Wednesday, June 3, 2009

FORMULATION: Pulmonary Drug Delivery

Breathe-Easy Biologics

Range of Therapeutic Inhalants Expected to Grow

Interest in the treatment of systemic disorders through deep-lung inhalation of protein-based therapeutics is increasing, as drug makers look for less invasive modes of administration for macromolecules currently available in parenteral formulations. However, producing pharmaceuticals that are bioavailable in the deep lung presents a number of challenges, including the need to meet tight specifications in the size and diffusion of drug particles.

Traditional non-invasive routes of administration - typically oral ingestion - do not work well for macromolecules, since the protein would rapidly degrade in the stomach from enzymes and hydrochloric acid. Transdermal administration systems are equally challenging, since size constraints preclude large molecules from crossing multiple dermal layers without use of enhancing agents or technologies that can irritate the skin.

Conversely, the deep lung offers a promising alternative to delivering a therapeutic into the blood stream, assuming the compound can pass through the trachea and the bronchial network to reach the deep lung. Once there, the alveoli epithelium provides a large (approximately 100 m2 in adults) and fairly thin, 0.1 to 0.5 microns (�m), surface area, through which therapeutics are absorbed rapidly into the blood stream.

Systemic delivery of biotherapeutics through the lung may provide greater convenience for patients, who previously required frequent dosing via subcutaneous or intramuscular injections and, as a consequence, may increase compliance with chronic drug regimens. Pulmonary inhalation also may present therapeutic advantages beyond convenience and compliance; if the drug is delivered efficiently into the deep lung, absorption into the blood stream is rapid and comparable to subcutaneous injections.

Drug makers, consequently, are looking to reformulate a wide range of therapeutic proteins as inhalation therapies. In addition to an inhaled insulin product approved for U.S. and European marketing in 2006, several peptides are in the development pipeline as inhalation therapies, among them human growth hormone and parathyroid hormone.

Advancements in Inhalation Therapy Technology


The development of the pressurized metered-dose inhaler (MDI) in the 1950s was a significant turning point in the treatment of asthma and chronic obstructive pulmonary disease in that it was reliable, efficient, and easy to use. Today, while older MDI units have fallen into disfavor because of the impact that chemical propellants have on the ozone layer, refinements to other inhalers have helped advance the treatment of asthma without risk to the environment. Modern delivery devices - such as dry powder inhalers and nebulizers - with a few technology enhancements, are proving to be useful vehicles for treating systemic disease and are being employed to disperse aerosol versions of high molecular weight proteins for the treatment of systemic disease.

Currently, most aerosol formulations are suspended in aqueous solutions for administration through nebulizer-type devices or produced as dry powder for inspiration using hand-held inhalers. For delivery of drug to the deep lung, development programs, in large part, are focusing on adapting biologics for dry powder inhalation (DPI), although some aqueous formulations and devices also are being employed.

There are advantages to each, based on the stability of the individual molecule and patient needs. DPI, in which medication is formulated into a fine powder, is particularly useful for the delivery of macromolecules and biotherapeutics, which frequently are unstable in liquids and costly.

Drug Formulation Challenges

To successfully produce inhaled biologics, however, drug makers must overcome a number of challenges in drug formulation and delivery. Aerosol dispersion of therapeutic proteins into the deep lung, and the subsequent absorption of those proteins into the blood stream, is affected by the size and type of drug particle, as well as other physical characteristics.

Size of drug microparticles is perhaps the most critical factor. To enable distribution throughout the lung, drug particles must be between 1to 5 �m in diameter, and they must be 1 to 3 �m in diameter to reach the deep lung. If the particles are too large, they cannot easily traverse the bronchial network. If they're too small, and thus more free floating, their descent into the deep lung is inefficient at best.

This is a particular issue with dry powder formulations of aerosolized drug, given that the properties of powders can differ widely, due to variances in chemical composition, morphology of individual particles, and the range of particle sizes. The ideal target is to have a very narrow distribution in the variation of particle sizes, with more than 80 percent in the 1-3 micron range.

Beyond size, the fluidity of an inhaled drug can be influenced by the structure of individual drug particles. Here, too, dry powder aerosol formulations are particularly challenging. To ensure proper inspiration of the aerosolized drug, particles must separate and flow smoothly into the lung. Therefore, drug formulations must overcome the tendency of dry particles to adhere to other particles because of electromagnetic relationships; surface features; and the presence of capillary forces, such as water, which cause particle surfaces to crystallize.

