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Title: Engineered inflated spherical lactose particle and its potential use as a carrier for dry powder formulation aerosols
Author: Thevarajah, Ursula
ISNI:       0000 0004 7963 6246
Awarding Body: University of Huddersfield
Current Institution: University of Huddersfield
Date of Award: 2019
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Dry powder inhalation aerosol is usually formed by blending lactose carrier with micronized drug particles using an order mix. In this thesis, blends of either Salbutamol Sulphate (SS), Beclomethasone Dipropionate (BDP) or Fluticasone Propionate (FP) and coarse lactose particles were employed to investigate the effects of lactose morphological features on drug delivery by dry powder aerosols in-vitroor ex-vivousing recorded patients'inhalation profiles. Two lactose carriers were used in this study namely Lactohale and engineered lactose. Engineered lactose was prepared by a novel crystallisation technique from solid state using spray dried amorphous lactose prepared from lactose solution alone (10% w/v) or in the presence of additives (1% w/v) such as Polyvinyl Pyrrolidone (PVP K90) or sodium chloride (NaCl). A 10 g of amorphous spray dried particles (< 5 μm) were introduced to a boiled ethanolic solution (100 mL) under stirring for 10 seconds or 30 seconds to form crystalline spherical porous hollow particles at least 10-fold larger in size compared to spray dried particles. The increase in size was possibly due to a combination of factors; crystal growth and the ethanol vapour pressure increase inside the hollow volume facilitating particles inflation causing an increase in the hollow volume of the particles. This method of crystallisation is predictable in forming spherical particles irrespective of the additive. The particles contacted with ethanol for 30 seconds (PSDL30) were more crystalline and rougher than those exposed for 10 seconds (PSDL10) to ethanolic solution. The same process was successfully applied to lactose spray dried from a suspension to form large spherical particles with rougher surface compared to those spray dried from solution. The engineered lactose particles were rougher than Lactohale lactose and were found to mix rapidly to stabilize the DPI formulations against segregation when compared to smooth Lactohale as confirmed by drug content uniformity and tribo-electrification study. Drug deposition in-vitro was dependent on the physico-chemical properties of drug particles. For SS, high drug deposition was obtained when smooth lactose was used, thus the fine particle dose (FPD) was higher for Lactohale followed by PSDL10 and finally PSDL30 suggesting that drug deposition increased with surface smoothness. A different trend was observed with hydrophobic drugs such as BDP and FP. A nano-surface roughness was favourable for both hydrophobic drugs BDP and FP and the order of FPD was PSDL10> Lactohale > PSDL30. A balanced drug roughness is needed for hydrophobic drugs to improve drug content uniformity and to facilitate drug detachment during aerosolisation. Ex-vivostudy using four patient profiles having the same inhaled volume (Vin) and acceleration (ACIM) at the start of the inhalation manoeuvre but having different maximum inhalation flow (MIF) were used to study the aerodynamic dose emission characteristics of SS with lactohale and engineered lactose carrier produced from spray dried lactose formed from spray dried suspension of lactose, which is commercially available(PSDL com). PSDLcom had the highest roughness in comparison to all carriers highlighted above and showed low FPD at all MIFs in comparison to Lactohale. This study confirmed again that smooth carrier such as Lactohale provides better drug deposition for hydrophilic drugs such as SS. In conclusion, the drug deposition study showed that there is no ideal carrier for all drugs with different physico-chemical properties such as hydrophilicity. To improve drug deposition from DPIs, hydrophilic drugs are better formulated with a smooth carrier and hydrophobic drugs require a moderate surface roughness.
Supervisor: Larhrib, El Hassane Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Q Science (General) ; QD Chemistry