INTRANASAL DELIVERY OF BIOLOGIC THERAPEUTICS AND VACCINES

Citation: Ward D, “Intranasal Delivery of Biologic Therapeutics and Vaccines”. ONdrugDelivery, Issue 114 (Nov 2020), pp 24–27.

David Ward looks at how the nasal route of drug administration offers the potential to improve the delivery of biologics, even for very complex molecules such as antibodies – and why strategic formulation is required to make this a reality.

Figure 1: A solid representation of the nasal cavity generated from MRI scans.

Typically, biologic therapeutics and many vaccines are large, complex molecules with a high molecular weight (MW). However, because intranasal delivery can target both topical and systemic delivery via the different tissue types in the nasal cavity (Figure 1), nasal administration has the potential to address a wide range of diseases. There is currently an increased focus on addressing both prophylactic and therapeutic potential against SARS-CoV-2 infection – but other successes to date include a nasal spray delivering the 3.5 kDa polypeptide hormone calcitonin, which has been used for many years to treat postmenopausal osteoporosis. Table 1 lists a selection of other marketed intranasal biologics, as well as some which are currently in development. Intranasal vaccines also promise multiple benefits, with the successful launch of influenza vaccines – for example, FluMist (MedImmune) – onto the market as far back as 2003.

Compound/ProductMoleculeTherapeutic TargetStatus
CalcitoninPeptideOsteoporosisMarketed
DesmopressinPeptideDiabetes insipidus, Haemophilia AMarketed
OxytocinPeptideStart or strengthen uterine
contractions during labour
Marketed
NafarelinPeptideAs part of a fertility
programme, endometriosis
Marketed
CyanocobalaminPeptideDeficiency of vitamin B12Marketed
Live attenuated
influenza vaccine
Virus-based vaccineInfluenzaMarketed

Table 1: Examples of marketed nasal biologics.

Biologic drugs are complex molecules; structure is just as fundamental to their function as chemical stability. They are susceptible to a wide range of degradation routes, which can impact the safety and efficacy of the drug.

ADVANTAGES

Potential Nose to Brain Route

The blood-brain barrier (BBB) presents a major obstacle to the delivery of therapeutics into the central nervous system (CNS), as the majority of large MW substances are severely restricted from crossing the BBB under normal conditions.1 Successful intranasal delivery of biologics such as peptides, proteins, monoclonal antibodies, oligonucleotides and gene and cell therapies via the nose-to-brain route presents a potential strategy for bypassing the BBB, enabling new treatments for Alzheimer’s, Parkinson’s and antipsychotic-induced symptoms, amongst others.

Efficacy and Fast Onset of Action

Most biologics are susceptible to enzymatic degradation in the gastrointestinal tract, so the typical route of administration is a subcutaneous injection. When drugs are administrated by the intranasal route, they enter through the respiratory region around the inferior turbinate where the respiratory nasal mucosa is highly vascularised and lined with columnar epithelium cell types, which present a large surface area (>150 cm2) for drug absorption2 and are highly permeable.3 Because the intranasal route avoids enzymatic degradation in the gastrointestinal tract and first-pass hepatic elimination, it therefore reduces the impact of common barriers which limit drug absorption and contributes to a fast onset of action.

Patient Adherence

Good patient adherence is important for treatment efficacy and this is particularly true for intranasal drug products, which must be administered regularly and consistently to ensure continued therapeutic benefit. Patient satisfaction and comfort with administering the drug according to the correct medication regime is therefore important. The intranasal route is both non-invasive and well tolerated, expanding the possibility for patient self-administration,1 although differences in delivery devices and their handling characteristics can be a factor.4

DISADVANTAGES

Mucociliary Clearance

The nasal anatomy, by design, is quick to clear material from entry to the airways via mucociliary clearance – a natural process where the nasal mucosa drag mucus and deposited material from the front of the nose to the throat, where it is swallowed. This means there is typically a short window for absorption of nasally delivered drugs to occur. The natural nasal cycle can also affect absorption rates. This is an approximate two-and-a-half-hour cycle where one side of the nose is more congested than the other, with the process alternating between sides.5 If your product dose consists of only one shot into the nose, then absorption could vary depending on which nostril is used.

