Back to the Future: Inhaled Drug Products

CLINICAL TRIALS AND TRANSLATIONAL MEDICINE COMMENTARIES Back to the Future: Inhaled Drug Products ANTHONY J. HICKEY Center for Aerosol and Nanomaterials, RTI International, Research Triangle Park, North Carolina 27709 Received 27 August 2012; revised 13 December 2012; accepted 11 January 2013 Published online 4 February 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.23465 ABSTRACT: Inhaled therapeutic aerosols continue to be an important treatment for asthma and pulmonary diseases. A variety of dosage forms are employed for different indications and demographics including pressurized or propellant-driven metered dose inhalers, dry powder inhalers, and nebulizers/nebules. Research and development in this field has shown remarkable innovation in the past decade. Important new drug products for the treatment of asthma, chronic obstructive pulmonary disease, cystic fibrosis, diabetes, and a range of neurological disorders have been developed. New devices in each of the dosage form categories also have been developed, and new formulation technologies have been adopted. Unlike many other dosage forms, as new inhaled products appeared few of the existing products were converted to generic form. This may be explained by the formulation and device complexity, the implications for degree of difficulty in obtaining regulatory approval, and the prevalence of intellectual property in the field. After the setback of the initial approval and subsequent R -inhaled insulin, there appeared to be reluctance to consider the withdrawal of the Exubera pulmonary route of administration for systemically acting agents, particularly peptides and proteins. However, recent product development activities and approvals suggest that attitudes may be changing in favor of systemic delivery following inhaled aerosol administration. The new inhaled drug technologies seem to be driving reconsideration of therapeutic categories for indications that were of interest at the inception of modern inhaled drug therapy in the past century. We should embrace the opportunity to use new drugs and technologies to go back to the future! © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:1165–1172, 2013 Keywords: aerosols; biotechnology; drug delivery systems; inhaled dosage forms; peptides and proteins; pulmonary

INTRODUCTION The technological revolution that swept the pharmaceutical and biopharmaceutical industry at the end of the past century obscured the significant advance achieved in the 1950s by the development of the metered dose inhaler.1,2 This device–drug technology demonstrated for the first time in the history of inhaled therapeutics, which can be traced back millennia, that very small potent doses of drug could be administered directly to the site of action, the lungs, in an efficient and reproducible manner.3 Prior to the middle of the past century, a variety of Correspondence to: Anthony J. Hickey (Telephone: 919-5416771; Fax: 919-541-6771; E-mail: [email protected]). Journal of Pharmaceutical Sciences, Vol. 102, 1165–1172 (2013) © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association

inhalers were available intended to relieve a range of pulmonary disorders with poorly controlled doses of drugs of anecdotal benefit.4 Subsequently, a controlled dose delivery option was established as the method of choice for disease therapy. The relief afforded asthmatic patients changed the way this disease was treated irrevocably.5,6 Demonstrating the importance of certain pharmacological agents whose mechanisms were understood and were clearly valuable in treating asthma also led to a new phase in drug discovery and longer lasting potent agents were sought to turn the treatment of asthma from acute to chronic therapy thus changing the quality of life for millions of individuals.7 The achievements of the past decade, which are the focus of the present discussion, are bracketed admirably by other published reviews published at the beginning and end of the first decade of the new millennium.8,9

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Inhaled products are the basis for a number of new disease therapeutics. These products consist of three major categories of dosage form: propellant-driven, metered dose inhalers, dry powder inhalers (DPIs), and nebulizers.10 Each has a role in the delivery of specific drugs based on the dose required and the nature of the disease. In the past decade, some novel delivery systems have been developed that have high delivery efficiencies and have been used for new disease indications. Notable among these are soft mist inhalers and evaporation-condensation inhalers.11 Pharmaceutical aerosol delivery systems consist of formulation, metering system, and device technology. Table 1 illustrates the elements of each dosage forms. The past decade has seen the publication of several excellent texts describing the fundamentals of pharmaceutical inhalation aerosol technology among these Finlay’s and Newman’s are admirable.12,13 Local lung disease therapy is the major application for pulmonary drug delivery. The incidence of asthma and chronic obstructive lung disease compose by far the largest groups of patients to employ aerosol delivery systems.14 Pharmacologically, the most significant drug categories involved in therapy are $2 -adrenergic agonists (long and short acting), anticholinergic or muscarinic (long and short acting), and corticosteroid agents.15 Bronchoconstriction is a symptom of both diseases. It can be relieved by action on the sympathetic nervous system through the use of $2 -adrenergic agonists (BA) or the parasympathetic nervous system through the use of cholinergic antagonist, frequently referred to as muscarinic antagonists (MA).16 BAs were first developed as short acting agents, e.g., albuterol, taken four times daily. One of the notable developments of the 1990s was the appearance of long acting BAs, which allowed for less frequent dosing with consequent improvement in patient compliance. MAs were originally short acting, e.g., ipratropium, but recently long acting MAs have been developed. Glucocorticosteroids are intended to treat the underlying inflammation associated with

