Neuroscientists has created a nasal spray to deliver antipsychotic medication directly to the brain

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A team of neuroscientists and engineers at McMaster University has created a nasal spray to deliver antipsychotic medication directly to the brain instead of having it pass through the body.

The leap in efficiency means patients with schizophrenia, bipolar disorder and other conditions could see their doses of powerful antipsychotic medications cut by as much as three quarters, which is expected to spare them from sometimes-debilitating side effects while also significantly reducing the frequency of required treatment.

The new method delivers medication in a spray that reaches the brain directly through the nose, offering patients greater ease of use and the promise of improved quality of life, including more reliable, effective treatment.

Ram Mishra, a Professor in the Department of Psychiatry, Neurosciences and Behaviour and Co-Director of McMaster’s School of Biomedical Engineering, and Todd Hoare, a Canada Research Chair and Professor of Chemical Engineering, describe their research in a newly published article in the Journal of Controlled Release.

They and their co-authors Michael Majcher, Ali Babar, Andrew Lofts, and Fahed Abuhijleh have proven the concept of their new delivery mechanism in rats, using PAOPA, a drug commonly prescribed to treat schizophrenia.

A problem for patients using antipsychotic medications, Mishra explains, is that taking them orally or by injection means the drugs must pass through the body before they reach the brain through the blood.

To be sure enough oral or injected medication reaches the brain, a patient must take much more than the brain will ultimately receive, leading to sometimes serious adverse side effects, including weight gain, diabetes, drug-induced movement disorders and organ damage over the long term.

When delivered through the nose, the spray medication can enter the brain directly via the olfactory nerve.

“The trick here is to administer the drug through the back door to the brain, since the front door is sealed so tightly,” Mishra says. “This way we can bypass the blood-brain barrier. By delivering the drug directly to the target, we can avoid side effects below the brain.”

Mishra and collaborator Rodney Johnson of the University of Minnesota had previously created a water-soluble form of the medication, which was used in the current research.

The new form they created was easier to manipulate, but they still lacked an effective vehicle for getting it to the brain. A particular issue was that drugs delivered via the nose are typically cleared from the body quickly, requiring frequent re-administration.

Hoare, in the meantime, had been working with an industrial partner to develop the use microscopic nanoparticles of corn starch for agricultural applications.

The two scientists, who work across campus from one another, came together after researchers in their labs met at an internal McMaster conference. Two of the researchers, Babar and Lofts, worked on the project in both labs.

The engineering team was able to bind the drug to the corn starch nanoparticles that, when sprayed together with a natural polymer derived from crabs, could penetrate deep into the nasal cavity and form a thin gel in the mucus lining, slowly releasing a controlled dose of the drug, which remains effective for treating schizophrenia symptoms over three days.

“The cornstarch nanoparticles we were using for an industrial application were the perfect vehicle,” Hoare says.

“They are naturally derived, they break down over time into simple sugars, and we need to do very little chemistry on them to make this technology work, so they are great candidates for biological uses like this.”

The gradual release means patients would only need to take their medication every few days instead of every day or, in some cases, every few hours.


Existing therapies have a noteworthy role in the panacea of CNS ailments, resulting in declined fatality rates. However, there are still unresolved issues, and an absolute cure is still elusive for most CNS ailments [1].

The main hindrance is the ability of drugs to cross the blood–brain barrier (BBB) in quantities sufficient to achieve therapeutic levels. It is estimated that the barrier obstructs the permeation of approximately 98% of low molecular weight drugs and of about 100% of macromolecules, leading to a significantly low CNS bioavailability [2].

Consequently, several strategies are being used for the local delivery of active therapeutics to the brain, such as intraparenchymal or intracerebroventricular injections, catheter infusions, mini-pump-assisted intracranial delivery, precise ultrasound methods, or electromagnetic force-field techniques.

Nevertheless, these methodologies are invasive, risky, and induce neurotoxic effects at the delivery site, and many of them are not appropriate for chronic treatments.
Thus, the presence of the BBB constitutes the primary limiting factor for drug delivery to the brain through systemic circulation [1].

Several methods are under process to bypass the BBB, and among these, one significant approach is nose-to-brain delivery. The intranasal route is a promising substitute to the above-listed invasive methods for brain drug delivery, as the nasal cavity provides a highly vascularized large absorption surface area for drug administration. This route permits circumvention of the BBB, thereby providing rapid and direct delivery to the brain [3].