Poor Absorption

Nasal delivery of biologics is limited by the low membrane permeability of large MW protein or peptide drugs. Currently marketed peptides, as shown in Table 2, have a MW in the region of 1000–3500 Da, with calcitonin having the highest MW of 3432 Da.2 This low permeability for some drugs means that formulation with absorption enhancers is necessary and, potentially, larger doses of the active are required to reach the appropriate therapeutic dose.

Marketed
Drug
Molecular
Weight
Desmopressin1183 Da
Nafarelin acetate1321 Da
Oxytocin1007 Da
Calcitonin3432 Da
Cyanocobalamine1355 Da

Table 2: Molecular weight of marketed intranasal peptides.

STRATEGIC FORMULATION REQUIREMENTS

Strategic formulation for intranasal biologic delivery is important. Formulation can be used to increase residency time in the nasal cavity using bioadhesives or viscosity adjusters to slow down the rapid mucociliary clearance and increase the amount of drug retained in the nasal cavity to allow sufficient absorption to occur. Absorption is a major factor to understand during formulation development and several strategies can be used to optimise this, including permeation-enhancing agents, mucolytic agents, mucoadhesive agents, in situ gelling agents and drug carrier technologies (Table 3).

AgentActionExamples
Permeation-enhancing agentsHelp to increase the transport
of proteins and peptides across
the nasal membrane by
several modes of action
n-dodecyl beta-D-maltoside (Neurelis’s Intravail), surfactants e.g. polysorbates and lecithin
Mucolytic agentsEnhance nasal absorptionN-acetyl-L-cysteine (NAC)
Mucoadhesive / bioadhesive agentsEnable prolonged retention at the site of application, providing a controlled rate of drug release for improved therapeutic outcomeHPMC, carbopol 934 and sodium alginate
In situ gelling agentsNon-Newtonian fluids –
free flowing when being mixed
or sprayed but then forming a
thick gel following actuation
Avicel RC591 (DuPont)
Drug-carrier technologiesAgents that enhance absorption through encapsulation or
surface modification
liposomes, emulsions, nanoemulsions,
nano/micro particles

Table 3: Potential formulation agents.

Mucoadhesive nasal gels are the most prominent non-invasive dosage forms through which a drug can reach systemic circulation directly, avoiding the first-pass effect and enhancing the underlying bioavailability of the drug.6

Making use of drug-carrying technologies, or technologies which modify the inhaled particle surface with agents that enhance their absorption, is a strong formulation strategy, provided that structural integrity can be maintained. For example, spray-dried, polymer-coated liposomes composed of soy phosphatidylcholine and phospholipid dimyristoyl phosphatidylglycerol coated with alginate, chitosan or trimethyl chitosan demonstrate increased penetration of the liposomes through the nasal mucosa compared with uncoated liposomes when delivered as a dry powder.7 Introduction of agents at the structural level – for example, enzyme-inhibiting agents – should be evaluated for additive activity or enhanced activity over and above the activity of the biologic on its own.

TESTING

Figure 2: Mass spectrometry is a key analytical tool for the characterisation of biologics.

In regulatory terms, inhaled and nasal biologics will require characterisation as per ICH Q6B, as well as the specific respiratory testing outlined in documents such as the EMA “Guideline on the pharmaceutical quality of inhalation and nasal products” (June 2006) or the US FDA “Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products – Chemistry, Manufacturing, and Controls Documentation” (July 2002). Testing programmes should aim to both fully characterise the biological entity and establish whether the device delivery mechanism (e.g. actuation) has adversely affected parameters, including structure, purity (aggregation, fragmentation, etc.) and the activity (potency), in line with the ICH Q6B guidance. Nasal products also require specific testing to assess delivered dose uniformity from the device and the droplet/particle size of the drug emitted.

Protein structures have limited stability and can easily unfold under only mild stress. Aggregation, where the protein self-associates, is one of the most common issues, whereas fragmentation, deamidation, hydrolysis, oxidation, isomerisation, succinimidation, deglycosylation, disulphide bond formation/breakage and other crosslinking reactions can all play their role in the stability of the biologic active. Table 4 illustrates the scope of tests required to determine critical quality attributes for protein or peptide therapeutics, which includes mass spectrometry (Figure 2).

