Surface modification of PLGA nanoparticles via human serum albumin conjugation for controlled delivery of docetaxel

Background

Poly lactic-co-glycolic acid (PLGA) based nanoparticles are considered to be a promising drug carrier in tumor targeting but suffer from the high level of opsonization by reticuloendothelial system due to their hydrophobic structure. As a result surface modification of these nanoparticles has been widely studied as an essential step in their development. Among various surface modifications, human serum albumin (HSA) possesses advantages including small size, hydrophilic surface and accumulation in leaky vasculature of tumors through passive targeting and a probable active transport into tumor tissues.

Methods

PLGA nanoparticles of docetaxel were prepared by emulsification evaporation method and were surface conjugated with human serum albumin. Fourier transform infrared spectrum was used to confirm the conjugation reaction where nuclear magnetic resonance was utilized for conjugation ratio determination. In addition, transmission electron microscopy showed two different contrast media in conjugated nanoparticles. Furthermore, cytotoxicity of free docetaxel, unconjugated and conjugated PLGA nanoparticles was studied in HepG2 cells.

Results

Size, zeta potential and drug loading of PLGA nanoparticles were about 199 nm, −11.07 mV, and 4%, respectively where size, zeta potential and drug loading of conjugated nanoparticles were found to be 204 nm, −5.6 mV and 3.6% respectively. Conjugated nanoparticles represented a three-phasic release pattern with a 20% burst effect for docetaxel on the first day. Cytotoxicity experiment showed that the IC50 of HSA conjugated PLGA nanoparticles (5.4 μg) was significantly lower than both free docetaxel (20.2 μg) and unconjugated PLGA nanoparticles (6.2 μg).

Conclusion

In conclusion surface modification of PLGA nanoparticles through HSA conjugation results in more cytotoxicity against tumor cell lines compared with free docetaxel and unconjugated PLGA nanoparticles. Albumin conjugated PLGA nanoparticles may represent a promising drug delivery system in cancer therapy.     

Preparation,characterization and optimization of sildenafil citrate loaded PLGA nanoparticles by statistical factorial design

Background and the aim of the study

The objective of the present study was to formulate and optimize nanoparticles (NPs) of sildenafil-loaded poly (lactic-co-glycolic acid) (PLGA) by double emulsion solvent evaporation (DESE) method. The relationship between design factors and experimental data was evaluated using response surface methodology.

Method

A Box-Behnken design was made considering the mass ratio of drug to polymer (D/P), the volumetric proportion of the water to oil phase (W/O) and the concentration of polyvinyl alcohol (PVA) as the independent agents. PLGA-NPs were successfully prepared and the size (nm), entrapment efficiency (EE), drug loading (DL) and cumulative release of drug from NPs post 1 and 8 hrs were assessed as the responses.

Results

The NPs were prepared in a spherical shape and the sizes range of 240 to 316 nm. The polydispersity index of size was lower than 0.5 and the EE (%) and DL (%) varied between 14-62% and 2-6%, respectively. The optimized formulation with a desirability factor of 0.9 was selected and characterized. This formulation demonstrated the particle size of 270 nm, EE of 55%, DL of 3.9% and cumulative drug release of 79% after 12 hrs. In vitro release studies showed a burst release at the initial stage followed by a sustained release of sildenafil from NPs up to 12 hrs. The release kinetic of the optimized formulation was fitted to Higuchi model.

Conclusions

Sildenafil citrate NPs with small particle size, lipophilic feature, high entrapment efficiency and good loading capacity is produced by this method. Characterization of optimum formulation, provided by an evaluation of experimental data, showed no significant difference between calculated and measured data.     

Enhanced antibacterial activity of roxithromycin loaded pegylated poly lactide-co-glycolide nanoparticles

Background and the purpose of the study

The purpose of this study was to prepare pegylated poly lactide-co-glycolide (PEG-PLGA) nanoparticles (NPs) loaded with roxithromycin (RXN) with appropriate physicochemical properties and antibacterial activity. Roxithromycin, a semi-synthetic derivative of erythromycin, is more stable than erythromycin under acidic conditions and exhibits improved clinical effects.

Methods

RXN was loaded in pegylated PLGA NPs in different drug;polymer ratios by solvent evaporation technique and characterized for their size and size distribution, surface charge, surface morphology, drug loading, in vitro drug release profile, and in vitro antibacterial effects on S. aureus, B. subtilis, and S. epidermidis.