Bypassing the BBB, the administered drug reaches the brain, thereby prolonging its residence time within the active site. This route also restricts the unnecessary systemic exposure of drugs and reduces systemic toxicity [4]. The olfactory region of the nasal cavity extends to the cranial cavity and can provide direct access to the brain.

Different factors and pharmacokinetic parameters affect the rate of drug transport that are required to be evaluated at the clinical level [5,6]. Presently, nanotechnology-based delivery systems are being given much emphasis for intranasal drug delivery to the brain. Nano-sized drug delivery systems have been extensively studied during the past few decades as a new strategy for circumventing the poor bioavailability of various pharmaceutical drugs [7].

Successful intranasal drug delivery to the brain through nanoemulsions, nanoparticles, liposomes, microspheres, dendrimers, carbon based nanoformulations, and others have been documented in the literature [8].
For example, the intranasal administration of talinolol in nanoemulsions showed higher brain concentrations in rats than with intravenous infusion after 15 min [9]. Various nanoemulsions have been commercialized for biological and medical applications [10].

During an extensive literature search from 2015 to January 2020, we found that 159 articles were published on intranasal drug delivery (Figure 1). It was observed that 26% of the reported research was on the nose-to-brain delivery via micro-/nanoemulsions.

The present review therefore focuses on the descriptive aspects on nanoemulsion-based nose-to-brain drug delivery. Furthermore, it compiles the research reports on classified CNS disorders and presents the gaps that need to be addressed in the said research arena.

Figure 1. Papers published on nanoemulsion-based nose-to-brain drug delivery systems. The search engine used was Google Scholar. A total of 159 papers were found. Other drug delivery systems included liposomes, transferosomes, ethosomes, metal nanoparticles, etc.

Pathways for Brain Delivery through the Intranasal Route
The understanding of anatomy and physiology of the nasal cavity is very important for the success of nasal drug delivery systems. The nasal cavity can be divided into three areas: vestibule, respiratory region, and olfactory region. The vestibule region has a small surface area, and drug absorption is insignificant through this region.

The respiratory region, on the other hand, is rich in blood capillaries, and thus, it can provide systemic drug absorption and, subsequently, indirect drug delivery to the brain after intranasal administration [11,12]. Trigeminal nerves that are located in the respiratory region can also provide a direct pathway for drugs to the brain [13].

It has been, for example, observed that the respiratory region is most appropriate for the delivery of vaccines through intranasal administration. The olfactory region also plays an important role in the direct drug delivery to the brain and to the cerebrospinal fluid (CSF). Notably, the olfactory region is situated in the upper part of the nasal cavity, which may limit drugs reaching this permeation area [1,14].

The major aim of these drug delivery pathways is to deliver the desired drug concentrations to the site of action. Additionally, the degradation of drugs through metabolism can be diminished, and physical clearance can also be minimized; the overview of drug transport is illustrated in Figure 2 [15].

Highly permeable nasal epithelium allows rapid drug absorption to the brain due to a high total blood flow, porous endothelial membrane, large surface area, and avoidance of first-pass metabolism. The intranasal method can deliver a wide variety of therapeutic agents (small molecules and macromolecules) to the CNS.

Several drugs have been shown to be more effective in the CNS when given nasally and provide their therapeutic effects in smaller doses. Further, nasal drug delivery neither requires any modification of the therapeutic agent nor requires the drug to be coupled to

any carrier. Nasal drug delivery consisting of various pathways has always been a key development area for both pharmaceutical and medical device companies, presenting compelling advantages over other drug delivery methods [16,17]. The pathways for nose-to-brain delivery have been elaborated on below.

Figure 2. Representative figure on the route of drug transport for nose-to-brain delivery.

Olfactory Pathway
The olfactory region that is situated in the roof of the nasal cavity is extensively recognized as a possible nose-to-brain drug delivery route for the treatment of various CNS diseases [15]. Drugs can cross olfactory epithelial cells by moving slowly through the tight interstitial space of cells by passive diffusion or across the cell membrane by endocytosis, or they can be transported by neurons [4,18].

