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1.
Pulm Pharmacol Ther ; 63: 101943, 2020 08.
Article in English | MEDLINE | ID: mdl-32889156

ABSTRACT

PURPOSE: The development of inhaled drug products is expensive and involves time-consuming pharmacokinetic (PK) and pharmacodynamic (PD) studies. There are few in vitro cell-based assays to evaluate the disposition and action of orally inhaled drugs to guide early product development and minimise risk. The aim of the present study was to develop a co-culture bioassay, combining an airway epithelial cell line (Calu-3) with cultured human primary airway smooth muscle cells (ASM), integrated with apparatus to deliver pharmaceutical aerosols. METHODS: An assay for measuring cyclic adenosine monophosphate (cAMP) in ASM derived from healthy donors was adapted to provide a biochemical surrogate for ASM relaxation. Concentration-response curves for cAMP were established for three drugs that elicit ASM relaxation: isoprenaline (ISO), forskolin (FOR) and salbutamol sulphate. The ASM bioassay was incorporated into a co-culture model in which air-interfaced Calu-3 cell layers, representing the permeability barrier of the airway epithelium, were grown on transwell inserts above ASM cells cultured in the well of the base-plate. The sensitivity of this bioassay to salbutamol delivered using different formulations and aerosol products was evaluated. RESULTS: ASM responded with concentration dependent increases in cAMP when exposed to 10-9 to 10-5 M ISO, FOR or salbutamol sulphate solutions for 15 or 30 min. Salbutamol formulated with different counter ions elicited differential cAMP responses in ASM (xinafoate > base = sulphate) suggesting that this bioassay could discriminate between formulations with different potency. A similar rank order of potency was observed for the different salbutamol salts when applied as aerosols to the co-culture model. DISCUSSION: We have developed a novel bioassay using human ASM in co-culture with human respiratory epithelial cells to better mimic various elements that contribute to the rate and extent of local drug availability in the lungs following topical administration. The bioassay offers an opportunity to investigate the factors determining the activity of inhaled bronchodilator drugs in a more biologically relevant system than that has previously been described and with further development and validation, this novel bioassay could provide a method to guide the more efficient development of inhaled bronchodilators, reducing the current reliance on in vivo studies.


Subject(s)
Muscle, Smooth , Albuterol/pharmacology , Biological Assay , Bronchodilator Agents/pharmacology , Humans , Muscle Relaxation/drug effects
2.
J Pharm Sci ; 106(1): 313-321, 2017 01.
Article in English | MEDLINE | ID: mdl-27837967

ABSTRACT

Dry powder inhalers are increasingly popular for delivering drugs to the lungs for the treatment of respiratory diseases, but are complex products with multivariate performance determinants. Heuristic product development guided by in vitro aerosol performance testing is a costly and time-consuming process. This study investigated the feasibility of using artificial neural networks (ANNs) to predict fine particle fraction (FPF) based on formulation device variables. Thirty-one ANN architectures were evaluated for their ability to predict experimentally determined FPF for a self-consistent dataset containing salmeterol xinafoate and salbutamol sulfate dry powder inhalers (237 experimental observations). Principal component analysis was used to identify inputs that significantly affected FPF. Orthogonal arrays (OAs) were used to design ANN architectures, optimized using the Taguchi method. The primary OA ANN r2 values ranged between 0.46 and 0.90 and the secondary OA increased the r2 values (0.53-0.93). The optimum ANN (9-4-1 architecture, average r2 0.92 ± 0.02) included active pharmaceutical ingredient, formulation, and device inputs identified by principal component analysis, which reflected the recognized importance and interdependency of these factors for orally inhaled product performance. The Taguchi method was effective at identifying successful architecture with the potential for development as a useful generic inhaler ANN model, although this would require much larger datasets and more variable inputs.


Subject(s)
Albuterol/administration & dosage , Bronchodilator Agents/administration & dosage , Dry Powder Inhalers/methods , Neural Networks, Computer , Salmeterol Xinafoate/administration & dosage , Albuterol/chemistry , Bronchodilator Agents/chemistry , Particle Size , Powders , Principal Component Analysis , Salmeterol Xinafoate/chemistry
3.
J Pharm Sci ; 104(11): 3861-3869, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26220184

ABSTRACT

A variety of capsule-based dry powder inhalers were used to evaluate formulation-device interaction. The in vitro deposition of salbutamol sulphate (SS) was compared directly to published data for salmeterol xinafoate (SX). A 3(2) factorial design was used to assess the effect of SS formulations with three blends of different grade coarse lactose supplemented with different levels of fine lactose. These formulations were tested for homogeneity and evaluated for their in vitro deposition using Aeroliser, Handihaler and Rotahaler devices. The performance of the SS-lactose formulations differed across the grade of lactose and amount of fine lactose used compared to the same powder compositions blended with SX. SX had a greater fine particle fraction than SS for most of the comparable formulations, probably because of the different cohesiveness of the drugs. A head-to-head comparison of 'matched' SX and SS formulations when aerosolised from the same three devices demonstrated that formulation-device interactions are as critical in determining the in vitro deposition of drug-lactose blends as the identity of the active pharmaceutical ingredient. This work has revealed the limitations of the interpretative value of published in vitro performance data generated with a single device (even at equivalent aerosolisation force), when designing formulations for a different device.


Subject(s)
Albuterol/administration & dosage , Bronchodilator Agents/administration & dosage , Dry Powder Inhalers/methods , Excipients/chemistry , Lactose/chemistry , Sulfates/administration & dosage , Administration, Inhalation , Albuterol/chemistry , Bronchodilator Agents/chemistry , Dry Powder Inhalers/instrumentation , Particle Size , Sulfates/chemistry
4.
Int J Pharm ; 490(1-2): 360-7, 2015 Jul 25.
Article in English | MEDLINE | ID: mdl-25987210

ABSTRACT

Using salmeterol xinafoate (SX) as an active pharmaceutical ingredient, the effects of carrier lactose particle type, total lactose fines content and device resistance on dry powder inhaler performance were investigated in vitro. To mimic drug levels in commercial preparations, interactive mixtures containing 0.58% w/w SX were prepared by low shear tumble mixing. Three types of milled inhalation grade lactose were used (Lactohale(®) LH 200, Respitose(®) ML006 and ML001) and the concentration of fine lactose (Lactohale(®) 300) added was varied. The in vitro deposition of each mixture was studied using a next generation impactor and inhaler devices exhibiting different resistances, Rotahaler(®)80% ED and MMAD ± GSD between 1-5 µm. The results confirmed the factors under investigation to be important determinants of product performance, but demonstrated using realistic conditions how individual factor impact may be enhanced or mitigated by inter-dependency.


Subject(s)
Chemistry, Pharmaceutical/instrumentation , Dry Powder Inhalers/instrumentation , Powders/chemistry , Salmeterol Xinafoate/chemistry , Administration, Inhalation , Aerosols/chemistry , Chemistry, Pharmaceutical/methods , Drug Carriers/chemistry , Equipment Design/instrumentation , Lactose/chemistry , Particle Size
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