Critical Reviews™ in Therapeutic Drug Carrier Systems, 19(4&5):425–498 (2002)
Pulmonary Drug Delivery Systems: Recent Developments and Prospects H. M. Courrier,1,2 N. Butz,1 & Th. F. Vandamme1,3* 1Laboratoire
de Chimie Thérapeutique et Nutritionnelle, Biodisponibilité Tissulaire et Cellulaire and 3Laboratoire de Chimie Bioorganique, Faculté de Pharmacie, Université Louis Pasteur, France; 2Chimie des Systèmes Associatifs, Institut Charles Sadron, Strasbourg, France; * Address all correspondence to Dr. Th. F. Vandamme, Laboratoire de Chimie Thérapeutique et Nutritionnelle, Biodisponibilité Tissulaire et Cellulaire, Faculté de Pharmacie, Université Louis Pasteur, 67401 Illkirch Cedex, France;
[email protected]
ABSTRACT: Targeting drug delivery into the lungs has become one of the most important aspects of systemic or local drug delivery systems. Consequently, in the last few years, techniques and new drug delivery devices intended to deliver drugs into the lungs have been widely developed. Currently, the main drug targeting regimens include direct application of a drug into the lungs, mostly by inhalation therapy using either pressurized metered dose inhalers (pMDI) or dry powder inhalers (DPI). Intratracheal administration is commonly used as a first approach in lung drug delivery in vivo. To convey a sufficient dose of drug to the lungs, suitable drug carriers are required. These can be either solid, liquid, or gaseous excipients. Liposomes, nano- and microparticles, cyclodextrins, microemulsions, micelles, suspensions, or solutions are all examples of this type of pharmaceutical carrier that have been successfully used to target drugs into the lungs. The use of microreservoir-type systems offers clear advantages, such as high loading capacity and the possibility of controlling size and permeability, and thus of controlling the release kinetics of the drugs from the carrier systems. These systems make it possible to use relatively small numbers of vector molecules to deliver substantial amounts of a drug to the target. This review discusses the drug carriers administered or intended to be administered into the lungs. The transition to CFC-free inhalers and drug delivery systems formulated with new propellants are also discussed. Fınally, in addition to the various advances made in the field of pulmonary-route administration, we describe new systems based on perfluorooctyl bromide, which guarantee oxygen delivery in the event of respiratory distress and drug delivery into the lungs. KEYWORDS: lung, specific drug delivery, pulmonary drug targeting, carrier, hydrofluoroalkane
I. INTRODUCTION The pulmonary route presents several advantages in the treatment of respiratory diseases (e.g., asthma, chronic obstructive bronchopneumopathy) over the administration of the same drugs by other routes leading to the systemic delivery of such drugs. Drug inhalation enables rapid deposition in the lungs and induces fewer side effects than does administration 0743-4863/02 $5.00 Document#CRT1904-05-425–498(107) © 2002 by Begell House, Inc., www.begellhouse.com
. . .
