**5.4 Intranasal administration (IN)**

Recently, intranasal (IN) route for the drug delivery to the brain proved to be a reliable and non-invasive mode to cross BBB while possessing the ability to deliver a wide range of drug moieties like smaller molecules, larger macromolecules, growth factors, viral vectors and even stem cells to the brain. The transport involves either olfactory or trigeminal nerve which has a direct link from the brain and terminated in the nasal cavity at respiratory epithelium or olfactory neuroepithelium [47]. The nasal mucosa is the target tissue for the drug administration and possessed features like a larger surface area, porous endothelial membrane, huge blood flow, the absence of first-pass elimination and readily accessible. Olfactory region of nasal

mucosa provide nose to brain targeting feature and could able to treat various CNS disorders like depression, pain, Alzheimer's disease, glioblastoma, multiple sclerosis etc. Several dosage forms, sprays, suspensions, nebulizers, aerosols, gel, solutions can be utilized for IN drug delivery [47]. On the other hand, barriers like mucociliary clearance from nasal mucosa, enzymatic degradation and low degree of permeability across nasal epithelium hinder the drug targeting efficiency to the brain. As a solution, nanopharmaceuticals were used which overcome the clearance and other nasal problems due to their unique nature.

One of the studies demonstrated IN administration of chitosan nanoparticle to deliver bromocriptine, a dopaminergic agonist, to minimize motor function disorder associated with prolonged levodopa usage in the Parkinson's disease. Results were promising in terms of motor function [48]. Didanosine-dideoxyinosine (ddI) is an antiretroviral therapy (HAART) and available in oral dosage forms, however, faced extensive degradation and elimination in GIT which decreases its bioavailability. To overcome the issues, dd loaded chitosan nanoparticles were administered through IN route. Results indicated higher brain to plasma, CSF to plasma and olfactory blood to plasma ratios in the case of IN delivered dd nanoparticles. It shows that nanoformulation can be directly delivered to the brain compartment through IN route [49].

Another research group fabricated rivastigmine loaded chitosan nanoparticle for inhibiting acetylcholinesterase in the brain through IN administration. The free drug had severe bioavailability issues and distributed to the non-targeted site with severe side effects when administered through oral or IV route. Here, chitosan nanocarrier and administration through nasal route enhanced brain uptake with higher brain/ blood ratio. It further highlighted the role of nanocarrier and route in brain targeting [50]. Similarly, Venlafaxine (VLF) chitosan nanoparticles were administered to the brain through the nasal route for the treatment of major depressive disorders and anxiety disorder with improved brain uptake and enhanced bioavailability [51].

Another study showed microemulsion and mucoadhesive delivering clonazepam, an anxiolytic, sedative, hypnotic, anticonvulsant drug to the brain. The brain/ blood uptake ratio of the intranasal microemulsion and mucoadhesive microemulsion were significantly higher than the IV administered microemulsion, indicating the effectiveness of IN route for brain-specific drug delivery [52]. Similarly, the microemulsion was used for the IN delivery of nimodipine to the brain cells. The microemulsion leads to 3-fold more drug uptake by the olfactory bulb than the IV route. AUC ratio of brain to plasma and cerebrospinal fluid (CSF) to plasma were higher after IN administration in comparison to IV injection. Thus, it could be a promising approach to treat neurodegenerative disorders [53]. Risperidone nanoemulsion and mucoadhesive nanoemulsion were administered through IN route for the treatment of schizophrenia. The composition of nanoemulsion included glyceryl monocaprylate as an oily phase, tween 80 as a surfactant and mixture of propylene glycol and transcutol as a co-surfactant. While mucoadhesive microemulsion had chitosan polymer which induces mucoadhesive properties. The nanoemulsion and mucoadhesive nanoemulsion improved risperidone bioavailability, prevent first pass metabolism and bypass BBB to achieve desired drug concentration at the targeted site. The brain/blood uptake ratio and drug transport efficiency were found to be significantly higher through nasal administration in comparison to the IV injection [54].

Furthermore, nanostructured lipid carriers comprising duloxetine was prepared and delivered to the brain via IN route for the treatment of the major depressive disorder. The results revealed prolonged drug release and therapeutic effect as demonstrated from improved behavior analysis after 24 hours [55].