Table 1.

the hyperreactive inflammatory disease that characterizes asthma.16 Cystic fibrosis, a genetic disease in a small patient population, is another significant disease treated with R , Genentech) aerosol therapy.17 DNase (Pulmozyme is employed to thin mucus by acting on leukocyte R , Novartis) is used to DNA and Tobramycin (TOBI treat Pseudomonas aeruginosa infection. These two drugs treat the most prominent manifestations of pulmonary disease in cystic fibrosis patients. Direct delivery of surfactant to relieve respiratory distress syndrome in neonates was an early application of the use of the physicochemical properties of a substance to alleviate symptoms of disease.18 The delivery of surfactant to the lungs lowers surface tension thereby increasing lower lung surface area and facilitating gaseous exchange.19 Delivery of drugs to the lungs for the treatment of systemic disease has been of interest for many years.20 Indeed, one of the first propellant-driven metered dose inhalers (pMDI) products approved was for the treatment of migraine headaches [MedihalerErgotamine, Ergotamine Tartrate, approved in 1960, 3M-Riker] The last decade in inhaled drug product development and disease therapy has been eventful with a number of new developments. It is interesting to note that medicinal chemistry texts of the late 1990s are likely to present some relatively novel drugs (e.g., glycopyrrolate and formoterol) but not others (salmeterol and tiotropium), which reflects the situation with regard to intellectual property and published data at the time.21 Table 2 illustrates new products that have appeared or are in development for the treatment of asthma and chronic obstructive pulmonary disR R /Seretide (salmeterol ease (COPD). In 2002, Advair xinafoate/fluticasone propionate) was launched and became the first example of a multibillion dollar DPI employed for maintenance treatment for asthma. R (tiotropium), a long acting musIn 2004, Spiriva carinic agent, was approved as the first inhaled

Inhalers and Their Major Components

Inhaler

Formulation

Pressurized or propellant driven metered dose inhaler Dry powder inhaler

Drug suspended or dissolved in propellant (with surfactant and cosolvent) Drug blend in lactose, drug alone, drug/excipient particles

Nebulizer and nebules

Aqueous solution or suspension

Soft mist sprays Evaporation/condensation inhaler

Metering System

capsules, blisters, multidose blister packs reservoirs

Nebule dispensed into reservoir chamber of nebulizer Aqueous solution or suspension Unit dose blisters or reservoirs Solid or liquid drug or drug solution Multiunit dose deposit or reservoir

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Device

Metering valve and reservoir Canister, valve, actuator

Each device matched to formulation. Usually with dispersion feature, tortuous path, baffles Air jet (venture principle) or ultrasonic (wave cavitation and bubble principle) or vibrating mesh device Compression through orifices, vibrating mesh Flow path over heated surface to carry vapor with spontaneous condensation

DOI 10.1002/jps

BACK TO THE FUTURE: INHALED DRUG PRODUCTS

Table 2.