Results and conclusion

NPs were spherical with a relatively mono-dispersed size distribution. The particle size of nanoparticles ranged from 150 to 200 nm. NPs with entrapment efficiency of up to 80.0±6.5% and drug loading of up to 13.0±1.0% were prepared. In vitro release study showed an early burst release of about 50.03±0.99% at 6.5 h and then a slow and steady release of RXN was observed after the burst release. In vitro antibacterial effects determined that the minimal inhibitory concentration (MIC) of RXN loaded PEG-PLGA NPs were 9 times lower on S. aureus, 4.5 times lower on B. subtilis, and 4.5 times lower on S. epidermidis compared to RXN solution. In conclusion it was shown that polymeric NPs enhanced the antibacterial efficacy of RXN substantially.     

Serum Concentration of Lignocaine After Pertubation: An Observational Study

Objective

The objective of this study was to report the serum concentration of lignocaine after pertubation in patients with endometriosis.

Design

Prospective observational study.

Setting

The study was carried out at a gynaecological outpatient unit in Stockholm, Sweden.

Population

Eligible patients had endometriosis with a dysmenorrhoic pain score of >50 mm on a visual analogue scale, and patent fallopian tubes.

Methods

Patients with endometriosis (n = 25) were included in the study. The patients received pre-ovulatory pertubations with lignocaine hydrochloride 10 mg (n = 16) or ringer acetate (placebo, n = 9). The procedure comprised passing the study solution through the uterus and the fallopian tubes via an intra-cervical balloon catheter. Serum samples were collected at 0, 5, 15 and 30 min after pertubation.

Main Outcome Measures

The serum samples were analysed for the concentration of lignocaine with an LCMS-SIM method.

Results

Low levels of lignocaine were detected in the serum samples following pertubation of 10 mg lignocaine hydrochloride. The highest observed concentration was seen after 30 min (mean 0.050 μg/ml), with an individual maximum of 0.124 μg/ml. Maximum concentration (C_max) and time to C_max (T_max) could not be calculated, since the highest values were observed in the 30-min samples, which was the last sample obtained. Lignocaine was not detected after pertubation with placebo.

Conclusions

The serum levels of lignocaine following pertubation of 10 mg lignocaine hydrochloride are detectable but low. Lignocaine pertubated through the fallopian tubes reaches the peritoneal cavity and diffuses through the peritoneum into the blood circulation. Pertubation with lignocaine is safe and has no lignocaine-related adverse events.     

Assessment of the Prophylactic Role of Aspirin and/or Clopidogrel on Experimentally Induced Acute Myocardial Infarction in Hypercholesterolemic Rats

Introduction

Hyperlipidemia is a risk factor for cardiovascular diseases such as acute infarction. Inflammation and platelet activation are critical phenomena in acute myocardial infarction (AMI).

Aim

The aim of the study was to assess potential protective effects of aspirin and/or clopidogrel on AMI in hypercholesterolemic rats.

Methods

Forty adult male Wistar rats were divided into five groups (eight rats in each). Group I included normal healthy rats. The other 32 rats were subjected to induction of hypercholesterolemia by high-fat diet for 3 weeks, followed by induction of AMI by subcutaneous injections of isoproterenol (85 mg/kg/day, for 2 days). Rats were divided into the following groups: group II, rats with induced hypercholesterolemia and AMI; group III, hypercholesterolemic rats that received aspirin 30 mg/kg/day orally for 7 days before induction of AMI; group IV, hypercholesterolemic rats that received clopidogrel 10 mg/kg/day orally for 7 days before induction of AMI; and group V, hypercholesterolemic rats treated with both aspirin and clopidogrel in the same doses for 7 days before induction of AMI. Serum levels of pentraxin 3 (PTX3), transforming growth factor-β1 (TGF-β1), creatine kinase (CK), lactate dehydrogenase (LDH), total cholesterol and triglycerides were estimated in all rats.

Results

Isoproterenol-induced AMI in hypercholesterolemic rats was associated with an increase in serum levels of PTX3, TGF-β1, CK and LDH. Aspirin and/or clopidogrel pretreatment for 1 week led to a reduction of their levels as compared with non-treated rats. However, the reduction caused by combination of aspirin and clopidogrel was more than that caused by each drug separately.

Conclusion

Combination of aspirin and clopidogrel could be a therapeutic option for hypercholesterolemic patients to attenuate the complex vascular inflammatory process which is a key step in the setting of AMI.     

