Shortened dental arch concept shown to be cost effective.

DESIGN: Randomised controlled trial. INTERVENTION: All patients received treatment to render them dentally fit. Patients were randomly allocated to either the removable dental prostheses (RPD) or the shortened dental arch (SDA) group. Patients in the RDP group were restored to complete arches with RDP using cobalt-chromium frameworks according to a standardised protocol. For the SDA group, patients were restored to a shortened arch of ten occluding pairs of natural and replacement teeth using resin-bonded bridgework (RBB). OUTCOME MEASURE: Treatment effect was measured using the change in oral health-related quality of life (OHrQOL). For each patient the costs of delivering treatment were recorded by a research nurse during the intervention period. Laboratory costs were recorded as part of normal hospital policy for all patients. All of the dental materials used were recorded and given a unit price. The cost of professional time per patient was estimated using the highest point of the salary scale for the Community Dental Service in Ireland. RESULTS: One hundred and thirty-two patients were randomised; 65 to the RPD group and 67 to the SDA group. Ninety-two patients (69.7%) completed the study (46 in RPD group; 46in SDA group). There was no difference in the success rates of the two treatments over the period. Five pieces of resin-bonded bridgework (RBB) debonded and were recemented over the 12-month period giving a success rate of 95.5% for the RBB. Four patients discontinued wearing their RPDs; all four RPDS were fitted in the lower arch and included bilateral free end saddles, a success rate of 95.9%. Both RPD and SDA groups demonstrated statistically significant improvements in OHrQoL scores after 12 months.The total cost of achieving the minimally important clinical difference (MID) in OHrQOL for an average patient in the RDP group was [euro ]464.64. For the SDA group, the cost of achieving the MID for an average patient was [euro ]252.00. The cost-effectiveness ratio was therefore 1:1.84 in favour of SDA treatment. CONCLUSIONS: With an increasingly ageing population, many patients will continue to benefit from removable prostheses to replace their missing natural teeth. From a purely economic standpoint, the results from this analysis suggest that the treatment of partially dentate older adults should be focused on functionally orientated treatment because it is simply more cost-effective.

Pulmonary formulations: what remains to be done?

Significant advances have been made in the last 50 years in developing safe and efficacious aerosol formulations for pulmonary delivery. The key to future innovation may lie at the interface between biology and particle engineering. Improved understanding of biological processes including particle clearance, cellular targeting, intracellular trafficking, and drug absorption are needed to better design formulations that deliver to the "target" with the optimal balance of pharmacodynamic, pharmacokinetic, and safety profiles. More specifically, continued advances are needed in the development of: (1) controlled release formulations; (2) formulations with improved regional targeting within the lungs (e.g., airway versus alveoli and vice versa); (3) formulations containing active targeting moieties; (4) formulation strategies for improving the systemic bioavailability of inhaled macromolecules; (5) formulation strategies for delivering macromolecules, including siRNA and DNA into cells; and (f) formulations with improved dose consistency. It is likely that such innovation will require the development of novel excipients and particle engineering strategies. Future innovation must also take into the account the changing marketplace and the diverse set of customers (patient, healthcare professional, heath authorities, payers, and politicians) who must be satisfied. The pharmacoeconomics of new delivery systems will be closely scrutinized, so it is imperative that cost factors be taken into account. Otherwise, the new technology option may overshoot the evolving inhalation marketplace.

Product Quality Research Institute evaluation of cascade impactor profiles of pharmaceutical aerosols. Part 3. Final report on a statistical procedure for determining equivalence.

The purpose of this article is to report final results of the evaluation of a chi-square ratio test proposed by the US Food and Drug Administration (FDA) for demonstrating equivalence of aerodynamic particle size distribution (APSD) profiles of nasal and orally inhaled drug products. A working group of the Product Quality Research Institute previously published results demonstrating some limitations of the proposed test. In an effort to overcome the test's limited discrimination, the group proposed a supplemental test, a population bioequivalence (PBE) test for impactor-sized mass (ISM). In this final report the group compares the chi-square ratio test to the ISM-PBE test and to the combination of both tests. The basis for comparison is a set of 55 realistic scenarios of cascade impactor data, which were evaluated for equivalence by the statistical tests and independently by the group members. In many instances, the combined application of these 2 tests appeared to increase the discriminating ability of the statistical procedure compared with the chi-square ratio test alone. In certain situations the chi-square ratio test alone was sufficient to determine equivalence of APSD profiles, while in other situations neither of the tests alone nor their combination was adequate. This report describes all of these scenarios and results. In the end, the group did not recommend a statistical test for APSD profile equivalence. The group did not investigate other in vitro tests, in vivo issues, or other statistical tests for APSD profile comparisons. The studied tests are not intended for routine quality control of APSD.

Analysis of cascade impactor mass distributions.

