. Optimized formulation ST1 has depicted zero-order drug release.

Supplementation frequency and amount modulate postweaning growth and reproductive performance of Bos indicus-influenced beef heifers.

This 2-yr study evaluated the growth and puberty attainment of Bos indicus-influenced beef heifers offered 2 different postweaning concentrate supplementation amounts and delivery frequencies. On day 0 of each year, 64 Brangus crossbred heifers were stratified by initial body weight (BW) and age (mean = 244 ± 22 kg; 314 ± 17 d) and assigned into 1 of 16 bahiagrass pastures (4 heifers/pasture/yr). Treatments were randomly assigned to pastures in a 2 × 2 factorial design (4 pastures/treatment/yr) and consisted of concentrate dry matter (DM) supplementation at 1.25% or 1.75% of BW which were offered either daily (7×) or 3 times weekly (3×) for 168 d. On day 56 of each year, heifers were assigned to an estrus synchronization protocol consisting of intravaginal controlled internal drug release (CIDR) insertion on day 56, CIDR removal on day 70, i.m. injection of 25 mg of prostaglandin F2α (PGF2α) on day 86, and i.m. injection of 100 µg of gonadotropin-releasing hormone and timed-AI at 66 h after PGF2α injection (day 89). Heifers were exposed to Angus bulls from day 89 to 168 (1 bull/pasture). Pregnancy diagnosis was assessed on day 213 of each year. Supplementation amount × frequency effects were not detected (P ≥ 0.12) for any variable, except for plasma concentrations of glucose (P = 0.10) and urea nitrogen (PUN; P = 0.01). Herbage mass, herbage allowance, and nutritive value did not differ (P ≥ 0.12) among treatments. Increasing supplementation DM amount from 1.25% to 1.75% of BW increased (P ≤ 0.05) plasma concentrations of insulin-like growth factor 1 (IGF-1), overall average daily gain (ADG), final BW, percentage of pubertal heifers on day 89, pregnancy and calving percentages, and percentage of heifers calving within the first 21 d of the calving season. However, reducing the supplementation frequency from daily to 3× weekly, regardless of supplementation amount, did not impact overall pregnancy and calving percentages (P ≥ 0.42), but caused (P ≤ 0.05) fluctuations in plasma concentrations of insulin and IGF-1 and decreased (P ≤ 0.03) overall ADG, final BW, puberty attainment on days 56, 89, and 168, and percentage of heifers calving during the first 21 d of the calving season. Hence, increasing the supplement DM amount did not prevent the negative effects of reducing the frequency of supplementation (3× vs. 7× weekly) on growth and reproduction of replacement Bos indicus-influenced beef heifers.

Self-regulating naturally occurring microcapsules for controlled release of Levodopa

Levodopa remains the gold standard treatment for patients suffering with Parkinson’s disease. Patients can become sensitive to fluctuations in plasma concentration of the drug, resulting in devastating side effects. This present paper reports the encapsulation of LV into sporopollenin exine microcapsules prepared in-house from Lycopodium Clavatum plant. The loaded sporopollenin exine microcapsules were prepared by removing the cellulosic intine, and then filling the internal cavity surrounded by the sporopollenin exine with a concentrated solution of LV. The trapped drug was then precipitated inside the microcapsules using pH change, followed by a thorough washing. The released amount of the drug in aqueous media resembling physiological conditions of human blood plasma was then quantified using UV-Vis spectrophotometer. The results showed that LV can be successfully encapsulated within the sporopollenin exine microcapsules, and a sustained release of the drug can be achieved. This paper also shows that the microcapsules loaded with the drug can act as a self-regulating device to release the drug in aqueous medium over a longer period.

Levodopa/carbidopa intestinal gel in treatment of non-motor symptoms in advanced Parkinson's disease