Sustained-Release Fampridine (4-Aminopyridine) in Multiple Sclerosis: Efficacy and Impact on Motor Function

Objective

The aim of this study was to determine the efficacy of sustained-release fampridine (4-aminopyridine) in veterans with multiple sclerosis (MS) with limited ambulatory ability, and its impact on motor function in an outpatient setting.

Design

Retrospective.

Setting

Tertiary referral center [Veterans Affairs (VA) Medical Center].

Participants

Veterans; 20 MS patients were prescribed dalfampridine (10 mg twice daily) due to their difficulty with walking based on patient and caregiver report and clinician impression of change in the ability to ambulate based on prior 10-meter (10M) and 2-minute walk tests (2MWTs).

Intervention

Not applicable.

Main Outcome Measures

The primary outcome measures were mean changes in walking speed (10M walk test), walking distance (2MWT), and Total Functional Independence Measure (TFIM). Improvement of >20 % in walking speed was indicated as a clinically meaningful change.

Results

Treatment with dalfampridine resulted in significant improvement in walking speed and endurance (p < 0.05). Walking speed increased by 33 % and walking endurance by 31 %, representing clinically meaningful improvement. This change was not influenced by change in muscle tone. This improvement in mobility was associated with a clinically significant change in motor function. Adverse effects, including insomnia, dizziness, and headache, were experienced by five patients who discontinued the medication after a minimum of 4 weeks.

Conclusion

Treatment with dalfampridine resulted in clinically relevant improvements in walking speed and endurance in MS patients with limited ambulation and helped improve their motor function.

Electronic supplementary material

The online version of this article (doi:10.1007/s40268-013-0020-x) contains supplementary material, which is available to authorized users.     

Poly(lactic acid-glycolic acid) nanoparticles markedly improve immunological protection provided by peptide P10 against murine paracoccidioidomycosis

Background and purpose:

The present study reports on the preparation and testing of a sustained delivery system for the immunomodulatory peptide P10 aimed at reducing the in vivo degradation of the peptide and the amount required to elicit a protective immune response against paracoccidioidomycosis.

Experimental approach:

BALB/c mice were infected with the yeast Paracoccidioides brasiliensis to mimic the chronic form of paracoccidioidomycosis. The animals were treated daily with sulfamethoxazole/trimethoprim alone or combined with peptide P10, either emulsified in Freund''s adjuvant or entrapped in poly(lactic acid-glycolic acid) (PLGA) nanoparticles at different concentrations (1 µg, 5 µg, 10 µg, 20 µg or 40 µg·50 µL⁻¹). Therapeutic efficacy was assessed as fungal burden in tissues and the immune response by quantitative determination of cytokines.

Key results:

Animals given combined chemotherapy and P10 nanotherapy presented a marked reduction of fungal load in the lungs, compared with the non-treated animals. After 30 days of treatment, P10 entrapped within PLGA (1 µg·50 µL⁻¹) was more effective than ‘free’ P10 emulsified in Freund''s adjuvant (20 µg·50 µL⁻¹), as an adjuvant to chemotherapy. After treatment for 90 days, the higher doses of P10 entrapped within PLGA (5 or 10 µg·50 µL⁻¹) were most effective. Treatment with P10 emulsified in Freund''s adjuvant (20 µg·50 µL⁻¹) or P10 entrapped within PLGA (1 µg·50 µL⁻¹) were accompanied by high levels of interferon-gamma in lung.

Conclusions and implications:

Combination of sulfamethoxazole/trimethoprim with the P10 peptide entrapped within PLGA demonstrated increased therapeutic efficacy against paracoccidioidomycosis. P10 incorporation into PLGA nanoparticles dramatically reduced the peptide amount necessary to elicit a protective effect.     

Inhaler Competence and Patient Satisfaction with Easyhaler?: Results of Two Real-Life Multicentre Studies in Asthma and COPD

Objective

The aim of this study was to investigate patients’ inhaler competence and satisfaction with the Easyhaler^® dry powder inhaler.

Design

Two open, uncontrolled, non-randomised studies.

Setting

Real life based on patients attending 56 respiratory clinics in Hungary.

Participants

Patients with asthma or chronic obstructive pulmonary disease (COPD) (n = 1016).

Intervention

In a 3-month study, adult patients (age range 18–88 years; n = 797) received twice-daily inhalations of formoterol via Easyhaler^®, and in a consequential study (from one visit to another, with 3–12 months in-between) children and adolescents (age range 4–17 years; n = 219) received salbutamol via Easyhaler^® as needed.

Main Outcome Measures

Control of six Easyhaler^® handling steps and patients’ satisfaction with Easyhaler^® based on questionnaires.