Furthermore, micellar nanocarrier (amphiphilic nanocarriers) of sumatriptan was developed to treat an acute migraine to improve cerebral blood flow. Limitations

**129**

*Nanopharmaceuticals: A Boon to the Brain-Targeted Drug Delivery*

of the drug associated with oral dosage forms and subcutaneous administration like poor bioavailability, shorter plasma half-life, and hepatic elimination have been resolved to much extent through incorporation in micellar nanocarrier. And increased brain concentration of the drug and site-retention can be achieved via nose to brain drug delivery [56]. Similarly, zolmitriptan-loaded micellar nanocarriers were prepared to target brain serotonin receptors and inhibit cranial vessel inflammation. Micellar nanocarriers were administered through nasal route with enhanced characteristics like lower particle size, higher permeation across nasal mucosa, appropriate flow rate, ability to load hydrophilic as well as hydrophobic drugs, enhanced site-retention and ultimately enhanced drug therapeutic activity [57]. Another polymer methoxy-PEG-polycaprolactone was used to encapsulate coumarin with promising brain penetration and myelin binding properties, while administered through nasal route [58]. Bioadhesive nanocarriers reported in the above studies overcome many hurdles associated with a nasal route like protection of drug against enzymatic degradation, enhanced permeability, and avoidance of mucociliary clearance. However, IN delivery of nanopharmaceuticals should be further improved with targeting moieties and incorporation of cost-effective approach.

Potential brain barriers can be by-passed by injecting the drug directly into the tissues using catheter. Such a direct delivery of therapeutic agent to the target site is termed as conventional enhanced delivery (CED). Many pre-clinical studies adapted CED to infuse nano-formulations directly into the brain [59]. C57BL/6 J mice were used to infuse a 10 μL solution of lipid nanocapsules (LNCs) having an average size of 70 nm into their skull at an infusion rate of 0.5 μL/min [60]. An alternate method for direct infusion was also reported in which drug-loaded micelles were injected by making small incisions on the skull. A foremost shortcoming CED technique is its invasiveness which requires high anesthetic doses prior to incisions, which resulted in the death of the experimental rats [61]. This technique also requires the optimization of certain factors like pH and osmolarity to surpass any brain damage [62].

Administering the drug into the carotid artery provides an alternative solution to direct delivery. This direct systemic delivery requires a catheter to directly inject drugs into the bloodstream. In a study, the efficacy of direct systemic delivery was reported almost twice to that of CED in terms of brain damage [63]. IV route is also used to deliver the drug directly into systemic circulation. Ferrociphenol-loaded lipid nanoparticles were infused to manage glioma via the IV route. The outcomes showed that mean survival of the rats was 28 days while mean survival rate

Polylactic acid (PLA) and poly-dimethylaminoethyl methacrylate (PDMAEMA) were used to synthesize amphiphilic star-branched co-polymeric nanoparticles for intratumor delivery of the drugs for treating brain tumors. In a study, this system was used to deliver combined DOX and miR-21 inhibitor (miR-21i) into LN229 glioma cells directly. These micelles protected miR-21i from lysosome degradation

*DOI: http://dx.doi.org/10.5772/intechopen.83040*

**6. Alternate routes and strategies**

**6.2 Intracarotid delivery**

**6.3 Intratumor delivery**

recorded foe CED was of 24 days [62, 64].

**6.1 Conventional enhanced delivery (CED)**

### *Nanopharmaceuticals: A Boon to the Brain-Targeted Drug Delivery DOI: http://dx.doi.org/10.5772/intechopen.83040*

*Pharmaceutical Formulation Design - Recent Practices*

nasal problems due to their unique nature.

mucosa provide nose to brain targeting feature and could able to treat various CNS disorders like depression, pain, Alzheimer's disease, glioblastoma, multiple sclerosis etc. Several dosage forms, sprays, suspensions, nebulizers, aerosols, gel, solutions can be utilized for IN drug delivery [47]. On the other hand, barriers like mucociliary clearance from nasal mucosa, enzymatic degradation and low degree of permeability across nasal epithelium hinder the drug targeting efficiency to the brain. As a solution, nanopharmaceuticals were used which overcome the clearance and other

One of the studies demonstrated IN administration of chitosan nanoparticle to deliver bromocriptine, a dopaminergic agonist, to minimize motor function disorder associated with prolonged levodopa usage in the Parkinson's disease. Results were promising in terms of motor function [48]. Didanosine-dideoxyinosine (ddI) is an antiretroviral therapy (HAART) and available in oral dosage forms, however, faced extensive degradation and elimination in GIT which decreases its bioavailability. To overcome the issues, dd loaded chitosan nanoparticles were administered through IN route. Results indicated higher brain to plasma, CSF to plasma and olfactory blood to plasma ratios in the case of IN delivered dd nanoparticles. It shows that nanoformulation can be directly delivered to the brain compartment through IN route [49].

