Delivered dose

Data should be provided on uniformity of delivered dose using the Ph Eur method. Products should be able to attain a range of nominal 20% or better. The specification should be based on data from satisfactory clinical batches of product, taking into account the tolerances of the device and the batch variability for lots used in clinical studies. 

An acute intravenous study can provide accurate rates of metabolism without interference from intestinal flora, plus rates of renal and biliary elimination, if urine and bile are collected. This route also avoids the variability in delivered dose associated with oral absorption and ensures that the maximum amount of radiolabel is excreted in the urine or bile for purposes of detection. Once IV data and parameters are available, they can be used with plasma concentrations from limited oral studies to compute intestinal absorption via the ratio of Areas Under the (plasma and/or urine) Curves or via simulations of absorption with gastrointestinal absorption models. 

Metered-dose inhalation aerosols Delivered dose per actuation, number of metered doses, color, particle-size distribution, loss of propellant, pressure, valve corrosion, spray pattern, and absence of pathogenic microorganisms... 

First, the procedure now used by the EPA for inhalation data differs from what we have described above, in that the ten-fold factor for interspecies extrapolation (animal-to-human) is dropped in favor of a specific model that describes the well-known physiological differences between animals and humans that affect the relative rates of movement of a given administered dose of a chemical in the respiratory tracts of animals and humans. These physiological models provide fairly accurate predictions of the relative doses of chemicals delivered into the respiratory regions of animals and humans who have received identical administered (inhaled) doses. The estimate of delivered dose offers a well-accepted scientific approach to at least part of the problem of interspecies differences. Details of the delivered dose calculations are beyond the scope of this book (see references in Sources and recommended reading). 

Interspecies differences in the rate of chloroform conversion were observed in mice, rats, and squirrel monkeys, with species differences in metabolism being highly dose-dependant. The conversion of chloroform to carbon dioxide was highest in mice (80%) and lowest in squirrel monkeys (18%) (Brown et al. 1974a). Similarly, chloroform metabolism was calculated to be slower in humans than in rodents. Therefore, it was estimated that the exposure to equivalent concentrations of chloroform would lead to a much lower delivered dose in humans (Corley et al. 1990). 

In a PBPK model that used simulations with mice, rats, and humans (Corley et al. 1990), the tissue delivered dose from equivalent concentrations of chloroform was highest in the mouse, followed by rats and then humans. The authors suggest that this behavior is predicted by the model because of the lower relative rates of metabolism, ventilation, and cardiac output (per kg of body weight) in the... 

Nicotine nasal spray is marketed as a pharmacy-only medication in the UK, and is available only by prescription in the USA. The nasal spray was designed to deliver doses of nicotine to the smoker more rapidly than other NRT products. The device is a multidose bottle with a pump that delivers 0.5 mg of nicotine per 50-pL squirt. Each dose consists of two squirts, one to each nostril. Nicotine from the nasal spray is absorbed into the blood more rapidly than from the gum (Schneider et al. 1996). Venous plasma concentrations after a single 1-mg dose range between 5 and 12 ng mL Time to peak plasma concentration (7j ax) with nasal administration is around 11-13 min for 1-mg doses. This rise time is slower than for cigarette delivery (Henningfield et al. 1993), but faster than for the other NRT products. 

The two critical attributes characterizing the performance of DPIs are the imiformity of the delivered dose and the aerodynamie assessment of partiele size distribution. To determine the imiformity of the delivered dose, an apparatus capable of quantitatively retaining the dose leaving the deviee is used. For aerodynamic particle size assessment, a multistage liquid impinger or easeade impaetor is used. All aerosol performance testing must be condueted under defined temperature and humidity conditions. 

Currently the U.S., European, and British pharmacopeias specify different requirements for delivered dose uniformity. Table 5 describes these requirements as well as proposed FDA expectations [33]. The Japanese pharmacopeia does not speeify a delivered dose uniformity requirement. Current compendia should be eonsulted as referenees. 

Of the four pharmacopeias, the U.S. pharmacopeia (USP) has the strietest requirements for delivered dose uniformity. Although the British pharmaeopeia (BP) allows the same performance range, the USP defines the range around the label claim and the BP defines the range around the average value. The FDA expeetation for delivered dose uniformity is currently tighter than that stated in all the pharmaeopeias. 

Various dry powder attributes are assessed at release and on stability. These include physieal eharaeteristies sueh as appearance, content uniformity, delivered dose uniformity, and partiele size distribution. Chemieal attributes that may be assessed include drug eontent, purity, and identity, as well as the water content. Dry powders may also undergo mieroseopie evaluation for foreign particulate matter, unusual agglomeration, and partiele size. Mierobial limits should also be examined, including the total aerobie, yeast, and mold eounts. The presence of specific pathogens should be ruled out. The dry powders may be dissolved to test for pH. 

