An Advancing Sphere

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Rising levels of COPD, including asthma are driving a lot of innovations in Inhalers with an aim to improve the overall effective management of these diseases

Chronic Obstructive Pulmonary Disease (COPD) was the fifth leading cause of death in 2002 and will become the third leading cause of death across the globe by 2030, according to WHO. Moreover, its incidence is expected to increase in the coming years due to higher smoking prevalence and ageing populations in many countries. The increase in COPD is one of the major growth drivers of pulmonary drug delivery market. According to markets and markets report, global pulmonary drug delivery market is projected to reach $52.37 billion by 2021 from $36.10 billion in 2016, at a CAGR of 6.5 per cent during the forecast period. The report stated that the growth in this market is mainly driven by rising incidences of respiratory diseases such as COPD, asthma, and cystic fibrosis, increasing preference of pulmonary route of drug delivery and increasing technological developments in the form of smart/ digital inhalers.

Although medication and treatment for COPD and asthma are available in oral, injectable dosage forms as well,  inhaled therapy is preferred globally, because of the high drug concentration which can be achieved locally within the lungs, with reduced risk of systemic side effects. Global clinical guidelines issued by the Global Initiative for Asthma (GINA) and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommend that persistent, moderate-to-severe asthma and COPD at high risk of exacerbations be treated with a combination therapy of inhaled corticosteroid (ICS) and long-acting beta-agonist (LABA), administered via an inhaler. The guidelines also recognise that this therapy is best administered in a fixed-dose combination (FDC) from a single inhaler, rather than from two separate inhalers. This is demonstrated by reduced adherence and increased discontinuation rates in patients using multiple inhalers versus those using FDC devices. Thus, inhalers remain a major part of asthma treatment.

Trends in inhalers

Currently, inhalers can be divided into three categories -nebulisers, pressurised metered dose inhalers (pMDI) and dry powder inhalers (DPI). Within and between these categories the inhalers differ in effectiveness of drug delivery and ease of use.

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Vinod Kumar Arora

Explaining the role of each category, Vinod Kumar Arora, Principal Advisor, Institute of Good Manufacturing Practices India says, “The route of pulmonary drug delivery offer advantages such as reduced dosage of drug, less adverse reaction and rapid onset of action. Most nebulised formulations fall into two categories – solution containing a drug that is typically dissolved in saline (or occasionally in another solvent or cosolvent with alcohol) or drug suspension containing a drug that is not soluble in saline or another solvent. In pMDI, the drug is either suspended or dissolved in a propellant that is pressurised. Release of metered volume of drug in propellant through a control valve causes a high velocity aerosol with expansion and evaporation of propellant. DPI’s combine powder technology with device design in order to disperse dry particles as an aerosol in the patient inspiratory air flow. Therefore, a balance between the design of an inhaler device, drug formulation and the inspiratory flow rate of patient is required.”

Another recent trend in applications of pulmonary drug delivery include insulin by aerosol (Afrezza marketed by  Mannkind, US), anxiety (Loxapine- marketed by Alexza Pharma), treatment of migraine (Dihydroergotamine- NDA submitted by Allergen, Zolmitriptan – Phase 1), Breakthrough pain management (Morphine/Fentanyl in Phase 2 by Aradigm), Parkinson’s disease (Levodopa in Phase 3 by Acorda Ther), nicotine aerosol for smoking cessation (AERx nicotine in Phase 2 by Aradigm), aerosols for angina, aerosol vaccination and inhaled drug delivery for tuberculosis therapy. Nanoparticles (NPs) are also effective targeted drug delivery systems because of their non-invasive approach and lesser bioavailability in the systemic circulation.

