Prefilled Cyclic Olefin Sterilized Syringes of Norepinephrine Injection Solution Do Not Need to Be Stabilized by Antioxidants

Norepinephrine is a potent α-sympathomimetic drug which plays an important role in the acute treatment of hypotension and shock. Commercially available norepinephrine solutions contain sodium metabisulfite (Na2S2O5) as an antioxidant. However, prefilled cyclic olefin polymer syringes are not compatible with sodium metabisulfite. The aim of this study was to develop a new formulation of 0.1-mg/mL norepinephrine solution without sodium metabisulfite which is chemically stable and sterile and can be stored in prefilled polymer syringes. Formulation studies were performed with 0.1-mg/mL norepinephrine solution with 0, 0.05, or 0.1% ascorbic acid added as antioxidant. The syringes were filled under nitrogen gassing, stored at 20 ± 5°C, and protected from daylight. Based on the formulation test results, the final formulation was defined and stability testing at 20 ± 5°C was performed measuring norepinephrine concentration, pH, clarity, color of the solution, subvisible particles, and sterility at time intervals up to 12 months. The norepinephrine concentrations at t = 22 weeks were 100.4%, 95.4%, and 92.2% for the formulations with no ascorbic acid and with 0.05% and 0.10% ascorbic acid, respectively. Three batches for the stability study were produced containing norepinephrine, sodium edetate, sodium chloride, and water for injections filled under nitrogen gassing and stored at 20 ± 5°C. Norepinephrine concentrations were respectively 98.8%, 98.6%, and 99.3% for batches 1, 2, and 3 at t = 12 months. It can be concluded that norepinephrine (0.1 mg/mL) solution without metabisulfite is stable for at least 12 months at room temperature when protected from daylight

Comparative in vitro evaluation of four corticosteroid metered dose inhalers:Consistency of delivered dose and particle size distribution

SummaryIntroductionRecent developments concerning pressurized metered dose inhalers (pMDIs) with inhaled corticosteroids (ICS) are the introduction of ciclesonide and the replacement of propellants. As the results of in vivo studies depend on pMDIperformance, it is necessary to evaluate pMDIs in vitro for delivered dose and particle size distributions under different conditions.MethodsFluticasone 125μg, budesonide 200μg, beclomethasone HFA100μg, and ciclesonide 160μg were compared for delivered dose and particle size using laser diffraction analysis with inspiratory flow rates of 10, 20 and 30l/s.ResultsThe volume median diameter of budesonide was 3.5μm, fluticasone 2.8μm, beclomethasone and ciclesonide both 1.9μm. The mouthpiece retention was up to 30% of the nominal dose for beclomethasone and ciclesonide, 11–19% for the other pMDIs. Lifespan, flow rate, and air humidity had no significant influence on particle size distribution. The delivered dose of beclomethasone, budesonide, and ciclesonide remained constant over the lifespan. The delivered dose of fluticasone 125 decreased from 106% to 63%; fluticasone 250 also decreased whereas fluticasone 50 remained constant.ConclusionsThere is a significant difference in median particle size distribution between the different ICS pMDIs. Air humidity and inspiratory flow rate have no significant influence on particle size distribution. Ciclesonide 160 and beclomethasone 100 deliver the largest fine particle fractions of 1.1–3.1μm. The changes in delivered dose during the lifespan for the fluticasone 125 and 250 may have implications for patient care

A levodopa dry powder inhaler for the treatment of Parkinson's disease patients in off periods

Adequate treatment of Parkinson's patients in off periods with orally administered levodopa is hindered by a poor bioavailability and a slow onset of action. Hence, there is a need for a fast and reliable alternative as for instance via pulmonary administration of the drug. We developed a levodopa containing powder formulation for pulmonary delivery by a recently presented high dose dry powder inhaler (Cyclops). The objective was to produce the drug formulation by means of simple techniques such as micronization, either as pure active substance or with a minimum amount of excipients. After an initial screening on dispersion behaviour, the most promising formulation in the Cyclops was characterized in vitro over a range of pressure drops (2-6 kPa) and doses (20, 30 and 40 mg), representative of those to be expected in practice. A co-micronized levodopa formulation with 2% l-leucine appeared to yield the best aerosol properties for inhalation and highest delivered dose reproducibility. The combination of this particular formulation and the Cyclops inhaler seems to meet the basic requirements for satisfactory deposition in the airways. This formulation is therefore expected to be a promising candidate for the treatment of Parkinson's patients in an off period