ABBREVIATIONS 9-NC: 9-nitrocamptothecin ACE: angiotensin-converting enzyme ACI: Andersen Cascade impactor ACI: Andersen Cascade Impactor ACTH: adrenocorticotropic hormone ADP: adenosine diphosphate AKP: alkaline phosphatase AM: alveolar macrophage A-PGI2: aerosolized prostacyclin ASES: aerosol solvent extraction system BAL: bronchoalveolar lavage BDP: beclomethasone dipropionate BGTC: bis-guanidinium-tren-cholesterol CAT: chloramphenicol acetyl transferase cBDP: crystalline beclomethasone dipropionate CD: cyclodextrin CF: carboxyfluorescein CFC: chlorofluorocarbon CHOL: cholesterol CIPRO: Ciprofloxacin CPT: camptothecin CsA: cyclosporine A CS-nanospheres: chitosan-modified nanospheres Cys A: cyclosporine A DEX: dexamethasone DEXP: dexamethasone palmitate DLPC: dilauroylphosphatidylcholine DMPC: dimyristoylphosphatidylcholine DMRIE/DOPE: N-(2-hydroxyethyl)-N,Ndimethyl-2,3-bis(tetradecytoxy)-1-propanaminium bromide/dioleoyl phosphatidylethanolamine DNA: desoxyribonucleic acid DOPE: dioleoyl phosphatidylethanolamine DOTAP-CHOL: 1,2-dioleoyl-Sn-glycero-3trimethylammonium propane/cholesterol DPI: dry powder inhaler DPPC: dipalmitoyl phosphatidylcholine DPPE: dipalmitoyl phosphatidylethanolamine DSPC: 1,2-distearoyl phosphatidylcholine DSPG: 1,2-distearoyl phosphatidylglycerol DX: detirelex decapeptide EDMPC: 1,2-dimyristoyl-Sn-glycero-3-ethylphosphatidylcholine
EE: encapsulation efficiencies EYPC: egg yolk phosphatidylcholine G/PFC: gentamicin/perfluorochemical GA: glycolic acid GSD: Geometric Standard Deviation HAL: halothane hCFTR: cystic fibrosis transmembrane regulator conductance of human HFA: hydrofluoroalkane HIV: immuno-deficient virus HPC: hydroxypropylcellulose HSPC: hydrogenated soya phosphatidylcholine i.t.: intratracheal i.v.: intravenous ICLC: polyriboinosinic-polyribocytidylic acid (poly IC) stabilized with poly--lysine:carboxymethylcellulose (LC) IEP: isoelectric point IL-1β: interleukin 1 beta IL-2: interleukin 2 INF-γ: interferon-γ KF: ketotifen fumarate L-9NC: 9-Nitrocamptothecin-liposomes L-CPT: camptothecin-liposome L-DEX: liposome-entrapped dexamethasone LPS: lipopolysaccharides L-PTX: paclitaxel-liposomes LUV: large unilamellar vesicles LV: liquid ventilation MAP: mean arterial pressure MDI: metered dose inhaler ML: multilamellar MLV: large multilamellar vesicles MMAD Mass Median Aerodynamic Diameter MMD: Mass Median Diameter MPLA: monophosphoryl lipid A MPO: myeloperoxydase MTB: mycobacterium tuberculosis MV: mechanical ventilation NS: nedocromil sodium PaO2: pressure arterial oxygen PAP: pulmonary arterial pressure PBC polybutylcyanoacrylate PBCA: polybutylcyanoacrylate PC: phosphatidylcholine
PCHS: phosphatidylcholine of hydrogenated soya PCS: phosphatidylcholine of soya PEI: polyethylenimine PFC: perfluorocarbon PGLA: poly(glycolic-co-lactic acid) PLA: poly(lactic acid) PLAL-lys: poly(acide lactique-co-lysine) PLV: partial liquid ventilation PMDI: pressurized metered-dose inhaler PTH: paratyroid hormone PTX: paclitaxel RB: rhodamine B
RDS: respiratory distress syndrome RF: respirable fraction R-PGLA: rifampicin-PGLA microspheres SC: salmon calcitonin SLN: solid lipid nanoparticles SUV: small unilamellar vesicles T½: half time of elimination TAP: triamcinolone acetonide phosphate TCA: triamcinolone acetonide TNF-α: tumor necrosis factor alpha UL: unilamellar VEE: Venezuelan equine encephalomyelitis
by other routes. The use of drug delivery systems for the treatment of pulmonary diseases is increasing because of its potential for localized topical therapy in the lungs. In addition, this route makes it possible to deposit large concentrations at disease sites, to reduce the amount of drugs administered to patients (20–10% of the amount administered by the oral route), to increase the local activity of drugs released at such sites, and to avoid the metabolization of drugs due to a hepatic first-pass effect.1 Recent medical advances have established that small-airway disease is a significant component in obstructive airway disease.2 It has also been demonstrated3 that emphysema classically involves the terminal bronchioles, but, increasingly, there is recognition that asthma—and in particular chronic persistent asthma—also involves the small airways. For these reasons and in order to improve the pulmonary targeting of a potentially useful therapy, numerous scientific contributions have been focused on the construction of suitable dosage forms to specifically target the small airways and to increase the local bioavailability of drugs combined with carrier systems. It was necessary to construct such carrier systems because of the limitations of chronic oral administration with respect to systemic side effects, including hepatic dysfunction, skeletal malformations, hyperlipidemia, and hypercalcemia.4 At present, the clinical results obtained with particular carrier systems suggest that some of these may offer