NASAL DRUG DELIVERY - Overcoming the Challenges of Formulation Development

INTRODUCTION

Nasal administration has emerged as a promising drug de­livery route in many different indications. Nasal drug delivery of­fers the potential for fast action, increased bioavailability, and an improved patient administration experience. The nasal drug de­livery market was worth US$19 billion in 2022 and is expected to grow to US$30 billion by 2030 as demand for intranasal drug products increases.¹ As well as offering an administration route for formulations containing new chemical entities (NCEs), nasal drug delivery can also be utilized in the repositioning of approved therapies through the 505(b)(2) regulatory pathway.

While nasal drug delivery offers many advantages, chal­lenges remain associated with formulation development in in­tranasal products. The pharmaceutical industry must successfully navigate these challenges to unlock the full potential of nasal drug delivery and deliver innovative therapies to the patients who need them.

The following will explore the nasal drug delivery landscape, including the benefits of nasal administration compared with other routes and the unique formulation challenges associated with this delivery method. The consequences of failing to address nasal product formulation challenges and approaches for over­coming challenges will also be discussed, along with product scaling and commercialization.

EXPLORING THE BENEFITS OF NASAL DRUG DELIVERY

With the progression of nasal drug delivery, the administra­tion route has gone from being used predominantly in local treat­ments for rhinitis and decongestion to more complex indications that benefit from the blood-to-brain delivery method that nasal sprays can exploit. More research studies and clinical data have emerged, increasing the understanding of nasal delivery and leading to its exploration in many other applications. Intranasal delivery is now an attractive administration route for many differ­ent indications, including Parkinson’s rigidity, migraine, panic at­tacks, Alzheimer’s disease, multiple sclerosis attacks, and cardiovascular events.²

One aspect of nasal administration that makes it an attrac­tive option for these, and other indications, is the rapid onset of action that can be achieved for both local and systemic delivery. The nasal mucosa is highly vascularized and rich in immune cell populations, which can result in rapid delivery and high systemic availability of administered drug products.³ By bypassing the liver, nasal drug delivery avoids first-pass metabolism, allowing drug products to be absorbed directly into the systemic circulation and increasing bioavailability.³ For inhaled vaccines, increased im­mune cells result in a rapid immune response and onset of action. Additionally, nasal administration offers local delivery by directly targeting drugs to the brain from the nasal cavity.^3,4

Aside from bioavailability benefits, nasal drug delivery also has the potential to improve the patient administration experi­ence. Nasal products are often relatively easy for patients to use compared with injectable drugs, leading to the potential for self-administration. This patient-centric delivery is also non-invasive, a distinct advantage when compared with other methods that need to be administered via injection.

Many pharmaceutical companies are interested in nasal drug delivery for the de­velopment of NCEs. However, nasal ad­ministration is also being explored as a method to create new, more competitive versions of drugs already on the market through reformulation. Repositioning of al­ready approved medications with reformu­lation can be achieved through the 505(b)(2) regulatory pathway. By reposi­tioning existing products, developers can deliver the benefits of non-invasive nasal administration to patients who need these therapies. Examples of therapies that could benefit from reformulation into nasal products include emergency in­jectable drugs and vaccines.

Taking all the advantages of nasal drug delivery into consideration, it is clear why many drug developers in the pharma­ceutical industry are increasingly choosing nasal administration for their products over oral or parenteral routes. However, to deliver on the potential of nasal drug de­livery, drug developers need to overcome the challenges associated with this admin­istration route, including the unique as­pects of formulation development and manufacturing.

THE UNIQUE FORMULATION CHALLENGES OF NASAL DRUG DELIVERY PRODUCTS

Nasal drug products are drug/device combinations, requiring a device to spray the formulation into the nasal cavity and onto the site of action. Nasal products therefore face challenges relating to the interaction between the drug formulation and the spray device as well as the devel­opment of the active pharmaceutical in­gredient (API) formulations themselves. Both the drug and the device need to work together in combination to ensure a safe and effective product.