In general, separation can be enhanced by producing particles that are spherical, porous, and of low density. Moreover, the choice of manufacturing processes and packaging can influence separation, since the characteristics of the powder are affected by temperature and humidity in production. Spray-drying technologies are used by some companies to limit morphology of particles without milling. A newer technology known as controlled-phase separation - in which protein is separated from water-soluble polymers using an aqueous separation process - appears to increase stability of the protein, allow control over particle size-distribution (i.e., narrow for deep-lung systemic delivery and large for compounds that target the lung), and aids in drug absorption.

Another consideration in the formulation of inhaled biologics is the use of inert carrier particles, which separate from drug particles upon inhalation, typically in the oropharyngeal region. Smooth-surface lactose carrier particles often are used to help disperse micronized drug and aid in dissolution and permeation. In DPI formulations, excipients are used to provide bulk and aid in metering of the drug and can comprise more than 99 percent of the product by weight. However, excipients are not always required.

The formulation and manufacturing technology employed to produce aerosolized drug will influence its fluidity and permeability and can help increase drug yield [source may be needed]. Using controlled-phase separation technologies, the drug candidate forms the microsphere matrix, allowing drug particles to be loaded with more than 90 percent of the active pharmaceutical ingredient (API). Such a technique effectively minimizes API waste during processing and reduces the volume of product required to achieve a therapeutic dose. Moreover, it could help reduce reliance on excipients, easing concerns of potential safety risks with carrier particles.

Delivery Devices: Critical Decisions for Drug Makers

To ensure therapeutic quantities of drug are absorbed into the blood system, delivery of drug particles to the deep lung must be efficient and precise with each inspiration. The effectiveness and efficiency of drug inspiration can be influenced not only by the drug formulation but also by the choice of delivery device.

Liquid Aerosols

Aqueous inhaled formulations, in which drug is suspended or dissolved in a polar liquid, typically are administered with the aid of a nebulizer, which delivers a dose of medication as a fine mist. Conventional nebulizers used for the treatment of breathing disorders are beneficial for patients who cannot use MDI or DPI inhalers due to poor breathing coordination. Moreover, nebulizers can deliver individual drug doses over a longer time period than other inhalation devices.

To use nebulizers for the treatment of systemic disorders, the challenge for drug companies is to improve efficiency of the device, which releases drug throughout the respiratory cycle, not just in coordination with patients' breathing. As a consequence, only 10-20 percent of active pharmaceutical ingredient (API) typically reaches the lung with a nebulizer or other conventional aerosol system. The inefficiency poses several problems for biologic drug makers: one, ensuring therapeutic quantities of drug are absorbed in the deep lung and, two, limiting drug waste, given the cost of protein-based therapeutics.

Several companies are looking to improve the efficiency of the devices, or are adapting the technology, in order to efficiently deliver biologics formulated in aqueous solutions. Genentech has employed the technology since 1994 for its protein-based therapeutic for the treatment of cystic fibrosis. The biologic is administered by inhalation of an aerosol mist produced by a compressed, air-driven nebulizer system. Moreover, at least one company has a liquid inhaled insulin product in development. The protein is encapsulated in droplets and administered using a modified nebulizer, which pushes the liquid formulation of the drug through an array of tiny holes, which produces a mist of uniform, ultra-fine droplets for inhalation.

Dry Powder Inhalation

Dry powder inhalers distribute medication into the lung through rapid inhalation without the use of chemical propellants that were employed with MDIs. Most DPI devices release drug through patient inspiration, although some devices employ gas- or motor-driven impellers or use electronic vibration to release drug.

There also is some variance in how a correct dose of drug is released through DPI devices. Drug is emitted using either a metering mechanism, which retrieves the correct dose from a reservoir of the compound, or a pre-metering device, in which individual doses are stored in blister disks, strips, or capsules.

Differences among first- and second-generation devices for deep-lung systemic delivery vary in size and, perhaps, production costs. First-generation devices require a dispersion chamber that is about the size of a 25-ounce water bottle. Second-generation devices are smaller with a simpler design; they also are easy to use and less expensive to manufacture.

