Advances in asthma and COPD management: Delivering CFC-free inhaled therapy using Modulite® technology

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Abstract

Inhaled corticosteroids (ICS) and long-acting β-agonists (LABA) are currently used in the management of asthma and chronic obstructive pulmonary disease (COPD). Localized targeted delivery of these drugs into the lungs is achieved by means of two types of inhalation devices; pressurized metered-dose inhalers (pMDIs) and dry powder-inhalers (DPIs). For environmental reasons, the chlorofluorocarbon (CFC) propellants used in pMDIs are now being replaced by ozone friendly hydrofluoroalkanes (HFAs). These new generation HFA-based pMDIs, developed to provide effective lung deposition of the active moiety, have a favorable safety and tolerability profile. However, HFA-based re-formulation of LABAs and ICS for pMDIs presents particular technical difficulties, especially in terms of ensuring dose content uniformity.

This review focuses on the technology and clinical efficacy of the HFA solution pMDIs using Modulite® platform technology (Chiesi Farmaceutici S.p.A). Modulite® technology allows the development of HFA solution formulations that can mimic the established CFC-based drug formulations on a microgram to microgram basis and provides formulations with novel particle size distributions that improve on existing delivery systems; by manipulation of aerosol clouds and particle size, the delivery of HFA-formulated drugs can be optimized to either achieve fine particle fractions and deposition patterns similar to established CFC-based drug formulations, thus facilitating the transition to new environment-friendly pMDIs in the clinical setting, or achieve finer drug particles able to penetrate deeper into the bronchi for targeted drug delivery as medical need may dictate.

Long-term, multiple-dose clinical studies of Modulite® formulations of beclomethasone dipropionate (BDP), budesonide and formoterol have been demonstrated to be therapeutically equivalent to their respective previously established CFC or DPI formulations. As a result, a number of Modulite® pMDIs have either recently gained regulatory approval in several European countries, or have completed clinical trials and are in the regulatory submission phase. Availability, in pMDI form, of drugs like formoterol, ICSs, and ICS/LABA combinations, all central to the effective management of asthma and COPD, is therefore expected to impact positively in assuring the continued availability of vital treatment options to patients and physicians.

Introduction

Inhaled corticosteroids (ICS) and long-acting β-agonists (LABA) are currently used in the management of asthma and chronic obstructive pulmonary disease (COPD) [1], [2], [3], [4], [5], [6]. Targeted drug delivery to the lung is achieved using two types of inhaler devices: pressurized metered-dose inhalers (pMDIs) and dry powder-inhalers (DPIs). The popular and widely used type of inhaler, the pMDI, utilized chlorofluorocarbon (CFC) gases known to damage the ozone layer. In 1987, the Montreal protocol [7], the international agreement on eradicating ozone-damaging gases, required CFC use in inhalers to be phased out and created the impetus to find effective, easy-to-use, economical, ozone-friendly alternatives. In order to minimize disruption and ensure patient well-being and safety, it was considered vital that there was a smooth transition from CFC to CFC-free inhalers.

Two new hydrofluoroalkane (HFA) propellants emerged as potential alternatives to CFC: HFA-134a (norflurane) and HFA-227a. Reformulation to HFA-based formulations for pMDIs progressed in two directions: HFA suspension and HFA solution aerosols [8]. HFA suspensions retain the same particle size, deposition, and efficacy profiles as their CFC counterparts, whereas HFA solutions can be manipulated to vary particle size distribution permitting precise control of delivered dose and optimize drug delivery to allow the drug to penetrate the peripheral regions of the lung more effectively.

Although HFA suspension pMDIs produce similar particle size and provide similar lung deposition to CFC-based pMDIs, it has proved difficult to reformulate a number of inhaled drugs due to differences in the physical and chemical properties of CFC and HFA, such as increased drug solubility in the new propellants. Problems have also arisen in the development of solution formulations; dosing problems on switching patients from their CFC to HFA-based pMDI drug formulations can occur unless the HFA solution can be effectively manipulated to ‘match’ the specific dose of the CFC pMDI formulation.

