Elsevier

Advanced Powder Technology

Volume 28, Issue 2, February 2017, Pages 534-542
Advanced Powder Technology

Original Research Paper
Optimized particle engineering of fluticasone propionate and salmeterol xinafoate by spray drying technique for dry powder inhalation

https://doi.org/10.1016/j.apt.2016.10.022Get rights and content

Highlights

  • Optimized DPI formulation of fluticasone and salmeterol was developed.

  • The effects of carrier, leucine and manufacturing technique were investigated.

  • The component of greatest influence on response variables was found to be leucine.

  • Spray drying of some fraction of carrier with drugs improved respirable fraction.

Abstract

Asthma is one of the most common respiratory diseases that can be efficiently managed through combined treatment of fluticasone propionate (FP) and salmeterol xinafoate (SX). In this study, we challenged the use of both spray drying and mixing techniques in sequential combination of lactose or mannitol with FP and SX as two steps in development of inhalable powder formulation of the drugs. Leucine was used as a dispersibility enhancer. The formulations were optimized using the Design-Expert software. The effects of three independent variables namely the type of carrier, percentage of spray-dried carrier and the amount of leucine were investigated on in vitro deposition. The results showed that the maximum fine particle fraction (FPF) and the minimum particle size was belonged to formulation in which the percentage of leucine was 20% with respect to the total solid content and 50% of mannitol was used during spray drying, while the remaining 50% of it was applied in the physical mixing process. This study showed that not only the choice of carrier and additives for every drug combination, but also an optimized ratios of them during both spray drying and physical mixing can be crucial in developing suitable inhalable dry powder formulations.

Introduction

Asthma and COPD are complex disease conditions of the airways that both are characterized by air flow limitation and airway inflammation [1]. In order to manage these respiratory complications, therapies are required to control symptoms, reduce exacerbations and improve health status in patients. The first-line treatment for both conditions is long-acting β2-agonists (LABA) and inhaled corticosteroids (ICS), which are employed to aid bronchodilation and reduce inflammation, respectively [2], [3].Inhalation dosage forms containing a LABA and ICS are available in both pressurized metered dose inhaler (pMDI) and dry powder inhaler (DPI) platforms [4]. Due to the concern about ozone depleting effects of chlorofluorocarbons used in pMDIs, the DPIs are emerging as an important noninvasive delivery approach in the new decade and beyond [5]. DPIs are currently used by an estimated 40% of European patients to treat asthma and COPD [6]. Among the inhalation products available for such diseases, the combination of salmeterol xinafoate (SX, LABA) and fluticasone propionate (FP, ICS) (Seretide®/Advair®, GlaxoSmithKline, UK) has achieved widespread acceptance among physicians and patients and is listed in the top ten best-selling pharmaceutical products of recent years [7]. This combination therapy shows greater efficacy compared to monotherapy treatments with the individual components [8], and reduced mortality rates in COPD beyond that achieved by single therapies [9].

The delivery efficiency of dry powder products through inhalation is dependent on drug formulation, the inhaler design, and the inhalation technique. Successful drug delivery depends on the interaction between the powder formulations and the device performance to generate a suitable aerosol. To achieve deep lung penetration, drug particles are often micronized to sizes between 1 and 5 μm [10]. However, small drug particles generally have poor flow properties and hindered dispersibility due to their highly cohesive nature. In other words, they tend to adhere and remain in the DPI device during the emission process which lead to low aerosol generation and unreliable dosing [11], [12].Therefore, to improve flow and dispersion, a population of coarse particles (50–100 μm) is incorporated into the DPI formulation to serve as carriers onto which the drug particles adhere during blending [13]. Such blends provide the essential improvement in powder flow properties to enable adequate metering and fluidization of the highly cohesive fine drug particles. Moreover, the drug particles must detach from the surface of the carrier during the process of aerosolization in order to reach their site of action [13]. This is the key process that governs the performance of such formulations, and is dependent upon the balance between the cohesive and adhesive forces between drug and carrier particles and the aerodynamic drag forces acting against them during aerosolization. It is, therefore, unsurprising that numerous studies have shown the influential role of carrier material on fine particle delivery and subsequent formulation performance, as such a change will also lead to different levels of drug-carrier adhesion [14], [15].

Spray drying has been routinely employed for the production of pharmaceutical particles for decades [13]. The compound is fed as a solution or suspension in a liquid medium and atomized into a hot drying environment. Particles produced by spray drying are usually amorphous, more spherical and possess a lower density compared to other methods [16].

The addition of various amino acids to DPI formulations obtained by spray drying has the potential to significantly improve the in vitro deposition profile of drug particles [13]. In particular, addition of leucine usually results in less cohesive particles with smaller sizes which is due to the surfactant behavior of leucine that leads to the reduction of droplets’ size during atomization and decreases particles adhesion [17].

In this study, we demonstrated how a rational approach to experimental design of a DPI formulation could generate highly respirable powder, which offered simultaneous and efficient in vitro delivery of SX and FP to the lungs. To this aim, we optimized the type of carrier, percentage of spray-dried carrier and the amount of leucine using the Design-Expert software (version 7.0.0, Stat-Ease, Inc., Minneapolis, MN, USA). To the best of our knowledge, this is the first systematic research investigating the combined use of spray drying and mixing techniques in sequential addition of common used carries to micronized drugs in development of dry powder inhalers and trying to optimize the partial amounts of co-processed carriers added in each step of the formulation process. Development of such optimization methods as an alternative to traditional ones offers better investigation of the influencing factors on the response(s) as well as the interaction effects between them, through usually less number of experiments. After spray drying, the formulations were physically blended with the remaining amount of the same coarse carrier, which was initially used in the feed solution. Particle size properties as well as in vitro aerosol performance were examined in different formulations in order to find the optima with desirable DPI attributes.

Section snippets

Materials

Micronized FP and SX were supplied from Cipla (India).α-lactose monohydrate was purchased from DMV International (The Netherland). Mannitol and l-leucine were from Crester (France) and Merck (Germany), respectively. The HPLC grade methanol, ammonium acetate, and absolute ethanol were all supplied from Merck (Germany).

Quantitative sample analysis by high pressure liquid chromatography (HPLC)

Quantitative analysis of the sample was done using HPLC system (Waters 6006, USA). The column used was a Hypersil ODS (4.6 mm × 150 mm), which was packed with 5 μmC18 stationary phase.

Content uniformity

The RSD of the drug content of the 19 tested formulations is shown in Table 3. According to the European and British pharmacopeia, the formulations with RSD < 10%, have good uniformity [19], [20]. The results showed that the content uniformity was less than 10% for different formulations so that all the samples could be used for further in vitro aerosolization testing. Regarding the RSD, it should be mentioned that small amplitude differences were found between the responses, indicating a minor

Conclusion

Currently, the generation of aerosol drugs from DPIs is being improved by changing formulation components and particle engineering of these systems. In this study, we developed engineered DPI formulations of combined FP and SX by co-spray drying with different partial amounts of lactose or mannitol followed by physical mixing of the resultant powders with the remaining considered amounts of these common used carriers, as the coarse carrier, to improve the inhalation performance of drug

Acknowledgments

This study was funded and supported by Tehran University of Medical Sciences (TUMS); grant no. 91-01-33-17106.

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