Results

Correct performances (minimum and maximum of the six steps) were noticed after one demonstration in 92–98 % of the adults, 87–99 % of the elderly, 81–96 % of the children and 83–99 % of the adolescents. These figures had markedly increased at the last visit. Repeat instructions were necessary in 26 % of the cases. Investigators found Easyhaler^® easy to teach in 87 % of the patients and difficult in only 0.5 %. Patients found Easyhaler^® easy to learn and use, and the patients’ (and parents’) satisfaction with the inhaler was very high. Lung function values [forced expiratory volume in 1 s (FEV₁), forced vital capacity (FVC), peak expiratory flow (PEF)] improved statistically significantly during the studies, indicating good inhaler competence and treatment adherence.

Conclusion

Investigators found Easyhaler^® easy to teach and patients found it easy to use, and their satisfaction with the device was high.     

Oral delivery of capsaicin using MPEG-PCL nanoparticles

Aim:

To prepare a biodegradable polymeric carrier for oral delivery of a water-insoluble drug capsaicin (CAP) and evaluate its quality.

Methods:

CAP-loaded methoxy poly (ethylene glycol)-poly(ε-caprolactone) nanoparticles (CAP/NPs) were prepared using a modified emulsification solvent diffusion technique. The quality of CAP/NPs were evaluated using transmission electron microscopy, powder X-ray diffraction, differential scanning calorimetry and Fourier transform infrared techniques. A dialysis method was used to analyze the in vitro release profile of CAP from the CAP/NPs. Adult male rats were orally administered CAP/NPs (35 mg/kg), and the plasma concentrations of CAP were measured with a validated HPLC method. The morphology of rat gastric mucosa was studied with HE staining.

Results:

CAP/NPs had an average diameter of 82.54±0.51 nm, high drug-loading capacity of 14.0%±0.13% and high stability. CAP/NPs showed a biphasic release profile in vitro: the burst release was less than 25% of the loaded drug within 12 h followed by a more sustained release for 60 h. The pharmacokinetics study showed that the mean maximum plasma concentration was observed 4 h after oral administered of CAP/NPs, and approximately 90 ng/mL of CAP was detected in serum after 36 h. The area under the curve for the CAP/NPs group was approximately 6-fold higher than that for raw CAP suspension. Histological studies showed that CAP/NPs markedly reduced CAP-caused gastric mucosa irritation.

Conclusion:

CAP/NPs significantly enhance the bioavailability of CAP and markedly reduce gastric mucosa irritation in rats.     

α-Lipoic Acid and Superoxide Dismutase in the Management of Chronic Neck Pain: A Prospective Randomized Study

Background and Objective

Since oxidative stress plays a pathogenetic role in chronic neck pain (CNP), we investigated whether a combination of α-lipoic acid (ALA) and superoxide dismutase (SOD) might improve pain control and the efficacy of physiotherapy (“multimodal therapy”) in patients with CNP.

Setting

This study was conducted in the Rehabilitation Unit of the Department of Surgical and Oncological Sciences at the University Policlinic in Palermo, Italy.

Design and Patients

This was a prospective, randomized, open study in outpatients.

Intervention

Patients randomly received either physiotherapy alone (group 2; n = 45) or a combination of ALA 600 mg and SOD 140 IU daily in addition to physiotherapy (group 1; n = 51), for 60 days. Pain was assessed by a visual analogue scale (VAS) and a modified Neck Pain Questionnaire (mNPQ). Treatment compliance and safety were also evaluated.

Results

Both groups experienced a significant reduction in the VAS and mNPQ scores after 1 month; however, while no further improvement was observed in group 2 at 60 days, group 1 showed a further VAS reduction (p < 0.001). In addition, in the mNPQ at 60 days, more patients in group 1 than in group 2 reported that their neck pain was improved (p < 0.01), and they showed greater compliance with prescribed physiotherapy (p = 0.048). No drug reaction was observed.

Conclusion

Use of ALA/SOD in combination with physiotherapy may be a useful approach to CNP, being antioxidants that act on nerve inflammation and disease progression.

Clinical Rehabilitation Impact

These preliminary observations suggest that some interesting goals (better pain control and physical wellbeing) can be achieved by multimodal therapy in CNP patients.     

Pharmacokinetics of Coadministration of Guanfacine Extended Release and Methylphenidate Extended Release

Background

α₂-Adrenoceptor agonists are used adjunctively to psychostimulants in treating attention-deficit/hyperactivity disorder (ADHD) when psychostimulants alone do not sufficiently reduce symptoms. However, data on the pharmacokinetic profiles and safety of combination treatments in ADHD are needed.

