Recent Advances in pMDI Technology

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Although the respiratory tract has been a therapeutic target for many centuries, the pMDI is generally considered the first generation of marketed inhalation products that adhere to the vigorous regulatory requirements. Marketed since their introduction by Riker Laboratories, Santa Barbara (now 3M Healthcare) (86) in 1956 and many authors have described their basic form and functionality (87,88). Fundamentally, pMDIs rely on aerosol propellant technology, in which a high vapor pressure gas (typically a liquid propellant) is contained in a pressurized canister, in a super-cooled state. By metering a given volume of propellant containing formulation (typically 25-100 ^l) within an integral metering valve, a reproducible dose of drug can be emitted and delivered. The high, internal energy of the propellant results in rapid expansion of formulation through the metering stem and vaporization via an actuator orifice. Subsequently, micron sized droplets are produced containing the formulation that are suitable for respiratory delivery. In pMDI based systems, the drug can either be homogeneously suspended (colloidal system) or solubilized in a propellant (either with or without the addition of co-solvents).

Until 1995, all marketed pMDI products contained CFCs as the delivery propellant. However, concerns over the possible detrimental ozone depleting effects of CFCs (89), reported in 1974, resulted in 150 nations signing the Montreal protocol in 1987, which committed the signatories to cease CFC production by 1996. In order to continue to use and develop pMDIs, pharmaceutical companies have subsequently committed significant resources to the development of CFC-free pMDI systems (90). The candidates that emerged from this research as potentially suitable CFC replacements were short-chain hydrofluoroalkanes (HFAs) (91): specifically, 1,1,1,2,3,3,3 Heptafluoropropane (HFA-227) and 1,1,1,2 Tetrafluoroethane (HFA-134a). Although these materials were accepted as reasonable replacements for the previously used CFCs, the HFA propellants possessed different physical and chemical proprieties and thus made a simple formulation propellant exchange impossible, spawning a whole new series of challenges for the formulation of pMDIs. Even though these challenges still exist, significant time and effort has been invested in overcoming these formulation hurdles, and many HFA formulations are currently available as marketed products or are currently under development (Table 1).

Table 1 Marketed and In-Development pMDI Products Based on Suspension Formulations

Active

Therapeutic

Trade name

compound

Manufacturer

use

Ventolin®/

Albuterol

GlaxoSmithKline

Bronchodilator

Proventil® -HFA

Azmacort®

TAA

Kos

Prophylactic

Pharmaceuticals

therapy of asthma

Inc..

Flovent® HFA

Fluricasone

GlaxoSmithKline

Corticosteroid

propionate

bronchodilator

Combivent®

Ipratropium

Boehringer

Anticholinergic

bromide and

Ingelheim

bronchodilator in

albuterol

Pharmaceuticals,

patients with

sulphate

Inc.

COPD

Aerobid® inhaler

Flunisolide

Forest

Corticosteroid anti-

system

Pharmaceuticals,

inflammatory,

Inc.

antiallergic

Tilade®

Nedocromil

Rhone-Poulenc

Anti-inflammatory

sodium

Rorer

Pharmaceuticals

Inc.

Azmacort

TAA

Aventis Pharma

Cortoicosteroid

(in development)

Symbicort®

Budesonide and

AstraZeneca (in

Corticosteroid and

formoterol

development)

selective beta2-

agonist

Pulmicort®

Budesonide

AstraZeneca (in

Corticosteroid

development)

Serevent®

Salmeterol

GlaxoSmithKline

Bronchodilator

Evohaler

xinafoate

Xopenex®HFA

Levalbuterol

Sepracor Inc..

Selective beta2-

tartrate

agonist

Mometasone

Schering-Plough

Corticosteroid

furoate

Research

Institute

Brycanil®

Terbutaline

AstraZeneca

Short-acting beta2-

sulphate

agonists

Abbreviations: COPD, chronic obstructive pulmonary disease; HFA, hydrofluoroalkanes; TAA, triamcinolone acetonide.

Abbreviations: COPD, chronic obstructive pulmonary disease; HFA, hydrofluoroalkanes; TAA, triamcinolone acetonide.

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