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Inhaled Asthma and COPD Drug Product Development, Approvals, and Launches in Past Decade

R Trade Name 

Active Ingredient(s) (Drug(s))

Advair

Salmeterol/Fluticasone

Foradil Ventolin HFA QVAR Spiriva ProAir HFA Atrovent HFA Xopenex HFA Asmanex Flovent HFA Symbicort

Formoterol Albuterol Beclamethsone Tiotropium Albuterol Ipratropium Levalbuterol Mometasone Fluticasone Formoterol/Budesonide

Brovana Alvesco Dulera

Arformoterol Ciclesonide Formoterol/Mometasone

Combivent Respimat Albuterol/Ipratropium Aerospan Flunisolide Relovair Vilanterol/Fluticasone Vilanterol/GSK Olodanterol/Tiotropium Glycopyrrolate Glycopyrrolate/Formoterol

Doses (:g) 50/100 50/250 50/500 12 90 40, 80 18 90 17 45 220 80 4.5/80 4.5/160 5, 15, 25 80, 160 5/100 5/200 100/20 80 25/100 ≤ 50 ≤5 /≤5 2.4 2.4/18

Initial Inhaler Type

Product Development/Approval

Manufacturer

DPI

November 1999

GlaxoSmithKline (GSK)

DPI pMDI pMDI DPI pMDI pMDI pMDI DPI pMDI DPI

February 2001 April 2001 September 2001 January 2004 September 2004 November 2004 March 2005 April 2005 March 2006 July 2006

Novartis GSK Teva Boehringer Ingelheim (BI) Teva BI Sepracor (Sunovion) Schering Plough (Merck) GSK AstraZeneca

Nebules pMDI DPI

October 2006 January 2008 June 2010

Sepracor (Sunovion) Nycomed Merck

SMI pMDI DPI DPI DPI pMDI pMDI

October 2011 September 2012 Anticipated filing In development Anticipated f iling 2013 In development In development

BI Acton GSK GSK/Theravance BI Pearl Therapeutics Pearl Therapeutics

Abbreviations: COPD, chronic obstructive pulmonary disease; DPI, dry powder inhaler; pMDI, pressurized or propellant driven metered dose inhaler; SMI, soft mist sprays.

treatment for chronic obstructive lung disease, opening a large and at the time of launch poorly treated R , inhaled insulin, was condition. In 2006, Exubera approved for the treatment of diabetes (Table 3). Unfortunately, it was subsequently withdrawn. However, the withdrawal was a voluntary business decision. Insulin continues to have potential for delivery as an aerosol product, and the leading second generation product is currently being pursued by MannKind Corporation. Recently, the use of hypertonic saline or the delivery of mannitol has been employed to hydrate the airways of cystic fibrosis patients. This application of the physicochemical properties of salt and sugar improves mucociliary transport and relieves the symptoms of this disease.22,23 The current status of aerosol delivery to the lungs is one of return to the concept of local delivery for local action. In the absence of novel mechanisms, combination drugs intended to treat both symptoms and underlying cause of disease in asthma and COPD are becoming the standard for maintenance therapy. Consistent with this view, other local diseases have received considerable attention, notably cystic fibrosis and concomitant infection. The use of antimicrobial agents to treat lung infections more broadly is also gaining popularity. Cystic fibrosis continues to be a disease for which new aerosol therapies are being developed (Table 3). DOI 10.1002/jps

There has been a subtle shift in the intent to employ the lungs as a route of administration for systemically active drugs. While chronic administration of peptides and proteins was in vogue for most of the last 20 years, enthusiasm for these drugs of biological origin has diminished in favor of rapidly absorbed potent agents for the treatment of neurological disorders such as general pain, migraine headaches, and depression. The ability to generate drugs in small doses that are rapidly absorbed and act to mitigate the condition has been facilitated by novel inhalers and drug delivery strategies. Technology has been developed to place the therapeutic aerosol on a specific portion of the inspiratory flow of the patient or to control the breathing maneuver to improve lung deposition.24 This approach has opened a new arena for the efficient delivery of potent and expensive therapeutic agents and acknowledges that an important variable, the patient, can be controlled when necessary. The delivery of potent agents that may be difficult to deliver by other routes, in regimens that encourage compliance, from devices that are easily operated will make many diseases in the future manageable with inhaled therapy. The future direction of aerosol therapy consists of direct extensions of the knowledge gained from previous activities and novel developments arising from discrete advances in pharmacology, medicinal JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 102, NO. 4, APRIL 2013

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Table 3.