The India scenario

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A Vaidheesh

However, the scenario in India is completely different. A Vaidheesh – MD, GSK Pharmaceuticals India informs, “Though inhalers are considered by global guidelines as the preferred treatment for asthma, almost 70 per cent of asthma patients in India are still on oral formulations – one of the reasons for this is a strong perception against use of inhalers. Even for the smaller cohort of patients who use inhalers, it is a common observation shared by physicians that patients may not be using their inhalers correctly. Most of the patients may not even be aware that their asthma is not well controlled despite being on medication.” According to National Center for Biotechnology (NCBI) reports, current pMDI and DPI inhalers require a complex administration procedure involving several steps like dose loading, inhaler priming, and breathing management in order to ensure maximal benefit of the medication. These steps require that patients display great dexterity and coordination. Failure to follow the instructions may lead to inhalation errors, some of which reduce, or prevent entirely, deposition of the medication in the lungs.

Arora says, “Currently there are around 300 million asthma and COPD sufferers rely on inhalation devices for effective delivery of their medication. However, using an inhaler is not easy as it takes skill and practice, whatever the design of device to ensure that inhalation and device actuation is synchronised, allowing the correct dose to be taken. To date focus has been on medications, the device design and optimising how both work together in the hand of patients who themselves are a diverse and varied group.”

Vaidheesh also believes that inhalation drug delivery, is very crucial part in treatment of asthma but comes with lots of complexities. In order to have a correct dose delivered at the intended site, the doctor needs to recommend a device specific to the needs of the patient. Though Indian asthmatics use inhalers such as controllers and relievers, a majority still prefer taking pills for asthma

A brighter future

However, Arora is also optimistic about the future of inhaler technologies. He says, “The future of inhalation therapy is bright as there exists a medical needs who currently have inadequate treatment options. Key drivers for growth of the global pulmonary drug delivery is rising prevalence of respiratory chronic such as tuberculosis, bronchitis and chronic obstructive pulmonary disease, increasing demand for non-invasive methods, technological advancements such as smart inhaler, increase in smoking, increasing geriatrics population, and change in lifestyle. However, regulatory approvals and patent expiration of blockbuster drugs may hinder growth of the global market.”

Arora also says, “More patients are now open to taking dry powder inhalers which are considered as the cornerstone of treatment for asthma. Though we have world class dry powder inhalers in India, battling the perception against inhalers and also ensuring the right technique is used during treatment are the biggest challenges faced by the respiratory segment. Incorrect inhalation technique is particularly common among older people and those with reduced inspiratory flow rate. Indeed, most patients with COPD are unable to use a pMDI or DPI correctly. Common errors include inadequate coordination of inspiration and actuation, and inability to achieve a sufficient inspiratory flow rate.”

Role of innovation

Briefing on the innovation in inhalers, Arora says, “With many players in the race to be first to market with inhaled insulin technology innovations developed rapidly. The initial pioneering focus was to develop new highly efficient devices for powder dispersion that used external energy supply to form the aerosols. Later sophisticated particle engineering strategies emerged allowing for the use of simpler and less expensive DPI with superior performance. The improved inhalation technologies – AERx system combined breath control features with a disposable nozzle that produced nearly monodisperse droplets ideal for alveolar deposition that practically eliminated deposition in the oropharangeal region and thus achieved intra subject variability equivalent or superior to SC injection.”

According to Vaidheesh, a lot of research goes behind improving drug and delivery systems in inhalers to improve patient compliance and keep the steps of usage of the device as simplistic as possible.

He says, “We are also witnessing the innovation of drugs that are long acting and novel devices that improve adherence to the treatment. New device engineering that now enables a combination of two drugs in a single inhalation and reduces device resistance that allows patients to take the medicine with ease are some of the other innovations that have a positive impact on treatment and better control of asthma symptoms.”

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Pierre Carlotti

Pierre Carlotti, VP, Strategic Marketing, Aptar Pharma, opines that the success of inhalation therapies hinges on multiple factors and involve multiple stakeholders including healthcare practitioners (HCPs), the patient, the drug product(s) coupled with the inhaler(s) selected in relation to the disease and patient abilities and preferences. It is a complex equation in which the patient-drug-device represents the corner stone. Unfortunately, for asthma it is reported that up to 60 per cent of patients fail to take their medication properly.  The medical, social, and economic burden associated with non-compliance is tremendous.