a practical alternative to systemic oral administration for chemoprevention trials or the treatment of lung diseases. This method may substantially increase the therapeutic index of targeted compounds by reducing the systemic complications associated with long-term administration. Although the lungs are rich in enzymes, they also contain several protease inhibitors. Therefore, there is some evidence that exogenous proteins may be protected from proteolytic degradation by these inhibitors. These characteristics also make the airways a useful route of drug administration in the inhaled or aerosol form. The mechanisms of delivery to the lungs are perhaps more complex than for other routes. The drug fraction that reaches the lungs depends on numerous factors, such as the amount and rate of inhaled air, the respiratory pause, and the particle size and characteristics (homogeneity, shape, electric charges, density, and hydrophobicity). In spite of such complex mechanisms, pulmonary delivery of a variety of drugs such as bronchodilators and steroids has enjoyed great success. Fortunately, the advantages of this route have been recognized, and research in the field has progressed steadily.5 The pulmonary route was long used only to treat local diseases. Recently, the use of this route to administer drugs systemically has been the subject of intensive research studies. At the present time, the delivery of DNAse, proteins, and peptides such as insulin, calcitonin,
. . .
α-interferon, and genetic material in general is of particular interest. In order to improve bioavailability and to optimize the release of drugs targeted to specific sites into the lungs, several strategies have been suggested. Among these are advances in the fields of aerosol therapy, aerosol generators, and drug delivery systems. The latter systems include liposomes, NanoCrystals technology, polymers, nano- and microparticles, dispersed systems, salt, and precipitates. In spite of the development of multidose inhalers containing dry powder and portable spray dryers, the pressurized metered-dose inhaler (pMDI) remains by far the most popular system for inhalation therapy. pMDIs have benefited from considerable technical advances, following the recent progressive switch from chlorofluorocarbon (CFC) to hydrofluoroalkane (HFA) propellants. The latter have all the qualities required for pharmaceutical use (chemically stable, no toxicological effects, etc.). (Incidentally, the FDA has recently published its intention with regard to CFC phase-out in the Federal Register.) However, because CFCs and HFAs do not have the same physicochemical characteristics (vapor pressures, densities, solubilities), the development of new pMDIs with HFAs as propellants can require complex reformulation, the use of new packaging materials, and the introduction of new production processes. This article reviews these issues and the adapted dosage forms that have been tried in order to assess the benefits of regional drug delivery and the ability to achieve this. In this article, the term carrier must be understood as a solid, liquid, or gaseous excipient making it possible to target a drug and, in some specific circumstances, to modulate the absorption kinetics and pharmacokinetics of drugs.
II. DESIGN CONSIDERATIONS II.A. Regional Histological Differences in Respiratory Tract The human lung is an attractive route for systemic drug administration5 in view of its enormous adsorptive surface area (140 m2) and thin (0.1–0.2µm) absorption mucosal membrane in the distal lung.6 Approximately 90% of the absorptive area of the lung is attributed to the alveolar epithelium, which primarily consists of type I pneumocytes. Because pulmonary drug administration is directly related to respiratory structure and function and to the administration routes of the drug formulation being introduced into the lung, a summary of the basics of the lung and of drug entrance mechanisms follows. 1. The Respiratory System In functional terms, the respiratory system consists of three major regions: the oropharynx, the nasopharynx, and the tracheobronchial pulmonary region. The conducting airway is composed of the nasal cavity and associated sinuses and the nasopharynx, oropharynx, larynx, trachea, bronchi, and bronchioles, including the first 16 generations of the airways of Weibel’s tracheobronchial tree. The conducting airway is responsible for the filtration, humidification and warming of inspired air. The respiratory region is composed of bronchioles, alveolar ducts, and alveolar sacs, including generation 17–23 of Weibel’s tracheobronchial tree (Fıg. 1). The
FIGURE 1. Tree structure of the lung. (Reprinted from Washington N, Washington C, Wilson CG. Pulmonary drug delivery. In: Physiological Pharmaceutics Barriers to Drug Absorption, 2000, p.224, with kind permission of Taylor & Francis Book Ltd., London, UK.)