Objective

The primary objective of this study was to evaluate the pharmacokinetic profiles of guanfacine extended release (GXR) and methylphenidate hydrochloride (MPH) extended release, alone and in combination.

Study Design

This was an open-label, randomized, three-period crossover, drug–drug interaction study.

Setting

The study was conducted at a single clinical research center.

Participants

Thirty-eight healthy adults were randomized in this study.

Interventions

Subjects were administered single oral doses of GXR (Intuniv^®; Shire Development LLC, Wayne, PA, USA) 4 mg, MPH (Concerta^®; McNeil Pediatrics, Titusville, NJ, USA) 36 mg, or GXR and MPH combined.

Main Outcome Measures

Guanfacine, dexmethylphenidate (d-MPH), and l-methylphenidate (l-MPH) levels were measured with blood samples collected predose and up to 72 h postdose. Safety evaluations included treatment-emergent adverse events (TEAEs), vital signs, and electrocardiograms (ECGs).

Results

Thirty-five subjects completed the study. Analyses of the 90 % confidence intervals (CIs) for the geometric mean ratios of the maximum plasma concentration (C_max) and area under the concentration–time curve extrapolated to infinity (AUC_∞) values for guanfacine and d-MPH following administration of GXR or MPH alone or combined met strict bioequivalence criteria (90 % CIs within the interval of 0.80–1.25). Overall, combining GXR and MPH did not alter the pharmacokinetic parameters of either medication. Sixteen subjects (42.1 %) had at least one TEAE. The most commonly reported TEAEs included headache and dizziness following GXR, MPH, and GXR and MPH combined. Two subjects had clinically significant abnormalities in ECG results following coadministration: both events were mild and resolved the same day.

Conclusions

In this short-term, open-label study of healthy adults, coadministration of GXR and MPH did not result in significant pharmacokinetic drug–drug interactions. No unique TEAEs were observed with coadministration of GXR and MPH compared with either treatment alone.     

A Multicenter,Open-Label Study of an Intravenous Short-Acting β1-Adrenergic Receptor Antagonist Landiolol Hydrochloride for Coronary Computed Tomography Angiography by 16-Slice Multi-Detector Computed Tomography in Japanese Patients with Suspected Ischemic Cardiac Disease

Background

During coronary computed tomography (CT) angiography (CCTA), β-blockers (β-adrenergic receptor antagonists) have commonly been used to lower heart rate and improve image quality.

Objectives

The aim of this study was to investigate the image quality-improving effect as well as the heart rate-lowering effect of landiolol hydrochloride (an intravenous short-acting β₁-adrenergic receptor antagonist) in CCTA by 16-slice multi-detector CT (MDCT).

Methods

A total of 39 subjects suspected of having ischemic cardiac disease and requiring CCTA received 0.125 mg/kg of landiolol hydrochloride to study the efficacy and safety of landiolol hydrochloride in a multicenter open-label clinical study. The endpoint was the diagnosable proportion (proportion of subjects whose coronary stenosis was diagnosable).

Results

The diagnosable proportions for the reconstruction images at mid-diastole were 56.0 %. The diagnosable proportions for the optimal reconstruction images were 65.4 %. The mean heart rate-lowering effect was observed soon after administration of landiolol hydrochloride; the peak of the effect was reached in 3–5 min, and the effect wore off in 30 min after completion of administration. The mean heart rate-lowering proportion at that time was −14.46 ± 8.4 %.

Conclusions

Landiolol hydrochloride was confirmed to reduce heart rate significantly and rapidly after intravenous injection and this suggests that the study drug is a safe and useful agent for improving the image quality of CCTA by 16-slice MDCT.     

Identification of an additional supraspinal component to the analgesic mechanism of action of buprenorphine

Background and purpose:

Buprenorphine displays attributes of opioids, but also some features distinct from them. We examined spinal and supraspinal signal transduction of buprenorphine-induced anti-nociception in mice compared with morphine and fentanyl.

Experimental approach:

The opioid receptor antagonist naloxone, Pertussis toxin (PTX), G_z protein antisense and nociceptin/orphanin-FQ receptor agonist nociceptin, and antagonist, JTC-801, were injected supraspinally (intracerebroventricular) and spinally (intrathecal). Also the cell-permeable Ser/Thr protein phosphatase inhibitor okadaic acid was given supraspinally.