Speaking on the innovation done by Aptar, Carlotti, says, “At Aptar Pharma, a major portion of our device innovation effort is oriented towards reducing the gap. One way to address the issue is to optimise existing devices and/ or create novel devices that are easier-to-teach and to-use such as Prohaler, one of our DPI platforms, that requires only one simple step before inhalation and after inhalation. We have verified the usability of Prohaler in partnership with hospitals clinicians and asthma and COPD patients. The development of simple though efficient Breath-Actuated Inhalers (BAIs) represents another innovative approach to resolve the hand-lung coordination issues that some asthma patients experience with pMDIs. Another approach contributing to reinforcing ease-of-use and compliance is device feedbacks typically answered by a few key questions: is my device ready-to-use? Did I take my dose properly? When do I need to refill my prescription? To answer the latter question, Aptar Pharma offer a range of robust and legible dose counters or dose indicators. Finally, digital health offers a variety of solutions that help tremendously to improve patient compliance and reduce the gap.”

Moving towards smart inhalers

Smart inhalers function in the same way as regular inhalers to deliver medication, but it includes technology for patients and health professionals to track inhaler use. Smart inhalers contain sensors attach to existing inhalers and record when somebody’s medication is taken. Smart inhalers use Bluetooth technology to paired wirelessly with a smartphone, tablet, or computer. The market for digital dose inhalers for asthma and COPD will be worth $3.56 billion in 2024, according to a new prediction from Grand View Research.

Increasing investment in research and development of advanced devices, collaborations and partnerships, and technological advancements in smart inhalers are expected to boost the growth of the market in coming years.

According to Smart Inhalers Market Research Report – Global Forecast to 2022, Globally North America is the largest market for Smart Inhalers which is anticipated to reach $888.4 million by 2023. Europe is the second-largest market in 2016 which is valued at $57.4 million. Furthermore Asia-Pacific market is expected to be the fastest growing market and is projected to grow at a CAGR of 55.3 per cent during the forecast period from 2016-2022.

However, Arora believes that certain measures have to taken to make smart inhalers more palatable in India. He says, “We need to have smart inhalers which should be able to resolve the clinical problem/ challenge – how much of the drug has entered the lung in the first place. Children having drug through device may be labelled as a sick child therefore adequate care needs to be taken to make the device attractive… With the rise of wearable devices and activity tracking could smart devices be tethered to a mobile phone through a specially designed app? If patients were not using the device correctly or had forgotten to take their medication could this information be gathered and feedback/ reminder mechanism to improve usage? Another opportunity area could be use of biometrics to improve security – safe delivery of the correct drug to the correct individual.”

Carlotti informs that they have already made several moves in this direction, “Several years ago, Aptar Pharma began developing digital health solutions. More recently, we partnered with Propeller Health to develop the first integrated connected pMDI. Aptar Pharma believe connected inhalers and digital health are significant contributors to improving patient compliance issues. Current trends will see mobile phone ownership grow to 70 per cent by 2019 (even higher in developed countries) which means more people will have access to data-driven mobile technology.”

Going forward

A digital health approach will help to identify the target patient populations with the highest levels of non-adherence. By effectively targeting challenging patients and providing them with precise information and prompts to take medication, greater levels of patient engagement and improved dose adherence can be expected, and therefore improved health outcomes.

It is also anticipated that smart inhalers will help create a supportive, informed and transparent ecosystem whereby the patient, the healthcare provider and the pharma company will have real-time access to information that will significantly help improve adherence for the patient. In the short term, it will help HCPs assess patients more accurately based on data, rather than patient interpretation. In the longer term, it will enable healthcare providers to shape care provisions more appropriately and help pharma companies deliver more effective solutions beyond just the drug and the device.

swati.rana@expressindia.com