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Background Extended‐release buprenorphine (XR) is indicated for pain management in rodents, but little is known about its use in mice. This study aimed to investigate whether high dose XR effectively attenuates post‐operative hypersensitivity better than low dose XR in a mouse model of incisional pain. Methods Mice (n = 44) were randomly assigned to 1 of 4 treatment groups: (a) saline (1 ml/kg SC, once); (b) sustained release buprenorphine (Bup‐SR, 1 mg/kg SC, once); (c) low dose extended‐release buprenorphine (XR‐lo, 3.25 mg/kg SC, once); (d) high dose extended‐release buprenorphine (XR‐hi, 6.5 mg/kg SC, once). On days −1, 0 (4 hours), 1, 2, and 3, mechanical and thermal hypersensitivities were evaluated, and plasma buprenorphine concentrations were measured. Results Mechanical (days 0‐2) and thermal (days 0‐1) hypersensitivities were observed in the saline group. Bup‐SR, XR‐lo, and XR‐hi attenuated mechanical hypersensitivity on days 0, 1, and 2. None of the treatment groups, except XR‐Lo on day 0, attenuated thermal hypersensitivity on days 0 or 1. Plasma buprenorphine concentration peaked at 4 hours (day 0) in all treatment groups and remained greater than 1 ng/mL on days 0‐2. No abnormal clinical observations or gross pathologic findings were seen in any groups. Conclusion The results indicate XR‐hi did not effectively attenuate post‐operative hypersensitivity better than XR‐lo. Thus both 3.25 and 6.5 mg/kg XR are recommended for attenuating post‐operative hypersensitivity for at least up to 48 hours in mice.

Injection of high-viscosity fluids into subcutaneous tissues may lead to a granulomatous reaction called sclerosing lipogranuloma (SL). Poly-(d,l-lactide-co-glycolide) (PLG or PLGA) microspheres are used as vehicles for extended-release drugs. Here we describe the histopathologic features of a case of SL induced by exenatide extended-release injections, and the staining pattern of PLG microspheres and microsphere remnants with carbol fuchsin.

Analgesic effects of ibuprofen immediate‐release/extended‐release (IR/ER) 600‐mg tablets were evaluated in 2 randomized, double‐blind, placebo‐controlled dental pain studies. Patients 16–40 years old with moderate–severe pain following third‐molar extraction received single‐dose ibuprofen 600 mg IR/ER (formulation A or B), naproxen sodium 220 mg, or placebo (2:2:2:1; study 1) or 4 doses of ibuprofen 600 mg IR/ER (formulation A) or placebo (1:1; study 2). In study 1 (n = 196), mean (standard deviation [SD]) time‐weighted sum of pain intensity difference scores for placebo, ibuprofen IR/ER A, ibuprofen IR/ER B, and naproxen, respectively, were 0.05 (9.2), 16.87 (9.4), 17.34 (10.5), and 12.66 (10.0) over 0–12 hours and ‐0.03 (4.1), 6.57 (4.4), 7.14 (5.2), and 5.14 (5.0) over 8–12 hours (all P

Two open-label, single-dose, parallel-group studies assessed effects of renal and hepatic impairment on the pharmacokinetics of a hydrocodone extended-release (ER) formulation developed with the CIMA Abuse-Deterrence Technology platform. Forty-eight subjects with normal renal function or varying degrees of renal impairment received hydrocodone ER 45 mg (study 1); 16 subjects with normal hepatic function or moderate hepatic impairment received hydrocodone ER 15 mg (study 2). Blood samples were obtained predose and through 144 hours postdose. Mean maximum observed plasma hydrocodone concentration (Cmax ) in subjects with normal renal function, mild, moderate, and severe impairment, and end-stage renal disease was 28.6, 33.4, 42.4, 36.5, and 31.6 ng/mL, and mean area under the plasma hydrocodone concentration-versus-time curve from time 0 to infinity (AUC0-∞ ) was 565, 660, 973, 983, and 638 ng·h/mL, respectively. Incidence of adverse events was 57%, 38%, 44%, 33%, and 56%, respectively. Mean Cmax with normal hepatic function and moderate impairment was 10.1 and 13.0 ng/mL, and mean AUC0-∞ was 155 and 269 ng·h/mL, respectively. Incidence of adverse events was 38% in both groups. Altered systemic exposure in renally or hepatically impaired populations (up to ∼70% higher) should be considered when titrating to an effective dose of hydrocodone ER.

