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Concept: Dosage forms

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Problems with the use of inhalers by patients were noted shortly after the launch of the metered dose inhaler (MDI) and persist today. We aimed to assess the most common errors in inhaler use over the last 40 years in patients treated with MDI or dry powder inhalers (DPI).

Concepts: Asthma, Patient, Metered-dose inhaler, Dry powder inhaler, Dosage forms, Inhaler, Nebulizer, Drug delivery devices

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Abstract A promising glipizide formulation comprising compression of four-layer coated beads into tablets was prepared. The tablet offered the advantages of: a two-hour lag time before drug release, retaining sustained release characteristics and providing approximately zero-order drug release. Drug release was nearly independent of paddle speeds of 50 and 100 rpm releasing 80% over 14 h similar to the commercial glipizide osmotic pump tablet during dissolution testing while keeping the benefits of multiparticular dosage forms. The tablets contain beads with four layers: (1) the innermost layer consists of 2.5 g glipizide and 3.75 g solid ethylcellulose (Surelease®) coated onto 71.25 g of sugar beads; (2) next a hardening layer of 5 g of hypromellose; (3) the controlled release layer of 7.5 g of Surelease®:lactose at a solids ratio of 100:7 and (4) an outermost layer of 20 g of lactose:sodium starch glycolate (Explotab®) at a 2:1 ratio. Then, beads were compressed into tablets containing 11 mg of glipizide using 1500 lbs of compression pressure. The dissolution test similarity factor (f(2)) was above 50 for all test conditions for formulation F13 and Glucotrol® with a high of 69.9. The two Surelease® layers both aid controlling drug release, with the Surelease®-drug layer affecting drug release to a greater extent.

Concepts: Pharmacology, Pharmaceutical formulation, Excipient, Dosage forms, Compression

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Pharmaceutical development and manufacturing process optimization work was undertaken in order to propose a potential paediatric rectal formulation of azithromycin as an alternative to existing oral or injectable formulations. The target product profile was to be easy-to-use, cheap and stable in tropical conditions, with bioavailability comparable to oral forms, rapidly achieving and maintaining bactericidal concentrations. PEG solid solution suppositories were characterized in vitro using visual, HPLC, DSC, FTIR and XRD analyses. In vitro drug release and in vivo bioavailability were assessed; a study in rabbits compared the bioavailability of the optimized solid solution suppository to rectal solution and intra-venous product (as reference) and to the previous, non-optimized formulation (suspended azithromycin suppository). The bioavailability of azithromycin administered as solid solution suppositories relative to intra-venous was 43%, which compared well to the target of 38% (oral product in humans). The results of three month preliminary stability and feasibility studies were consistent with industrial production scale-up. This product has potential both as a classical antibiotic and as a product for use in severely ill children in rural areas. Industrial partners for further development are being sought.

Concepts: Pharmacology, Medicine, In vivo, In vitro, Pharmaceutical drug, Rectum, Dosage forms, Suppository

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AIMS: Fostamatinib (R788) is an orally-dosed prodrug designed to deliver the active metabolite R940406 (R406), a spleen tyrosine kinase (SYK) inhibitor, for the treatment of rheumatoid arthritis. The objectives were to evaluate the human pharmacokinetic properties of fostamatinib and R406. METHODS: Three clinical studies were conducted in healthy subjects: (A) A single ascending-dose study for R406 with doses ranging from 80-600 mg, (B) A single and multiple-dose study of fostamatinib in aqueous suspension, with single doses ranging from 80-400 mg and multiple doses at 160 mg bid, and © A study comparing suspension and tablet of fostamatinib, with the latter tested in both fed and fasted states. RESULTS: These studies demonstrated that when administered as a solution, R406 was rapidly absorbed. Increases in exposure were observed with doses up to 400 mg. A terminal half-life of 12-21 h was observed. Similar R406 exposure could be achieved with fostamatinib suspension, and steady-state was achieved after 3-4 days following twice-daily administration. Fostamatinib tablet and suspension exhibited similar R406 exposure. Upon coadministration with food, a delay in peak time and lower peak concentrations of R406 were observed, at the same time the overall exposure did not change. CONCLUSIONS: Fostamatinib demonstrates rapid and extensive conversion to R406, an inhibitor of SYK. Solid dosage forms of fostamatinib overcome the challenge of low aqueous solubility of R406. The PK profile of R406 could potentially allow once-daily or twice-daily oral administration of fostamatinib.

Concepts: Pharmacology, Rheumatoid arthritis, Solubility, Protein kinase, Dose, Pharmacokinetics, Syk, Dosage forms

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Context: Continuous processing is becoming popular in the pharmaceutical industry for its cost and quality advantages. Objective: This study evaluated the mechanical properties, uniformity of dosage units and drug release from the tablets prepared by continuous direct compression process. Materials and methods: The tablet formulations consisted of acetaminophen (3-30% (w/w)) pre-blended with 0.25% (w/w) colloidal silicon dioxide, microcrystalline cellulose (69-96% (w/w)) and magnesium stearate (1% (w/w)). The continuous tableting line consisted of three loss-in-weight feeders and a convective continuous mixer and a rotary tablet press. The process continued for 8 min and steady state was reached within 5 min. The effects of acetaminophen content, impeller rotation rate (39-254 rpm) and total feed rate (15 and 20 kg/h) on tablet properties were examined. Results and discussion: All the tablets complied with the friability requirements of European Pharmacopoeia and rapidly released acetaminophen. However, the relative standard deviation of acetaminophen content (10% (w/w)) increased with an increase in impeller rotation rate at a constant total feed rate (20 kg/h). A compression force of 12 kN tended to result in greater tablet hardness and subsequently a slower initial acetaminophen release from tablets when compared with those made with the compression force of about 8 kN. Conclusions: In conclusion, tablets could be successfully prepared by a continuous direct compression process and process conditions affected to some extent tablet properties.