Most drugs deposited on the olfactory region are transported extracellularly between cells. Several experimental in-vitro and in-vivo results indicated the clinical relevance of P-glycoprotein in intranasal drug administration.

Further, in-vitro experiments have been performed for the testing of drug penetration efflux transporter substrates at the nasal barrier in RPMI 2650 cells and in 3D MucilAir™ nasal models [19].

Olfactory neurons have an important role in drug targeting to the brain by intranasal administration [20]. Drugs are transported into the olfactory bulb through the intracellular axonal channel and subsequently distributed into the brain [21]. The diameter of the olfactory axon in humans is about 0.1–0.7 µm, which indicates that molecules or nanoparticles having diameters within

Trigeminal Pathway
The trigeminal pathway for nose-to-brain drug delivery has been less explored. The main function of the trigeminal nerve is to pass chemosensory and thermosensory information to the nasal, oral, and ocular mucosa [22,23]. The trigeminal nerve innervates the dorsal nasal mucosa, which reaches the frontal brain and olfactory bulb [24]. Thus, the trigeminal nerve pathway can be one of the potential sites for drug delivery to the brain from the nasal cavity. For instance, a solution of insulin-like growth factor 1 was delivered to brain through the trigeminal and olfactory pathways [25].

Lymphatic Pathway
Drugs can be transported by several extracellular pathways, such as perivascular, perineural, and lymphatic channels from the submucosal area of the olfactory region. These extracellular pathways are linked to olfactory nerves arising from the lamina propria into the olfactory bulb of the brain [8,26]. Therefore, the lymphatic pathway also has a significant role in nose-to-brain drug delivery.

Systemic Pathway
The systemic pathway is an indirect transport system from the nose to brain, and it can be a promising approach for lipophilic drugs with low molecular weights [27,28]. Drugs are then absorbed by the vascular regions of the epithelium membrane of the nasal mucosa and lymphatic system and are further transported to the systemic circulation, thus avoiding the first-pass metabolism [27,29].

Nanoemulsions
Nanoemulsions (NEs) are lipophilic systems with nanoscale globules that can be absorbed through the nasal mucosa. These can be either oil-in-water (o/w) or water-in-oil (w/o) emulsions. Especially, o/w NEs are a promising option for the encapsulation of lipophilic drugs, protecting them from enzymatic degradation, increasing their solubility in liquid media, modulating their drug release, and improving their bioavailability [30].

NEs may be modified to mucoadhesive systems to increase the residence time of the formulation and to overcome the nasal clearance to achieve enhanced mucosal absorption. NEs have also been proven to mitigate the side effects and toxicity of drugs. Several NE formulations, primarily of the o/w type, have been developed for nose-to-brain delivery [31]. Some significant parameters of NEs for intranasal administration are presented in Figure 3. NEs may be developed through different methods by using oil, surfactants, cosurfactants, and water, all of which play a significant role in the permeation of drugs through the nasal mucosa.
3.1. Overview of Nanoemulsion Components

Oils
The major problem of new molecular entities in the drug discovery and development pipeline is their poor water solubility, which affects several key properties of therapeutic agents, such as the pharmacokinetic and pharmacodynamic parameters. Hence, oils are used for the development of NE to achieve the maximum solubility of drugs. The lipophilicity of oils is directly proportional to the solubility of drugs [32]. The solubilizing capacity of oils decreases in the order of vegetable oils medium-chain triglycerides > medium-chain mono- and diglycerides [33]. Further, the solubility of drugs also depends on the concentration of oils in the NE formulations. The globule size of NE

increases with an increase in the oil concentration [34]. At the same time, a larger globule size reduces drug permeation from the nasal mucosa. Some oils have permeation-enhancing properties as well. NEs showed selectivity in the uptake of some drugs, such as linolenic acid, polyunsaturated and omega-6 fatty acids, and pinolenic acid [35]. Edmond et al. proved that oleic acid with one cis-double bond did not get transported across the BBB, while linoleic acid with two cis-double bonds and 18 monocarboxylic acids efficiently entered the brain after intranasal administration [36].




Figure 3. Significant features of nanoemulsions for nasal administration.

The maximum solubility of a drug can be achieved by striking a correct balance between the concentration of the emulsifying agent (surfactant) and oils. Here, one needs to select the region having maximum emulsification in the phase diagram [34].

