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32 Pharmaceutical Technology ® Trends in Formulation eBook September 2024 PharmTech.com Inhal atIon tegrated way at the formulation and device develop- ment levels," says Eunice Costa, R&D director–Inha- lation and Advanced Drug Delivery, Hovione. Attributes such as formulation particle size and densit y and inhaler dispersion performance need to be controlled to ensure successful deposit of the product into the lungs, according to Costa. "Once deposited, bioava i labi l it y of t he dr ug becomes a f u nc t ion of add it ion a l fac tors such a s i nt r i n sic chemical proper ties as well as solid state and for- mulation composition, being that dissolution and/or permeation needs to occur at a faster rate than the clearance mechanisms in place in the local diseased microenvironment," Costa says. Excipients for inhalation The safety of excipients used in inhalation formula- tion is imperative, Gupta pointed out. "[W]hen any- thing is administered into the lungs, they tend to accumulate. They may or may not get metabolized, depending on what kind of environment, [the] kind of enzymes [needed] for metabolism, and the safety chal- lenges [these excipients] pose. [Most] of the excipients that are used for inhaled dosage forms are more or less the same that have been approved for other routes of administrations as well. However, the quality of those excipients could be different," Gupta stressed. "[T he] foc us tends to be on excipient s t hat a re soluble and/or native to the lung that can easily be eliminated, especially when developing products for chronic indications," says Costa. "The type of excip- ients depends on the specific dosage form, whether nebulizers, pressurized metered dose inhalers or dry powder inhalers (DPI)." According to Brennan, lactose is the excipient of choice for DPI. "There are specialized grades of lac- tose for inhalation delivery, which were developed in accordance [with] the deliver y mechanism/de- vice," says Brennan. "While lactose is a well-known diluent in tableting, grades are listed specific to the type of application." "There has been more research on dual excipients in DPI," says Bren nan. "Magnesium stearate, IID listed at levels of 0.08 and 0.13 mg, and lactose have been used together, and is documented as assisting in delivery and deposition of the active pharmaceu- tical ingredient. Leucine has also gained traction in developments as a dispersibility enhancer." "[C]urrent pipelines include higher target doses than those in known commercial DPI medicines and where biologics that are not amenable to conventional lac- tose carrier-based, require alternative excipients to stabilize and maximize delivery efficiency, such as glass formers (e.g., sugars with high glass transition temperatures) and dispersability enhancers (e.g., hy- drophobic aminoacids, lipids)," Costa says. According to Gupta, excipients used in inhaled dosage for m s a re si m i l a r to t hose approved for other dosage forms. "However, the quality of those excipients could be different. For example, lactose is a ver y commonly used excipient for dr y powder inhaled formulations, and is available in multiple grades. One of the grades is specific for inhaled dos- age forms, and the dif ference in those grades pri- marily is in terms of particle size of the powder that you end up seeing," said Gupta. "And that size will impact its deposition, its processability when you're developing the dosage form, and also its accumula- tion across the respiratory tract." "[T]here are some excipients that are new; there are some excipients that are the same, but maybe d i f ferent qu a l it y; a nd t he e xc ipient it sel f [h a s] slightly dif ferent f unctions as well when they go into inhaled dosage form development," Gupta con- tinued. "For example, there are a few things we are looking at when you talk about, let's say, dry powder inhaled combinations. We are looking at an excip- ient that is able to not on ly encapsulate the dr ug, but is also able to improve the f low proper ties, so the powder does not get stuck or get expirated after bei ng del ivered by t he d r y powder i n ha ler. [For] nebulized dosage forms, we are not only looking for something that is homogeneous in system, [but] we are also looking for a dosage form that is stable, that does not get bacterial growth, or any of the contam- ination at the same time, which is amenable to the lungs environment." One of the challenges of choosing excipients for inhalation drugs, specified Gupta, are the limited number of excipients t hat have been approved, wh ich he rema rked cou nt s for about on ly 10% versus those excipients approved for other routes of ad m i n i st rat ion. "[T h i s n a r row ava i labi l it y] makes [development] extremely challenging and ver y limited in terms of options [of ] what we can and cannot do," he said. "And you know, given di- verse physical chemical properties of the drug mol- ecules, … none of the excipients that [are] currently approved … by FDA could be usef ul for [inhaled dr ugs]." T herefore, Gupta expla ined, scient ists often have to use excipients that are not approved for inhalation and then argue the case for that ex- cipient's use to FDA. "The lack of physiologically relevant in-vitro tools to suppor t formulation development in weighing relative benefits of different excipients in terms of safet y and f ina l dr ug disposition is a major cha l- lenge," Costa agrees. "Another major challenge is to find the right balance in terms of product com- position to address all the needs, such as maximize dose, bioavailability, dispersion, and stability, some of them conf licting in terms of excipient classes."