Introduction We assessed the efficacy and safety of extended-release gabapentin in a 15-week, open-label, single-arm, single-center study in patients with fibromyalgia (FM). Methods Subjects with documented diagnosis of FM were allowed to participate in the study. We opened enrollment to those who have tried and failed gabapentinoids such as gabapentin or pregabalin due to side effects. Subjects with autoimmune conditions, and or taking opioids for management of their FM pain, were excluded from the study. Subjects were given an extended-release gabapentin starter pack and treated for total of 12 weeks. The primary study endpoint of pain relief was measured using Numeric Pain Rating System (NPRS) scores, and secondary study endpoints were measured with Fibromyalgia Impact Questionnaire (FIQ), Patient's Global Impression of Change (PGIC), and Medical Outcome Sleep questionnaires (MOS). Results A total of 34 subjects were enrolled and 29 subjects completed the starter pack (85%). Patients reported significant pain relief on NPRS by end of 4 weeks (P

The use of an extended release ceftiofur crystalline-free acid formulation (CCFA, Excede For Swine(®) , Pfizer Animal Health) in koi was evaluated after administration of single intramuscular (i.m.) or intracoelomic (i.c.) doses. Twenty koi were divided randomly into a control group and four treatment groups (20 mg/kg i.m., 60 mg/kg i.m., 30 mg/kg i.c., and 60 mg/kg i.c.). Serum ceftiofur-free acid equivalents (CFAE) concentrations were quantified. The pharmacokinetic data were analyzed using a nonlinear mixed-effects approach. Following a CCFA injection of 60 mg/kg i.m., time durations that serum CFAE concentrations were above the target concentration of 4 μg/mL ranged from 0.4 to 2.5 weeks in 3 of 4 fish, while serum CFAE concentrations remained below 4 μg/mL for lower doses evaluated. Substantial inter-individual variations and intra-individual fluctuations of CFAE concentrations were observed for all treatment groups. Histological findings following euthanasia included aseptic granulomatous reactions, but no systemic adverse effects were detected. Given the unpredictable time vs. CFAE concentration profiles for treated koi, the authors would not recommend this product for therapeutic use in koi at this time. Further research would be necessary to correlate serum and tissue concentrations and to better establish MIC data for Aeromonas spp. isolated from naturally infected koi.

Objective To evaluate the efficacy and safety of USL255, Qudexy™ XR (topiramate) extended-release capsules, as an adjunctive treatment for refractory partial-onset seizures (POS) in adults taking one to three concomitant antiepileptic drugs. Methods In this global phase III study (PREVAIL; NCT01142193), 249 adults with POS were randomized 1:1 to once-daily USL255 (200 mg/day) or placebo. The primary and key secondary efficacy endpoints were median percent reduction in weekly POS frequency and responder rate (proportion of patients with ≥50% reduction in seizure frequency). Seizure freedom was also assessed. Safety (adverse events, clinical and laboratory findings), as well as treatment effects on quality of life (QOLIE-31-P) and clinical global impression of change (CGI-C), were evaluated. Results Across the entire 11-week treatment phase, USL255 significantly reduced the median percent seizure frequency and significantly improved responder rate compared with placebo. Efficacy over placebo was observed early in treatment, in patients with highly refractory POS, and in those with the most debilitating seizure types (i.e., complex partial, partial secondarily generalized). USL255 was safe and generally well tolerated with a low incidence of neurocognitive adverse events. USL255 was associated with significant clinical improvement without adversely affecting quality of life. Significance The PREVAIL phase III clinical study demonstrated that once-daily USL255 (200 mg/day) significantly improved seizure control and was safe and generally well tolerated with few neurocognitive side effects.