The purpose of this paper is to review the approaches for analyzing cascade impactor (CI) mass distributions produced by pulmonary drug products and the considerations necessary for selecting the appropriate analysis procedure. There are several methods available for analyzing CI data, yielding a hierarchy of information in terms of nominal, ordinal and continuous variables. Mass distributions analyzed as a nominal function of the stages and auxiliary components is the simplest approach for examining the whole mass emitted by the inhaler. However, the relationship between the mass distribution and aerodynamic diameter is not described by such data. This relationship is a critical attribute of pulmonary drug products due to the association between aerodynamic diameter and the mass of particulates deposited to the respiratory tract. Therefore, the nominal mass distribution can only be utilized to make decisions on the discrete masses collected in the CI. Mass distributions analyzed as an ordinal function of aerodynamic diameter can be obtained by introducing the stage size range, which generally vary in magnitude from one stage to another for a given type of CI, and differ between CIs of different designs. Furthermore, the mass collected by specific size ranges within the CI are often incorrectly used to estimate in vivo deposition at various regions of the respiratory tract. A CI-generated mass distribution can be directly related to aerodynamic diameter by expressing the mass collected by each size-fractionating stage in terms of either mass frequency or cumulative mass fraction less than the aerodynamic size appropriate to each stage. Analysis of the aerodynamic diameter as a continuous variable allows comparison of mass distributions obtained from different products, obtained by different CI designs, as well as providing input to in vivo particle deposition models. The lack of information about the mass fraction emitted by the inhaler that is not size-analyzed by the CI may be perceived as a disadvantage from the standpoint of comparing the total mass per actuation emitted from the inhaler mouthpiece. However, this is a limitation of the CI measurement technique rather than the data analysis procedure. Data reduction techniques can enable the large quantity of information conveyed in a mass-size distribution to be summarized in terms of representative parameters, but care needs to be exercised if utilizing model size distribution function fitting routines to avoid introducing error by the fitting procedure.

Dose delivery characteristics of the AIR pulmonary delivery system over a range of inspiratory flow rates.

The purpose of this study was to evaluate the in vitro and in vivo dose delivery characteristics of the AIR pulmonary delivery system over a range of flow rates. A 5-mg placebo powder of engineered particles with low densities (<0.4 g/cc) and large geometric diameters (>5 microm) was delivered via a simple, capsule based, passive dry powder inhaler. The emitted dose, geometric and aerodynamic particle size distributions (aPSDs) were obtained over a range of flow rates (15-60 LPM). The in vitro results demonstrated improved powder dispersion with increasing flow rate through the inhaler. The in vivo dose delivery characteristics were obtained by gamma scintigraphy. Twelve healthy subjects performed the following three inhalation maneuvers: (i) a targeted peak inspiratory flow rate (PIFR) of 20 +/- 10 LPM, (ii) a deep comfortable inhalation, and (iii) a deep forced inhalation. PIFR and inhaled volume were obtained during the inhalation of the dose using a spirometer. In vivo dose delivery was characterized by high and reproducible emitted doses (mean = 87%; inter and intra-subject CV = 5%) and high lung deposition (mean = 51% of the total dose), with low inter and intra-subject CVs (18% and 13%, respectively) across a range of PIFRs (12-86 LPM). Lung deposition of the total dose was shown not to be dependent on PIFR by analysis of variance across the range of inspiratory flow rates (p = 0.29). This was due to the competing effects of smaller aPSDs, increased extrathoracic deposition and higher emitted doses with increasing PIFR. Fully characterizing the effect of inspiratory flow rate requires analysis of the therapeutic response, as well as in vitro dose delivery and lung deposition.

Reducing bounce effects in the Andersen cascade impactor.

The collection efficiency of the Andersen cascade impactor (ACI) can be affected by particle bounce, overload and re-entrainment (or blow-off), collectively referred to as bounce effects. Reduction of bounce effects in the ACI operated at 60 LPM was investigated for placebo large porous particles. Aerodynamic particle size distributions (aPSDs) obtained with the ACI and multi-stage liquid impinger (MSLI) were compared by observation of modes and statistical comparisons of the mass median aerodynamic diameter (MMAD) and geometric standard deviation (sigmag). Particle bounce effects were prevalent in the ACI with uncoated plates, i.e., bi-modal distribution with statistically significant differences in MMAD and sigmag (P<0.05). Coating the impaction plates with a thin layer of vacuum grease and decreasing the ACI stage jet velocities reduced, but did not minimize bounce effects. Bounce effects were minimized using 20-microm pore glass fiber filters saturated in water placed on inverted impaction plates, with good agreement obtained between the ACI and MSLI aPSDs, i.e., mono-modal with no statistically significant differences in MMAD and sigmag (P>0.05). Selection of the impaction substrate material and solvent must be evaluated with the drug product and analytical methods to minimize bounce effects and obtain an accurate measure of the aPSD.

In vitro and in vivo dose delivery characteristics of large porous particles for inhalation.

