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Capsugel.es2

Inhalation Technology
A breath of fresh air in drug delivery! Dr. Thilo Schmierer, Business Development ManagerCorinne Malica, Pharmaceutical Market Specialist Inhalation Technology – A breath of fresh air in drug delivery!
approach. Generally, patients express preference for devices that are small, portable and easy to use whilst The inhalation route is a fast and effective way of always ensuring that an accurate dose is dispensed. delivering medication locally to the lungs and also From the company's point of view, the selected device for the systemic administration of certain agents. must meet stringent manufacturing requirements in Inhalation drug therapy is used extensively to treat terms of its robustness, efficiency and precision whilst respiratory conditions such as asthma and Chronic remaining environmentally friendly.
Obstructive Pulmonary Disease (COPD). Recently, it has been shown that pulmonary drug delivery could also be an effective route to deliver drugs to the systemic Inhalers –
circulation thanks to the large surface area of the lungs opening up the airways in respiratory disease with highly vascularised epithelia.1 Research is ongoing The burden of chronic respiratory diseases such as to develop inhalation systems to treat neurological asthma and COPD on patients is significant in both disorders, cystic fibrosis, pain management and to physical and psychological ways. Narrowing of the airways deliver vaccines. causes breathlessness which, during an acute attack, can lead to asphyxia and death if medication is not ad- The Metered Dose Inhaler (MDI) is the original and most ministered rapidly. Even normal physical activity can be widely used device to deliver inhalation therapies. It uses exhausting, whilst smoke, al ergens, or even expressions pressurized gas to release its dose when activated by of emotion such as laughter or crying can trigger an the patient. More recently, the Dry Powder Inhaler (DPI) asthmatic attack or cause an exacerbation of COPD. Fear has been gaining popularity because it does not rely on of provoking an acute attack makes patients anxious, propel ant to deliver the medication and patients find it forcing them to limit their daily activities and making them convenient and easy to use.2 Other systems available completely reliant on their inhalation product. on the market include liquid droplet inhalers and nebulisers. When developing a new product, researchers "COPD is extremely disabling for me. can select either a standard inhaler device or decide to It's exhausting not being able to climb stairs develop a customized solution that is more tailored to without pausing between each floor." the requirements of their product and the particular Female COPD patient
"Asthma is a disease still considered as "easy Whatever solution is chosen by the company, the to manage". You just need to have the proper effectiveness of the technology will also depend on medication. However, living with it is a constant the ease of use and the patient's ability to administer handicap for all activities." his or her own medication. It is therefore essential Male asthma patient
that the device is designed using a patient-centered Easy to use
• To avoid additional stress during an acute attack• Simple treatment implies a less "serious" disease that is under control • The device should not attract attention during administration • Small – it should fit into the palm of the hand• Unobtrusive style without bright colours to avoid appealing to children • Should fit easily into a trouser or jacket pocket • Remaining doses should be visible to allow the patient to anticipate when a new prescription will be required Easy dose loading
• Should be possible to load dose into the device quickly and hygienically Clean and hygienic
• Should be simple to protect and clean the mouthpiece Separate device and doses
• To avoid additional costs and wastage Figure 1: Key physical attributes for an inhaler delivery system

Inhalation Technology – A breath of fresh air in drug delivery!
General y, chronic respiratory patients are knowledgeable During the same study, experienced patients were about their disease and its treatment; they become asked to assess the relative merits of the main experts in juggling between different inhaler devices inhalation systems currently available: sprays, blisters for everyday use or crisis management and in adapting and capsules. Sprays have been on the market for their lifestyles, as wel as their medications, to meet the a long time and the metered dose inhaler (MDI) is demands of their il ness. Nevertheless, patients often the reference inhaler device. MDIs are prescribed feel embarrassed about appearing "sick" and being mainly for emergency use whilst dry powder inhalers stigmatized in the outside world where such diseases (blisters or capsules) tend to be preferred for everyday are poorly understood.2 This means that inhaler systems maintenance therapy (Figure 2).2 used to treat respiratory disease should not only be effective in delivering precise doses, they should also be Although sprays are small and simple to use, they do smal , discreet, easy to carry and easy to use. have some drawbacks: for instance there is no indicator for the number of remaining doses in the device so Recent market research highlighted various practical that in a life-threatening situation, like an acute asthma aspects mentioned by patients familiar with inhaler attack, the patient cannot check whether sufficient use.2 The men and women interviewed were between doses have been delivered. As sprays can discharge 20 and 60 years old and were suffering from COPD or accidentally, the lack of dose counting is even more chronic asthma. They had all been using inhalers on a worrying. Also the mouthpiece tends to get dusty and regular basis for at least a year and had experienced at requires scrupulous cleaning. Finally, patients using least two different systems (blister, capsule or aerosol). MDIs need to carefully regulate their breathing to When questioned, the patients defined key design ensure that the full dose is inhaled. criteria for inhalers as straightforward dose loading, being able to clean and protect the mouthpiece, and Blister based inhalation devices are perceived as a that the device and the dose should be available more modern approach. These devices are easy to separately to avoid wastage (Figure 1). load and to clean. However, their design is bigger and bulkier than other inhalers and the devices are more  "A ‘good' inhalation system for me is a conspicuous when used in public. system that is efficient (fast action) and easy to use, because when a crisis occurs a state Patients involved in the market research considered of ‘panic' can set in, and so there should capsule-based systems to be very effective in ensuring be no additional stress with a system that is precise dose measurement.2 There is less wastage complicated, and finally it should be correctly compared to blisters because the capsules and the dosed and well adapted to the degree device are available separately and the capsules are of asthma and the patient's pathology" biodegradable and hence environmental friendly. Loading is considered to be straightforward by the • Need for a quick, fast-acting, all-in-one ready
• Need for a safe, reliable, to use solution, for all kinds of situations long-lasting system
• Patients seek immediate efficacy • Need for a quick, fast-acting, all-in-one ready
• Patients seek efficacy over the long-term • Need for a safe, reliable, to use solution, for all kinds of situations long-lasting system • SIMPLICITY is valued • SOPHISTICATED, ADDITIONAL FEATURES • Patients seek immediate efficacy like counting remaining doses are valued • Patients seek efficacy over the long-term • SIMPLICITY is valued • SOPHISTICATED, ADDITIONAL FEATURES like counting remaining doses are valued Figure 2: Comparison of inhalation systems: Patient perception influenced by device usage
Inhalation Technology – A breath of fresh air in drug delivery!