The nature of drug/device combina­tions means that nasal products require an interconnected approach to development. Pre-formulation and formulation develop­ment, nasal spray device selection and spray method development activities should be undertaken in unison. These studies are required to gain an under­standing of the physicochemical properties of the API and the parameters that could affect how readily the formulation atom­izes when it is released from the device (such as viscosity, surface tension, and density). Both the design of the spray de­vice and the interaction between the device and the formulation can affect how the final drug product performs. Performing activities, such as formulation develop­ment and nasal spray device selection at the same time, also helps to ensure that the final product is functional and safe.

Specific factors that need to be con­sidered throughout nasal drug/device pre-formulation, formulation, spray device selection and spray method development include:

• The choice of aqueous suspension, hy­droalcoholic, or co-solvent formula­tions, or non-aqueous systems if the drug substance is relatively insoluble in water.
• If the final drug product needs to be preservative-free and how aseptic man­ufacturing will be achieved.
• If any excipients or preservatives need to be added to produce stable and ef­fective formulations.
• The number of doses that will be deliv­ered per device.
• Any spray characteristics that could affect device selection, such as priming, pump delivery, droplet size distribution and spray pattern, as these could affect the performance of the final product.

CONSIDERATIONS FOR API FORMULATIONS & EXCIPIENTS

Other challenges in formulation de­velopment relate to the API being explored and its chemical properties. Although nasal administration as a delivery method avoids first-pass metabolism, poor solubil­ity of a growing number of APIs can still negatively impact bioavailability and must be overcome. It is predicted that as many as 90% of APIs in the development pipeline face difficulties with solubility and bioavailability.⁵

The addition of excipients should be considered to help during formulation de­velopment. Excipients can improve bioavailability and achieve the desired sta­bility and shelf-life of the final product. However, choosing which excipients to add to a formulation can be challenging.

Some excipients can act as penetra­tion enhancers or mucoadhesives in the formulation of liquid nasal sprays by in­creasing contact/residence times in the nasal cavity or increasing absorption by enhancing permeability.

As APIs become more complex, se­lecting appropriate excipients becomes more challenging. Novel excipients are in­creasingly being used to address these problems, which bring their own chal­lenges. Developers need to ensure that ex­cipients are safe, of high quality, and comply with regulations, which requires more work with novel excipients that have not been used previously.

Finally, nasal drug delivery is also being explored for the treatment of mental health disorders, such as depression, anx­iety, and schizophrenia. For these applica­tions, nasal delivery provides the benefit of local administration and directly targeting the brain through the nasal cavity. Many of these applications include the use of controlled substances, which require fur­ther compliance with the Drug Enforce­ment Agency (DEA).

Overcoming the challenges associ­ated with formulation development and device selection is critical for the safety and performance of the final nasal product. In turn, ensuring the safety and efficacy of the final product helps to meet the demand for nasal administration, which means that these innovative therapies can be deliv­ered to the patients who need them.

The formulation development chal­lenges in nasal drug delivery are not straightforward, and delivering on the po­tential of nasal administration is a compli­cated undertaking. A proactive approach is required to solve issues, prevent possible delays, and deliver nasal drug products to patients. Pharmaceutical companies are therefore increasingly partnering with con­tract development and manufacturing or­ganizations (CDMOs) that have expertise and experience in nasal drug delivery. By leveraging CDMO partnerships, nasal drug developers can successfully navigate the challenges of formulation development and build a solid foundation for scaling their products to commercial levels.

OVERCOMING FORMULATION CHALLENGES IN NASAL DRUG DELIVERY

Partnerships with CDMOs can help to overcome the unique formulation chal­lenges associated with nasal product drug/device combinations. The main chal­lenge involves performing all of the pre-formulation, formulation, nasal spray selectio,n and spray method development studies all at the same time. This requires teams to work closely together, with good communication and collaboration to achieve this and successfully develop a new nasal spray product. Partnering with a CDMO can bring together all the re­quired processes under one roof to streamline this aspect of formulation de­velopment and avoid any potential delays.