The objective of the present study was to carry out a pharmacokinetics evaluation of an oral modified release formulation [Aquarius EKX 19102 SRX–2 based osmotic pump (OP)] containing highly soluble milnacipran HCl (MH) as a model drug. It was also aimed at developing an in vitro–in vivo correlation (IVIVC) model for a developed OP. In vivo plasma concentration data were obtained from six healthy male New Zealand albino rabbits after administration of immediate-release milnacipran HCl solution (IRMHSOL) and milnacipran HCl osmotic pump (MHOP). In vitro samples were analysed using an in house developed spectrophotometry method and in vivo samples were analysed using a RP-HPLC method developed by the author. A deconvolution based Level A model was attempted through a correlation of the percent in vivo input obtained through deconvolution and the percent in vitro dissolution obtained experimentally. A good correlation between the percentages dissolved vs absorbed (R2 = 0.978) was obtained using level A correlation. Evaluation of the internal predictability of level A correlation was calculated in terms of the percent prediction error, which was found to be below 15%. In a nutshell, the success of the present study warrants further studies in patient volunteers to assess the ability of the MHOP to provide an effective therapy for depression. Copyright © 2013 John Wiley & Sons, Ltd.

Objective This study assessed whether the subjective experience of patients with schizophrenia improved after switching from an oral antipsychotic to flexibly-dosed paliperidone extended-release. Methods We conducted a 24-week, multicenter, non-comparative, open-label trial. A total of 387 patients with schizophrenia participated the study. The primary study outcome was the change in subjective symptoms measured by the Symptom Checklist-90-Revised version (SCL-90-R) from baseline. Visual analogue scales were used for sleep and daytime somnolence as secondary subjective assessments. The clinical global impression-schizophrenia-severity scale was used to assess overall symptom severity. Social functioning was evaluated by the personal and social performance scale. Adverse events were also evaluated. Results All subjective symptoms measured by the SCL-90-R improved significantly. The early responders, who achieved >20% reduction in the SCL-90-R within 1 week, maintained significantly lower severity through the 24 weeks. The clinical global impression-schizophrenia-severity scale and personal and social performance scores also improved significantly. The visual analogue scales revealed that daytime somnolence improved significantly, whereas nocturnal sleep quality was unaltered. Conclusion Our results suggest that switching to paliperidone extended-release was associated with improvements in various subjective symptoms, decreased overall symptom severity, and increased social functioning. The results also suggest that early detection and reduction of subjective symptoms are important for treatment outcome. Copyright © 2013 John Wiley & Sons, Ltd.

Background: Metformin is increasingly accepted as an alternative to insulin therapy in gestational diabetes mellitus (GDM). The Metformin in Gestational Diabetes (MiG) trial reported similar pregnancy outcomes for metformin versus insulin; however, supplemental insulin was required in 46% of women on metformin. Aims: We aimed to identify predictors of response to metformin monotherapy in women with GDM attending a general hospital antenatal clinic. Methods We offered extended-release metformin to women diagnosed with GDM (ADIPS 1998 criteria) at ≥24 weeks of gestation. If glucose targets were not achieved (≤5.0 mmol/L fasting, ≤6.7 mmol/L two-h post-meal), women were changed to insulin. We carried out an audit to determine characteristics of metformin responders versus nonresponders. Results: Twenty-five women chose initial metformin therapy; 16 (64%) achieved satisfactory glycaemic control (responders). Nine women (36%) were changed to insulin: seven due to inadequate control (nonresponders) and two had metformin intolerance. Fasting glucose at oral glucose tolerance test (OGTT) was significantly lower in metformin responders versus nonresponders; two-h glucose and BMI did not differ. Ninety-three percent of women with fasting glucose ≤5.2 mmol/L responded to metformin: conversely, at fasting glucose >5.2 mmol/L, 33% responded ( P = 0.005). Neonatal outcomes were similar in metformin responders and nonresponders, women who chose initial insulin therapy ( n = 25), or were diet-controlled ( n = 21). Conclusions: In women with GDM, fasting glucose on OGTT predicted response to metformin: at fasting glucose ≤5.2 mmol/L, the probability of response was 93%. Antenatal clinics should determine locally relevant predictors of response to metformin in women with GDM.

