FORMULATION FORUM - Nanoparticle Technology for Nose-to-Brain Drug Delivery

INTRODUCTION

Central nervous system (CNS) disorders affect millions globally. Many of those life ailments are not treatable due to restricted passage through the blood brain barrier (BBB), making the drug impassable through the tight junctions. As a result, it creates challenges for treatment of diseases like Alzheimer’s disease, Parkinson’s epilepsy, schizophrenia, and brain tumors like glioblastoma.¹ Oral administration of drugs could have low bioavailability in the brain due to poor GI absorption and/or first-pass hepatic metabolism, requiring frequent dosing to maintain the concentration of drugs in plasma passing through the BBB. All these factors thus diminish the efficacy of drugs via the oral (po) route. Therefore, a more efficient method is highly desirable to deliver drugs to the brain through the BBB without compromising its efficacy. Though the BBB plays an important role in protecting the CNS from toxins, pathogens, inflammation, and other diseases, the BBB with extensive tight junctions also severely restricts cell permeability.²

Nasal delivery is one of the most ideal routes of administration for delivery of drugs through the BBB, which first bypass the hepatic clearance, and second yield better efficacy by directly penetrating the membranes in the nasal cavity to brain.³ The nasal cavity with its relatively low volume of 25 cm³ allows only limited liquid volume (ca. 100-200 ml). The nasal cavity is composed of a vestibular area, respiratory area, and olfactory area. The drugs are mainly absorbed through epithelial cells as they contain a large number of pharyngeal cells, cilia cells, intermediate cells, and basal cells.⁴ Thus, absorption through epithelia cells allows drug to enter the systemic circulation.⁵ Whereas the olfactory region, composed of sustentacular cells, basal cells, and sensory neurons, helps penetrate drug molecules to the brain through membrane permeation.⁶ Taken collectively, there are two key mechanisms by which the drugs enter the brain; one through systemic circulation and via lungs or GI tract by overcoming the BBB, and the other through the olfactory system, as shown in Figure 1.⁷

LIPID NANOPARTICLES FOR NOSE-TO-BRAIN (N2B) DELIVERY

Intranasal (IN) is a non-invasive route of administration to overcome the BBB. Hydrophilic drugs with higher molecular weight have lesser tendency to penetrate the BBB, but when formulated and protected in polymeric and lipid nanoparticles, their permeation increases significantly due, in part, to enhanced permeability, better stability, and longer resident time. These nanoparticles armed with surface-modified specific ligands and antibodies can further enhance longer resident time by interacting with the specific transporters or receptors.

Lipid-based carriers are considered safe for intranasal delivery of drug because of their low toxicity, improved stability, and higher drug encapsulation efficiency. Designed as liposomes, nanoemulsions, solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NCLs) among others, they have been investigated in IN drug delivery. In fact, these lipid nanocarriers help protect drug molecules from degradation by nasal mucosa in the nasal cavity while targeting the brain. Table 1 cites a few examples of drugs in lipid carriers composed of different assemblies.

As indicated in the Table 1, there are a number of drugs investigated via the IN route of administration to overcome the BBB. Lipid nanoparticles are comprosed of lipids and often stabilized with surfactants or Pegylated lipids for yielding longer circulation and stability. LNPs are prepared by several methods, including reverse phase evaporation, extrusion, microfluidics, sonication, and high pressure homogenization depending upon lipid components and drugs.⁷

PLGA-BASED DRUG DELIVERY

Polymeric nanoparticles are another dosage form that have widely been investigated in nasal delivery of molecules. For example, PLGA, which is a biocompatible polymer composed of lactic acid and glycolic acid, has been investigated extensively via the IN route. PLGA nanoparticles containing olanzapine have shown a 10-fold increase in Cmax versus solution.¹³ Likewise, oxcarbazepine containing PLGA nanoparticles showed significantly higher pharmacokinetic behavior versus solution.³ Table 2 lists a few of the selected studies with polymeric nanocarriers aimed at improving the bioavailability of drugs via intranasal routes to brain.¹⁴

NANOCRYSTALS FOR N2B DRUG DELIVERY

Nanocrystal (NC) drugs are often used to improve the solubility of drugs. Essentially stabilized with polymers, lipids, and surfactants, the NC can be used as liquid suspensions and administered via the IM or subcutaneous and oral routes. When administered intranasally to target the brain, NC can potentially pose challenges like local irritation due to high concentration, lower absorption, and lack of in vivo fate about undissolved molecules. Given the low volume of drug in the nasal cavity, NC can help to increase drug loading, dissolve slowly, and promote drug permeation across the mucosal barrier leading to prolonged residence time with the help of mucus adhesive polymer, and hence, enhanced targeting to brain. Table 3 lists a number of NC-based drugs investigated for targeting the brain via intranasal route.