Inhaled Drug Product Developments, Approvals, and Launches in Past Decade for Cystic Fibrosis, Diabetes, and PAH

R Trade Name 

Drugs

Initial Inhaler Type

Doses (mg)

Bronchitol Cayston TIPTM ARD3100

Mannitol Aztreonam Tobramycin Ciproflaxacin

400 75 112

ARD-3150 ARD-1100 Exubera

Ciprofloxacin Ciprofloxacin Ciprofloxacin Insulin

AIR Insulin AerX Inhaled Insulin

Insulin Insulin

0.9 (2U), 2.6 (6U) 4.7

DPI SMI

Afrezza Ventavis Tyvasco

Insulin Iloprost Treprostinil

1.8 (4U), 3.6 (8U)

DPI Nebulizer Nebulizer

1, 3

DPI Nebulizer DPI Nebulizer Nebulizer Nebulizer DPI DPI

Product Development/Approval Fast track US January 2010 July 2011 Orphan Drug Designation (ODD) August 2009 ODD August 2009 ODD March 2010 January 2006 withdrawn 2007 Terminated Terminated by Novo Nordisk (NN) but Aradigm Active Program Late development December 2004 July 2009

Manufacturer Pharmaxis Gilead Novartis Aradigm Aradigm Aradigm Bayer/Novartis Pfizer/Nektar Lilly/Alkermes NN/Aradigm

Mannkind CoTherix, Inc. United Therapeutics

Abbreviations: DPI, dry powder inhaler; PAH, pulmonary arterial hypertension; SMI, soft mist sprays.

chemistry, and delivery and device technology. There is no question that one of the largest investments made in drug delivery related to the treatment of diabetes with inhaled insulin.25–27 Table 3 shows the insulin products that have been or are in development and the timelines with regard to development, submission, and regulatory approval. Many companies had interests in developing this product and one, Pfizer/Nektar, succeeded. The subsequent withdrawal R , remains a disappointment. of this product, Exubera There has been considerable speculation on the reasons for the ultimate demise of this product. These range from formulation and device issues (dose in milligram rather than international units, very large device), through apparent safety considerations to marketing and sales inadequacies.28,29 The most significant questions appear to surround pricing and sales in the final analysis, but certainly the debate will continue among those interested in protein and peptide delivery. However, the achievements of those invested in this pursuit should not be understated. Not only were many new technologies developed in pursuit of pulmonary delivery of insulin, but also many of the leading proponents of inhaled drug delivery spent their formative years in this highly innovative environment. It should be noted that the biotechnology industry of the 1990s was experiencing drug administration difficulties by the conventional oral and parenteral routes. Therefore, many promising molecules were delayed in development.30 For much of the time, insulin was the leading product among a number of proteins and peptides that demonstrated properties suitable for administration by this route. The period R has been characsince the withdrawal of Exubera terized by a reluctance of major pharmaceutical companies and investment groups to pursue delivery of JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 102, NO. 4, APRIL 2013

protein and peptide drugs by the pulmonary route. This phenomenon has been exacerbated by the impact of the economy on investment in recent years and the specter of adverse effects the severity of which reR (Dornase mains the topic of debate.31 Pulmozyme alpha or DNase, Genentech) received regulatory approval in 1993 and has been a mainstay of therapy for cystic fibrosis, as mentioned earlier, for many years. Therefore, there is a history of protein delivery to the lungs routinely without adverse events. The continued interest in the delivery of alpha-1antitrypsin for the treatment of emphysema and cystic fibrosis (Kamada),32 human growth hormone,33 and more recent developments with the use of interferon gamma to treat idiopathic pulmonary fibrosis and mycobacterial disease (InspiRx Pharma/Nostrum Pharmaceuticals)34,35 is indicators of the enthusiasm for development of protein and peptide therapeutics, and the modest impact that the inhaled insulin story will have on future developments. In addition, the increase in interest in the lungs as a route of administration of vaccine antigens and the focus on local immunology and safety may contribute to a reemergence of a more general interest in protein and peptide drugs for administration to and via the lungs.36 The rationale for adopting this route in the 1990s has not changed, and the knowledge and understanding of materials processing and delivery technology has progressed enormously. The current inhaled insulin products in development at MannKind Corporation (dry powder inhaler) and Dance Pharmaceuticals (vibrating mesh, soft mist spray) suggest a general confidence in this approach to diabetes treatment. Pulmonary arterial hypertension (PAH) is a particularly insidious disease. Differentiating its treatment from effects on systemic blood pressure has been a DOI 10.1002/jps