Key results:

Spinal naloxone (20 µg) or PTX (1 µg) attenuated morphine, fentanyl and buprenorphine (s.c.) anti-nociception. Supraspinal naloxone or PTX attenuated morphine and fentanyl, but not buprenorphine anti-nociception. Spinal G_z protein antisense did not alter buprenorphine, morphine or fentanyl anti-nociception and supraspinal G_z-antisense did not alter morphine or fentanyl anti-nociception. However, supraspinal G_z-antisense (not random sense) reduced buprenorphine anti-nociception. Peripheral JTC-801 (1 mg·kg⁻¹, i.p.) enhanced the ascending (3 mg·kg⁻¹) and descending (30 mg·kg⁻¹) portions of buprenorphine''s dose–response curve, but only spinal, not supraspinal, nociceptin (10 nmol·L⁻¹) enhanced buprenorphine anti-nociception. Intracereboventricular okadaic acid (0.001–10 pg) produced a biphasic low-dose attenuation, high-dose enhancement of buprenorphine(3 or 30 mg·kg⁻¹, s.c.) anti-nociception, but did not affect morphine or fentanyl anti-nociception.

Conclusions and implications:

Buprenorphine has an opioid component to its supraspinal mechanism of analgesic action. Our present results reveal an additional supraspinal component insensitive to naloxone, PTX and nociceptin/orphanin-FQ, but involving G_z protein and Ser/Thr protein phosphatase. These data might help explain the unique preclinical and clinical profiles of buprenorphine.     

Evaluation of clinical activity and safety of Daflon 500 mg in type 2 diabetic female patients

Background

The incidence of cardiovascular disease in patients with type 2 diabetes mellitus is approximately twice as high as in the non-diabetic population.

Aim

To investigate the hypoglycemic and hypocholesterolemic effects of Daflon^® 500 mg (DF) administration together with its tolerability and efficacy in reducing the cardiovascular metabolic risk factors in female patients with type 2 diabetes.

Methods

In a well-adequate controlled single-blinded randomized parallel design the tolerability and the efficacy of Daflon^® (500 mg) either alone or with oral hypoglycemic, twice daily for 45 days, was studied in 36 female patients with type 2 diabetes.

Results

None of the patients in the studied groups were reported to have any adverse events throughout the treatment period (45 days), liver and kidney function tests were within normal limits and there was no significant difference between the pre-treatment (day 0) and post-treatment (day 45) values. Female patients receiving Daflon^® either alone or with oral hypoglycemic showed significant decrease in serum glucose; fructosamine; total cholesterol; LDL–cholesterol; triglycerides; malondialdehydes (as index of lipid peroxidation) and C-reactive protein (CRB) levels along with increase in the levels of nitric oxide and blood glutathione.

Conclusion

This study has shown that Daflon^® (500 mg, twice daily for 45 days) is helpful in reducing glucose level and the risk of cardiovascular disease in type 2 diabetic patients.

Recommendation

Further clinical trials are essential for strengthening the evidence base on the role of this drug in the cardiovascular risk in diabetic patients.     

An In Vitro Analysis of Disintegration Times of Different Formulations of Olanzapine Orodispersible Tablet: A Preliminary Report

Background

Orodispersible tablets (ODTs) are tablet or wafer forms of medication that disintegrate in the mouth, aided only by saliva. ODTs rely on different fast dissolve/disintegration manufacturing technologies.

Objectives

Disintegration time differences for several olanzapine ODT forms were investigated. Risperdal M-Tab^® was included as a non-olanzapine ODT comparator.

Research Design and Methods

Eleven olanzapine ODT examples and orodispersible risperidone strengths were evaluated in vitro for formulation composition, manufacturing method, disintegration and dissolution characteristics, and formulation differences in comparison with freeze dried Zydis^® ODT. Automated dissolution test equipment captured ODT dissolution rates by measuring real-time release of active ingredient. A high-speed video camera was used to capture tablet disintegration times in warm simulated saliva.

Main Outcome Measure

The main outcome measure was the disintegration and dissolution characteristics of the ODT formulations.

Results

The ODT manufacturing method was associated with time to disintegrate; the fastest were freeze dried tablets, followed by soft compressed tablets and then hard/dense tablets. Olanzapine Zydis^® was the only ODT that completely disintegrated in less than 4 s for all strengths (5, 10, 15, and 20 mg), followed by 5-mg Prolanz FAST^® (12 s) and then risperidone ODT 4 mg (40 s). Reasons for slow dissolution of the olanzapine generics may include low product potency, excipient binding, excipient solubility, active ingredient particle size and incomplete disintegration.

