Abstract
The pulmonary route of drug delivery can provide an excellent alternative to other routes both for local lung disease as well as systemic delivery. The year 2006 marks the 50th year since the invention of metered dose inhalers, yet inhalation is a very much underutilized route of delivery, possibly because inhalation drug development is perceived as being too difficult and expensive. However with proper knowledge these purported difficulties can be overcome. The process begins with identifying the target tissue and then utilizing technologies such as particle size adjustments through formulation techniques and delivery devices to most efficiently deliver the desired dose. There are a variety of new and existing inhaled excipients available to accomplish this goal. The active molecule can also be modified to increase solubility, decrease immunogenicity, and protect it from unwanted metabolism using PEGylation. Sustained release of an inhaled drug is also possible using biocompatible matrices such as oligolactic acid.
Introduction
The concept of inhaling medications has been present for many centuries, but it was not until 1956 when 3M Riker (Northridge, CA) scientists invented the metered dose inhaler (MDI) that inhaled medications reached the status of being safe, effective, and convenient enough for widespread public use. The field of inhalation drug delivery was again reinvented in 1987 with the signing of the Montreal Protocol banning CFCs, the major propellants used in MDIs (Montreal Protocol, 1987). The multibillion dollar and growing CFC-powered MDI industry would eventually disappear, so the market was wide open to new ideas for inhalation devices.
The 1990s brought over 300 new patents for inhalation technology. Concurrent to the CFC changeover was the recognition that inhalation could be applied to new therapies such as proteins, peptides, antibodies, and many small molecules useful for systemic activity. The lung provides a unique portal for drugs intended for CNS, cardiovascular and hormonal application because of the potential high bioavailability, rapid absorption, and distribution via the circulation often resulting in fast onset of action, and the ability to utilize very insoluble drugs not suited for oral or parenteral applications.
Medical Inhalers and the Ozone Layer
Ozone resides in the stratosphere where it filters out ultraviolet-B (UV-B) radiation. UV-B radiation causes skin cancer, cataracts, infectious disease susceptibility, decreased crop yields, and increased global warming. Excessive UV-B can eventually alter aquatic food chains and cause a general disruption of ecological processes leading to global catastrophe (Hayman, 1995). Chlorofluorocarbons (CFCs) have been shown to deplete ozone once they reach the stratosphere (Molina and Rowland, 1974). The Montreal Protocoladopted in 1987 along with its modifications requires a complete phase-out of the CFCs although there is a temporary medical exemption for metered dose inhalers.
CFCs provide the propellant energy in MDIs that deliver medication. The first consortia to examine the replacement of CFCs in medical use was the International Pharmaceutical Aerosol Consortium for the study of HFA-134a (IPACT-1) made up of 12 of the world’s largest pharmaceutical companies. The second consortium, IPACT-2 was formed to study HFA-227 for use in MDIs. HFAs are hydrofluoroalkanes and are also known as hydrofluorocarbons (HFCs). The HFAs contain carbon, fluorine, and hydrogen atoms. The 2 new propellants were HFA-134a (C2H2F4) and HFA-227 (C3HF7). These molecules contain hydrogen atoms, so they can be more readily metabolized by the environment, but they do not contain chorine and so they have no potential to deplete the ozone layer (Manzer, 1990).
Large safety programs conducted in animals and humans showed that the new HFA propellants were as safe or safer than the CFCs (Alexander, 1995; Leach, 1998a). The new HFA propellants, however, presented new technical challenges and many problems needed to be resolved prior to receiving approvals (Gabrio, 1999). New understanding of the diseases such as asthma coupled with new ways to target the disease has led to better MDIs. The ban on CFCs has also spurred new dry powder inhaler technology as well as many other classes of specialty inhalers.
The original Montreal Protocol allowed for the essential use CFCs to continue until appropriate alternatives were available. The pharmaceutical use of CFCs accounted for less than 0.5% of the global consumption. There were many factors that influenced the continued use of propellant-driven MDIs such as the increasing prevalence of asthma and chronic obstructive pulmonary disease (COPD), new diagnosis and treatment guidelines encouraging MDI use, and changes in health care practices. In addition no inhaler technology can match the low price per dose of the CFC MDIs for use in asthma.