Concepts: Pharmacology, Pharmaceutical industry, Silicon dioxide, Pharmaceutical formulation, Tablet, Pill splitting, Dosage forms, Tablet press

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The purpose of this study was to directly compare the pharmacokinetic (PK) profile of 22-mg sumatriptan powder delivered intranasally with a novel Breath Powered™ device (11 mg in each nostril) vs a 20-mg sumatriptan liquid nasal spray, a 100-mg oral tablet, and a 6-mg subcutaneous injection.

Concepts: Pharmacology, Pharmacokinetics, Nose, Dosage forms, Subcutaneous injection, Nasal administration, Nasal spray

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Acapella® 27 produces high frequency oscillations and positive expiratory pressure (HFOPEP) for use in bronchial hygiene. However, its performance in aerosol delivery has not been described. The aim of this study was to evaluate the effect of nebulizer configuration in relation to the HFOPEP device on deposition of radiotagged aerosols with healthy subjects.

Concepts: Asthma, Aerosol, Dosage forms, Nebulizer, Aerosol spray, Configuration management, CS gas

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An interaction between device resistance and inhalation flow provides the ‘energy’ to de-aggregate the metered dose of a dry powder inhaler (DPIs). Hence all dry powder inhalers demonstrate flow dependent dose emission but information on this at low flows is not available. We have adapted the compendial method for the Andersen Cascade Impactor (ACI) to include a mixing inlet to determine the aerodynamic dose emission characteristics of a salbutamol Diskus® [DSK], Easyhaler® [EASY] and Clickhaler® [CLICK] and the terbutaline Turbuhaler® [TBH] using flows of 10-60L/min and inhalation volumes of 2 and 4L. All DPIs demonstrated flow dependent dose emission (p<0.001) but there was no difference in the measurements between 2 and 4L. The flow dependent dose emission properties of each DPI started to plateau when the pressure change inside each device, during an inhalation, was between 1-1.5kPa. This corresponds to inhalation flows of 40.1-49.1, 25.4-28.9, 23.6-28.9 and 29.7-36.3L/min through DSK, CLICK, TBH, and EASY. The adapted methodology allows measurements at low flows. The results highlight that the compendial methodology to use an inhaled volume of 4L with the ACI could be replaced by 2L and that the recommendation to make measurements using a pressure drop of 4kPa should be revised.

Concepts: Asthma, Volume, Thermodynamics, Metered-dose inhaler, Dry powder inhaler, Dosage forms, Inhaler, Nebulizer

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Inhalers are devices employed to deliver medication to the airways in the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease. A dry powder inhaler (DPI) is a breath actuated inhaler that delivers medication in dry powder form. When used correctly, DPIs improve patients' clinical outcomes. However, some patients are unable to reach the peak inspiratory flow rate (PIFR) necessary to fully extract the medication. Presently clinicians have no reliable method of objectively measuring PIFR in inhalers. In this study, we propose a novel method of estimating PIFR and also the inspiratory capacity (IC) of patients' inhalations from a commonly used DPI, using acoustic measurements. With a recording device, the acoustic signal of 15 healthy subjects using a DPI over a range of varying PIFR and IC values was obtained. Temporal and spectral signal analysis revealed that the inhalation signal contains sufficient information that can be employed to estimate PIFR and IC. It was found that the average power (Pave) in the frequency band 300-600 Hz had the strongest correlation with PIFR (R(2) = 0.9079), while the power in the same frequency band was also highly correlated with IC (R(2) = 0.9245). This study has several clinical implications as it demonstrates the feasibility of using acoustics to objectively monitor inhaler use.

Concepts: Medicine, Asthma, Chronic obstructive pulmonary disease, Respiratory system, Metered-dose inhaler, Dry powder inhaler, Dosage forms, Inhaler

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Objectives: The objective of this randomised, cross-over study was to compare a new single-dose dry powder inhaler (Elpenhaler (EH)), with a widely used, multi-dose dry powder inhaler (Diskus (DK)) on critical errors, patient preference, and satisfaction with the inhalers. Methods: First, patients read the instructions of one device, followed by a first inhalation attempt. Inhalation errors were assessed and if mistakes were made, correct inhaler use was demonstrated. Then patients had to demonstrate again and mistakes were registered. This was repeated up to four times. After completing the first device, the same procedure was started with the second inhaler. Primary outcome was the percentage of patients making at least one critical error after reading the insert. Secondary outcomes were inhaler preference and satisfaction with the inhalers. Results: After reading the insert, 19 of 113 patients (17%) made at least one critical error with DK and 40 (35%) with EH (p = 0.001); 73% preferred the DK and 27% the EH (p < 0.001). The mean overall satisfaction score (1 = very satisfied; 5 = very dissatisfied) for DK was 1.59 and for EH 2.48 (p < 0.001). Conclusion: With DK fewer errors were made, more patients preferred DK over EH and patients were more satisfied with DK. This may enable DK to improve treatment outcomes more than EH.

Concepts: Asthma, Chronic obstructive pulmonary disease, Error, Metered-dose inhaler, Dry powder inhaler, Dosage forms, Inhaler, Drug delivery devices