Comprehensive services that can be performed in parallel, all at the same time, with the help of CDMOs include:

• Pre-formulation and formulation stud­ies
• Analytical development and validation
• Spray device selection studies
• Spray characterization method develop­ment and validation
• Process development and validation
• Quality-by-design services
• On-site stability programs
• Validation and regulatory support

Nasal drug developers can also rely on support from CDMOs to overcome the challenges associated with API chemical properties and excipient selection. The les­sons learned from years of experience in nasal drug development and working with similar products can be leveraged to quickly troubleshoot issues and help to de­velop a safe, stable, and efficacious drug product. Products that contain controlled substances can also benefit from CDMOs that offer DEA-specific services and have experience working toward compliance.

In addition to helping overcome the challenges associated with nasal product formulation development, pharmaceutical companies can benefit from CDMO part­nerships in other ways. Nasal specialist CDMOs can provide access to cutting-edge technologies and carefully designed facilities that can help support successful nasal drug development. These include multiple manufacturing lines supporting unit-dose, bi-dose, and multi-dose nasal spray formulation, filling, and assembly. Facilities are also continuously updated so that CDMOs can continue to support the unique needs of nasal product develop­ment in the future.

Working with a CDMO from the early stages of nasal product formulation devel­opment also helps define a clear pathway of progression for the developer. With years of experience in the nasal drug de­livery space, CDMOs can provide valuable insights to help ensure success. These in­clude advising on areas where timelines could be expedited, identifying potential risks that could cause delays, and navigat­ing regulatory requirements.

ENSURING SEAMLESS SCALABILITY & COMMERCIAL SUCCESS

In nasal drug delivery, successful for­mulation development sets the foundation for product scalability and commercializa­tion in

the future. Pharmaceutical compa­nies must carefully consider how the challenges with formulation development can impact the later stages of the project and product scalability. Ultimately, this en­ables the successful development of inno­vative nasal drug products and delivery to the patients who need them.

Taking a proactive approach to nasal drug delivery from early in formulation de­velopment sets a solid foundation when it comes to product scaling and commercial­ization. By bringing services together all under one roof, communication and col­laboration between different teams are im­proved, helping to overcome the challenges of formulation development and enabling product scaling and com­mercialization in the future.

REFERENCES

1. Clearview Healthcare Partners.
2. Touitou E, Illum L. Nasal drug delivery. Drug Deliv Transl Res. 2013 Feb;3(1):1-3. doi: 10.1007/s13346-012-0111-1. PMID: 25787862.
3. Lim ST, Forbes B, Brown MB, Martin GP. Physiological factors affecting nasal drug delivery. In: Touitou E, Barry BW, editors. En­hancement in drug delivery. Boca Raton: CRC Press; 2007.
4. Pillon DJ, Arnold JJ, Meezan E. Nasal deliv­ery of peptides. In: Touitou E, Barry BW, edi­tors. Enhancement in drug delivery. Boca Raton: CRC Press; 2007.
5. https://www.pharmaceutical-technology.com/comment/cphi-experts-90-current-pipeline-apis-poorly-soluble/?cf-view.

Eric Kaneps, VP of Sales & Marketing, has over 25 years of experience in Sales, Business Development, and Account Management in the pharmaceutical industry. He worked at DPT Laboratories as the Director of Business Development from 2001- 2016. In this role, he transitioned the OTC/Consumer Health based business toward Pharmaceutical-based Nasal and Injectable Products, which became the foundation for the new re-named entity-Renaissance Lakewood, LLC. In between his roles at the Lakewood site, He was Sr. VP of Business Development for Pharma-Tech Industries, a contract manufacturing organization that specializes in prescription and OTC ingestible and topical products. He earned his BS BA in International Business & Economics from The Ohio State University.