Conclusions

Differences in the formulation and manufacturing process of olanzapine ODTs appear to have a strong influence on the disintegration time of the active compound; differences that may potentially impact their use in clinical practice.

Electronic supplementary material

The online version of this article (doi:10.1007/s40268-013-0030-8) contains supplementary material, which is available to authorized users.     

Massive Naproxen Overdose with Serial Serum Levels

Context

Massive naproxen overdose is not commonly reported. Severe metabolic acidosis and seizure have been described, but the use of renal replacement therapy has not been studied in the context of overdose.

Case Details

A 28-year-old man ingested 70 g of naproxen along with an unknown amount of alcohol in a suicidal attempt. On examination in the emergency department 90 min later, he was drowsy but had normal vital signs apart from sinus tachycardia. Serum naproxen level 90 min after ingestion was 1,580 mg/L (therapeutic range 25–75 mg/L). He developed metabolic acidosis requiring renal replacement therapy using sustained low efficiency dialysis (SLED) and continuous venovenous hemofiltration (CVVH) and had recurrent seizure activity requiring intubation within 4 h from ingestion. He recovered after 48 h.

Discussion

Massive naproxen overdose can present with serious toxicity including seizures, altered mental status, and metabolic acidosis.

Conclusion

Hemodialysis and renal replacement therapy may correct the acid base disturbance and provide support in cases of renal impairment in context of naproxen overdose, but further studies are needed to determine the extraction of naproxen.     

Stealth Amphotericin B nanoparticles for oral drug delivery: In vitro optimization

Purpose

Amphotericin B (AmB) is an effective anti-fungal and anti-leishmanial agent. However, AmB has low oral bioavailability (0.3%) and adverse effects (e.g., nephrotoxicity). The objectives of this study were to improve the oral bioavailability by entrapping AmB in pegylated (PEG) poly lactide co glycolide copolymer (PLGA–PEG) nanoparticles (NPs). The feasibility of different surfactants and stabilizers on the mean particle size (MPS) and entrapment efficiency were also investigated.

Materials and methods

NPs of AmB were prepared by a modified emulsification diffusion method employing a vitamin E derivative as a stabilizer. Physicochemical properties and particle size characterization were evaluated using Fourier Transform Infra-Red spectroscopy (FTIR), differential scanning calorimetry, scanning electron microscopy and transmission electron microscopy. Moreover, in vitro dissolution profiles were performed for all formulated AmB NPs.

Results

MPS of the prepared spherical particles of AmB ranged from 26.4 ± 2.9 to 1068 ± 489.8 nm. An increased stirring rate favored AmB NPs with a smaller MPS. There was a significant reduction in MPS, drug content and drug release, when AmB NPs were prepared using the diblock polymer PLGA–PEG with 15% PEG. Addition of three emulsifying agents poly vinyl pyrrolidone (PVP), Vitamin E (TPGS) and pluronic F-68 to AmB formulations led to a significant reduction in particle size and increase in drug entrapment efficiency (DEE) compared to addition of PVP alone. FTIR spectroscopy demonstrated a successful loading of AmB to pegylated PLGA–PEG copolymers. PLGA–PEG copolymer entrapment efficiency of AmB was increased up to 56.7%, with 92.7% drug yield. After a slow initial release, between 20% and 54% of AmB was released in vitro within 24 h phosphate buffer containing 2% sodium deoxycholate and were best fit Korsmeyer–Peppas model. In conclusion, PLGA–PEG diblock copolymer with 15% PEG produced a significant reduction (>70%) in MPS with highest drug content. The percentage of PEG in the copolymer and the surfactant/stabilizer used had a direct effect on AmB release in vitro, entrapment efficiency and MPS. These developed formulations are feasible, effective and improved alternatives to other carriers for oral delivery of AmB.     

Disposition and Metabolism of Setipiprant,a Selective Oral CRTH2 Antagonist,in Humans

Background

Setipiprant, a tetrahydropyridoindole derivative, is a CRTH2 (chemoattractant receptor-homologous molecule expressed on T-helper [Th]-2 cells) antagonist that has the potential to be effective in the treatment of patients with diseases with an allergic etiology, such as allergic rhinitis and asthma.

Objectives

This study investigated the disposition, metabolism, and elimination of setipiprant.

Study design

In this open-label study, a single oral dose of 1,000 mg ¹⁴C-labeled setipiprant was administered.