To identify the advantages of LCIG in the treatment of NMS among APD patients and appraise the currently available literature to identify the gaps in the available evidence. background:Levodopa is the most commonly used drug for the treatment of motor symptoms of Parkinson's Disease (PD). For managing non-motor symptoms (NMS) in advanced Parkinson's disease (APD), levodopa-carbidopa intestinal gel (LCIG) infusion is preferred over oral levodopa-carbidopa because it bypasses the gastrointestinal tract and overcomes fluctuation and variation in the plasma drug levels. Levodopa is the most commonly used drug for the treatment of motor symptoms of Parkinson's Disease (PD). For managing non-motor symptoms (NMS) in advanced Parkinson's disease (APD), levodopa-carbidopa intestinal gel (LCIG) infusion is preferred over oral levodopa-carbidopa because it bypasses the gastrointestinal tract and overcomes fluctuation and variation in the plasma drug levels. LCIG has been found to be beneficial in improving or relieving various NMS. (central nervous system symptoms, cardiovascular system symptoms, gastrointestinal tract symptoms, systemic symptoms, urinary symptoms, reproductive system symptoms) in patients with APD. LCIG provides an uninterrupted intestinal levodopa infusion by percutaneous endoscopic gastrojejunostomy (PEG-J). It effectively decreases fluctuations in plasma concentrations of levodopa, reduces NMS burden and motor fluctuations in APD, however; adequate dose modification and individualization of therapy are essential for optimal effect.

Sustained Release Bilayer Tablet of Ibuprofen and Phenylephrine Hydrochloride: Preparation and Pharmacokinetics in Beagle Dogs.

Cold is a global common infectious disease accompanied by symptoms such as headache and stuffy nose. Ibuprofen (IBU) and phenylephrine hydrochloride (PE) were commonly used for common cold due to their different effects in relieving fever and the main symptoms such as nasal congestion and high sinus pressure. However, the commercial tablets of IBU and PE have to be administered 2 to 3 times per day due to their short half-life, with inconvenience for patient and fluctuations of plasma concentration. Bilayer tablet technology was utilized to design the IBU-PE sustained release tablets because of the significantly different solubility of IBU and PE in release media. The formulations of IBU layer and PE layer contain different viscosity grades of hydroxypropyl methylcellulose (HPMC) as sustained-release matrix, hydrophilic diluent, and traditional glidant and lubricant. The sustained release bilayer tablet exhibited satisfying sustained release performance with the mechanisms of diffusion and matrix erosion. Compared with the conventional tablets, the IBU-PE sustained release bilayer tablet expressed significantly sustained-release behavior with decreased Cmax and prolonged Tmax in fasted conditions for IBU and PE. Though IBU of IBU-PE sustained release bilayer tablet was bioequivalent to the commercial IBU tablet, the relative bioavailability of PE from the bilayer tablets was 87.49 ± 20.00% (90% confidence interval was 72.3 to 102.5%), indicating bioinequivalence probably due to the "first pass" effect.

Contact dermatitis due to transdermal therapeutic systems: a clinical update.

Transdermal therapeutic systems (TTS) have become a popular method of drug delivery because they allow drugs to be delivered in a rate-controlled manner, avoiding first-pass metabolism and the fluctuating plasma concentrations encountered with oral medications. Unfortunately, TTS may provoke adverse skin reactions as irritating contact dermatitis and allergic contact dermatitis: TTS seem to be ideally suited to produce sensitization because they cause occlusion, irritation, due to the repeated placement of the allergen in the same skin location. Since TTS consist of an adhesive, an active pharmaceutical drug and enhancing agents, sensitization may develop owing to one of these three agents. The purpose of this manuscript is to review known responsible allergens of contact dermatitis due to TTS. (www.actabiomedica.it)

Pharmacokinetics and safety/efficacy of levodopa pro-drug ONO-2160/carbidopa for Parkinson's disease.

We conducted a phase I study investigating the efficacy, safety, and tolerability of ONO-2160, a newly developed levodopa pro-drug, and carbidopa compared with levodopa and carbidopa to stabilize levodopa plasma concentration fluctuations in Japanese patients with Parkinson's disease. In an open-label two-period design, patients (n = 12) with Parkinson's disease received levodopa and carbidopa for 3 days before 7 days of treatment with ONO-2160 and carbidopa. Patients were primarily evaluated using the Unified Parkinson's Disease Rating Scale Part III, a Parkinson's disease symptom diary, and analysis of adverse events. Pharmacokinetic analysis of plasma levodopa concentration was also performed.ONO-2160 and carbidopa therapy stabilized effective plasma levodopa concentration. No adverse events with safety concerns were observed. The combination of ONO-2160 and carbidopa produced a prolonged and stable plasma levodopa concentration with a reduction in Unified Parkinson's Disease Rating Scale Part III total scores. The combination was well tolerated, with no safety concerns, when administered to Japanese patients with Parkinson's disease.