respiratory gases circulate from air to blood and vice versa through 140 m2 of internal surface area of the tissue compartment. This gas-exchange tissue is called the pulmonary parenchyma. It consists of 130,000 lobules, each with a diameter of about 3.5 mm and containing approximately 2200 alveoli. The terminal bronchioles branch into approximately 14 respiratory bronchioles, each of which then branches into the alveolar ducts (Fıg. 2). The ducts carry 3 or 4 spherical atria that lead to the alveolar sacs supplying 15–20 alveoli. Additional alveoli are located directly on the walls of the alveolar ducts and are responsible for approximately 35% of total gas exchange. It has been estimated that there are 300 million alveoli in an adult human lung. The diameter of an alveolus ranges from 250 to 290 µm, its volume is estimated to be 1.05 × 10-5 mL, and its air–tissue interface to be 27 × 10–4 cm2. For these calculations, it is assumed that the lung has a total volume of 4.8 L and a respiratory volume of 3.15 L and that the air–tissue alveolar interface is 81 m2.
. . .
FIGURE 2. Structure and perfusion of the alveoli. (Reprinted from Washington N, Washington C, Wilson CG. Pulmonary drug delivery. In: Physiological Pharmaceutics Barriers to Drug Absorption, 2000:225, with kind permission of Taylor & Francis Book Ltd., London.)
2. Barriers Pulmonary Surfactant. The elastic fibers of the lung and the wall tension of the alveoli could cause the lungs to collapse if this were not counterbalanced by the presence of the pulmonary surfactant system. This covers the alveolar surface to a thickness of 10–20 nm and is constantly renewed from below. The surfactant is composed of 90% in weight of phospholipids, including 40–80% in weight of dipalmitoyl phosphatidylcholine (DPPC). The other main ingredients are phosphatidylcholines, phophatidylglycerols, other anionic lipids, and cholesterol.7 The other fraction (10% in weight) is composed of 4 specific proteins—the hydrophiles SP-A and SP-C and the hydrophobes SP-B and SP-D.8 Enzymes, lipids, or detergents can destroy this surfactant. If the pulmonary surfactant is removed quickly by pulmonary irrigation, no damage occurs because it is quickly replaced (half-life: ∼30 hours). The surfactant is only produced at the time of birth, which is why premature babies suffer from respiratory distress syndrome (RDS). In this case, replacement surfactants are administered to substitute for the missing natural surfactant.9-11 Epithelial Surface Fluid. A thin fluid layer called the mucus blanket, 5 µm in depth, covers the walls of the respiratory tract. This barrier serves to trap foreign particles for subsequent removal and prevents dehydration of the surface epithelium by unsaturated air during inspira
tion. Hypersecretion of mucus is a result of cholinergic or α-adrenergic antagonists, which act directly on the secreting cells of the submucosal glands. Peripheral granules, in which mucus is stored, release a constant discharge and form a reservoir that will be secreted after exposure to an irritating stimulus. A state of disease can modify the distribution of the cell goblets and the composition of the fluids of the respiratory tracts. Epithelium.12 The upper respiratory tract is made up of pseudostratified, ciliated, columnar epithelium in cells with goblet cells. The bronchi, but not the bronchioles, have mucous and serous glands present. However, the bronchioles possess goblet cells and smooth muscle cells capable of narrowing the airway. The epithelium of the terminal bronchioles consists mainly of ciliated, cuboidal cells and a small number of Clara cells (Fıg. 3). Each ciliated epithelial
FIGURE 3. Typical lung epithelia in the different pulmonary regions and thickness of the surface fluid. (a) The bronchial epithelium (Ø 3–5 mm) showing the pseudostratified nature of the columnar epithelium, principally comprising ciliated cells 6 µm (c), interspersed with goblet cells (g) and basal cells (b). (b) The bronchiolar epithelium (Ø 0.5–1 mm) showing the cuboidal nature of the epithelium, principally comprising ciliated cells (c), and interspersed with Clara cells (cl). (c) The alveolar epithelium showing the squamous nature of the epithelium, comprising the extremely thin (Ø 5 µm) type I cell (I), which accounts for approximately 95% of the epithelial surface, and the cuboidal (Ø 10–15 µm) type II cell (II).