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great challenge for which local therapy would appear to be the ideal solution.37 Consequently, treatment of PAH with inhaled Iloprost or Treprostinil (Table 3) is a major inhaled therapeutic achievement. Moreover, the innovator companies should be commended for using traditional nebulizer technology and formulation strategies to allow a straightforward regulatory pathway to approval bringing these much needed treatments to the clinic and ultimately to commercialization. Tissue/organ rejection is another significant unmet medical need. Where lungs are the transplanted, organ-system aerosol therapy is a logical consideration.38 Unfortunately, significant investment and development activities in cyclosporine did not result in product approval by the U.S. Food and Drug Administration (FDA). It appears that this was the result of equivocal efficacy despite the product’s apparent safety. The development of generic products is a related topic, which may deserve consideration independently but should be noted here. pMDIs with chlorofluorocarbon propellants were the first drug products to appear in generic form, and for which a regulatory pathway was established. The ease with which these drug products could be developed was dependent on the components (canister, valve, actuator, and formulation materials) being commodities that could easily be replicated. However, the requirement for reformulation in hydrofluoralkane (HFA) propellants by innovator companies slowed down the development of generic pMDIs. In contrast, it has been more difficult to construct a regulatory pathway for generic DPI products. One reason for this is that the matching of device to formulation renders the components somewhat unique and difficult to reproduce without infringing the intellectual property rights of the innovator company. Also, there is a requirement of both “bioequivalence” and “pharmaceutical equivalence” in the United States. The latter form of equivalence relates to the technique employed to access the dose, actuate the device, and administer drug. These actions should not require the patient to be retrained, which suggest a very similar device to the comparitor system in terms of operating principles and again may infringe on the intellectual property rights of the innovator company. The U.S. FDA has begun to consider approaches to this problem, and other organizations such as IPAC-RS have sponsored meetings in an attempt to suggest a way forward for these products.39 However, it is unlikely that a generic DPI guidance document will appear in the near future. The future of device formulation technologies for pulmonary drug delivery hinges on the development and regulatory risk that can be tolerated. We live in an age of rapid technology development in the fields of materials science, data storage and manipulation, DOI 10.1002/jps

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communication, and gaming. It is evident that many industries are availing themselves of the benefits of advances in these fields to remain competitive in a rapidly evolving commercial environment with an informed and demanding patient population. Several generations of people have grown up in this rapidly innovating environment and have their expectations set by the convenient and familiar tools that are now available. As new and more complicated therapeutic strategies become possible a change will be required in the historically conservative approach of the pharmaceutical industry, and the regulatory environment into which products are launched. This is not to say that there should be any deviation from high standards of quality and safety but to recognize, as has begun to occur with quality by design and process analytical technology, that efficient approaches can be adopted to accelerate development of pharmaceutical products.40 In addition, as telemedicine gains popularity the application to individual dosing and dose monitoring may require more complex and probably electronic devices to fulfill medical and societal needs and expectations. Some success has been achieved in electronic devices with handheld nebulizers. Vibrating mesh systems are notable in this regard.41 Forays into the development of electronic metered dose inhalers and DPIs have been encouraging but have yet to result in new products.42 This can be explained in terms of the number of components that these devices require and the controls on manufacturing to meet specifications that ensure quality and performance consistent with a robust product thereby mitigating the risk associated with product failure.39 Few drug products have been conceived that would justify the assumption of the higher level of risk associated with more complicated devices and technologies. However, as manufacturing and process controls improve and different, potentially unmet, medical needs arise, there may be a greater appetite among investors and the pharmaceutical industry to aggressively pursue these options. Trends in clinical development for asthma and COPD are currently focused on the coadministration of a range of drugs discussed previously. Recent developments in particle technology and inhaler design render the delivery of combination drugs an increasingly common strategy. Combinations of old and new drugs should be anticipated in the drive to greater safety and efficacy (Table 2). The ability to generate small doses of drug efficiently has opened an apparently new therapeutic strategy of treating neurological disorders, which require rapid onset pulsatile delivery of drug.43 Notable among products recently approved, or in development, R loxapine, evaporationinclude AdasuveTM (Staccato condensation inhaler, Alexza Pharmaceuticals, Mountain View, CA, approved December 2012) JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 102, NO. 4, APRIL 2013

