Optimizing the primary particle size distributions of pressurized metered dose inhalers by using inkjet spray drying for targeting desired regions of the lungs.

Conventional suspension pressurized metered dose inhalers (pMDIs) suffer not only from delivering small amounts of a drug to the lungs, but also the inhaled dose scatters all over the lung regions. This results in much less of the desired dose being delivered to regions of the lungs. This study aimed to improve the aerosol performance of suspension pMDIs by producing primary particles with narrow size distributions. Inkjet spray drying was used to produce respirable particles of salbutamol sulfate. The Next Generation Impactor (NGI) was used to determine the aerosol particle size distribution and fine particle fraction (FPF). Furthermore, oropharyngeal models were used with the NGI to compare the aerosol performances of a pMDI with monodisperse primary particles and a conventional pMDI. Monodisperse primary particles in pMDIs showed significantly narrower aerosol particle size distributions than pMDIs containing polydisperse primary particles. Monodisperse pMDIs showed aerosol deposition on a single stage of the NGI as high as 41.75 ± 5.76%, while this was 29.37 ± 6.79% for a polydisperse pMDI. Narrow size distribution was crucial to achieve a high FPF (49.31 ± 8.16%) for primary particles greater than 2 µm. Only small polydisperse primary particles with sizes such as 0.65 ± 0.28 µm achieved a high FPF with (68.94 ± 6.22%) or without (53.95 ± 4.59%) a spacer. Oropharyngeal models also indicated a narrower aerosol particle size distribution for a pMDI containing monodisperse primary particles compared to a conventional pMDI. It is concluded that, pMDIs formulated with monodisperse primary particles show higher FPFs that may target desired regions of the lungs more effectively than polydisperse pMDIs.

The interaction between the oropharyngeal geometry and aerosols via pressurised metered dose inhalers.

PURPOSE: This study investigated the effect of oropharyngeal geometry on inhaled aerosol characteristics via pressurised metered dose inhalers (pMDIs), both with or without spacers. METHODS: Seven adult oropharyngeal models with different centreline lengths, total volumes, and degrees of constriction were employed as induction ports for a laser diffraction particle size analyser and cascade impactor. Particle size change over time, mass median aerodynamic diameter (MMAD), average median volume diameter (D(V)50), inhaled doses, and oropharyngeal depositions (percentage of the nominal dose) for aerosols via suspension and ultrafine pMDIs with or without spacers at 30 l/min airflow were determined. RESULTS: Variations in oropharyngeal geometry caused significant variations in inhaled particle size distributions, doses, oropharyngeal drug depositions, and particle size change over time when pMDIs were used without spacers. However, inhaled aerosol characteristics had marginal variations for the ultrafine pMDI plus large volume spacer (MMAD range: 0.69-0.78 microm, D(V)50 range: 1.27-1.36 microm, inhaled dose range: 46.46-52.92%). It was found that the amounts of inhaled aerosol particles with aerodynamic size of less than 0.83 microm via pMDIs plus large volume spacer were slightly affected by the oropharyngeal geometry. CONCLUSION: Inhaling ultrafine aerosols via spacers may reduce the effect of oropharyngeal geometry on inhaled aerosol properties.

Investigating improving powder deagglomeration via dry powder inhalers at a low inspiratory flow rate by employing add-on spacers.

The aim of this study was to investigate whether small add-on spacers alone or equipped with a passive deagglomerating component would improve aerosol performances of passive low airflow resistance dry powder inhalers (DPIs) at a low inhalation flow rate. Depositions of beclometasone dipropionate (BDP) and salbutamol sulphate (SS) via the Asmabec Clickhaler and Asmasal Clickhaler at 30 L/min airflow rate in an oropharyngeal model and attached filter were determined. Three add-on spacers, one with 5.0 cm length, and the other with the same features but incorporating a fine mesh, and the third one with the length of 8.5 cm (long add-on spacer) were used. Incorporating mesh did not improve the filter dose for SS, and significantly reduced this dose for BDP. The long add-on spacer was the most efficient spacer as it had minimal effects on the filter doses, also significantly reduced drug depositions in the model. In conclusion, an optimum length of an add-on spacer is required to minimise oropharyngeal drug deposition via a low airflow resistance DPI at a low inspiratory flow rate without considerable reduction of the respirable dose. Incorporating sieves within add-on spacers may diminish aerosol performances of the DPIs at low airflow rates.