Aspects of Drug Delivery Through the Lung
The internal surface area of the lung parenchyma and conducting airways that is available for drug delivery is over 70 m2 and 10,000 cm2, respectively. This means that the relative concentration of drug per unit area of tissue can be very small thus reducing toxic effects that depend on high local surface area concentrations. The lung contains about 30 milliliters of fluid that line the internal surface area of the parenchyma. Thus the fluid lining represents a layer that is only a few microns thick. This lung lining fluid also contains proteins and lipids that aid in translocating hydrophobic and hydrophilic drugs.
In addition to many mechanisms of active and passive transport of drug across the pulmonary air-blood barrier, there are specialized transport mechanisms such as caveoli (Renigunta et al., 2006) formation in the parenchyma. Small vesicles can engulf large molecules, pinch off and be transported through epithelial tissue, basement membranes and then across endothelial cells directly to the blood. Large molecules can also cross the lungs through tight junctions. These junctions are normally less tight in conducting airways than they are in alveoli.
Thus, large molecules that need “loose” tight junctions for transport may be better suited for targeted delivery to the conducting airways. The lymphatics system undoubtedly plays a role in drug absorption across the lungs but few studies exist which confirm this mechanism. All of these mechanisms collectively mean that onset of action for inhaled drugs can be very short when needed. For example pain, migraine, emesis, and smoking cessation can be treated very quickly with fentanyl, sumatriptan, tetrahydrocannabinol (THC), and nicotine for relief in seconds. It has been established that nicotine can reach the brain within 6 heartbeats of inhalation.
With such direct access to systemic circulation the amount of drug can be dramatically reduced. This is because a patient can inhale a small amount of drug, wait a short period of time for relief, and then dose more if needed or stop with the initial dose. This is not the case with oral pain relievers where the onset of action can be quite long so the patient may take far more drug than is needed.
A general rule of thumb is that 5% of the intravenous dose actually gets to the lungs and likewise perhaps 2% of an oral dose gets to the lungs. The rest is either not absorbed, eliminated harmlessly, or contributes to unwanted side effects. Thus delivering drugs directly to the lungs to treat local lung disease almost always results in lower doses and an increase in benefit-to-risk ratio.
The Development of New HFA MDIs
The change from 40 years of MDIs containing CFCs appeared simple on the surface but technically it was very difficult (Tansey, 1997). Approved formulation surfactants used in CFC MDIs were not soluble in HFAs. Valve seal materials did not work with HFAs. The thermodynamics of the HFAs dictated new actuator designs to achieve smaller particle sizes. There was no high boiling point HFA replacement for CFC-11, so new formulation concepts utilizing co-solvents had to be developed. Thus the replacement of the CFCs forced everyone to reconsider approaches and develop new and better ways to deliver medication by the inhalation route (Leach, 1995).
The $7 billion CFC inhaler market had to be replaced and this represented new opportunities for inhaler improvement. Companies with successful CFC inhalers wanted the new HFA MDIs to contain the same drug with the same dose and the same particle size distribution as their existing products. However many R&D people knew that new technology and understanding the disease states could lead to better products. At present there are a mix of products, some resembling the original and some quite different from those they replaced. HFA albuterol sulfate (Airomir in Europe; Proventil-HFA in the United States, 3M Pharmaceuticals, St. Paul, MN, USA) was the first CFC-free MDI and it was introduced in 1994 and gained approval in over 40 countries (Leach, 1997). It was “comparable” to the CFC albuterol inhalers. The U.S. FDA has now required all CFC-albuterol MDIs to be removed from the market by 2008 (FDA, 1997).