The pharmacokinetics of antibiotics in cystic fibrosis

Introduction Dosing of antibiotics in people with cystic fibrosis (CF) is challenging, due to altered pharmacokinetics, difficulty of lung tissue penetration, and increasing presence of antimicrobial resistance. Areas covered The purpose of this work is to critically review original data as well as previous reviews and guidelines on pharmacokinetics of systemic and inhaled antibiotics in CF, with the aim to propose strategies for optimization of antibacterial therapy in both children and adults with CF. Expert opinion For systemic antibiotics, absorption is comparable in CF patients and non-CF controls. The volume of distribution (Vd) of most antibiotics is similar between people with CF with normal body composition and healthy individuals. However, there are a few exceptions, like cefotiam and tobramycin. Many antibiotic class-dependent changes in drug metabolism and excretion are reported, with an increased total body clearance for ss-lactam antibiotics, aminoglycosides, fluoroquinolones, and trimethoprim. We, therefore, recommend following class-specific guidelines for CF, mostly resulting in higher dosages per kg bodyweight in CF compared to non-CF controls. Higher local antibiotic concentrations in the airways can be obtained by inhalation therapy, with which eradication of bacteria may be achieved while minimizing systemic exposure and risk of toxicity

A systematic review and meta-analysis of microbial contamination of parenteral medication prepared in a clinical versus pharmacy environment

Purpose Preparation of parenteral medication in hospitals is a complex process with a risk of microbial contamination of the product, especially when inappropriately prepared. Contaminated parenteral medications can cause severe complications to patients and increase morbidity in hospitals. The aim of this literature review is to systematically evaluate the contamination rate of parenteral medications in hospitals prepared in a pharmacy environment and a clinical environment. Methods A literature search of PubMed and EMBASE from 2000 to 2018 was performed. Two different environments where preparation may be carried out were defined. Point estimates and 95% confidence intervals for contamination rates were calculated for each environment of medication preparation. The meta-analysis was performed using a random effects model. Results The contamination rates in the clinical environment (n = 13 studies) varied between 1.09 and 20.70%. In the pharmacy environment (n = 5), all contamination rates were 0.00% except for one study (0.66%). The point estimates (random effect model) for the overall contamination rate of doses prepared in the clinical environment was 7.47% (5.16-9.79%), and 0.08% for doses prepared in the pharmacy environment. The point estimates (random effect model) for the overall contamination rate of doses prepared by nursing/ medical staff was 7.85% (5.18-10.53%), and 0.08% for doses prepared by pharmacy staff. Conclusions Significantly higher contamination rates were found for the preparation of parenteral medication in the clinical environment compared to pharmacy environment. In accordance with recent guidance, the almost 100-fold higher changes of contamination when reconstitution is performed in the clinical environment should urge hospitals to review their reconstitution process and apply risk-reducing measures to improve patient safety of parenteral therapy

pH-dependent ileocolonic drug delivery, part I:in vitro and clinical evaluation of novel systems

After the pH dependency of novel pH-dependent ileocolonic drug delivery systems is confirmed in vitro, their performance should be evaluated in human volunteers

Can 'extrafine' dry powder aerosols improve lung deposition?

There is increasing interest in the use of so-called ‘extrafine’ aerosols to target the small airways in the management of asthma and COPD. Using previously presented deposition data, we assessed whether submicron (<1 μm) particles can improve central and deep lung deposition. Our data show instead that particles in the range 1–3 μm are much more relevant in this respect. Based on this finding the Symbicort Turbuhaler, Seretide Diskus, Rolenium Elpenhaler and Foster (Fostair) NEXThaler ICS/LABA combination DPIs were tested in vitro as a function of the pressure drop (2, 4 and 6 kPa) across the inhaler. Obtained fine particle fractions (FPFs) <5 μm (as percent of label claim) were divided into subfractions <1, 1–3 and 3–5 μm. Differences of up to a factor of 4 were found between the best (Turbuhaler) and worst performing DPI (Elpenhaler), particularly for the FPF in the size range 1–3 μm. The NEXThaler, described as delivering ‘extrafine’ particles, did not appear to be superior in this size range. The marked differences in amount and size distribution of the aerosols between the devices in this study must cause significant differences in the total lung dose and drug distribution over the airways

Tolerability and pharmacokinetic evaluation of inhaled dry powder hydroxychloroquine in healthy volunteers

