Study of pressurised metered dose inhalers for the purpose of standardization of quality attributes characterizing uniformity of dosing

Aim. The purpose was to provide the rationale of test in regard to uniformity of fine particles dose for pressurised metered dose inhalers (pMDIs). Materials and methods. The pMDIs containing suspensions of salbutamol sulfate (SS) or solutions of beclometasone dipropionate (BD) were studied by laser diffraction and high performance liquid chromatography (HPLC). The particle size distribution of SS, the average dose mass and uniformity of dose mass, the average delivered dose and the uniformity of delivered dose, the average fine particles dose and uniformity of fine particles dose were determined. Apparatus A was used for assessment of fine particles dose. Results. The two analytical procedures for the quantitative determination of SS and BD by HPLC were validated in the ranges with low concentrations of these substances. The 5 medicinal products in pMDI dosage form were studied: 3 preparations were with SS and 2 ones contained BD. It was shown that three products with SS were very similar in regard to particle size distribution in containers and the average values of delivered dose were almost the same, but these products were different in the average dose mass and fine particle dose. According to the research results, the expediency of determining the average dose mass and the tests concerning uniformity of dosing of preparations by dose mass and by fine particle dose was substantiated. It was shown that in the case of pMDI the dosing of solutions of BD was more uniform compared to suspensions of SS. The approaches of leading and other pharmacopoeias concerning uniformity of dosing for pMDIs were critically discussed. The expediency of determination of uniformity of fine particle dose at the stage of pharmaceutical development was substantiated, as the therapeutic effect depends on fine particle dose. Issues concerning standardization pMDIs in regard to uniformity of fine particle dose were discussed. Conclusions. The expediency of standardization and quality control of pMDIs in regard to such attributes as the average dose mass, which characterizes the volume of the metering chamber of the valve as well as the uniformity of the dose mass and the uniformity of fine particle dose, which assure the therapeutic effect of each dose of the product was substantiated

Biosafety of mesoporous silica nanoparticles: a combined experimental and literature study

Mesoporous silica (MS) particles have been explored for various healthcare applications, but universal data about their safety and/or toxicity are yet to be well-established for clinical purposes. Information about general toxicity of hollow MS (HMS) particles and about immunotoxicity of MS particles are significantly lacked. Therefore, acute toxicity and immunotoxicity of HMS particles were experimentally evaluated. A systematic and objective literature study was parallelly performed to analyze the published in vivo toxicity of MS particles. Lethal acute toxicity of MS particles is likely to arise from their physical action after intravenous and intraperitoneal administrations, and only rarely observed after subcutaneous administration. No clear relationship was identified between physicochemical properties of MS particles and lethality as well as maximum tolerated dose with some exceptions. At sub-lethal doses, MS particles tend to accumulate mainly in lung, liver, and spleen. The HMS particles showed lower inflammation-inducing ability than polyinosinic-polycytidylic acid and almost the same allergy-inducing ability as Alum. Finally, the universal lowest observed adverse effect levels were determined as 0.45, 0.81, and 4.1 mg/kg (human equivalent dose) for intravenous, intraperitoneal, and subcutaneous administration of MS particles, respectively. These results could be helpful for determining an appropriate MS particle dose in clinical study.

Inspiratory flows and the aerosol cloud from dry powder inhalers

The relationship between the delivered dose, the fine particle fraction and the fine particle dose and the value of inspiratory flow generated by the patient is one of the most important features of dry powder inhalers (DPIs). It significantly affects the amount of pulmonary deposition of the inhaled drug and the clinical effect of the drug. The results of research evaluating these relationships for popular in Poland dry powder inhalers are presented. Flow-dependent, relatively flow-dependent and relatively flow-independent inhalers are demonstrated.

First measurements of the radiation dose on the lunar surface

Human exploration of the Moon is associated with substantial risks to astronauts from space radiation. On the surface of the Moon, this consists of the chronic exposure to galactic cosmic rays and sporadic solar particle events. The interaction of this radiation field with the lunar soil leads to a third component that consists of neutral particles, i.e., neutrons and gamma radiation. The Lunar Lander Neutrons and Dosimetry experiment aboard China’s Chang’E 4 lander has made the first ever measurements of the radiation exposure to both charged and neutral particles on the lunar surface. We measured an average total absorbed dose rate in silicon of 13.2 ± 1 μGy/hour and a neutral particle dose rate of 3.1 ± 0.5 μGy/hour.