Background The aim of the present prospective observational study was to assess the tolerability and antihyperglycemic efficacy of metformin extended-release (MXR) in the routine treatment of patients with type 2 diabetes mellitus (T2DM) from six Asian countries. Methods Data from 3556 patients treated with once-daily MXR for 12 weeks, or until discontinuation, were analyzed. Results Treatment with MXR was well tolerated, with 97.4% of patients completing 12 weeks of treatment. Only 3.3% of patients experienced one or more gastrointestinal (GI) side-effects and only 0.7% of patients discontinued for this reason (primary endpoint). The incidence of GI side-effects and related discontinuations appeared to be considerably lower during short-term MXR therapy than during previous treatment (mean 2.71 years’ duration), most commonly with immediate-release metformin. A 12-week course of MXR therapy also reduced HbA1c and fasting glucose levels from baseline. Conclusions The present study provides new insights into the incidence of GI side-effects with MXR in Asian patients with T2DM and on the tolerability of MXR in non-Caucasian populations. Specifically, these data indicate that once-daily MXR not only improves measures of glycemic control in Asian patients with T2DM, but also has a favorable GI tolerability profile that may help promote enhanced adherence to oral antidiabetic therapy.

Background Attention deficit hyperactivity disorder (ADHD) is the most diagnosed behavioural disorder in children and adolescents; prevalence has been estimated around 5%. Studies have shown an increase in the use of ADHD medications during the last years. The aim of the present study was to learn the pattern and the evolution of ADHD medication consumption in Castilla y Leon (Spain). Method Consumption data for the period 1992–2009 were obtained from databases containing information upon consumption and cost of medications dispensed by pharmacies at the expense of the Spanish National Health System. The data were expressed in defined daily doses (DDDs) per 1000 inhabitants per day (DDD/1000 inhabitants/day). A model to forecast consumption was built. Results Attention deficit hyperactivity disorder medication consumption increased in Castilla y Leon from 0.1 DDD/1000 inhabitants/day in 1992 to 1.5 DDD/1000 inhabitants/day in 2009; expected consumption will reach 2.5 DDD/1000 inhabitants/day by 2013. The drugs accounting for this increase were mainly made up of methylphenidate preparations (1.4 DDD/1000 inhabitants/day in 2009). From 1992 to 1999, there was a slight reduction in methylphenidate use; following amphetamine withdrawal, the consumption of stimulants began to increase, and figures showed a sharp rise after marketing of extended-release formulations in 2003. Conclusions There has been an enormous increase in ADHD medication consumption in Castilla y Leon in the last few years; increase rocketed when extended-release methylphenidate was marketed. A rapid increase in the consumption is a warning on possible overdiagnosis and inappropriate prescription. Copyright © 2012 John Wiley & Sons, Ltd.

Objective: To evaluate the efficacy of extended-release (ER) tolterodine 4 mg/day for the treatment of neurogenic detrusor overactivity (NDO) and/or low-compliance bladder by assessing urodynamic parameters. Methods: Forty-six patients (25 male, 21 female; mean age 57.6 ± 20.7 years) with NDO (n = 39) and/or low-compliance bladder (n = 7) were included in this 12-week single-arm study. Twenty-one patients (46%) were on clean intermittent catheterization and other patients could void on their own. A video urodynamic study was performed before and at 3 months after treatment. Changes in Overactive Bladder Symptom Score (OABSS), International Consultation on Incontinence Questionnaire–Short Form (ICIQ-SF), and King's Health Questionnaire (KHQ) as well as changes in number of voids, amount of each void, and number of leaks in 24 h according to the 3-day voiding diary were also evaluated before treatment and at weeks 4 and 12 after treatment. Results: Bladder capacity at first sensation and maximum cystometric capacity increased significantly, by an average of 36.8 mL (P = 0.0402) and 82.3 mL (P

The pharmacokinetics of a once-daily formulation of tramadol (Tramadol Contramid OAD 200-mg tablets) following single-dose and multiple-dose administration was compared with that of an immediate-release product (tramadol IR 50-mg tablets) in 2 separate studies. In both studies, AUC parameters met bioequivalence criteria, whereas C(max) of Tramadol Contramid OAD was lower than that of tramadol IR following a 200-mg daily dosage. After single-dose administration, the mean tramadol concentration at 1 hour postdose was within the range associated with analgesic efficacy (>100 ng/mL), and the mean concentration remained above this level for the remainder of the dosing interval. Steady state was attained within 48 hours following multiple-dose administration. Tramadol Contramid OAD provides a rapid rise in plasma concentrations and an equivalent daily systemic exposure as tramadol IR, with a reduction in peak plasma concentrations.