. . .
FIGURE 4. Alveolar–capillary membrane.
cell has around 20 cilia with an average length of 6 µm and a diameter of 0.3 µm. Clara cells, which are secretory cells, become prevalent in respiratory bronchioles. In the alveolar ducts and alveoli, the epithelium is flatter at 0.1–0.5 µm thick. The alveoli are packed narrowly and do not have partitioning walls; the adjacent alveoli are separated by an alveolar septum with communication between alveoli via alveolar pores. The alveolar surface is covered with a lipoprotein film, which is the pulmonary surfactant. The alveolar surface is mainly composed of a single layer of squamous epithelial cells—type I alveolar cells—approximately 5 µm thick. Type II cells, cuboidal in shape, 10–15 µm thick, and situated at the junction of septa, are responsible for the production of alveolar lining fluid and the regeneration of type I cells during repair following cell damage from viruses or chemical agents. The alveolar-capillary membrane, which separates blood from alveolar gases, is composed of a continuous epithelium, 0.1–0.5 µm thick (Fıg. 4). The maximum absorption occurs in
the area where the interstitium is the finest (80 nm) because the pulmonary surfactant is also thin in this area (15 nm). The thickness of the air–blood barrier ranges from 0.2 to 10 µm. The most efficient gas exchange takes place when the air–blood barrier is less than 0.4 µm in thickness. Interstitium. The lung interstitium is the extracellular and extravascular space between cells in tissue. In order for a molecule to be absorbed from the airspaces to the blood, it must pass through the interstitium. Within the interstitium are fibroblasts, tough connective fibers (i.e., collagen fibers and basement membrane), and interstitial fluid, which slowly diffuses and percolates through the tissue. Vascular endothelium. The endothelium is the final barrier to a molecule being absorbed from the airspace into the blood. Endothelial cells form capillaries that lie under Type I cells in the alveoli (Fıg. 4). The basic alveolar structure is the septum, which is composed of capillaries sandwiched between two epithelial monolayers.13 II.B. Controlling the Site of Aerosol Deposition in the Respiratory Tract 1. Factors Affecting Disposition of Particles
Deposition of aerosol particles in the bronchial tree is dependent on the granulometry of the particles and the anatomy of the respiratory tract. Aerosols used in therapy are composed of droplets or particles with different sizes and geometries. Generally, four parameters can be used to characterize the granulometry of an aerosol: 1. Mass median diameter (MMD) corresponding to the diameter of the particles for which 50% w/w of particles have a lower diameter and 50% w/w have a higher diameter. 2. Percentage in weight of particles with a geometrical diameter of less than 5 µm. 3. Geometric standard deviation (GSD) corresponding to the ratio of the diameters of particles from aerosols corresponding to 84% and 50% on the cumulative distribution curve of the weights of particles. The use of a geometric standard deviation to describe the particle size distribution requires that particle sizes are log-normally distributed. If, as is frequently the case, particles are not log-normally distributed, the geometrical standard deviation is meaningless and a misleading representation of the distribution. Heterogeneous aerosols have, by definition, a GSD of greater than or equal to 1.22.14 4. Mass median aerodynamic diameter (MMAD), which makes it possible to define the granulometry of aerosol particles by taking into account their geometrical diameter, shape, and density: MMAD = MMD × Density½
2. Mechanisms of Particle Deposition in the Airways
There are three main particle deposition mechanisms in the lung: inertial impaction, sedimentation, and Brownian diffusion. The deposit of particles administered by aerosol
. . .