Another research group fabricated rivastigmine loaded chitosan nanoparticle for inhibiting acetylcholinesterase in the brain through IN administration. The free drug had severe bioavailability issues and distributed to the non-targeted site with severe side effects when administered through oral or IV route. Here, chitosan nanocarrier and administration through nasal route enhanced brain uptake with higher brain/ blood ratio. It further highlighted the role of nanocarrier and route in brain targeting [50]. Similarly, Venlafaxine (VLF) chitosan nanoparticles were administered to the brain through the nasal route for the treatment of major depressive disorders and anxiety disorder with improved brain uptake and enhanced bioavailability [51]. Another study showed microemulsion and mucoadhesive delivering clonazepam, an anxiolytic, sedative, hypnotic, anticonvulsant drug to the brain. The brain/ blood uptake ratio of the intranasal microemulsion and mucoadhesive microemulsion were significantly higher than the IV administered microemulsion, indicating the effectiveness of IN route for brain-specific drug delivery [52]. Similarly, the microemulsion was used for the IN delivery of nimodipine to the brain cells. The microemulsion leads to 3-fold more drug uptake by the olfactory bulb than the IV route. AUC ratio of brain to plasma and cerebrospinal fluid (CSF) to plasma were higher after IN administration in comparison to IV injection. Thus, it could be a promising approach to treat neurodegenerative disorders [53]. Risperidone nanoemulsion and mucoadhesive nanoemulsion were administered through IN route for the treatment of schizophrenia. The composition of nanoemulsion included glyceryl monocaprylate as an oily phase, tween 80 as a surfactant and mixture of propylene glycol and transcutol as a co-surfactant. While mucoadhesive microemulsion had chitosan polymer which induces mucoadhesive properties. The nanoemulsion and mucoadhesive nanoemulsion improved risperidone bioavailability, prevent first pass metabolism and bypass BBB to achieve desired drug concentration at the targeted site. The brain/blood uptake ratio and drug transport efficiency were found to be significantly higher through nasal administration in comparison to the

Furthermore, nanostructured lipid carriers comprising duloxetine was prepared and delivered to the brain via IN route for the treatment of the major depressive disorder. The results revealed prolonged drug release and therapeutic effect as

Furthermore, micellar nanocarrier (amphiphilic nanocarriers) of sumatriptan was developed to treat an acute migraine to improve cerebral blood flow. Limitations

demonstrated from improved behavior analysis after 24 hours [55].

**128**

IV injection [54].

of the drug associated with oral dosage forms and subcutaneous administration like poor bioavailability, shorter plasma half-life, and hepatic elimination have been resolved to much extent through incorporation in micellar nanocarrier. And increased brain concentration of the drug and site-retention can be achieved via nose to brain drug delivery [56]. Similarly, zolmitriptan-loaded micellar nanocarriers were prepared to target brain serotonin receptors and inhibit cranial vessel inflammation. Micellar nanocarriers were administered through nasal route with enhanced characteristics like lower particle size, higher permeation across nasal mucosa, appropriate flow rate, ability to load hydrophilic as well as hydrophobic drugs, enhanced site-retention and ultimately enhanced drug therapeutic activity [57].

Another polymer methoxy-PEG-polycaprolactone was used to encapsulate coumarin with promising brain penetration and myelin binding properties, while administered through nasal route [58]. Bioadhesive nanocarriers reported in the above studies overcome many hurdles associated with a nasal route like protection of drug against enzymatic degradation, enhanced permeability, and avoidance of mucociliary clearance. However, IN delivery of nanopharmaceuticals should be further improved with targeting moieties and incorporation of cost-effective approach.