The purpose of this study was to evaluate the in vitro and in vivo dose delivery characteristics of two large porous particle placebo formulations with different mass median aerodynamic diameters (MMAD approximately equal to 3 and 5 microm). In vitro dose delivery characteristics were measured using the multistage liquid impinger (MSLI). In vitro lung deposition was predicted by calculating the extrathoracic deposition using the ICRP model, with the remaining fraction assumed to deposit in the lungs. Healthy subjects were trained to inhale through the AIR delivery system at a target peak inspiratory flow rate (PIFR) of 60 l/min, The in vivo dose delivery of large porous particles were obtained by gamma-scintigraphy and was characterized by high ( approximately 90%), reproducible emitted doses for both the small and large MMAD powders. The mean in vivo lung deposition relative to the total metered dose were 59.0 and 37.3% for 3 and 5 microm MMAD powders, respectively. The AIR delivery system produced high in vivo lung deposition and low intersubject CVs (approximately 14%) across the range of PIFRs obtained in the study (50-80 l/min), This is relative to a variety of dry powder inhalers (DPI) that have been published in the literature, with in vivo lung deposition ranging from 13 to 35% with intersubject CVs ranging from 17 to 50%. The ICRP model provided a good estimate of the mean in vivo lung deposition for both powders. Intersubject variability was not captured by the ICRP model due to intersubject differences in the morphology and physiology of the oropharyngeal region. The ICRP model was used to predict the regional lung deposition, although these predictions were only considered speculative in the absence of experimental validation.

Bioengineering of therapeutic aerosols.

The new field of therapeutic aerosol bioengineering (TAB), driven primarily by the medical need for inhaled insulin, is now expanding to address medical needs ranging from respiratory to systemic diseases, including asthma, growth deficiency, and pain. Bioengineering of therapeutic aerosols involves a level of aerosol particle design absent in traditional therapeutic aerosols, which are created by conventionally spraying a liquid solution or suspension of drug or milling and mixing a dry drug form into respirable particles. Bioengineered particles may be created in liquid form from devices specially designed to create an unusually fine size distribution, possibly with special purity properties, or solid particles that possess a mixture of drug and excipient, with designed shape, size, porosity, and drug release characteristics. Such aerosols have enabled several high-visibility clinical programs of inhaled insulin, as well as earlier-stage programs involving inhaled morphine, growth hormone, beta-interferon, alpha-1-antitrypsin, and several asthma drugs. The design of these aerosols, limited by partial knowledge of the lungs' physiological environment, and driven largely at this stage by market forces, relies on a mixture of new and old science, pharmaceutical science intuition, and a degree of biological-impact empiricism that speaks to the importance of an increased level of academic involvement.

Generation of gelatin aerosol particles from nebulized solutions as model drug carrier systems.

PURPOSE: Aerodynamically stable, nebulized aerosols are desirable to achieve optimum asthma therapy. Stabilizing droplet size using gel-forming polymers may assist in achieving this goal. Semisolid particles may be generated through aerosolization of a polymer solution. Gelatin was employed as a model polymer in a process optimization study using the marker, disodium fluorescein, and the drug, budesonide delivered from two commercially available air-jet nebulizers. METHODS: The aerosol delivery system consisted of either of the air-jet nebulizers attached to a 30 cm drying column. The nebulizers employed were the Aerotech II and Salter SL8900. Two gelatin solutions (0.1 and 0.7% w/v) were evaluated following initial density and viscosity measurements. Particle characterization was conducted by scanning electron microscopy, eight-stage cascade impaction (CI), and phase-Doppler analysis. Disodium fluorescein (NaF, 5 and 7% w/v) and budesonide (B, 0.05% w/v) were added to the gelatin solutions in a 2(4)-factorial design study and the follow-up drug formulation study, respectively. The factorial design experiment evaluated the influence of device, operating pressure, marker, and gelatin concentrations on mass median aerodynamic diameter (MMAD) and fine particle fraction (FPF). Spectrophotometry of the CI samples was performed at wavelengths of 486 (NaF) and 254 (B) nm. RESULTS: The factorial design experiment utilizing NaF showed that MMADs were not influenced significantly be the device, operating pressure, marker, or gelatin concentrations (p > 0.05). However, FPFs were significantly influenced by marker concentration and device (p < 0.05). In the presence of budesonide, the MMADs and FPFs for Aerotech and Salter, respectively, were: MMAD = 1.39 +/- 0.30 microns and 1.75 +/- 0.63 microns, FPF = 93.5 +/- 4% and 68.5 +/- 5%, (n = 3). These values were consistent with those predicted in the designed experiment. CONCLUSIONS: A range of semisolid particle sizes were produced (1.3 < MMAD < 1.8 microns) for the 0.7% w/v gelatin formulation using different nebulizers. The budesonide formulation produced FPFs of 69-93%.