in specific areas of the respiratory tract depends on the deposition mechanism versus the particle diameter.15 1. Inertial impaction is the most significant mechanism for the deposition of aerosol particles with an MMAD of more than 5 µm. It occurs in the upper respiratory tracts when the velocity and mass of the particles involve an impact on the airway. It is supported by changes in direction of inspired air and when the respiratory tracts are partially blocked. Hyperventilation can influence impaction. 2. Sedimentation occurs in the peripheral airways and concerns small particles from an aerosol with an MMAD ranging from 1 to 5 µm. Sedimentation is a phenomenon resulting from the action of gravitational forces on the particles. It is proportional to the square of the particle size (Stokes law) and is thus less significant for small particles. This kind of deposition is independent of particle motion. Sedimentation is influenced by breath holding, which can improve deposition. 3. Brownian diffusion is a significant mechanism for particles with an MMAD of less than or equal to approximately 0.5 µm. The particles move by random bombardments of gas molecules and run up against the respiratory walls. Generally, 80% of particles with an MMAD of less than or equal to 0.5 µm are eliminated during exhalation. The behavior of the aerosolized particles in the body is summarized in Fıgure 5.
Losses of particles in atmosphere and in device
Deposit into mouth or nose
Inhalation of particles
Deposit by impact and sedimentation in lower respiratory tract
Deposit into alveolar area
FIGURE 5. Behavior of aerosolized particles into the body.
• Specific activity • Systemic activity • Crossing into gastrointestinal tract
• Specific activity by diffusion of drug into alveolar liquids • Systemic activity by diffusion into capillaries of bloodstream • Activity on walls of capillaries by carrying through alveolocapillary membrane
FIGURE 6. Dependance of deposition of particulates on particle size. (Reprinted from Washington N, Washington C, Wilson CG. Pulmonary drug delivery. In: Physiological Pharmaceutics Barriers to Drug Absorption 2000:224, with kind permission of Taylor & Francis Book Ltd., London, UK.)
3. Influence of Particle Size
Big particles (>10 µm) come into contact with the upper respiratory tract and are quickly eliminated by mucociliary clearance. Particles with a diameter of 0.5–5 µm settle according to various mechanisms. The optimum diameter for pulmonary penetration was studied on monodispersed aerosols and is around 2–3 µm.16 Smaller particles can be exhaled before they are deposited; holding the breath prevents this. Extremely small particles (γ-CD > HP- β-CD. Pharmacokinetic analysis also revealed near complete insulin uptake from the pulmonary sacs upon coadministration with 5% DM-β-CD. However, an absolute bioavailability of only 22% was obtained in the presence of 5% HP-β-CD. Relatively low acute mucotoxicity was observed. The absolute bioavailabilities following pulmonary insulin administration with CD revealed that the thinner epithelial cell layer of the respiratory mucosa in comparison with the intestinal mucosa offered less resistance to CD-promoted insulin uptake.100 8. Enhancer of Pulmonary Delivery
CDs are absorption enhancers that are effective for the formulation of dry powder101 and are also used for the transmucosal and systemic delivery of peptides and proteins, such as salmon calcitonin.75
III.E. Aqueous and Nonaqueous Solutions and Suspensions 1. Aqueous Solutions and Suspensions a. Aqueous Solutions
The pulmonary delivery of detirelex decapeptide (DX) was studied in dogs by i.v. and i.t. administration and by aerosol inhalation of aqueous solutions of detirelex.102 The bioavailability of DX by i.t. administration and aerosol was 29 ± 10%. The plasma absorption rate
profiles were identical and relatively slow: 6.5 ± 3.6 and 7.6 ± 2.2 hours, respectively. A histopathological examination showed that the lung was normal. Aqueous particles of cidofovir were administered by aerosol in variola-infected mice103 infected with the variola virus one day before, the same day, or one day after, by aerosol. Cidofovir was not toxic and was more effective by aerosol administration than by subcutaneous (s.c.) administration; its antiviral effect was identical, or even higher, for solutions from 20 to 200 times less concentrated than those used by subcutaneous injection. The effect of cidofovir aerosol administration was the highest when cidofovir was administered close to the moment of infection (±1 day), while cidofovir administration by the intravenous route was more suitable for a therapy starting just after infection. In any case, cidofovir solution administered by aerosol had a prophylactic and therapeutic effect on the variola virus. An aqueous aerosol delivery system (AERx Pulmonary Delivery system) was used to examine the feasibility of the pulmonary route for noninvasive systemic administration of morphine.104 The percentage of loaded dose emitted as an aerosol was 61%, of which 87% contained aerosol droplets in the respirable range ( 100%, respectively at 1% w/v). In addition, some water-in-fluorocarbon emulsions stabilized with F8H11DMP and F10H11DMP surfactants appear to be biocompatible for pulmonary drug delivery (Fıg. 30). Currently, the acute toxicity of water-in-PFOB emulsions, stabilized by F8H11DMP, is being investigated in mice, as well as the delivery of insulin contained in these emulsions administered by the i.t. route.