Table 3 highlights some of the recent advances in nasal drug delivery targeting the brain for a variety of ailments by using NCs. Most of them have been targeted for CNS diseases and marketed also by the parenteral or oral route of administration. N2B delivery; however, offers advantages for accumulating the drug in the brain by direct administration through the nasal cavity and absorption via olfactory lobes. The physiochemical properties, such as molecular weight and lipophilicity, influence the diffusion of drugs from nose to brain. For example, molecules like proteins, peptides, or nucleic acids with a size of 300 D or highly hydrophilic drugs, have a tendency to lower permeability compared to more lipophilic molecules.²⁴ These molecules hence are likely to be transported through receptor mediator receptors like insulin and oxytocin.^{25, 26}

ROLE OF PENETRATION OR PERMEATION ENHANCERS

Biomolecules in combination with permeation enhancers can lead to N2B transport more effectively. For example, nanoparticles linked with permeation enhancers, such as trans-activator of transcription (TAT) protein composed of 13 amino acids, can lead to efficient delivery of insulin over 6-fold through PLGA NPs when administered intranasally.²⁷ Other example includes siRNA delivery via PEG-PCL micelles, which is more effective, attributed primarily due to smaller particle size (20-35 nm) when modified with TAT protein.¹⁹ There are other examples of permeation enhancers, such as surfactants, which enable the transport of drugs from N2B by nanoparticles. Inclusion of the enhancers in NPs should be limited to alleviate any long-term adverse effects or prevent any immunological issues.²⁸ Bioavailability of simvastatin in polymeric micelles via the intranasal route was dependent upon the particle size. In fact, the particles ranging between 100-700 nm showed significantly higher transportation through the nasal cavity to the brain. Other factors, such as surface properties and composition of NPs, are equally important in influencing the penetration of drug to the brain. For instance, polysorbate 80 (PS80) used in polycaprolactone (PCL) nanoparticles influenced the permeability of drugs through mucus via diffusion.²⁹

CONCLUSION & FUTURE PERSPECTIVE

In the past, nanotechnology has gained considerable attention in drug delivery, especially in N2B delivery. The challenges, however, remain in finding the right lipid components to penetrate the BBB and also in designing and scaling up of LNPs. Multiple nanocarriers now well-designed and characterized, such as liposomes, NEs, SLNs, NLCs, and others like polymeric nanocarriers, micelles, nanogels, have yielded a much better understanding of drug delivery and targeting to the brain. A majority of nanocarriers range in particle size 50-200 nm; however, the smaller ones have a greater chance to succeed in transporting the drug to the brain via the IN route. The nanoparticles bearing negative or neutral surface charge might have a greater impact on N2B transport. Use of permeation enhancers and pegylated compounds will also aid in transport of drugs via N2B.

Many other obstacles remain with high molecular weight peptides and proteins, lower membrane permeability, mucociliary clearance, and enzymatic degradation in the nasal cavity. Using innovative formulation strategies, novel excipients, and devices could help improve the bioavailability of drugs via the IN route. With the emergence of microfluidics, membrane emulsion technology among others, scale up is possible, which could help expedite the manufacturing of nasal NP product formulations to the clinic faster. As we continue our investigation of innovative delivery routes for drug molecules besides the parenteral and oral routes, the IN route remains the future method for drug delivery to the brain. Several biomolecules, including proteins, peptides, and biologics, are currently in clinical studies awaiting successful outcomes. Only a limited number of trials are listed on the clinicaltrials.gov site for nasal delivery of drug through the BBB.³⁰

Ascendia’s LipidSol™, a lipid-based enabling platform technology offers an opportunity for exploring small and larger molecules in nanoparticles.³¹ Designed with FDA approved lipids, polymers, and surfactants, LipidSol (Figure 2) can help create a variety of nanoparticles to improve the permeability and enhance bioavailability of molecules for absorption through olfactory systems. Other enabling technologies, such as EmulSol® and NanoSol®, could also be applicable for small and large molecules destined to be delivered intranasally.

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Shauket Ali, PhD
Sr. Director, Scientific Affairs & Technical Marketing
Ascendia Pharmaceuticals
shaukat.ali@ascendiapharma.com
www.ascendiapharma.com

Dr. Shaukat Ali joins Ascendia Pharmaceuticals Inc. as Senior Director of Scientific Affairs and Technical Marketing after having worked in the pharma industry for many years. His areas of expertise include lipid chemistry, liposomes, lipid nanoparticles, surfactant-based drug delivery systems, SEDDS/SMEDDS, oral and parenteral, topical and transdermal drug delivery, immediate- and controlled-release formulations. He earned his PhD in Organic Chemistry from the City University of New York and carried out his post-doctoral research in Physical Biochemistry at the University of Minnesota and Cornell University. He has published extensively in scientific journals and is inventor/co-inventor of several US and European patents.

Jim Huang, PhD
Founder & CEO
Ascendia Pharmaceuticals
j.huang@ascendiapharma.com
www.ascendiapharma.com

Dr. Jim Huang is the Founder and CEO of Ascendia Pharmaceuticals, Inc. he earned his PhD in Pharmaceutics from the University of the Sciences in Philadelphia (formerly Philadelphia College of Pharmacy and Sciences) under Joseph B. Schwartz. He has more than 20 years of pharmaceutical experience in preclinical and clinical formulation development, manufacturing, and commercialization of oral and parenteral dosage forms. His research interests are centered on solubility/bioavailability improvement and controlled delivery of poorly water-soluble drugs through nano-based technologies.