Better drug permeation can be achieved through a minimum globule size; hence, formulations having higher globule sizes have less permeation through the nasal mucosa. Several oils have significant permeation-enhancing properties through the nasal mucosa. For example, NE of quetiapine fumarate containing butter oil showed significant nose-to-brain delivery [37]. It was deduced that polar lipids from butter oil enhanced the permeation through the nasal mucosa.

Surfactants
Surfactants are essential components of NE formulation and signify an important role in the surface tension reduction. Surfactants stabilize NE by preventing the phase separation and coalescence of globules. Further, surfactants affect solubilization of the drugs and increase the permeation of drugs through the nasal mucosa due to alterations of the fluidity and damage to the tight junctions of epithelial layers [38].

Several studies report that the globule size of NEs decreases with increasing the concentrations of the surfactants. The lower the globule size, the better the permeation and, hence, the drug concentration in the brain. Nevertheless, the structural integrity of the nasal mucosa is critically affected by surfactants. Hence, the surfactant concentration should be selected carefully, keeping in view the safety considerations of the nasal mucosa [39,40].

Cosurfactants
Surfactants alone are not able to reduce the surface tension to the desired level, because most of the surfactants used in the development of NEs are single-chain surfactants. Therefore, cosurfactants are incorporated to achieve the desired hydrophilic-lipophilic balance (HLB) [41,42].

Cosurfactants increase the fluidity of the formulations by reducing the interfacial tension, which can facilitate emulsification and stabilize the NE. For the development of stable NE, a judicious combination of surfactant and cosurfactant is crucial. The construction of ternary-phase diagrams is a commonly used methodology to optimize the working range and the optimum concentration(s) of oil, surfactant, and cosurfactant.

An increase in the concentration of the cosurfactant deceases the globule size of the NE, and, ultimately, the drug concentration will be enhanced. Some most commonly used cosurfactants in the development of NEs for intranasal administration are transcutol-P, butan-1-ol, chiral alcohols, sorbitol, and polyethylene glycol [33].

Significant Factors of Nanoemulsions for Nose-to-Brain Delivery
Several research reports have shown evidence for better drug permeation to the brain from the nasal mucosa by NEs than after conventional oral drug delivery. Apart from the drug permeation-enhancing properties of the surfactants and cosurfactants, NEs have several significant features tailored for brain targeting [10]. Some major features of the NEs are outlined below.

Globule Size
The globule size of the NE plays a very significant role in drug permeation through the nasal cavity. As stated earlier, olfactory and trigeminal transport routes are the major channels for drug delivery to the brain by nasal drug delivery. The average diameter of an olfactory axon is approximately 200 nm in different preclinical species, but in humans, it ranges between 100 to 700 nm [43].

Hence, the globule size of novel formulations should be below 200 nm for successful drug permeation. Ahmad et al. reported that NEs with an average globule size of 100 nm exhibited a higher rate and extent of drug absorption than the average globule size of 700 nm through the olfactory pathway [43].

In addition, the globule size of the NE also affects the retention time of the formulations on the nasal mucosa. Smaller globule size formulations have longer retention times than the larger globule NEs that can be easily removed by nasal clearance, thus having reduced drug absorption [44].

For example, while NEs with average globule sizes larger than 200 nm may exhibit retention times up to 4 h after intranasal administration, NEs having globule sizes of 80 and 200 nm have shown retention times of 16 and 12 h, respectively. Hence, globule sizes of nanoemulsions play a significant role for drug delivery to the brain through intranasal administration [45].

Zeta Potential
The colloidal stability of NE is connected to the zeta potential of the developed formulations. For any colloidal system, zeta potential values exceeding ±30 mV provide electrostatically stabilized systems [46]. Moreover, several reports have shown that the zeta potential has a significant role in the drug retention time of the NE formulations.

Mucin found in the nasal mucosa bears a negative charge; hence, formulations carrying positive charges depict good attachment to the nasal mucosa [25]. Several studies have shown that, usually, most of the nasal NEs developed for brain delivery bear negative charges. The values of zeta potential higher than −10 mV of the emulsion indicate the instability of NEs. Therefore, zeta potential is also an important consideration in the development of NEs for nose-to-brain delivery [40].

reference link : doi:10.3390/pharmaceutics12121230


Journal information: Journal of Controlled Release

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