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Use of inhaled drugs in obstructive pulmonary diseases Author: Nikola Obertová 1 Tutor: Josef Malý 1 1 Department of Social and Clinical Pharmacy, Faculty of Pharmacy in Hradec Králové, Charles University Introduction and objectives: Chronic respiratory diseases are emerging health problem. The administration of the medication is mostly performed by the process of inhalation. Therefore, a proper inhalation technique plays a crucial role in symptom reduction and achievement of adequate control over the disease. The aim of the thesis was partly to assess the level of inhalation technique in elderly patients in nursing home settings, partly to evaluate the knowledge of nurses and their role in advice provision related to the proper inhalation technique. Methods: The data were collected from June to September 2016 from 18 nursing homes located in South Wales (Great Britain). The study was realized in two arms. The evaluated group (first arm) was composed of patients (residents) with having asthma bronchiale or chronic obstructive pulmonary disease diagnosed and being older than 65 years. Second arm consisted of nurses responsible for giving advices about inhalation technique to the residents. Nursing home visits were composed of three parts. First one was a controlled interview based on the...

There has been a desire to accurately interpret the inhaled pharmacokinetic (PK) profiles of drugs in humans to aid successful inhaled drug and product developments. However, challenges are layered, as 1) the drug dose delivered to the lung (DTL) from inhalers is a portion of the formulated dose but rarely determined; 2) lung delivery and regional deposition differ, depending on drug, formulation and inhaler; 3) drugs are not only absorbed from the lung but may also be from the gastrointestinal (GI) tract; and 4) in addition to absorption into the systemic circulation, multiple non-absorptive processes also eliminate drugs from the lung, such as mucociliary clearance, metabolism, phagocytosis and tissue binding. Hence, this thesis project aims to develop new lung disposition model-based analyses to derive the meaningful kinetic descriptors for lung disposition from inhaled PK profiles in humans. Two approaches, curve fitting- and moment-based approaches, were developed. Both approaches modeled the kinetics of lung disposition rate-controlled by absorption (ka) and non-absorptive loss (knal), assuming no contribution of GI absorption. An exhaustive literature review found necessary data sets for three drugs, tobramycin, calcitonin and ciprofloxacin. In the curve fitting-based approach, each inhaled PK profile was fitted to the lung disposition model, while the DTL was obtained from corresponding -scintigraphic lung deposition and the kinetic parameters of systemic disposition were fixed by separate intravenous PK profile model analysis. In the moment analysis-based approach, the mean lung residence times (MLRT) and the DTL-based bioavailability (FL) were estimated and used to determine the ka and knal values in the lung disposition model, given FL = MLRTka = ka/(ka+knal). The ka and knal values were successfully derived for all the three drugs delivered by dry powder inhalers (DPIs) and/or nebulizers (NEB) through both approaches. Their “goodness-of-fit” was reasonably satisfactory. The ka values appeared to be primarily described by partition-based diffusion affected by the three hydrophilic drug’s molecular weight. In contrast, the knal values differed, yet appeared to become plausible, with a notion of additional non-absorptive confoundedness due to lung tissue binding (tobramycin) and metabolism (calcitonin), in addition to mucociliary clearance. The ka and knal values derived by the two approaches were comparable in majority of the cases. The success of these PK modeling analyses enabled further attempts to identify most influential attributes by simulation. The systemic PK and lung exposure profiles were predicted by simulation upon ±20 % changes in each of the DTL, ka and knal values to examine changes in the systemic PK metrics (Cmax, AUC and Tmax) and local lung exposure metrics (AUClung and LRT0.5). For all three drugs, the Cmax and AUC changes were identical to changes in the DTL without changing the Tmax. In contrast, impacts of the ka and knal changes differed between drugs, depending on the relative contribution of the rate constant to their sum (ka+knal). It appeared that the major contributor of the sum (ka+knal) was that rate-controlling the kinetics of lung disposition. In conclusion, this thesis project has successfully proposed two new approaches of curve fitting and moment-based analysis by accurately deriving the kinetic descriptors of lung disposition (ka and knal) for three drugs from the inhaled PK profiles in humans. Their applications were extended to predict likely changes in the systemic PK and local lung exposure metrics by simulation. While attempts should continue with more drugs, these approaches are believed to be useful in identifying critical attributes to determine the lung disposition kinetics and thus predicting the lung kinetic behavior and systemic PK profiles of new drug entities in humans.