Effect of oropharyngeal length in drug lung delivery via suspension pressurized metered dose inhalers.

PURPOSE: To determine the effect of the oropharyngeal length in adults on the lung dose of a suspension pressurized metered dose inhaler, and whether employing small volume spacers can alter this role. METHODS: Depositions of Ventolin Evohaler (100) microg in the oropharyngeal models of two healthy adult subjects with 17.1 cm (short cast) and 19.9 cm (long cast) centerline lengths via three small volume spacers [two spacers with 3 cm effective length but one with 6.5 cm2 (L3) and the other with 24.6 cm2 (L3W) cross sections, and the Optimiser] were studied. RESULTS: Without using spacers, lung dose of the long cast (19.52 +/- 2.32 microg, mean +/- standard deviation) was significantly larger than that for the short cast (8.08 +/- 1.01 microg, p < 0.006). However, using the L3 spacer with the short cast made the lung dose (18.59 +/- 3.33 microg) similar to that for the long cast alone. Lung doses of the short cast (20.43 +/- 1.42 microg) and the long cast (30.81 +/- 1.84 microg) with the L3W spacer were similar to those with the L3 spacer. However, using the Optimiser spacer increased the lung dose for the short cast (22.27 +/- 6.03 microg) and significantly for the long cast (35.61 +/- 2.19 microg, p < 0.006) compared to those for the L3 spacer. Using spacers increased drug deposition in the oropharynx part of the short cast, and this reduced the lung dose compared to that for the long cast. CONCLUSION: The oropharyngeal length in adults may affect the lung dose via the pMDIs, which may not be eliminated by using small volume spacers.

Suitability of the upper airway models obtained from MRI studies in simulating drug lung deposition from inhalers.

PURPOSE: In this study, the suitability of the upper airway models, obtained by applying a magnetic resonance imaging method, in simulating in vivo aerosol deposition data is determined. METHODS: Depositions of salbutamol sulfate from two nebulizers in two models, one with constriction at the oropharynx (the constricted cast) and another model without that constriction (the wide cast), were determined. RESULTS: For the Sidestream and Ventstream nebulizer, 76 +/- 3% (mean +/- standard deviation) and 81 +/- 2% of the emitted dose deposited in the constricted cast, whereas 51 +/- 2% and 49 +/- 3% of the emitted dose deposited in the wide cast, respectively. These values were in good agreement with in vivo data. Mostly, increasing nebulizer charge volume (by normal saline) from 2.5 ml to 5 ml increased significantly the lung dose. However, the lung doses from the Sidestream and Ventstream nebulizer with 2.5 ml charge volume via the wide cast were (1.37 +/- 0.06 and 1.38 +/- 0.05 mg) significantly larger than those for the constricted cast with 5 ml charge volume (0.87 +/- 0.15 and 0.86 +/- 0.21 mg, respectively) (p = 0.005). CONCLUSIONS: The upper airway models closely simulated the in vivo deposition data. Optimizing the upper airway posture during inhalation via the nebulizers would be more efficient in increasing drug lung delivery than diluting their contents.

Controlled release of macromolecules from PLA microspheres: using porous structure topology.