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for the treatment of schizophrenia and bipolar R (dihydroergotamine pMDI, MAP disorder, Levadex Pharmaceuticals, Mountain View, CA) for treatment or prevention of migraine headaches, and CVT-301 (L-dopa, DPI ARCUSTM Platform, Civitas Therapeutics) for treatment of Parkinson’s disease. Intranasal delivery devices are generally beyond the scope of the present article since their performance characteristics, regulation, and therapeutic uses differ from those of inhaled products. However, there seems to be convergence of their application for systemic delivery with that of inhaled products. There is increasing interest in the nasal route for delivery of therapies for neurological disorders. The link between the nose and the brain through the olfactory bulb continues to be of interest.44 The ability to deliver analgesics, such as fentanyl and morphine, has been pursued by the pulmonary route,45,46 [pMDI, SmartMistTM and SMI, AerX TM Aradigm Corporation, Hayward, CA; DPI, TaifunTM , LAB International, Canada] and also by intranasal delivery.47 Indeed, observation of insulin tolerance in the brain and its link to Alzheimer’s disease 48–50 may resurrect interest in nasal delivery of insulin, which was pursued avidly in the 1980s.50 The impact of smoking on individual and public health and its implications for healthcare costs and resource allocation worldwide continue to justify investment in long-term strategies for smoking cessation. Since their introduction, electronic cigarettes have met with commercial success as an alternative to conventional cigarettes. It has been inferred from the absence in electronic cigarettes of combustion products, which are known to result in carcinogenicity, cardiovascular, and other disease, that they may be safer than conventional cigarettes. However, electronic cigarettes were not introduced to the market as a “drug delivery system” and were not subjected to the rigorous regulatory review that would accompany a new drug product application. Consequently, “in September 2010 the U.S. FDA issued a number of warning letters to electronic cigarette distributors for various violations of the Federal Food, Drug and Cosmetic Act including violations of good manufacturing practices, making unsubstantiated drug claims, and using devices as delivery mechanisms for active pharmaceutical ingredients.”51 There is a growing body of literature that describes the safety benefits or harm associated with the use of electronic cigarettes. The reported studies and ensuing discussion seems equally balanced between the benefits and hazards of using this product, and as there does not appear to be a clear conclusion it is not proposed to present the merits of each argument here. However, the success of this product does indicate the important opportunity for the use of inhaled drug products, after rigorous regulatory review, in smoking cessation programs. At least one such product is currently under developJOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 102, NO. 4, APRIL 2013

ment ARD-1600 (nicotine, soft mist inhaler, Aradigm Corporation, Hayward, CA). Throughout the past decade, the frequency of corporate name changes, mergers and acquisitions, and licensing and marketing agreements has contributed to an ever-changing commercial landscape. This poses some difficulty in tracking the history of certain products that appear to have changed ownership several times or to have become part of competitor products. In addition, the absence of regulatory harmonization is responsible for discontinuity in the global pharmaceutical market, which in turn leads to varying product approvals in different geographical regions. This complexity is challenging to the industry and frustrating to patients but is likely to continue for the foreseeable future.

CONCLUSIONS Aerosol technology has been one of the more successful technologies of the last half-century. In the past decade, the diversity of new drugs, formulation, and device technologies has resulted in a number of new products that have brought significant benefits to patients suffering with asthma, chronic obstructive lung disease, cystic fibrosis, PAH, and more recently neurological disorders. The initial success of inhaled insulin R only was undermined by the withdrawal of Exubera a year after launch. While this is a disappointment, the knowledge gained from these programs gives a solid foundation to those interested in future protein and peptide delivery. One curiosity of the significant developments of the last 10 years is that a leading new candidate for pulmonary delivery is intended for the treatment of migraine headaches, as noted earlier dihydroergotamine pMDI (MAP Pharmaceuticals), and in the modern era of inhaled therapeutics this was one of the early indications for which a pMDI product was approved. However, the recent product benefits from technological advances in delivering a new drug.52 Back to the future!

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