RATIONALE: Inhaled antimicrobials enable high local concentrations where needed and, compared to orally administration, greatly reduce the potential for systemic side effects. In SARS-CoV-2 infections, hydroxychloroquine sulphate (HCQ) administered as dry powder via inhalation could be safer than oral HCQ allowing higher and therefore more effective pulmonary concentrations without dose limiting toxic effects. OBJECTIVES: To assess the local tolerability, safety and pharmacokinetic parameters of HCQ inhalations in single ascending doses of 5, 10 and 20 mg using the Cyclops dry powder inhaler. METHODS: Twelve healthy volunteers were included in the study. Local tolerability and safety were assessed by pulmonary function tests, electrocardiogram and recording adverse events. To estimate systemic exposure, serum samples were collected before and 0.5, 2 and 3.5 h after inhalation. RESULTS AND DISCUSSION: Dry powder HCQ inhalations were well tolerated by the participants, except for transient bitter taste in all participants and minor coughing irritation. There was no significant change in QTc-interval or drop in FEV1 post inhalation. The serum HCQ concentration remained below 10 μg/L in all samples. CONCLUSION: Single doses of inhaled dry powder HCQ up to 20 mg are safe and well tolerated. Our data support that further studies with inhaled HCQ dry powder to evaluate pulmonary pharmacokinetics and efficacy are warranted

Colistin dry powder inhalation with the Twincer (TM):An effective and more patient friendly alternative to nebulization

BACKGROUND: Nebulization of antimicrobial drugs such as tobramycin and colistin is a cornerstone in the treatment of patients with cystic fibrosis (CF) infected with Pseudomonas aeruginosa. However, nebulization has a high treatment burden. The Twincer™ is a dry powder inhaler specifically developed for the inhalation of antibiotics such as colistin. The aim of this study was to compare patient outcomes and experience with colistin dry powder by the Twincer with nebulization of colistin or tobramycin in adult CF patients in a real-life setting. METHODS: This was a retrospective study from 01-01-2015 until 01-07-2018. Effectiveness was evaluated by comparing FEV1 decline and exacerbation rate during a mean of 4.1 years of nebulization therapy prior to the initiation of the Twincer against the same values during a mean of 1.7 years of treatment with the Twincer. RESULTS: Twenty-one patients were evaluated, of whom twelve could be included in the effectiveness analysis, with a total of twenty patient years. Of all patients 71.4% preferred therapy with the Twincer over nebulization. Twincer use resulted in high treatment adherence with an average adherence rate of 92.5%. There was no significant difference in annual decline in FEV1%pred prior to and after start changing from nebulization to the use of the Twincer powder inhaler (median decline -1.56 [-5.57-5.31] and 1.35 [-8.45-6.36]) respectively, p = 0.45 (linear mixed effect model)). No significant difference was found in the number of intravenous or combined total intravenous and oral antibiotic courses during Twincer therapy compared to when using nebulization (1.68 and 2.49 courses during Twincer therapy versus 1.51 and 2.94 courses during nebulization, p = 0.88 and p = 0.63). CONCLUSION: Colistin dry powder inhalation with the Twincer is a more patient friendly alternative to nebulization, and we did not observe significant differences in the clinical outcome, regarding lung function and exacerbation rates

Tolerability and Pharmacokinetic Evaluation of Inhaled Dry Powder Tobramycin Free Base in Non-Cystic Fibrosis Bronchiectasis Patients

Rationale Bronchiectasis is a condition characterised by dilated and thick-walled bronchi. The presence of Pseudomonas aeruginosa in bronchiectasis is associated with a higher hospitalisation frequency and a reduced quality of life, requiring frequent and adequate treatment with antibiotics. Objectives To assess local tolerability and the pharmacokinetic parameters of inhaled excipient free dry powder tobramycin as free base administered with the Cyclops dry powder inhaler to participants with non-cystic fibrosis bronchiectasis. The free base and absence of excipients reduces the inhaled powder dose. Methods Eight participants in the study were trained in handling the device and inhaling correctly. During drug administration the inspiratory flow curve was recorded. Local tolerability was assessed by spirometry and recording adverse events. Serum samples were collected before, and 15, 30, 45, 60, 75, 90, 105, 120 min; 4, 8 and 12 h after inhalation. Results and Discussion Dry powder tobramycin base was well tolerated and mild tobramycin-related cough was reported only once. A good drug dose-serum concentration correlation was obtained. Relatively small inhaled volumes were computed from the recorded flow curves, resulting in presumably substantial deposition in the central airways-i.e., at the site of infection. Conclusions In this first study of inhaled dry powder tobramycin free base in non-cystic fibrosis bronchiectasis patients, the free base of tobramycin and the administration with the Cyclops dry powder device were well tolerated. Our data support further clinical studies to evaluate safety and efficacy of this compound in this population