Use of inspiratory profiles from patients with chronic obstructive pulmonary disease (COPD) to investigate drug delivery uniformity and aerodynamic dose emission of indacaterol from a capsule based dry powder inhaler.

Most patients using dry powder inhalers (DPIs) are unable to achieve the inhalation parameters recommended for pharmacopoeial in-vitro dose emission testing. The dose emission characteristics of indacaterol Breezhaler (IB) have been measured using COPD patients' inhalation profiles (IPs) when using IB and replayed in-vitro using a breath simulator attached to an Andersen Cascade Impactor. The peak inhalation flow (PIF) of the profiles ranged from 28.3 to 87.8 L/min and inhaled volumes (Vin) from 0.7 to 3 L. The indacaterol total emitted doses (TED), fine particle dose (FPD) and mass median aerodynamic diameter (MMAD) were measured. TED varied between 61% to 83% of the 150 µg nominal dose, the FPD was found to vary between 19% and 30% and the MMAD from 3.7 µm to 2.3 µm with the increase of the profiles' PIF and Vin. The mean (SD) values were 113.4(8.9) µg, 39.7(5.0) µg and 2.7(0.5) µm, respectively. The quantity and the quality of the emitted dose from the indacaterol Breezhaler® are dependent on the capability of a patient generating an optimal inhalation profile. Therefore, when using the IB patients should be encouraged to inhale as fast as they can from the start of their inhalation and for as long as possible.

Study of the Emitted Dose After Two Separate Inhalations at Different Inhalation Flow Rates and Volumes and an Assessment of Aerodynamic Characteristics of Indacaterol Onbrez Breezhaler® 150 and 300 µg.

Onbrez Breezhaler® is a low-resistance capsule-based device that was developed to deliver indacaterol maleate. The study was designed to investigate the effects of both maximum flow rate (MIF) and inhalation volume (Vin) on the dose emission of indacaterol 150 and 300 µg dose strengths after one and two inhalations using dose unit sampling apparatus (DUSA) as well as to study the aerodynamic characteristics of indacaterol Breezhaler® using the Andersen cascade impactor (ACI) at a different set of MIF and Vin. Indacaterol 150 and 300 µg contain equal amounts of lactose per carrier. However, 150 µg has the smallest carrier size. The particle size distribution (PSD) of indacaterol DPI formulations 150 and 300 µg showed that the density of fine particles increased with the increase of the primary pressure. For both strengths (150 µg and 300 µg), ED1 increased and ED2 decreased when the inhalation flow rate and inhaled volume increased. The reduction in ED1 and subsequent increase in ED2 was such that when the Vin is greater than 1 L, then 60 L/min could be regarded as the minimum MIF. The Breezhaler was effective in producing respirable particles with an MMAD ≤5 µm irrespective of the inhalation flow rate, but the mass fraction of particles with an aerodynamic diameter <3 µm is more pronounced between 60 and 90 L/min. The dose emission of indacaterol was comparable for both dose strengths 150 and 300 µg. These in vitro results suggest that a minimum MIF of 60 L/min is required during routine use of Onbrez Breezhaler®, and confirm the good practice to make two separate inhalations from the same dose.

Effect of maximum inhalation flow and inhaled volume on formoterol drug deposition in-vitro from an Easyhaler® dry powder inhaler.

Most patients using dry powder inhalers (DPIs) do not achieve the inhalation parameters recommended for pharmacopoeial in-vitro dose emission testing. The dose emission characteristics of formoterol from an Easyhaler® have been measured using the Andersen Cascade Impactor (ACI) with a maximum inhalation flow (MIF) of 28.3, 60 and 90L/min and inhaled volumes (Vin) of 240, 750, 1500 and 2000mL. The total emitted dose (TED) was significantly higher at 90L/min (p<0.05), but the difference in the TED between low (28.3L/min) and high (90L/min) flow rate was significantly reduced by increasing the Vin. The fine particle dose (FPD) was higher (p<0.05) at 90L/min for all Vin values compared to 28.3 and 60L/min. Similarly the mass median aerodynamic diameter (MMAD) was smaller at 90L/min across all Vin values. Dose emission characteristics were lower at 240mL for both MIFs. The results for 240mL could be due to an insufficient Vin pulled through the ACI or incomplete emptying of the dose metering cup. This study shows that the FPD, %FPF and MMAD were not significantly affected by the vin≥750mL and that an inhaled volume as low as 750mL could be used with the ACI.