majority of patients although for some non-users Another indication for the use of DPIs is for the there is a perception that capsules could be more treatment of viral infections. Zanamivir® (Relenza®) from GSK is a neuraminidase inhibitor that is used for the treatment and prevention of influenza. It is Although MDIs are the market leader with 48% of retail formulated as a dry powder and packaged in four 5mg sales in Europe versus 39% for DPIs and only 13% for blisters on a Rotadisk® for inhalation via the Diskhaler®. nebulisers3, they are gradually losing their popularity to be replaced by technically superior and more eco- In February 2010, Daiichi Sankyo filed a New Drug Application in Japan for its influenza drug CS-8958, which is delivered using Hovione's TwinCaps® inhaler. Applications are expected soon via Hovione's licensee Dry Powder Inhalers –
Biota for Europe and the US markets.
not only for respiratory diseaseThe progress of DPI technology has created opportuni- Proprietary DPI technology –
ties in other therapeutic areas where systemic expo- how to stand out from the crowd sure is required. Low dosed drugs and large molecules have been successfully delivered via the respiratory To take advantage of opportunities for inhalation drug tract for the treatment of systemic diseases. Potential delivery in both respiratory and systemic diseases, indications include pulmonary arterial hypertension, manufacturers of inhalation drug therapy are focusing neurological disorders such as Parkinson's, hereditary on the development of proprietary technology platforms diseases, and pain management including migraines for efficient development and manufacturing as well as to differentiate themselves from the competition. Inhaled drug therapy is an appealing option for patients Strategic decisions are primarily based on: because of its painless and flexible administration • Cost efficiency compared to injections. Compared to oral administration, • Patient acceptability it has the advantage of a more rapid onset of action, • Development timelines lower dosing, avoidance of first pass metabolism and • Patent protection of the proprietary solution potential y fewer side-effects (Figure 3).1 "We use a capsule-based system. We were granted a patent for a combination using HPMC capsules • Less drug could be required compared to oral and a capsule-based DPI device" R&D director, Pharmaceutical Company
• Onset of action can be more rapid via The choice of the system can be made at a very early inhalation compared to the oral route stage before product development has begun. Input • Adverse effects are potentially less severe and is usual y sought from business development and marketing specialists to ensure that the proposed system • Drugs that are not absorbed orally can be is in line with market trends and wil meet customer delivered via the lung needs. In early development stages, R&D works closely • Compared to injectable dosage forms, with management to look at product performance, inhaled drug therapy is painless and relatively feasibility and timing in addition to the cost of goods and comfortable for the patient which encourages the position of the new product within the company's pipeline and product portfolio. As the project moves ahead studies are required for formulation development, compatibility and stability, feasibility and scaling up as Figure 3: Advantages of inhaled drug delivery for treating
wel as for the clinical programme.
The overall approach to the choice of technology and One area of interest for DPIs is in inhaled antibiotics the device will depend on the company's business for the unmet medical need of treating cystic fibrosis, strategy. A big pharmaceutical, R&D based company a life threatening lung disease and several studies are will prefer to develop or use its own existing proprietary ongoing in this indication4. In 2010, Novartis gained technologies and will work on formulating the Active EU approval for a dry powder inhaler for tobramycin Pharmaceutical Ingredient (API) to fit the inhalation (TOBI® Podhaler®)5 and the FDA granted Orphan Drug
drug delivery system. Smaller companies, if not Designation for a ciprofloxacin DPI6. specialized in inhalation drug therapy, will usually seek outside help from device manufacturers to find the Inhalation Technology – A breath of fresh air in drug delivery!