Guanfacine, an alpha(2A) adrenoceptor agonist, is U.S. Food and Drug Administration (FDA)-approved for the treatment of hypertension in adolescents and adults. It also has been used "off-label" for several years in children as a possible treatment for attention-deficit/hyperactivity disorder (ADHD) and pervasive developmental disorders (PDDs). Small placebo-controlled trials support the use of guanfacine for the treatment of ADHD. There is more limited research on the use of guanfacine in treating hyperactivity occurring in children diagnosed with PDD. Recently, guanfacine extended release (GXR), a once-daily formulation has been manufactured and studied in phase III clinical trials. Based on preliminary scientific presentations, it also appears to be efficacious in improving ADHD in children. The most common adverse effects associated with guanfacine and GXR treatment is sedation. Adverse cardiovascular effects are uncommon, although modest reductions in blood pressure and heart rate are common. If GXR is FDA-approved, it would be the first alpha(2A) adrenoceptor agonist marketed for ADHD.

This study evaluated the clinical effects and pattern of use of AVINZA((r)), morphine sulfate extended-release tablets, under real-world treatment conditions. Opioid-naive subjects or subjects who have failed other opioids were eligible if they had chronic moderate-to-severe noncancer pain with an average pain score > or =4 (0-10 scale) in the preceding month. Subjects answered in-depth monthly questionnaires in three months. For the 491 evaluable subjects enrolled, the median AVINZA dose was 30 mg at baseline, titrated to 60 mg by month 1, and remained at 60 mg through month 3. Adherence was high, with almost 90% of the subjects reporting never having forgotten to take AVINZA. Mean daily pain scores (scale 0-10) significantly improved from 7.83 at enrollment to 5.77 at month 1 (P < 0.01) and then remained at this level through month 3. Significant improvements were seen in all sleep measures, and the mean Composite Sleep Score, a global measure of sleep quality (scale 0-10), significantly improved from 5.73 at baseline to 4.96 at month 3 (P < 0.01). Physical functioning was improved for activities requiring a moderate effort (P = 0.053), such as climbing one flight of stairs (P = 0.008). Two hospitalizations for nausea and vomiting were the only reported drug-related serious adverse events. This study showed that once-daily AVINZA significantly reduced pain scores, and resulted in improved sleep and physical functioning in patients with chronic moderate-to-severe pain. These results were achieved with a stable daily morphine dose over the three-month study period.

The objective of this study was to determine whether 3 months of treatment with extended-release metoprolol succinate would reduce C-reactive protein (CRP) levels. Seventy-five patients aged 30-65 years with uncontrolled hypertension were treated with extended-release metoprolol at 25-50 mg, titrated up to 100-200 mg daily. CRP was evaluated at baseline and at 1 and 3 months. In the 61 hypertensive patients who completed the study, CRP decreased from 6.2+/-7.5 mg/L at baseline to 5.4+/-7.0 mg/L (p=0.03) at 1 month and showed no further change at 3 months (5.6+/-6.5 mg/L; p=0.13). The 13 patients who received 200 mg of extended-release metoprolol had a 32% decline in CRP from 7.0+/-9.0 mg/L to 4.8+/-6.6 mg/L (-2.2 mg/L) (p=0.005) over the 3-month period, whereas lower doses did not reduce CRP (p0.05). Age, race, sex, and change in blood pressure were not related to the reduction in CRP in multivariate analysis. If CRP evolves into a confirmed modifiable risk factor, a beta blocker such as metoprolol may be a useful addition to pharmacotherapy options.