MDIs containing steroids presented an opportunity to introduce new concepts in inhaled drug delivery. Albuterol inhalers are considered most effective when the drug particles are delivered to large and medium sized airways and then become attached to the smooth muscle receptors. Achieving a particle size appropriate for this target tissue was relatively easy with the CFC and HFA-albuterol inhalers. However, steroid delivery was quite different. In the past, clinicians thought asthma was primarily a disease of the large airways. Because of this assumption and the lack of formulation choices, CFC steroid inhalers delivered aerosols with relatively large particle sizes on the order of 3.5 microns (mass median aerodynamic diameter) that deposited in the large airways.
New research and understanding showed that asthma was a disease of the entire respiratory tract including the small airways (Hamid et al., 1997). Small airways are defined as 2 mm or less in diameter. In addition, steroid receptors are present in almost all cells but their density is higher in the cells of the small airways compared with the large airways. Human radiolabeled deposition studies showed that the CFC steroid MDIs did not reach the small airways in meaningful amounts (Leach, 1998b). Some HFA steroid MDIs (e.g., QVAR, 3M Pharmaceuticals) can produce aerosols in the 1.0–1.5 microns with a sufficient range of sizes to cover the entire respiratory tract (Leach et al., 2002).
Furthermore, CFC MDIs produced a large amount of oropharyngeal deposition which increased unwanted side-effects such as infection with Candida albicans as well as contributing to systemic absorption and the subsequent side effects on the HPA axis (Shaw and Edmonds, 1986). Table 1 shows the correlation of particle size versus lung deposition. Particle sizes of approximately 1.1 microns from HFA-beclomethasone (QVAR, 3M Pharmaceuticals) produced lung drug deposition greater than 50% compared with 20% or less with the CFC steroid MDIs (Leach et al., 1998b). Additional benefits of the smaller particle size included reduced dependence on coordination of inhaling and actuating the MDI, and greater independence of lung deposition on inspiratory airflow.
The smaller particle size of HFA-beclomethasone (QVAR) resulted in high lung deposition in children, a population known to be difficult to achieve high lung deposition. Children 11–14 years showed 53%, 8–10 years 45%, and 5–7 years 41% lung deposition (Devadason et al., 2003). The many physical advantages of the smaller particle size improved clinical outcomes in short- and long-term clinical studies (Leach et al., 1998c; Busse et al., 1999).
Dry Powder and Specialty Inhalers
The number of inhaler related patents was approximately 5 per year through 1985. After the Montreal Protocol, the number jumped to over 350 granted patents in the 1990s. This huge increase encompassed MDIs and dry powder technologies as well as novel specialty inhalers. The number of MDIs sold annually is over 400 million and MDIs remain the most dominant inhaler technology. MDIs are also the least expensive technology with the manufacturing cost of some asthma medications being as low as 2 cents per dose. It is unlikely that any other inhaler technology will match this low cost. Price is a significant consideration for the 45 million uninsured Americans as well as most of the world’s developing countries where just a few cents makes the difference in affordability for millions of otherwise untreated people.
Dry powder inhalers (DPIs) have become important products with combination therapy becoming the most profitable product in the asthma inhaler market. Combination therapies such as steroids and long acting beta-agonists are popular, but there is much debate about their safety and the inability to titrate the beta-agonist when asthma is well controlled. However marketing strategies have convinced general practitioners that patient compliance is better with combination therapies.
A major milestone in inhaler technology as well as a renewed excitement for inhaled drugs has been achieved with the approval of inhaled insulin in the United States and Europe. Inhaled insulin is important for many direct clinical reasons and also for indirect reasons because it will be the first commercial peptide delivered through the lungs for systemic application. Dry powder technology can be considered to have undergone 3 developmental phases.
The first generation dry powder inhalers were small capsule-based passive devices such as the Rotahaler. Particle sizes were large, agglomeration was a major issue, and there were dose limitations. The second phase DPIs were more complex using reservoirs and micronized powders (e.g., Turbohaler). These inhalers still suffered from delivering very large particles and were also subject to agglomeration, and temperature and humidity effects. Lung deposition values were at most 35% and often quite a bit less. This low effi-ciency meant that the remainder of the drug is going to tissues where it is not needed and either wasted or more commonly resulted in unwanted side effects. The third phase (and not yet approved DPI technology) is engineered powders that are highly dispersible and can utilize very simple, inexpensive devices.