The size and behavior of the human upper airway during inhalation of aerosols.

INTRODUCTION: The mouth, the pharynx and the larynx are potential sites of aerosol deposition in the upper airway during inhalation of aerosolized drugs. The right angle bend of the lumen at the back of the mouth, the position of the tongue, the variable size and shape of the lumen in the pharynx and the larynx, and the breathing pattern could increase aerosol deposition in the upper airway and decrease lung deposition. Areas covered: In this review, the anatomy of the upper airway from the oral cavity to the glottis and the impact of mandibular protrusion and incisal opening on the size of the upper airway are highlighted. In addition, the impact of inhalation maneuvers, inhaler mouthpiece geometries and a stepped mouthpiece on the size of the upper airway are discussed. Expert opinion: The structure of the upper airway lumen does not have a fixed cross sectional area and is susceptible to both constriction and distension during inhalation. The size of the upper airway can be enlarged through mandibular protrusion and/or incisal opening which might decrease aerosol deposition in the upper airway and increase lung deposition.

An approach to engineer paracetamol crystals by antisolvent crystallization technique in presence of various additives for direct compression.

Paracetamol is a popular over-the-counter analgesic and a challenging model drug due to its poor technological and biopharmaceutical properties such as flowability, compressibility, compactibility and wettability. This work was aimed to alter the crystal habit of paracetamol from elongated to polyhedral-angular via particle engineering whilst maintaining the stable polymorphic form (form I: monoclinic form). The engineered paracetamol crystals obtained in the present investigation showed better technological and biopharmaceutical properties in comparison to the commercial paracetamol. Engineered paracetamol crystals were obtained using antisolvent crystallization technique in the presence of various concentrations (0.1, 0.5 and 1%, w/w) of additives, namely, polyvinyl alcohol (PVA), Avicel PH 102 (microcrystalline cellulose), Brij 58, methylcellulose (MC) and polyethylene glycol having different molecular weights (PEGs 1500, 6000 and 8000). Paracetamols crystallized in the presence of Avicel (or physically mixed with Avicel), Brij 58 and PEG 6000 demonstrated the best compactibility over a range of compaction pressures. Brij-crystallized paracetamol provided the fastest dissolution rate among all the paracetamol batches. Paracetamols crystallized in the presence of PVA or Avicel, or physically mixed with Avicel demonstrated a reduced degree of crystallinity in comparison to the other paracetamols. This study showed that the type, the grade and the concentration of additives could influence the physical stability such as flow, crystallinity and polymorphic transformation of paracetamol, the technological and biopharmaceutical properties of paracetamol. Stable polymorphic form of paracetamol with optimal tableting characteristics can be achieved through particle engineering.

The effect of pH and ionic strength of dissolution media on in-vitro release of two model drugs of different solubilities from HPMC matrices.

The evaluation of the effects of different media ionic strengths and pH on the release of hydrochlorothiazide, a poorly soluble drug, and diltiazem hydrochloride, a cationic and soluble drug, from a gel forming hydrophilic polymeric matrix was the objective of this study. The drug to polymer ratio of formulated tablets was 4:1. Hydrochlorothiazide or diltiazem HCl extended release (ER) matrices containing hypromellose (hydroxypropyl methylcellulose (HPMC)) were evaluated in media with a pH range of 1.2-7.5, using an automated USP type III, Bio-Dis dissolution apparatus. The ionic strength of the media was varied over a range of 0-0.4M to simulate the gastrointestinal fed and fasted states and various physiological pH conditions. Sodium chloride was used for ionic regulation due to its ability to salt out polymers in the midrange of the lyotropic series. The results showed that the ionic strength had a profound effect on the drug release from the diltiazem HCl K100LV matrices. The K4M, K15M and K100M tablets however withstood the effects of media ionic strength and showed a decrease in drug release to occur with an increase in ionic strength. For example, drug release after the 1h mark for the K100M matrices in water was 36%. Drug release in pH 1.2 after 1h was 30%. An increase of the pH 1.2 ionic strength to 0.4M saw a reduction of drug release to 26%. This was the general trend for the K4M and K15M matrices as well. The similarity factor f2 was calculated using drug release in water as a reference. Despite similarity occurring for all the diltiazem HCl matrices in the pH 1.2 media (f2=64-72), increases of ionic strength at 0.2M and 0.4M brought about dissimilarity. The hydrochlorothiazide tablet matrices showed similarity at all the ionic strength tested for all polymers (f2=56-81). The values of f2 however reduced with increasing ionic strengths. DSC hydration results explained the hydrochlorothiazide release from their HPMC matrices. There was an increase in bound water as ionic strengths increased. Texture analysis was employed to determine the gel strength and also to explain the drug release for the diltiazem hydrochloride. This methodology can be used as a valuable tool for predicting potential ionic effects related to in vivo fed and fasted states on drug release from hydrophilic ER matrices.