In addition, eertain eompendial requirements for content and delivered dose uniformity should be measured. The USP and EP propose that the total aerobic count not exceed 100 CFU/g (colony-forming imits) that the total yeast and mold counts not exceed 10 CFU/g and that no specific pathogens be detectable. Specifications for the other attributes should be based on the intended use and the historical performance of the product. As with other dosage forms, specifications must be met throughout the intended shelf life of the product. 

In Section 3.5.3, dry powder inhalers have been referred to as breath-controlled devices. The efficacy of dry powder inhalation is a function of many factors, influencing the delivered dose of fine particles and the deposition of these particles in the respiratory tract. Figure 3.4 shows that DPI performance is influenced both directly and indirectly by the design of the inhalation system. The powder formulation, the dose (measuring) system and the powder disintegration principle have to be designed correctly for release of sufficient fine drug particles in... 

It is also noted that there is overlap in the individual UFs and that the application of five UFs of ten for the chronic reference value (yielding a total UF of 100,000) is inappropriate. In fact, in cases where maximum uncertainty exists in all five areas, it is unlikely that the database is sufficient to derive a reference value. Uncertainty in four areas may also indicate that the database is insufficient to derive a reference value. In the case of the RfC, the maximum UF would be 3,000, whereas the maximum would be 10,000 for the RfD. This is because the derivation of RfCs and RfDs has evolved somewhat differently. The RfC methodology (US-EPA 1994) recommends dividing the interspecies UF in half, one-half (10° ) each for toxicokinetic and toxicodynamic considerations, and it includes a Dosimetric Adjustment Factor (D AF, represents a multiplicative factor used to adjust an observed exposure concentration in a particular laboratory species to an exposure concentration for humans that would be associated with the same delivered dose) to account for toxicokinetic differences in calculating the Human Equivalent Concentration (HEC), thus reducing the interspecies UF to 3 for toxicodynamic issues. RfDs, however, do not incorporate a DAF for deriving a Human Equivalent Dose (HED), and the interspecies UF of 10 is typically applied, see also Section 5.3.4. It is recommended to limit the total UF applied for any particular chemical to no more than 3000, for both RfDs and RfCs, and avoiding the derivation of a reference value that involves application of the full 10-fold UF in four or more areas of extrapolation. 

The data in Table 8.2 are taken from a study reported by Hindle et the purpose of which was to determine whether a new dry powder inhaler (DISK) was equivalent to a traditional metered-dose inhaler (MDI) in its ability to deliver doses of a bronchodilator to the lungs of volunteers. The data are the percentages of an inhaled dose of salbutamol recovered in a urine sample taken 30 min post-inhalation for each method of delivery in nine volunteers. Ameasure of treatment effect is the difference in percentages within volunteers, shown in the fourth column. Of these differences seven are negative and two are positive (fifth column) and the question we need to answer is how likely is it that if there is no difference between the inhalers, we would see this degree of imbalance between negatives and positives ... 

Absorption - The majority of a delivered dose is deposited in the Gl tract and, to a lesser extent, in the lung, the intended organ. The absolute bioavailability of 19.5% suggests that the fraction reaching the lung is highly bioavailable. Maximum tiotropium plasma concentrations were observed 5 minutes after inhalation. 

DPIs do not utilize Freon propellants, but use either with or without lactose as vehiculum. These devices have a clinical efficacy similar to standard metered-dose inhalers, but may be easier to use in selected patients, since a minimal inspiratory flow rate is necessary to inhale from a DPI. Therefore, the DPI may be difficult for patients with an insufficient inspiratory flow rate, which occurs in children, the elderly, people with severe COPD shared with diaphragm dysfunction, and during an exacerbation. The inspiratory flow rate is associated with the internal resistance of the device used. For instance the turbuhalor has a significant internal resistance and its delivered dose is dependent from the inspiratory flow rate. 

Delivered dose The ratio of the dose rate and the line speed ... 

Delivered dose = Dose rate/Line speed... 

At a given dose rate, the line speed can be adjusted to obtain the desired dose. On the other hand, the beam current can be controlled by the line speed to maintain a constant delivered dose at all line speeds. 

Yield factor Yield factor is used to characterize the curing performance of an electron processor. It is a constant that relates the delivered dose to the beam current and line speed ... 

Delivered dose = Yield factor x Beam current/line speed... 

Dose-speed capacity Product of the delivered dose and the line speed at the maximum beam power ... 

Linearity of the response of personal monitors is determined by delivering dose equivalents over the range of a few mSv to many Sv. 

Process parameters involve line speed if dose rate and line speed are combined, the dose delivered to the product to be cured can be calculated. A processor-specific yield factor depends on the relationship between the beam current and line speed. The dose-speed capacity of a processor is given by the product of the line speed and the delivered dose at maximum electron beam power.27... 

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