Hydromorphone hydrochloride extended release (HHER) is a multiparticulate melt-extrusion pellet capsule formulation administered q24h. Study 1 investigated the bioavailability of 24-mg HHER fed, as well as 24-mg and 12-mgHHER and 8-mg hydromorphone hydrochloride immediate-release (HHIR) tablets fasting. No clinically significant food effect was observed on hydromorphone C m a x orAUCfor the 24-mg HHER, and dose proportionality (AUC) was demonstrated between 12- and 24-mg HHER. Study 2 demonstrated dose strength proportionality for 3×12-mg HHER versus 1 x 32-mg HHER. Study 3 evaluated 12-mg HHER q24h versus 3-mg HHIR q6h at steady state. HHER produced relatively constant steady-state concentrations over 24 hours. HHER and HHIR were equivalent for AUC s s . C s s m a x was 26% lower for HHER than HHIR, C s s m i n was 43% higher for HHER, and peak-to-trough fluctuation was 126% for HHER versus 328% for HHIR, which are ideal attributes of a once-daily oral extended- release dosage form. HHER administration resulted in fewer adverse events than HHIR in study 3.

The influences of some formulation variables and manufacturing processes of the release rates of propranolol from gelation of hydroxypropylmethylcellulose (HPMC) matrices tablets were investigated. The amount of propranolol was determined by UV–Vis spectroscopy at 290 nm. The effects of extended release of matrices tablets were evaluated by the in vitro dissolution test and were compared to the United States Pharmacopoeia (USP) monograph specifications. The results showed that the lowest viscosity grade of HPMC (Metolose 4000) used gave the least burst effect in the earlier stage. The drug/Metolose ratio was an important influence on the drug release; increasing the polymer content decreased the dissolution rate of the drug. The release rate was increased with increase in the tablet content of avicel. The release curve of experimental formulation with 17% avicel was optimal compared with the USP monograph specification; there was no burst effect in the earlier stage (the release percent at 1.5 h was 26.6%) and almost total drug was released from matrices tablet after 24 h (97.4%). The other factors such as lubricant level (0.5 to 2.0%), compaction pressure (100 to 200 kPa), brand of HPMC (HPMC 4000 from Shin Etsu or Methocel K4MP from Dow Chemical Co.), and manufacturing process (tabletted from wet-massed granules or by direct compression) appeared not to modify release rates. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 93: 1886–1890, 2004

The efficacy and safety of lipid-lowering agents in elderly individuals have not been extensively assessed. This population generally takes more drugs concurrently than middle-aged patients, and are therefore at higher risk of drug-drug interactions. This large-scale, randomized, double-blind, placebo-controlled study investigated the efficacy and safety of extended-release (XL) fluvastatin 80 mg once daily for up to 1 year in elderly patients with primary hypercholesterolemia. A total of 1229 patients (mean age, 75.5 years) were randomized. After 2 months of treatment, fluvastatin XL 80 mg significantly decreased plasma lipid levels from baseline compared with placebo; fluvastatin reduced total cholesterol by 25% compared with a decrease of 2.5% in the placebo group, low-density lipoprotein cholesterol was -33% vs. -2.5%, respectively, and triglycerides were -13.3% vs. 2.9%, respectively (p

The aim was to assess the bioequivalence of Sandoz methylphenidate osmotic-controlled release (OCR) tablets (Sandoz [Methylphenidate[ MPH OCR) with Concerta®, a methylphenidate formulation indicated for the treatment of attention deficit/hyperactivity disorder (ADHD). Four open-label, randomized, single-dose, two-way crossover bioequivalence studies were conducted in healthy subjects: three fasting studies with 54-, 36- and 18-mg doses of methylphenidate, and one fed study with the 54-mg dose. The d- and l-threo-methylphenidate plasma levels were quantified using liquid chromatographic methods with tandem mass spectrometry (LC MS/MS). Bioequivalence of the formulations was accepted if the 90% geometric confidence intervals of the ratio of least-squares means of Sandoz MPH OCR to Concerta® of ln-transformed area under the curve (AUC0-t ) and C max were within the acceptance range of 80-125%. All studies met the bioequivalence criteria, and 90% geometric confidence intervals for AUC0-t and C max were within the predefined range. All plasma concentration time curves for Sandoz MPH OCR under fasting conditions showed a biphasic profile comparable with Concerta®, confirmed by bioequivalence of the partial metrics AUC0-2h, AUC2-24 h, C max(0-2 h) and C max(2-24 h). Both products were well tolerated and no relevant differences in the safety profiles were observed. It was concluded that Sandoz MPH OCR is bioequivalent to Concerta® in terms of rate and extent of absorption when administered as a single dose of one extended-release tablet of 54, 36, or 18 mg under fasting conditions and at a dose of 54 mg under fed conditions.