As more companies investigate the formulation of compounds for delivery through the lung, researchers continue to gain knowledge on how the design of the inhaler mouthpiece, air inlet, drug-release mechanism, and other features can impact the dispersion of fine powder into the bronchial tubes and lung. A key goal is to limit the impact of external variables - such as a patient's inspiratory flow rate, cleaning practices for the device, or use of concomitant drug therapy - on the effectiveness of the units.

Trends: Improving Technology, Expanding Therapeutic Uses

Advancements in drug formulation technologies and delivery devices are being driven by the growing interest by the biologic drug industry in inhaled therapeutics. Development of inhaled biologics is occurring at various stages in product life-cycles, but is primarily being investigated for older therapeutics, as a means of extending the marketing life of a compound, forestalling generic competition, and improving the ease of administration for injectable compounds.

However, converting injectable compounds into inhaled therapeutics is a challenging area for drug makers, many of which may lack the infrastructure to complete development and manufacturing of a biologic as a pulmonary formulation. Given that the technology associated with inhalation therapy for systemic disease is relatively young, drug makers often turn to research partners to solve the multiple formulation and design challenges and to stay ahead of the competition.

In an effort to enhance patient convenience, beyond altering the mode of administration, research partners are helping large pharmaceutical companies refine delivery devices and drug formulations in a number of interesting ways, including by improving control of microsphere size and structure, increasing API ratios, and ensuring higher levels of drug per puff than had been possible before. Beyond that, trends in biologic drug and device redevelopment include the following:

  • Delivery devices may become disposable, as companies look to improve patient convenience, reduce the need for cleaning the device, and ease concerns over stability.

  • Excipients are becoming expendable, as companies move toward less reliance on carrier microparticles for systemic delivery. The goal is to improve efficiency, reduce waste, and ease concerns over the risk of immunological reactions to the excipient.

  • Some companies hope to make sustained-release formulations of inhaled biologics by encapsulating the microparticle in a biodegradable polymer or by modifying the size of the particle.

As of yet, these technologies have not yielded viable extended-release compounds. Currently, sustained-release formulations of biologic drugs are available only through subcutaneous injection.


As drug makers overcome the challenges in drug formulation and delivery inherent with inhaled biologics, the range of therapeutic categories for inhaled protein-based compounds is expected to grow dramatically. It is now considered feasible to treat systemic disorders, such as diabetes and pain, with inhaled therapy. Current areas of research for biologic therapeutics - in addition to multiple projects for inhaled insulin - include endocrinology, rheumatology, hematology, and oncology. Although many of these projects are years from market availability, analysts predict sales of inhaled biologics to grow by more than 27 percent by the end of the decade.

To be part of that growth, large pharmaceutical and biotechnology companies with mature product lines are turning to research partners to expand their capabilities in formulation, development, and production of inhaled compounds. �


Agu RU, Ugwoke MI, Armand M, Kinget R, Verbeke N. The lung as a route for systemic delivery of therapeutic proteins and peptides. Respir Res. 2001; 2(4):198-209.

Bromberg L, Rashba-Step J, Scott T. Insulin Particle Formation in Supersaturated Aqueous Solutions of Poly(Ethylene Glycol). Biophysical Journal. 2005; 89:3424-3433.

Chan HK. Dry powder aerosol delivery systems: current and future research directions. J Aerosol Med. 2006; 19(1):21-7.

Edwards DA, Hanes J, Caponetti G, et al. Large porous particles for pulmonary drug delivery. Science. 1997; 276 (5320):1868.

Exubera approved by European Commission. Medical News Today. Accessed May 22, 2006.

Garcia-Contreras et al. Am.J. Drug Del. 3,1(2005).

Krishnamurthy R. Protein stability in pulmonary delivery formulations: A review. BioPharm. 1999; 12(3);34.

Patton JS. Deep-lung delivery of therapeutic proteins. Chemtech. 1997;27(12),34-38.

Pulmozyme (dornase alfa),, Accessed June 13, 2006 Service RF. Drug delivery takes a deep breath. Science. 1997; 277(5330)1199.

Telko MJ, Hickey AJ. Dry powder inhaler formulation. Respir Care. 2005; 50(9):1209-27.

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