Release of hydrophilic macromolecules (FITC-dextran, M(w)=71 and 2000 kDa) from porous poly (D,L-lactic acid), PLA, microspheres was studied by applying percolation theory. Microspheres were prepared by the double emulsion method using high molecular weight PLA. The microspheres showed a percolation threshold, rho(C), at porosity 0. 34. From this parameter, the effective diffusion coefficients, D(eff), and the accessible porosity (total releasable active ingredient), rho(A), of the microspheres were calculated using the Bethe lattice model with coordination number 4. Decreasing porosity of the microspheres decreased the release rate of the active ingredients and a long-term release was observed for the microspheres with porosity close to rho(C). The calculated rho(A) agreed with the experimental data and also the calculated D(eff) for the microspheres with larger porosity (>0.4) was a good estimation to predict the experimentally determined release profiles by applying the continuum structure model (CSM). For microspheres with porosity larger than 0.4 which contained FITC-dextran M(w)=71 kDa, a lag time was observed, which was attributed to delayed saturation of the microspheres with release medium. For microspheres with porosity close to rho(C), the limited number of exit holes on the exterior surface changed the mechanism of release and controlled the release rate rather than the tortuosity of the porous structure of the microspheres.

Hydrogen bonding and electrostatic interaction contributions to the interaction of a cationic drug with polyaspartic acid.

PURPOSE: To determine the mechanism and identify forces of interaction between polyaspartic acid and diminazene (a model drug). Such knowledge is essential for the design of polymeric drug delivery systems that are based on molecular self-assembly into complexes or micellar type systems. METHODS: Complex formation was studied by isothermal titration microcalorimetry and the McGhee von Hippel model was applied to obtain K(obs), deltaH(obs), and n(obs). The calorimetry data were compared with both an optical density study and the amount of free/complexed drug. RESULTS: The diminazene-polyaspartic acid interaction is enthalpically driven, whereby one diminazene molecule interacts with two monomers of polyaspartic acid. The dependence of K(obs) on salt concentration reveals a contribution of electrostatic interactions. However, applying Manning's counter ion condensation theory shows that the major driving force for the complex formation is hydrogen bonding, with interfacial water molecules remaining buried within the complex. The modelling of the pH dependence of K(obs) and deltaH(obs) demonstrates that the ionization of carboxylic groups of polyaspartic acid is a prerequisite for the interaction. CONCLUSIONS: Complex formation between diminazene and polyaspartic acid is driven by both electrostatic interactions and hydrogen bonding, with the latter being the dominating force. Although electrostatic interactions are not the major driving force, ionization of the drug and polymer is essential for complex formation.

Defining the drug incorporation properties of PLA-PEG nanoparticles.

The drug incorporation and physicochemical properties of PLA-PEG micellar like nanoparticles were examined in this study using a model water soluble drug, procaine hydrochloride. Procaine hydrochloride was incorporated into nanoparticles made from a series of PLA-PEG copolymers with a fixed PEG block (5 kDa) and a varying PLA segment (3-110 kDa). The diameter of the PLA-nanoparticles increased from 27.7 to 174.6 nm, with an increase in the PLA molecular weight. However, drug incorporation efficiency remained similar throughout the series. Incorporation of drug into the smaller PLA-PEG nanoparticles made from 3:5, 15:5 and 30:5 copolymers did not influence the particle size, while an increase was observed for the larger systems comprising 75:5 and 110:5 copolymers. An increase in drug content for PLA-PEG 30:5 nanoparticles was achieved by increasing the theoretical loading (quantity of initially present drug). The size of these nanoparticles remained unchanged with the increasing drug content, supporting the proposed micellar type structure of the PLA-PEG 30:5 nanoparticles. The morphology of these systems remained unchanged both at low and high theoretical drug loadings. Formulation variables, such as an increase in the aqueous phase pH, replacement with the base form of the drug and inclusion of lauric acid in the formulation did not improve the incorporation efficiency of drug into PLA-PEG 30:5 nanoparticles. While poly(aspartic acid) as a complexation agent did not improve the drug incorporation efficiency of procaine hydrochloride, it did so for another water soluble drug diminazene aceturate. This may be attributed to a stronger interaction of diminazene aceturate with poly(aspartic acid) relative to procaine hydrochloride, as confirmed by thermodynamic analysis of isothermal titration calorimetric data. The drug incorporation and physicochemical characterisation data obtained in this study may be relevant in optimising the drug incorporation and delivery properties of these potential drug targeting carriers.