Participants

Six healthy male subjects were enrolled in this study.

Results

The radioactive dose was almost completely recovered in feces (88.2 %) and to a smaller extent in urine (11.7 %). The main recovery route for unchanged setipiprant was feces (50 % of the radioactive dose). The recovered amount of unchanged setipiprant in urine accounted for 3.7 %. The two main metabolites were M7 and M9 with the intact tetrahydropyridoindole core of setipiprant. M7 and M9 are supposedly two distinct dihydroxy-dihydronaphthalene isomers assumed to be formed by intermediate epoxidation of the naphthyl ring followed by a hydrolytic epoxide ring-opening. M7 and M9 accounted for 20.0 and 15.3 % of the administered radioactive dose. Both metabolites were mainly excreted via feces and to a lesser extent via urine. M7 was the only metabolite quantifiable in plasma, but at concentrations consistently below 10 % of those of the parent drug.

Conclusion

Setipiprant is mainly excreted in feces in the form of the parent drug and in smaller amounts as its metabolites M7 and M9.     

Saudi young patient understanding of information about side effects: Verbal versus numerical expression

Objective

To determine the effect of providing different formats about side effect information (verbal versus numerical) to acne patients in Saudi Arabia that are newly prescribed Roaccutane.

Design

A prospective study assessing patients’ degree of estimation about side effect information.

Participants

One hundred and forty-one acne patients newly prescribed Roaccutane.

Settings

Four dermatology clinics in Riyadh. Two in tertiary hospitals and the other two in private clinics.

Intervention

Each patient received information about two different side effects for Roaccutane. The side effect provided was supplemented with the probability of occurrence, which was written either in words or in numbers. (Dry eye “very common” or “30%”; Loss of hair “rare” or “0.01%”).

Main outcome measures

Patient’s estimation of side effect occurrence. Other outcomes were the likelihood of experiencing the side effect, the severity of the side effect, their perception of risk of the side effects to their general health, their satisfaction with the information provided and, whether the information provided will influence their decision to take the medicine.

Result

The mean estimate for side effect occurrence for the dry eyes was 46% in the verbal group and 41% in the numerical group (p = 0.5); for loss of hair it was 50% in the verbal group and 39% in the numerical group (p = 0.03). There are no significant differences between verbal and numerical groups regarding the remaining measures.

Conclusion

Patients overestimate the probability of occurrence of side effect. Verbal format of probability of occurrence is associated with higher estimation than the numerical format.     

Investigation of the Hemostatic Effect of a Transdermal Patch Containing 0.55?mg Ethinyl Estradiol and 2.1?mg Gestodene Compared with a Monophasic Oral Contraceptive Containing 0.03?mg Ethinyl Estradiol and 0.15?mg Levonorgestrel: An Open-Label,Randomized, Crossover Study

Background

Transdermal delivery of contraceptives offers several advantages over combined oral contraceptives (COCs), including effective absorption and the provision of relatively constant serum concentrations. Ethinyl estradiol (EE) and the progestin gestodene are well-absorbed through the skin and, therefore, well-suited for use in a transdermal contraceptive patch.

Objective

The objective of this study was to investigate the impact of a once-weekly transparent, transdermal patch delivering low doses of EE and gestodene equivalent to a COC containing 0.02 mg EE and 0.06 mg gestodene on hemostasis parameters compared with a monophasic COC containing 0.03 mg EE and 0.15 mg levonorgestrel.

Methods

In this single-center, open-label, randomized, crossover study, 30 women (aged 18–35 years) received three cycles of each treatment, separated by a two-cycle washout period. The primary outcome measure was the absolute change from baseline in prothrombin fragments 1 + 2 and d-dimer.

Results

For both treatments, prothrombin fragments 1 + 2 remained stable during the first treatment period, and increased only slightly in the second period (mean absolute change 0.025 and 0.028 nmol/L in the novel Bayer patch and COC groups, respectively). Increases in d-dimer were observed in both periods (mean absolute change 107.0 ± 147.2 ng/L for the novel Bayer patch and 113.7 ± 159.0 ng/L for the COC). There were no statistically significant treatment differences in prothrombin 1 + 2 or d-dimer (p = 0.667 and p = 0.884, respectively) and no statistically significant treatment sequence or period effects.

Conclusion

A COC containing 0.03 mg EE and 0.15 mg levonorgestrel and the novel Bayer patch have comparable influence on hemostatic endpoints. Both treatments were well-tolerated by subjects.