The past 30 years of biotechnology discoveries unleashed a wave of therapeutic proteins, also known as biomolecules, macromolecules, biotherapeutics, and biologicals. Most are administered via injection or intravenous methods to avoid degradation in the gastrointestinal tract.Patients, however, fear and avoid injections and IV treatments, which are painful, inconvenient, and expensive. This opened up an avenue for drug delivery to enter the picture and explore new avenues for delivering these drugs.
One of these, pulmonary delivery, offers a patient-friendly, non-invasive alternative to injections and can also be a more efficient and effective way to deliver a drug and achieve patient compliance.It can also potentially solve storage problems such as the need to refrigerate therapeutic proteins.
The systemic delivery of biomolecules via the lungs is an under-exploited route today. About 85 protein and peptide therapeutics are currently marketed, and about 350 more are undergoing clinical evaluation. In 2002, drug companies sold $33 billion in protein therapeutics, and sales of $71 billion are projected by 2008 (Market for Bioengineered Protein, 2004). This same report predicts that the market for protein drugs will grow at an annual rate of 12.2 per cent from 2003 to 2008, faster than the industry's overall annual growth rate of eight per cent. Sales of drugs using pulmonary delivery systems also are predicted to grow from $8 billion in 2001 to $15 billion by 2006 (Minter, 2003).
Although today, most of these drugs include those that treat local lung disease such as asthma and COPD.With the approval of Pfizer's Exubera (insulin human [rDNA origin]) inhalation powder, the promise of pulmonary delivery has finally been delivered and this advance opens up a myriad of possible candidates for pulmonary delivery.Many of these biologics are already under development and being tested in clinical trials.
Also under development by drug delivery companies are methods to develop improved therapeutic proteins that allow for the reduction of the number of injections while, at the same time, overcoming some of the challenges of proteins, such as pharmacokinetics and immunogenicity. One such proven method is called pegylation, the attachment of polyethylene glycol molecules to a drug.
Humans have inhaled a wide range of substances since ancient times. Until recently, pulmonary delivery of drugs focused on medications to treat asthma and other lung diseases. Aerosol systems that deliver bronchodilators to relax airways and corticosteroids to control inflammation in asthma and chronic obstructive pulmonary disease (COPD) are widely used today and carry a proven track record.
Today's inhaled drug delivery market is dominated by this class of treatments. More than 300 million people worldwide suffer from asthma, and annual sales of asthma products in the U.S. and Europe in 2003 reached $11.8 billion, up from $9.7 billion in 2002. The current market for COPD therapies is estimated at $4 billion yearly, with predicted growth to $10 billion by 2010 (Asthma and COPD Market Outlook, 2004).Currently it appears that the future of asthma/ COPD therapy lies in combination products or novel single agents with convenient dosing and so it appears to be a market that will continue to grow.
Considering the rapid, local action of asthma and COPD drugs, and looking beyond therapeutic proteins, inhaled medicines also seem a practical consideration for nearly every lung disease. Inhaled anti-infectives already provide local control of respiratory infections, such as pneumonia and Cystic Fibrosis.The first inhaled protein ever approved, Genentech's Pulmozyme (dornase alfa), was marketed in 1993 to treat CF. This aerosol treatment reduces the incidence of respiratory infections requiring intravenous antibiotics and improves overall lung function. US sales of Pulmozyme have grown from $22 million in 1994 to $44 million in 2004.
Nektar Therapeutics (San Carlos, Calif.) and Chiron, a Novartis company (Emeryville, Calif.) are collaborating on a next-generation, dry powder tobramycin to treat lung infections in cystic fibrosis patients.This product which is currently in Phase III trials is called Tobramycin inhalation powder or TIP. Chiron introduced TOBI in 1998 as the first inhaled antibiotic given by nebulizer to CF patients.Nektar is also collaborating with Bayer HealthCare AG to develop an inhaled, dry powder formulation of ciprofloxacin to treat CF and other chronic lung infections.
Inhaled gentamicin is an established treatment for chronic Pseudomonas aeruginosa (PA) infections in CF. Heinzl (2002) demonstrated that daily inhalations of gentamicin delays the acquisition of chronic PA infections and decreases disease progression in children with CF.Pentamidine, an inhaled treatment for Pneumocystis carinii pneumonia (PCP), sells generically or under the brand names Nebupent or Pentam.
Intravenous pentamidine causes serious side effects of anemia, low blood sugar, arrhythmias, and kidney problems. In contast, inhaled pentamidine produces milder side effects like chills, headache, and cough.
An inhaled antifungal product to prevent pulmonary aspergillosis in immunosuppressed patients is also being evaluated. ABIP (amphotericin B inhalation powder) is designed to target the site of infection directly with a novel formulation of amphotericin B, a broad spectrum, "gold-standard" antifungal drug. Pulmonary delivery directly at the site of infection could potentially eliminate systemic, dose-limiting toxicities found with current formulations of amphotericin B that are delivered intravenously. Aspergillosis has a high mortality rate of over 50%, and in some immunosuppressed patient groups the mortality rate may be as high as 100%, according to Lin et al.
The success of inhaled asthma/COPD drugs is continuing to lead to attempts to deliver other therapies via the lung, particularly biomolecules. Developers of pulmonary delivery first focused on inhaled insulin. Other efforts include pulmonary treatments for pain, osteoporosis, infections, and gene delivery.
Indeed, the rapid relief asthmatics experience from inhaled drugs could be extended to patients experiencing pain, anxiety attacks, hypertensive crisis, insomnia, arrhythmias, Parkinson's "lock up", and several others conditions. These conditions are treated with oral small molecule drugs. A few are slowly making the conversion to inhaled formulations, but no inhaled small molecules are yet approved.
The introduction of inhaled versions of oral drugs have typically boosted a drug's popularity and sales, reduced side effects, improved efficacy, or repositioned off-patent drugs for new indications. For example, Novartis originally developed Migranal as an injected drug for migraines. When reformulated as a nasal spray, the drug soared in popularity and captured half the sales for its class (CNS Market Outlook, 2004). A nasal formulation of AstraZeneca's migraine drug zolmitriptan brings pain relief within 15 minutes, compared to 2 hours for oral zolmitriptan.
The more than 10-year history of Exubera illustrates not only the long journey that biomolecules face, but also the evolution of drug delivery itself.Its approval opens up a gateway to exploring the pulmonary delivery of other therapeutic proteins but also a wide range of other medicines.Traditionally, pharmaceutical companies designed oral drugs, and other delivery routes might be explored to extend a product's life.
Today, delivery methods are important considerations from the outset, particularly for biomolecules. Much work went into engineering insulin and its development represents a merging of pharmaceutical, biotechnology and engineering skills - a necessary component of successful drug deli-very development.
The 1980s and 1990s saw the development of new biotherapeutics and pulmonary delivery devices that suit them. The 21st century will most certainly see the combination result in products that benefit patients, the first of these being Exubera.As inhaled products gain both regulatory and patient approval, pulmonary delivery will continue to evolve into additional areas as a true gold standard of care.
(Sarma P Duddu is MD & Rao Vadlamudi is vice-president, R&D Nektar Therapeutics (India) Pvt Ltd, Hyderabad)