IV. TRANSITION TO CFC-FREE INHALERS A. Aerosol generators 1. Technical Transition to CFC-Free Inhalers
Aerosol generators make it possible to administer a predetermined amount of drug into the lungs. In order to specifically target the drugs, these devices have been extensively studied and technically improved over the last decade and are described in the literature.142 They include aerosol generators of (i) drug powders (Spinhaler, Cyclohaler, Turbuhaler); (ii) autoactivated aerosols (Maxair, Prolair, Autohaler); (iii) spray diffusers (Pulmicort Nebulization, Bricanyl).143
FIGURE 30. Viability of HLEC treated with either solutions (white) or emulsions (grey) of F8H11DMP or F10H11DMP, as assessed by MTT method. Viability of cells treated with PFOB or PFOB/PFDB is represented by the dot line (. . .) and dash/dot (- . -) line, respectively.
Pressurized metered-dose inhalers. Pressurized metered-dose inhalers (pMDI) represent approximately 80% of prescribed aerosols, despite the fact that they are complicated to use, requiring good coordination between activation of the dose and inspiration (hand–mouth coordination). Nevertheless, the main advantage of pharmaceutical metered-dose aerosols is that they allow outpatient treatment, and for this reason, they remain the most popular device used to administer drugs to the lungs. For various reasons, only chlorofluorocarbons (CFC) have been used as propellants in pressurized dosage forms intended for inhalation.144 Indeed, they are nontoxic for humans, stable, nonflammable, and, from a technical point of view, ideal for the formulation of pressurized aerosols. However, because of the presence of chlorine in their molecules and their long lifetime in the atmosphere (half-life approximately 75–120 years), several authors have demonstrated their role in the destruction of the ozone layer.145 The harmful effects of CFCs on the environment have led to the signature of international agreements (Montreal protocol) leading to the production of CFCs being completely halted.146 The alternative propellants selected were hydrofluoroalkanes (HFAs), which do not contain chlorine and, therefore, do not deplete the ozone layer.147,148 Toxicological trials demonstrated that these new propellants are not toxic,149,150 are not carcinogenic, are not mutagenic,150 and do not accumulate in the body.152 HFA-134a is rapidly absorbed and is eliminated with a half-life of 5.1 min.153 Two HFAs—HFA-134a and HFA-227—have been investigated, and the former was selected for development in the first non-CFC pMDI. pMDIs comprise two main parts: (i) the contents, consisting of a medicinal liquid preparation (solution, suspension, emulsion) and one or more propellant(s); and (ii) a container, which is pressure resistant, and a metering valve. The latter permits accurate administration
. . .