AttributeCharacteristicsAnalytical Method
Comparative physiochemical & structural characterisationPrimary sequence confirmationPeptide mapping approach
(LC-MS/MS) ) covering full sequence confirmation, PTMs information
(if applicable) and confirmation
of di-sulphide (if peptide contacts cysteine), N/C terminus profiling
N-terminal sequenceEdman degradation
Free thiol determinationEllman’s reagen
Amino acid compositionAmino acid analyser/HPPLC
Intact mass analysisMALDI TOF/LCMS/ESI MS
High order structureCD (near, far and thermal denaturation), FTIR, DSC, NMR -1D (1H & C13), 2D (TOCSY & NOESY), fluorescence spectroscopy, HDX
Optical purityGCMS
Chiral confirmation
(typically for peptides)
GCMS/LCMS
Impurity profilingOligomer/aggregationUV-SEC-MALS, SV-AUC,
DLS, SDS-PAGE, CE SDS
Charge variant profilingiCIEF/IEX
Peptide-related
impurity profiling
UPLC/HPLC- HR-MS/MS, RP-HPLC
Biological activityCell-based assay/immunoassayIn vitro cell-based method,
based on the intended mode
of action of the protein/peptide

Table 4: Analytical methods to be considered in relation to development of a nasal protein or peptide product.

CONCLUSION

Intranasal is a promising route for biologic administration, which is reflected in the growing number of marketed products treating chronic diseases, as well as a large number of clinical trials currently in progress, particularly those focused on development of a treatment for the respiratory illnesses caused by SARS-Cov-2 infection or of vaccines. The nasal route of drug administration offers the potential to improve the delivery of biologics, even for very complex molecules such as antibodies. However, strategic formulation is required to make this a reality.

A FOCUS ON PEPTIDES

As peptides offer greater efficacy, safety and tolerability in humans compared with small molecules, and are also, due to their smaller size, better able to penetrate cell membranes compared with proteins, peptides have emerged as potential drug candidates for both therapeutics and vaccines against covid-19.

Overall, the development pipeline is robust, with more than 100 peptides in late-stage clinical development and more than 200 in the preclinical stage, with intranasal delivery being explored for many candidates. Within this pipeline, over 20 peptides are being assessed to address the recent global outbreak of covid-19/SARS-CoV-2 infection, including 15 synthetic peptides.8 Studies on the intranasal application of peptides have explored these candidates, either pre- or post-challenge with coronavirus, with outcomes that suggest these may have both prophylactic and therapeutic potential against SARS-CoV-2 infection.9

INTERTEK SOLUTIONS

The recent expansion at Intertek’s Centre of Excellence for Inhaled and Nasal Drug Development in Melbourn (UK) has focused on new, powerful analytical strategies, integrated with formulation, stability and clinical trial material manufacturing to drive understanding of clients’ products and processes, enabling clients’ key decision-making activities throughout the product development life cycle.

The Intertek team supports the design and optimisation of formulations for biologics or small molecules, powders, capsules, liquids, solids and semi-solids for inhaled, nasal, nebulised, pressurised and topical drug formulations. It delivers focused development strategies from an early stage which can be tailored to new chemical entities (NCEs) or generic products, from feasibility studies through to development support, Phase I and Phase II clinical trials, scale-up and transfer to commercial manufacturing.

Intertek’s expertise helps accelerate project timelines and includes pre-formulation, excipient-API compatibility assessment and optimisation, physicochemical testing, formulation screening, lab-scale formulation and accelerated stability studies to achieve the desired product characteristics.

It offers a broad range of analytical capabilities, including protein structure, physico-chemical properties characterisation and potency alongside solubility assessment, dissolution, solid state characterisation, particle morphology (Malvern Morphologi 4 ID), forced degradation and stability screening, in order to select the optimal development candidates.

With a holistic approach to service provision, including raw material quality control, scale-up, pilot-scale batch manufacturing and testing, GMP clinical batch manufacturing, stability storage and impurities testing, as well as release testing with qualified person (QP) release, Intertek offers a one-source solution for material supplies for use in Phase I and II clinical trials. The company understands the need to invest time to establish rugged methodology with a focus on identifying and controlling critical quality attributes as an integral part of product development. Its experienced scientists deliver analytical programmes to support all stages of development for both innovative and generic products, as well as maintaining involvement in the development of new and improved techniques and technologies.

REFERENCES

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  4. Fromer LM, Ortiz GR, Dowdee AM, “Assessment of Patient Attitudes About Mometasone Furoate Nasal Spray: The Ease-of-Use Patient Survey”. World Allergy Organ J, 2008, article number 156.
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