Double-layered osmotic pump controlled release tablets of actarit: In vitro and in vivo evaluation

The aim of the study was to develop actarit double-layered osmotic pump tablets to overcome the weak points of actarit common tablets, such as short half-life and large plasma concentration fluctuations. Single factor experiment and orthogonal test were applied to optimize the formulation; the pharmacokinetic study was performed in beagle dogs adopting actarit common tablets as reference tablets. The optimal formulation was as follows: drug layer: 150 mg actarit, 240 mg PEO-N80, 50 mg NaCl; push layer: 140 mg PEO-WSR303, 20 mg NaCl; coating solution: 30 g cellulose acetate and 6 g PEG 4000 in 1000 ml 94% acetone solution, 60 mg coating weight gain. The pharmacokinetic study showed that Tmax was prolonged by the contrast of commercial common tablets with constant drug release rate, but the bioavailability was equivalent. And a good in vivo–in vitro correlation of the actarit osmotic pump tablets was also established. The designed actarit osmotic pump tablets can be applied for rheumatoid arthritis, proposing a promising replacement for the marked common products.

Design and in vivo pharmacokinetic study of a newly developed lamivudine transdermal patch

The aim of this study was to formulate a soft and easy to handle matrix-type transdermal patch consisting of a simple and cost-effective monolithic polymeric film as an attempt to deliver lamivudine (LAM) transdermally and overcome the problems associated with its biological short half-life and fluctuations in plasma concentration upon oral administration.First, LAM-polymer compatibilities between LAM and three polymers; methylcellulose (MC), sodium alginate (SA) and chitosan (CS) were studied using Fourier transform infrared (FT-IR) and differential scanning calomerty (DSC). Placebo polymeric monolithic films were prepared using MC, SA and CS as the polymers and glycerin, propylene glycol (PG) and polyethylene glycol 400 (PEG400) as plasticizers. Then, the organoleptic properties of the films were examined. Using glycerin, medicated monolithic films (25 mg LAM each) were prepared and their physicochemical properties were determined. Matrix-type transdermal patches were fabricated using the medicated films as drug supply layers. The patches were evaluated for their ex vivo permeation. Male Spargue-Dawley rats were used for in vivo pharmacokinetic comparative study between MC-based matrix-type transdermal patches and oral LAM solution and the pharmacokinetic parameters were calculated.Drug-polymer compatibility studies ruled out the possibility of interaction between LAM and the selected polymers. Based on the organoleptic properties, glycerin was selected as a plasticizer. Among the tested films, the glycerin-plasticized MC films had acceptable physicochemical properties. The MC-based matrix-type transdermal patches showed the highest steady state flux, the highest permeability coefficient and the highest cumulative amount of LAM permeated without appearance of lag time. The transdermal patches enhanced the pharmacokinetic parameters of LAM. They exhibited absence of the high fluctuations of LAM plasma concentration and increasing the biological half-life by about 40 folds.It was concluded that the MC-based transdermal patches could serve as a potential innovative drug delivery system of LAM for sustained transdermal delivery as an alternative to the conventional oral approaches.

Improved Bioavailability of Levodopa Using Floatable Spray-Coated Microcapsules for the Management of Parkinson’s Disease

Oral administration of levodopa (LD) is the gold standard in managing Parkinson's disease (PD). Although LD is the most effective drug in treating PD, chronic administration of LD induces levodopa-induced dyskinesia. A continuous and sustained provision of LD to the brain could, therefore, reduce peak-dose dyskinesia. In commercial oral formulations, LD is co-administrated with an AADC inhibitor (carbidopa) and a COMT inhibitor (entacapone) to enhance its bioavailability. Nevertheless, patients are known to take up to five tablets a day because of poor sustained-releasing capabilities that lead to fluctuations in plasma concentrations. To achieve a prolonged release of LD with the aim of improving its bioavailability, floatable spray-coated microcapsules containing all three PD drugs were developed. This gastro-retentive delivery system showed sustained release of all PD drugs, at similar release kinetics. Pharmacokinetics study was conducted and this newly developed formulation showed a more plateaued delivery of LD that is void of the plasma concentration fluctuations observed for the control (commercial formulation). At the same time, measurements of LD and dopamine of mice administered with this formulation showed enhanced bioavailability of LD. This study highlights a floatable, sustained-releasing delivery system in achieving improved pharmacokinetics data compared to a commercial formulation.