of small volumes of propellant containing even smaller quantities of drug, which has made MDIs possible. In the field of aerosols, for which some liquefied gases must be used, the pressure required in the container intended for aerosolization of the particles is governed by the vapor pressure at the temperature of use.154 This pressure remains constant throughout the use of the pMDI: when the level of the contents falls in the container, the free space is occupied by the gaseous phase of the propellant. Until then, the latter is present in the liquid state. The pressure inside the container remains equal to the vapor pressure. The liquid propellants used in the field of pharmaceutical aerosols are mainly chlorofluorocarbons and the hydrofluoroalkanes (Solkane 127a and Solkane 227 Pharma). The use of HFAs for pMDI formulations has imposed numerous modifications in terms of composition, technology, and manufacture. The reformulation of CFC–MDIs with hydrofluoroalkanes (HFAs) 134a and 227 is also an opportunity to improve these widely accepted systems in terms of ease of handling, compliance, dosing, and more reliable and efficient lung deposition.155,156 New formulation technologies combined with improved valves and actuators should help to overcome dose uniformity and priming problems and will increase the percentage of fine particles capable of reaching the deeper regions of the lungs.157 However, replacing CFCs with HFAs in the manufacture of pMDIs is not easy, although the canisters of the latter are similar. Indeed, this substitution has involved some modifications to the technology and manufacture of pMDIs because of differences in the physicochemical properties of the new propellants (Table 10). The construction of the new pMDIs will not be the same, either technically or pharmacologically, and new clinical trials will therefore be required. 2. Reformulation
pMDIs containing HFAs operate in a similar manner and the components are like those used with CFCs. The new pMDIs differ from the previous through a combination of modifications to the composition of the formulas, the valve,158 the inner polymeric coating of the canister, and the industrial manufacturing processes. For example, as far as the conventional surfactants used to manufacture pMDIs with CFCs are concerned, they are not soluble in HFAs159,160 (Table 11). When the dosage form inside the canister is a suspension, the density and the viscosity of the propellants affect the physical stability of the suspension. Surfactants are used to maintain the drug in suspension and to lubricate the valve. For pMDI formulations containing CFCs, the most commonly used surfactants are oleic acid, lecithin, and sorbitan trioleate, which are insoluble in both HFA 134a and HFA 227 propellants. Changing the propellants modifies the physical stability of the suspension159 and, in some cases, the solubility of the drug in the new propellants.161 For reformulation, three solutions can be considered: (i) not using any surfactant if this is compatible with the formulation; (ii) adding an extra excipient to dissolve a conventional surfactant (for example ethanol for oleic acid)162; or (iii) designing new surfactants that would require their toxicological evaluation. Furthermore, the trials conducted with some drugs that are stable in suspension with CFCs have shown that these are not stable in the presence of HFAs. Accordingly, all the reformulations must be considered for each drug and the solutions studied in order to realize that the substitution of propellants may differ from one drug to another.157
16 –16.5°C 3.90 bar 1.415 kg/l
Atmospheric life (years)
Boiling point at 1,013 bar
Vapor pressure at 20°C
Liquid density at 20°C
Stocking conditions
Physical form
HFA 227ea, HFC 227 ea
Laboratory code
1.23 kg/l
5.72 bar
–26.1°C
33
Uncolored gas
CFC 11
Monofluortrichlormethane
CFCl3
Freon 11
60
1.49 kg/l
0.87 bar
+23.8°C
1.33 kg/l
5.60
–29.8°C
125
CFC 12
Difluordichlormethane
CFCL2
Freon 12
Liquefied by compression in steel containers
HFA 134a, HFC 134a
1,1,1,2 – Tetra fluoroethane
CF3CH2(F)
CF3CH(F)CF3 1,1,1,2,3,3,3, – Heptafluoro propane
Solkane 134a pharma
Solkane 227 pharma
Chemical name
Structural formula
Registered trademark
TABLE 10. Physicochemical Properties of Propellants Used to Manufacture pMDIs
1.47 kg/l
1.81
+3.6°C
200
CFC 114
Tetrafluor dichlorethane
(CF2Cl)2
Freon 114
. . .
TABLE 11. Apparent Solubilities of Surfactants in HFAs Surfactant
HLB
Apparent solubility (% ; w/w) in : CFC 11
Oleic Acid
1.0
HFA 134a
∞