The clinical characteristics of formulations delivered by pMDI are defined by the physical characteristics of the aerosol generated. CFC pMDIs generate coarse, fast-moving aerosols. In these, it is generally considered that the drug is unable to effectively penetrate the lung and is mainly destined to be deposited either in the nasal and oral cavities or the back of the throat and then swallowed. The particle size is a major determinant of the proportion of drug that reaches the lung. Since asthma and COPD both involve some degree of inflammation in the peripheral as well as the central airways of the lung, the increased lung penetration with HFA solution formulations may provide clinical advantage over CFC or HFA suspension pMDIs and DPIs.

This review focuses on the technology and clinical efficacy of the HFA solution pMDIs using Modulite® platform technology (Chiesi Farmaceutici S.p.A, developed in collaboration with Coordinated Drug Development (now Vectura), and its role in providing a smooth, safe transition from CFC- to HFA-based formulations for patients with obstructive airways disease. It also addresses the means by which this technology offers substantial and innovative improvements to the existing CFC pMDI and DPI delivery systems in terms of dose content uniformity and targeted drug delivery.

Section snippets

Modulite® technology

Modulite® platform technology [9] is a solution aerosol system based on the propellant HFA-134a. The original aim of the Modulite® technology, to provide CFC-free formulations and to match CFC-based pMDIs in terms of aerosol characteristics and particle size allowing a CFC transition on a 1:1 nominal dose ratio basis, was accomplished. In addition, Modulite® technology allows the size and distribution of particles to be tailored, enabling drug delivery to be targeted to different parts of the

Effect of particle size

Although Modulite® pMDIs were developed to allow direct 1:1 microgram per microgram transition from existing CFC pMDI or DPI formulations to HFA-based ones, Modulite® pMDIs have also been developed with differing particle size and aerosol characteristics to improve delivery patterns seen with existing CFC pMDIs or DPIs. With CFC pMDIs and DPI devices, the majority of inhaled drug is deposited in the oro-pharyngeal tract rather than in the respiratory tract [24], [25]. The amount and site of

Efficacy of Modulite® pMDIs in asthma

BDP and budesonide are well established ICS medications for maintenance therapy of chronic asthma [36]. The LABA formoterol is currently recommended in treatment guidelines as an add-on bronchodilator therapy to improve lung function and symptoms in patients who do not respond adequately to ICS. Some evidence also supports its use in acute asthma attacks [37]; however, the use of formoterol should strictly adhere to formulation and country specific regulations.

The clinical efficacy of Modulite®

Patient acceptability

The newer HFA solution formulations are associated with equivalent or greater patient acceptability than HFA suspension formulations as demonstrated in a study comparing HFA BDP solution (Beclojet HFA®) with HFA fluticasone dipropionate suspension (Flixotide®). The efficacy in terms of morning FEV1 was similar with both products and the tolerability profile was also similar [50].

Formoterol Modulite® in COPD

Long-acting bronchodilator medications such as formoterol are central to the symptomatic management of COPD [1]. Formoterol provides rapid onset of action and long-acting bronchodilation and greater improvement of lung function than short-acting inhaled anticholinergic or methylxanthine medications [51]. In view of this, use of formoterol Modulite® may confirm additional benefit for patients in the treatment of COPD. Taking into consideration the difficulty in differentiating asthma and COPD,

Conclusion

Modulite® technology is an effective replacement of the CFC-based drug delivery systems, combining the ease of use of a pMDI with the accuracy of DPI dosing. In addition to providing a seamless transition from CFC to non-CFC alternatives, this technology also offers considerable advantages over CFC-based pMDIs, DPIs and HFA suspension-based pMDIs by enabling the size and distribution of particles to be modulated.

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