Compatible Stability and Aerosol Characteristics of Atrovent® (Ipratropium Bromide) Mixed with Salbutamol Sulfate, Terbutaline Sulfate, Budesonide, and Acetylcysteine

(1) Background: It is common practice in the treatment of respiratory diseases to mix different inhalation solutions for simultaneous inhalation. At present, a small number of studies have been published that evaluate the physicochemical compatibility and aerosol characteristics of different inhalation medications. However, none of them studied Atrovent®. Our work aims to address the lack of studies on Atrovent®. (2) Methods: Portions of admixtures were withdrawn at certain time intervals after mixing and were tested by pH determination, osmolarity measurement, and high-performance liquid chromatography (HPLC) assay of each active ingredient as measures of physicochemical compatibility. The geometrical and aerosol particle size distribution, active drug delivery rate, and total active drug delivered were measured to characterize aerosol behaviors. (3) Results: During the testing time, no significant variation was found in the pH value, the osmotic pressure, or the active components of admixtures. With the increase in nebulization volume after mixing, fine particle dose (FPD) and total active drug delivered showed statistically significant improvements, while the active drug delivery rate decreased compared to the single-drug preparations. (4) Conclusions: These results endorse the physicochemical compatibility of Atrovent® over 1 h when mixed with other inhalation medications. Considering aerosol characteristics, simultaneous inhalation is more efficient.

Generation of High Dose Inhalable Effervescent Dispersions against Pseudomonas aeruginosa Biofilms

Purpose Novel particle engineering approach was used in this study to generate high dose inhalable effervescent particles with synergistic effects against Pseudomonas aeruginosa biofilms. Methods Spray dried co-amorphous salt of ciprofloxacin (CFX) and tartaric acid (TA) was prepared and coated with external layer of sodium bicarbonate and silica coated silver nanobeads. Design of experiments (DOE) was used to optimize physicochemical properties of particles for enhanced lung deposition. Results Generated particles were co-amorphous CFX/TA showing that CFX lost its zwitterionic form and exhibiting distinct properties to CFX/HCl as assessed by FTIR and thermal analysis. Particles exhibited mass mean aerodynamic diameter (MMAD) of 3.3 μm, emitted dose of 78% and fine particle dose of 85%. Particles were further evaluated via antimicrobial assessment of minimum inhibitory concentrations (MIC) and minimum biofilm eradication concentration (MBEC). MIC and MBEC results showed that the hybrid particles were around 3–5 times more effective when compared to CFX signifying that synergistic effect was achieved. Diffusing wave spectroscopy results showed that the silver containing particles had a disruptive effect on rheological properties as opposed to silver free particles. Conclusions Overall, these results showed the potential to use particle engineering to generate particles that are highly disruptive of bacterial biofilms.

Automated Filling Equipment Allows Increase in the Maximum Dose to Be Filled in the Cyclops® High Dose Dry Powder Inhalation Device While Maintaining Dispersibility

In recent years there has been increasing interest in the pulmonary delivery of high dose dry powder drugs, such as antibiotics. Drugs in this class need to be dosed in doses far over 2.5 mg, and the use of excipients should therefore be minimized. To our knowledge, the effect of the automatic filling of high dose drug formulations on the maximum dose that can be filled in powder inhalers, and on the dispersion behavior of the powder, have not been described so far. In this study, we aimed to investigate these effects after filling with an Omnidose, a vacuum drum filler. Furthermore, the precision and accuracy of the filling process were investigated. Two formulations were used—an isoniazid formulation we reported previously and an amikacin formulation. Both formulations could be precisely and accurately dosed in a vacuum pressure range of 200 to 600 mbar. No change in dispersion was seen after automatic filling. Retention was decreased, with an optimum vacuum pressure range found from 400 to 600 mbar. The nominal dose for amikacin was 57 mg, which resulted in a fine particle dose of 47.26 ± 1.72 mg. The nominal dose for isoniazid could be increased to 150 mg, resulting in a fine particle dose of 107.35 ± 13.52 mg. These findings may contribute to the understanding of the upscaling of high dose dry powder inhalation products.