To develop and validate internally an in vitro-in vivo correlation (IVIVC) for a diltiazem multi-particulate bead extended release formulation. In vitro dissolution of diltiazem capsules was examined using the following methods: USP Apparatus II (paddle) at 100 rpm and USP Apparatus III at 30 dpm. Seven healthy subjects received three diltiazem formulations (90 mg): slow (S), moderate (M), fast (F) releasing and an oral solution (90 mg). Serial blood samples were collected over 48 h and analyzed by a validated HPLC assay using ultraviolet detection. The f(2) metric (similarity factor) was used to analyze the dissolution data. Linear and non-linear (quadratic, cubic, and sigmoid functions) correlation models were developed using pooled fraction dissolved (FRD) and fraction absorbed (FRA) data from various combinations of the formulations. Predicted diltiazem concentrations were obtained by convolution of the in vivo dissolution rates. Prediction errors were estimated for C(max) and AUC to determine the validity of the correlation. Apparatus II using purified water was found to be the most discriminating dissolution method. Significant intersubject (CV%>50) was observed for C(max) and AUC. The quadratic M/F IVIVC model provided a significant relationship between FRD and FRA when using either two or three of the formulations. An average percent prediction error for C(max) and AUC for all formulations was 12.4% and 9.2%, respectively. The prediction errors observed for C(max) and AUC suggest that the predictability of the quadratic IVIVC model is inconclusive, as such, external validation studies are required.

Nosocomial infection are estimated to involve more than 2 million patients annually and in 1992 cost more than $4,5 billion in the USA (1). The surfaces of indwelling medical devices are an excellent platform for the formation of life-threatening infections. Although aseptic techniques can reduce the incidence of these infections, a significant risk remains. The coupling or incorporation of antimicrobial substances to or into catheter materials may be a suitable way to prevent the development of catheter associated infections as suggested by in vitro and in vivo studies. Various surface treatments are emerging as important. Early efforts that concentrated on adsorption of antibiotics to device surfaces achieved limited results as shown in several clinical studies. The promising approach features the incorporation of antimicrobial drugs into the polymer matrices that entrap but do not bind the drugs, allowing for extended release. Incorporation of antimicrobials in the bulk material that constitutes a device can be effective as shown in several in vitro and in vivo studies. In future, modification of both short-term and long term catheters by biofilm-active antimicrobials creating slow delivery systems may provide an effective method to protect patients from nosocomial infection. Antimikrobielle Kathetermaterialien: Schwierige Suche nach wirksamen Wirkstoffliberations-Systemen In den USA werden jedes Jahr mehr als zwei Millionen nosokomiale Infektionen gezahlt mit geschatzten Kosten von mehr als 4,5 Milliarden $ (1). Die Oberflachen von Implantatmaterialien sowie invasiver Medizinprodukte bieten ideale Wachstums- und Ausbreitungsbedingungen fur nosokomiale Keime. Unter strikter Beachtung steriler Kautelen lasst sich die Haufigkeit Implantat-assoziierter Infektionen reduzieren; trotzdem verbleibt eine „physiologische”, kaum vermeidbare Infekthaufigkeit. Die Kopplung antimikrobiell aktiver Substanzen an oder in Implantatmaterialien vermag in naher Zukunft die Haufigkeit dieser Infektionen reduzieren, worauf inzwischen in vitro und auch klinische Studien hinweisen. Die in der Vergangenheit haufig beschrittene oberflachliche Implantatbeschichtung mit antimikrobiellen Substanzen konnte sich aufgrund widerspruchlicher klinischer Resultate nicht durchsetzen. Physikalisch in der Implantatmatrix gebundene Biofilm-aktive Wirkstoffe konnen mittels Diffusion uber einen langeren Zeitraum freigesetzt werden und eroffnen somit ein effizientes pharmakologisches Wirkprinzip zur Pravention dieser Infektionen.