There has been very little research into the bioanalytical application of Microemulsion High Performance Liquid Chromatography (MELC), a recently established technique for separating an active pharmaceutical ingredient from its related substances and for determining the quantity of active drug in a dose. Also, the technique is not good at separating hydrophilic drugs of very similar chemical structures. Different phase diagrams of oil (octane or ethyl acetate), co-surfactant (butanol), surfactant (sodium dodecyl sulphate (SDS) or Brij-35) and buffer (Phosphate pH 3) were developed and several nanoemulsion mobile phases identified. Nanoemulsion mobile phase that is, prepared with SDS, octane, butanol and a phosphate buffer, failed to separate hydrophilic compounds with a very close chemical structure, such as terbutaline and salbutamol. A nanoemulsion mobile phase containing a non-ionic surfactant (Brij-35) with ethyl acetate, butanol and a phosphate buffer, was, however, successful in achieving a base line separation, and the method was validated for simultaneous determination of terbutaline and salbutamol in aqueous and urine samples. An oil-in-water (O/W) NELC method was developed and validated for the determination of formoterol in an Oxis® Turbuhaler® using pre-column fluorescence derivatisation. Although the same mobile phase was extended for separation of formoterol in urine, the formoterol peak's overlap with endogenous peaks meant that fluorescence detection could not determine formoterol in urine samples. Solid phase extraction, concentrating the final analyte 40 times, enabled determination of a low concentration of formoterol in urine samples by UV detection. The method was validated and an acceptable assay precision %CV <4.89 inter-day and %CV <2.33 intra-day was achieved. Then after the application of O/W nanoemulsion mobile phase for HPLC was extended for the separation of lipophilic drugs. The nanoemulsion liquid chromatography (NELC) method was optimised for the determination of salmeterol and fluticasone propionate in good validation data was achieved. This thesis shows that, in general, the performance of O/W NELC is superior to that of conventional High Performance Liquid Chromatography (HPLC) for the analysis of both hydrophilic and lipophilic drugs in inhaled dosage formulations and urine samples. It has been shown that NELC uses cheaper solvents and that analysis time is faster for aqueous and urine samples. This considerable saving in both cost and time will potentially improve efficiency within quality control.

There has been very little research into the bioanalytical application of Microemulsion High Performance Liquid Chromatography (MELC), a recently established technique for separating an active pharmaceutical ingredient from its related substances and for determining the quantity of active drug in a dose. Also, the technique is not good at separating hydrophilic drugs of very similar chemical structures. Different phase diagrams of oil (octane or ethyl acetate), co-surfactant (butanol), surfactant (sodium dodecyl sulphate (SDS) or Brij-35) and buffer (Phosphate pH 3) were developed and several nanoemulsion mobile phases identified. Nanoemulsion mobile phase that is, prepared with SDS, octane, butanol and a phosphate buffer, failed to separate hydrophilic compounds with a very close chemical structure, such as terbutaline and salbutamol. A nanoemulsion mobile phase containing a non-ionic surfactant (Brij-35) with ethyl acetate, butanol and a phosphate buffer, was, however, successful in achieving a base line separation, and the method was validated for simultaneous determination of terbutaline and salbutamol in aqueous and urine samples. An oil-in-water (O/W) NELC method was developed and validated for the determination of formoterol in an Oxis® Turbuhaler® using pre-column fluorescence derivatisation. Although the same mobile phase was extended for separation of formoterol in urine, the formoterol peak¿s overlap with endogenous peaks meant that fluorescence detection could not determine formoterol in urine samples. Solid phase extraction, concentrating the final analyte 40 times, enabled determination of a low concentration of formoterol in urine samples by UV detection. The method was validated and an acceptable assay precision %CV <4.89 inter-day and %CV <2.33 intra-day was achieved. Then after the application of O/W nanoemulsion mobile phase for HPLC was extended for the separation of lipophilic drugs. The nanoemulsion liquid chromatography (NELC) method was optimised for the determination of salmeterol and fluticasone propionate in good validation data was achieved. This thesis shows that, in general, the performance of O/W NELC is superior to that of conventional High Performance Liquid Chromatography (HPLC) for the analysis of both hydrophilic and lipophilic drugs in inhaled dosage formulations and urine samples. It has been shown that NELC uses cheaper solvents and that analysis time is faster for aqueous and urine samples. This considerable saving in both cost and time will potentially improve efficiency within quality control.