First order release rate from porous PLA microspheres with limited exit holes on the exterior surface.

We applied the finite element method (FEM) to calculate release profiles from computer simulated slabs, one with a limited number of exit holes on the exterior surface, and the other with uniform structure. The former slab showed a first order release rate, and a nearly uniform drug concentration distribution within the device during the release process. It was concluded that circulation of the drug molecules within the slab resulted in the uniform concentration and consequently first order release rate. This theoretical work was used to explain the first order release rate of an active ingredient (flourescin-4-isothiocyanate-dextran, M(W)=71000 Da) from porous PLA (poly(D,L)-lactic acid) microspheres, which by canning electron microscopy (SEM) examination showed only a few exit holes on their exterior surface. Calculations indicated that the internal surface adsorption of the active ingredient, or the pore size distribution of the microspheres, could not influence the mechanism for the first order release rate, and the small number of exit holes on the exterior surface was likely to be the rate-determining factor. The exit holes could be observed by SEM and their size and number is consistent with our interpretations.

Complex formation between the anionic polymer (PAA) and a cationic drug (procaine HCI): characterization by microcalorimetric studies.

PURPOSE: Due to the importance of drug-polymer interactions in, inter alia, drug loading/release, supramolecular assemblies and DNA delivery for gene therapy, the aim of this study was therefore to establish the mechanism of interaction between a model polymer (Polyacrylic acid, PAA) and a model drug (procaine HCl). METHODS: This was performed by studying the effect of salt (KCl) concentration on their heat released values using Isothermal Titration Microcalorimetry (ITM). The integrated released heat data were computer fitted to a one class binding model and the thermodynamic parameters (Kobs, deltaH, and N) were determined. RESULTS: As the KCl concentration was increased, Kobs decreased thus establishing the salt dependence of the interaction. The linear variation of deltaGobs with deltaSobs indicated that their interaction was entropically driven. The stoichiometry of the interaction was calculated to be one procaine molecule per monomer of PAA. Dissection of the total observed free energy at each KCI concentration indicated that the contribution of the non-electrostatic attractions to the interaction of PAA with procaine HCl was greater than those of the electrostatic attractions. CONCLUSIONS: We have shown that the interaction between PAA and procaine HCl is dependent upon the presence of counterions (monovalent ions) and is mainly entropically driven. The calculated stoichiometry indicated that one procaine HCl molecule neutralised one carboxylic acid group on PAA. Although electrostatic interactions were necessary for initiating complex formation, the non-electrostatic forces were dominant in stabilising the PAA-procaine HCl complex.

Determination of the internal morphology of poly (D,L-lactide) microspheres using stereological methods.

The morphological characteristics of the internal structure of poly (D,L-lactide) microspheres have been determined by stereological methods in two different formulations of microspheres, with different internal structures, prepared by using a double emulsion method. In one formulation the internal emulsion was produced by homogenisation at 3000 rpm, whilst the other was prepared at 11000 rpm. As expected the formulation prepared at the lower speed contained larger and more broadly distributed pores than that prepared at the higher speed. The porosity, pore size distribution and total internal surface area of the microspheres were obtained by stereological methods from electron microscopic measurements of the sectioned microspheres. It was found that whilst the porosity of the microspheres was 0.6 in both formulations, the preparation method gave rise to large differences in their pore size distribution characteristics. The pore size distribution was simulated by computer modelling to validate and compare alternative stereological algorithms. It was found that the Saltykov unfolding method predicts the measured pore size distribution more accurately than the Cruz-Orive unfolding method (at significance level alpha=0.1). This finding was attributed to the violation of one of the basic assumptions of the Cruz-Orive unfolding method.