Develop the devices
Unit device
Early clinical
2. Formulation to
match reference drug
➤ Trying to offer similar single dose device inhalation technology 1. Formulation to fit in
"Our difficulty is to understand what criteria available devices
need to be 100% followed and on which on we have margin". "As we are a generics company we try to be similar to the reference product, if the product is in DPI, we would do DPI system". Use different devices and
Reference drug manufacturer
technologies for benchmark
3. In-house or partner
to develop device
Figure 4: Development processes for inhalation systems
best available system for their drug (Figure 4). customers particularly appreciate the development and manufacturing support provided by Capsugel The considerations that influence the manufacturer's throughout the development and commercialization decision process when developing a DPI include process that ranges from dosing, performance, cost efficiency, device size, number of doses, and functionalities that can offer ".consultation to services for development and added value and product differentiation in terms of manufacturing" R&D, Pharma company
patient acceptability e.g. simple to use, eco-friendly, hygienic and portable (Figure 5). The choice of the capsule and capsule supplier is as important as the selection of the inhalation device in The most popular DPI technologies are either blister or terms of the technological suitability, patient needs, capsule based.7 Both delivery systems offer comparable product performance and possibilities for product performance in high accuracy dosing. However, blisters differentiation (e.g. device design, capsules branding). rely on more cumbersome, high precision devices Customisation of capsule-based inhalation systems for their administration. The blister devices tend not remains the most effective way of adding value and to be so popular with patients and seem to be more making the product stand out from its competitors.
expensive to produce compared to capsule systems.2,7 The advantage of blister based systems may be their suitability for highly moisture-sensitive products.
When the decision has been made to opt for a capsule-based system, a capsule supplier is the ideal development partner. A recent market survey found that Capsugel, the market leader in two piece capsules, was the first supplier mentioned by respondents.7 Researchers noted that existing Inhalation Technology – A breath of fresh air in drug delivery!
CRITERIA
LIMITING FACTORS
• Cost per dose • Enhance administration of drug • Protection of dose • Lowest resistance to airflow• High lung deposition Size of device depending on number of doses
Functionalities ➞ bring added value
and differentiation for patients
• Convenience of usage
• Number of manipulations
• Ease of loading the device
• Number of doses to be delivered
• Compliance of patient
Figure 5: Criteria for the development of an inhaled delivery system
Conclusions
Inhalation technology is used extensively for the local
Nowadays, the ideal development partner for capsule treatment of chronic respiratory diseases such as systems has to offer both standardized inhaled delivery asthma and COPD and also in other indications such solutions for smaller pharmaceutical and generic as influenza or pain management that require a rapid companies or more original, tailor-made solutions for onset of action and can be treated systemically via the larger companies.
Whether it concerns a standard or tailor-made capsule The global market for pulmonary drug delivery is based inhalation system Capsugel assists customers with: growing rapidly and is expected to reach US $37.7 • Formulation and analytical development capabilities billion within the next five years with the US and Europe • Customization of capsules and device selection to accounting for 75% share. There is a move away from achieve performance targets the traditional MDIs towards newer, more sophisticated • Laboratory scale manufacturing DPIs reflecting the increased research into powder • Clinical supplies of placebos and comparators formulations and innovations in particle engineering.8 Capsule-based devices in particular, offer many "Capsugel is widely used in the pharmaceutical benefits to patients in terms of precise dosing, ease market: big volume, big experience!" of use and dose visibility. The devices are hygienic to R&D director, Pharmaceutical company
use and simple to clean and are presented in attractive designs.
For manufacturers capsule-based DPI technology provides greater freedom to innovate and differentiate their products whilst benefiting from straightforward development, speed to market and efficiency in later manufacturing. In addition, capsule-based DPIs meet the practical requirements expressed by patients whilst ensuring effective treatment delivery. Inhalation Technology – A breath of fresh air in drug delivery!
1. Dry Powder Inhalation: Devices, Drugs, Therapeutics, 5. Media Releases: Novartis receives EU approval Markets and Forecasts, Greystone Associates, July 2009.
recommendation for TOBI® Podhaler®, a fast and simple therapy that helps reduce treatment burden 2. DPI Solutions – Overall landscape and patients' for cystic fibrosis patients, September 2010 expectations, Market Research Study by Vision Critical for Capsugel, April 2011. 6. Newsroom: FDA Grants Bayer HealthCare 3. Lavorini F, Corrigan CJ, Barnes PJ, Dekhuijzen PR, Levy Pharmaceuticals Orphan Drug Designation for ML, Pedersen S, Roche N, Vincken W, Crompton GK; on Investigational Ciprofloxacin Dry Powder Inhaler for behalf of The Aerosol Drug Management Improvement the Treatment of Cystic Fibrosis, March 2010 Team (ADMIT). Retail sales of inhalation devices in European countries: So much for a global policy. Respir Med. 2011 Jul;105(7):1099-1103. 7. DPI Solutions – Overall landscape and clients' expectations, Market Research Study by Vision Critical 4. Heijerman H et al. Inhaled medication and inhalation for Capsugel, January 2011. devices for lung disease in patients with cystic fibrosis: A European consensus J Cyst Fibros. 2009 Sep;8(5):295- 8. PRWeb. Global pulmonary drug delivery technologies report. March 2010.
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