Aqueous and hydro-alcoholic media effects on polyols.

The ingestion of drug products with alcohol can have an adverse effect on drug levels in a patient's blood. The Food and Drug Agency (FDA) issued an alert in 2005 after hydromorphone was withdrawn from the market after clinical trials showed ingestion with alcohol to potentially result in lethal drug peak plasma concentrations. The potential impact of alcohol on extended release (ER) tablet matrices and the need to develop ER matrices robust to alcohol effects has then been of interest. This study investigated the compaction properties of polyols and their effect on drug release. Polyols (erythritol, xylitol, mannitol and maltitol) with increasing hydroxyl groups were used as diluents for HPMC matrices containing theophylline. Release profiles were determined in pH 1.2 and 6.8 dissolution media with hydro-alcoholic concentrations of 5-40%. Increases in the polyols' hydroxyl groups brought about an increase in tablet strength and a decrease in the drug release rates. This is likely due to stronger bond formation with increasing hydroxyls. The impact of alcohol on drug release was studied further for maltitol formulations. Maltitol was resilient to the presence of ethanol (5-40% v/v) at pH 1.2 (f2=57-74) but not at pH 6.8 (f2=36-48). Drug release was not different above 5% alcohol concentration at pH 6.8. The results of this in vitro study suggest that ethanol concentrations as high as 40% do not substantially alter the drug release properties of theophylline from maltitol matrix tablets. However, care and consideration should be given to the choice of polyol or mixture of polyols in obtaining a desired drug release profile.

The effect of engineered mannitol-lactose mixture on dry powder inhaler performance.

PURPOSE: To co-crystallise mannitol and lactose with a view to obtaining crystals with more favourable morphological features than either lactose or mannitol alone, suitable for use as carriers in formulations for dry powder inhalers (DPIs) using simultaneous engineering of lactose-mannitol mixtures. METHODS: Mannitol and lactose individually and the two sugars with three different ratios were crystallised/co-crystallised using anti-solvent precipitation technique. Obtained crystals were sieved to separate 63-90 µm size fractions and then characterised by size, shape, density and in vitro aerosolisation performance. Solid state of crystallized samples was studied using FT-IR, XRPD and DSC. RESULTS: At unequal ratios of mannitol to lactose, the elongated shape dominated in the crystallisation process. However, lactose exerted an opposite effect to that of mannitol by reducing elongation ratio and increasing the crystals' width and thickness. Crystallised ß-lactose showed different anomers compared to commercial lactose (α-lactose monohydrate). Crystallised α-mannitol showed different polymorphic form compared to commercial mannitol (ß-mannitol). Crystallised mannitol:lactose showed up to 5 transitions corresponding to α-mannitol, α-lactose monohydrate, ß-lactose, 5α-/3ß-lactose and 4α-/1ß-lactose. In vitro deposition assessments showed that crystallised carriers produced more efficient delivery of salbutamol sulphate compared to formulations containing commercial grade carriers. CONCLUSION: The simultaneous crystallization of lactose-mannitol can be used as a new approach to improve the performance of DPI formulations.

The influence of physical properties and morphology of crystallised lactose on delivery of salbutamol sulphate from dry powder inhalers.