The efficiency of DPIs has evolved similarly to MDIs in that the low density, porous powder technologies show increased lung deposition from 5–20% for past dry powder devices to 40–60% for the engineered powders. Low density, porous powders can also deliver high drug mass loads of 50 mg of powder per inhalation. MDIs cannot currently deliver high doses per puff, but MDIs can more consistently deliver smaller doses in the range of 25–500 micrograms per inhalation. Future inhalers will be developed using both types of devices as well as niche specialty devices.
Technologies That Modify the Inhaled Drug
There are many issues contributing to safety and efficacy of inhaled drugs besides achieving optimal particle sizes. Some drugs pass through the lungs so quickly that they do not have enough opportunity to interact with the appropriate receptors. Other drugs such as proteins and peptides may be metabolized quickly within the lungs and consequently have low bioavailability. There are no known absolute size limits for proteins because of specialized transport mechanisms, but generally the smaller proteins and peptides cross the lung more readily. Formulation aids such as oligolactic acid (OLA) have been shown to produce sustained release within the lungs for a variety of therapeutic categories such as soft steroids (i.e., steroids that have low oral bioavailability and are metabolized by the lung or serum enzymes very quickly), immune response modifiers, phosphodiase –IV (PDE-IV) inhibitors, and 5-lipoxygenase (5-LO) inhibitors (Leach et al., 2000). OLAs work by forming a particle that contains a drug intercalated in an OLA matrix. PEGylation technology is also being applied to inhaled drugs.
Normally, polyethyleneglycol (PEG) molecules have been used in conjunction with iv administration. It has been shown that by utilizing smaller PEGs (e.g., less than 2000 daltons), the duration of activity of inhaled insulin can be extended by many hours (Leach et al., 2004). This may eliminate the need for long-acting, overnight insulin currently only available by injection. The PEGylated insulin also shows higher bioavailability presumably because the insulin is more protected from insulin degrading enzyme within the lungs. PEG molecules have also been shown to be less immunogenic than nonPEGylated drugs when given by injection but this has not yet been demonstrated within the lungs.
Vaccines Delivered to the Respiratory Tract
The number of people affected by diseases for which vaccines are either available now or in development is over 1 billion. There were 94 licensed vaccines in the United States in the year 2000 that targeted 27 different pathogens. More than half of those pathogens were related to the respiratory tract. Yet, 87 of those vaccines were delivered by injection, 7 orally and only 1 by nasal inhalation. This hardly seems logical especially considering that in addition to the normal immune response of the lungs, there is an extra response by IgA, the mucosal antibody. The other consideration is that needle reuse causes over 1 million cases per year of HIV and hepatitis.
The utility of respiratory mucosal vaccine has been clearly demonstrated by the nebulized measles vaccine study of 1600 children in Mexico. The seroconversion rate was much better with inhaled vaccine than with the traditional injection at one-fifth of the injected dose. Side effects were also fewer with the aerosolized vaccine (Bennett et al., 2002). This study was confirmed with the South Africa study of 4000 children inhaling measles vaccine where one-half of the injected dose was inhaled. The aerosolized and injected vaccines exhibited the same seroconversion rates but there were fewer side effects with the inhaled route (Dilraj et al., 2000).
Conclusions
Utilizing the inhalation route for drug delivery has been purported as being too difficult, expensive, limited in application and risky. It is clearly one of the most complicated dosage forms but also one of the most versatile. The transition away from CFCs created new paradigms in inhalation drug delivery sprouting the rebirth of old technologies and the creation of new technologies (Dolovich et al., 2000, 2005). Traditional inhaled drugs like beta-agonists and steroids have been re-engineered and improved in many ways.
New dry powder formulations and device strategies have opened new possibilities for higher doses and more formulation options. There are now real-world methods to make viable inhalation products for just about any type of drug. The near future will see inhaled peptides such as insulin, proteins, antibodies, oligonucleotides, hormones, nicotine substitutes, antibiotics, pain relievers, anticancer drugs, drugs for COPD, vaccines, and many other applications.