The aim of this work was to investigate the mechanistic evaluation of physicochemical properties of new engineered lactose on aerosolisation performance of salbutamol sulphate (SS) delivered from dry powder inhaler (DPI). Different crystallised lactose particles were obtained from binary mixtures of butanol:acetone. The sieved fractions (63-90 µm) of crystallised lactose were characterised in terms of size, shape, flowability, true density and aerosolisation performance (using multiple twin stage impinger (MSLI), Aerolizer(®) inhaler device, and salbutamol sulphate as a model drug). Compared to commercial lactose, crystallised lactose particles were less elongated, covered with fine lactose particles, and had a rougher surface morphology. The crystallised lactose powders had a considerably lower bulk and tap density and poorer flow when compared to commercial lactose. Engineered carrier with better flow showed improved drug content homogeneity, reduced amounts of drug "deposited" on the inhaler device and throat, and a smaller drug aerodynamic diameter upon inhalation. Aerodynamic diameter of salbutamol sulphate increased as lactose aerodynamic diameter decreased (linear, R(2)=0.9191) and/or as fine particle lactose content increased (linear, R(2)=0.8653). Improved drug aerosolisation performance in the case of crystallised lactose particles was attributed to lower drug-carrier adhesion forces due to a rougher surface and higher fine particle content. In conclusion, this work proved that using binary combinations of solvents in crystallisation medium is vital in modification of the physicochemical and micromeritic properties of carriers to achieve a desirable aerosolisation performance from DPI formulations. Among all lactose samples, lactose particles crystallised from pure butanol generated the highest overall DPI formulations desirability.

Characterisation and deposition studies of engineered lactose crystals with potential for use as a carrier for aerosolised salbutamol sulfate from dry powder inhalers.

Lactose particles with different elongation ratio, roundness, polymorphic form and crystallinity were prepared by a one-step crystallisation process using varying ratios of acetone/water. The crystals were characterised using image analysis optical microscopy, scanning electron microscopy, differential scanning calorimetry and X-ray powder diffraction. The elongation ratio was found to increase with increasing acetone ratio which therefore, appears to accelerate the growth in length rather than width and/or thickness. The crystallinity and polymorphic forms were also acetone-concentration dependent. For example, the crystals formed using 65-80% v/v acetone were almost all of the alpha-form whereas at 85% v/v a small amount of beta-form was precipitated, as detected by a peak at the reflection angle 2 theta=10.4 in the X-ray diffractogram. When 90% v/v acetone was incorporated a mixture of alpha- and beta-forms were produced in almost equal quantity, whereas, with 95% v/v acetone the beta-form predominated. At high acetone concentration (90 and 95% v/v), the crystallisation proceeded rapidly leading to the creation of some amorphous content. The 63-90-microm sieve cut of either commercial grade lactose (CL) or crystallised lactose was mixed with salbutamol sulfate and dispersibility was determined using the twin stage liquid impinger. All the formulations containing carrier particles generated by crystallization from solvent showed higher dispersibility and fine particle fraction (FPF) of the drug compared to the formulation made containing CL. The carrier that showed the highest elongation ratio (produced from an 85% acetone 15% water solution), when mixed with salbutamol sulfate produced the highest dispersibility (38.5%) and highest FPF (29.24%). These parameters were six times higher than the values obtained with the formulation containing CL.

The influence of carrier and drug morphology on drug delivery from dry powder formulations.

Lactose was crystallised either from neutralised Carbopol 934 gel or from water-ethanol solution without stirring, with a view to obtaining lactose alpha-monohydrate of favourable shape and smooth surface, suitable for use as carriers in formulations for dry powder inhalers (DPIs). Crystallisation of salbutamol sulphate was carried out in the presence of water, lecithin and ethanol to form salbutamol crystals with defined shape and smooth surface. The crystals formed were needle-shaped, with a length of less than 6 microm and a width between 0.5 and 1 microm. DSC and TGA showed that lactose crystals produced from Carbopol gel or from water-ethanol solution existed as alpha-lactose monohydrate. The DSC thermograms of micronised and crystallised salbutamol sulphate showed two similar endothermic transitions at 200 and 290 degrees C, respectively. The first transition was initially thought to correspond to the melting of salbutamol sulphate. However, the shape of the particles as observed by optical microscopy was not altered after heating the sample to 250 degrees C, suggesting that no transition from solid to liquid state occurred at 200 degrees C. This was confirmed by observations made using hot stage microscopy. The two endothermic transitions are suggested to correspond to the decomposition of the salbutamol sulphate molecule. The elongation ratio of the commercial lactose crystals, lactose crystallised from Carbopol and from water-ethanol were 1.69+/-0.05, 2.01+/-0.13 and 6.25+/-0.17, respectively. As the elongation ratio increased the flow properties of the carrier were affected detrimentally and this consequently reduced the content uniformity of salbutamol sulphate and drug emission from the inhaler device. Whereas, increasing the elongation ratio of the carrier or drug improved the deposition profiles of salbutamol sulphate, suggesting that the more elongated particles would be more aerodynamic and favour deep lung penetration.