**5.1 Oral administration**

The oral route is the most convenient, non-invasive and compliant mode of administration. However, brain targeting through the oral route was not investigated largely mainly due to indirect systemic entry through absorption from the gastrointestinal tract (GIT). Harsh GIT environment, slow onset of action, shorter half-life, first pass elimination and reduced systemic absorption hampered drug

**123**

**Route**

Oral Oral Oral Oral Intraperitoneal (IP)

Intranasal (IN)

IN IN IN IN IN IN IN

Duloxetine

137.2 ± 2.88 nm

Nanostructured lipid carriers

—

Diadanosinedideoxyinosine (dd)

Rivastigmine

Venlafaxine

167 ± 6.5 nm

143.1 to 3300 nm

Nimodipine Risperidone

30.3 ± 5.3 nm 15.5 nm-nanoemulsion;

16.7 nm-mucoadhesive

nanoemulsion

269–382 nm

Chitosan nanoparticles

Chitosan nanoparticle

Chitosan nanoparticles

—

Major depressive

[51]

disorders and anxiety

disorder

Behaviorial

[55]

improvement in major

depressive disorder

—

—

Increase brain/plasm,

[12]

CSF/plasma ratio

Alzheimer's disease

[50]

Microemulsion

Nanoemulsion; mucoadhesive

nanoemulsion

—

—

Bromocriptine

Clonazepam

161.3 ± 4.7 nm

15 ± 10 nm

Chitosan nanoparticle

Microemulsion

—

—

Parkinson's disesase

Increase brain/blood

uptake ratio

High brain uptake

Schizophrenia

treatment

[53]

[54]

[48]

[52]

None

220 ± 35 nm

Estradiol

138.8 ± 4.3 nm

Saquinavir

100–200 nm

Indomethacin

~320 nm

**Drug** Dalargin

**Particle size**

~100 nm

**Nano component**

poly (butylcyanoacrylate) nanoparticle

Lipidic core polyunsaturated fatty acids (PUFA), Lipoid-80 and deoxycholic acid

polylactide-co-glycolide (PLGA) nanoparticles

Tween 80 coated

Alzheimer's disease treatment Brain cells localization

[36]

[34]

Iron oxide (Fe3O4) nanoparticles

coated with a carbon shell derived from glucose

poly (ε-caprolactone) coat

Glioblastoma treatment Increase oral bioavailability and brain distribution

[32]

[31]

**Active ligand** Tween 80-PEG 20000

**Indication** Analgesic effect

[33]

**References**

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

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

**Figure 2.** *Nanopharmaceuticals classification on the basis of route and nanocarriers.*


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

*Pharmaceutical Formulation Design - Recent Practices*

**administration**

**5.1 Oral administration**

Some other nanoparticulate systems like nanoemulsion and nanogel can be functionalized with targeting moieties (transferrin, insulin, peptides) for CNS drug delivery. Nanogels made up of PEG-polyethylenimine (PEI) and N-vinylpyrrolidone/ isopropyl acrylamide have been tested to ensure CNS drug delivery potential [30].

BBB mediated drug uptake restrictions prompt scientists to investigate drug delivery potential of the nanopharmaceuticals to the brain through various routes. The ultimate objective was to enhance drug penetration across BBB and to reduce disease index. Up till now, the most commonly employed route was systemic administration through Intravenous (IV) injection. Other natural routes like oral, intranasal (IN), intrathecal (IT), intraperitoneal (IP) have been used as well. Some novel strategies like cerebral devices, implants, Ultrasound-guided nanoparticle delivery, osmotic delivery gain much attention in the recent era. Different nanopharmaceuticals are illustrated in **Figure 2**. List of all nanopharmaceuticals deliv-

The oral route is the most convenient, non-invasive and compliant mode of administration. However, brain targeting through the oral route was not investigated largely mainly due to indirect systemic entry through absorption from the gastrointestinal tract (GIT). Harsh GIT environment, slow onset of action, shorter half-life, first pass elimination and reduced systemic absorption hampered drug

**5. Nanopharmaceuticals classification on the basis of routes of** 

ered through different routes have been mentioned in **Table 2**.

*Nanopharmaceuticals classification on the basis of route and nanocarriers.*

**122**

**Figure 2.**


**125**

**Route** Convection- enhanced delivery

Intrathecal Intracranial Neural probes

Dexamethasone

**Table 2.** *Nanopharmaceuticals administration through various routes.*

400–600 nm

Paclitaxel

3 mm

Fasudil

100 nm

**Drug** CPT-11

**Particle size**

96–101 nm

**Nano component**

Liposomes Liposomes Nanoscale PLGA implants

PLGA nanoparticles in alginate hydrogel *PEG, polyethylene glycol; PLA, polylactic acid; FITC, fluorescein isothiocyanate; SPAnH, poly[aniline-c-sodium N-(1-one-butyric acid)] aniline; PBCA, poly(n-butyl cyanoacrylate); HCFU, N-hexylcarbamoyl-5-fluorouracil.*

**Active ligand**

**Indication** Intracranial tumor

Subarachnoid hemorrhage

Intracranial glioblastoma Glial inflammation

[95]

[94]

[93]

[92]

**References**

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

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

*Pharmaceutical Formulation Design - Recent Practices*

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

*Pharmaceutical Formulation Design - Recent Practices*

[80]

[81]

**124**

**Route**

IN IN IN IN IN Intravenous (IV)

IV IV IV IV and

Docetaxel/SiRNA

110–150 nm

intratumoral

IV/Intranasal

IV IV (MRI)

IV IV Focused

FE

O3

4/SPAnH

—

Nanoparticles

ultrasound+IV

Sunitinib/

<190 nm

anti-miR-21

oligonucleotide

Monocolonal

300–600 nm

PEG-chitosan NPs

antibody (OX26)

Curcumin

<100 nm

Catalase

HCFU

9.5 nm 50 nm

Valproic acid

Tacrine Cabazitaxel

35.58 ± 4.64 nm

24–68 nm

Azidothymidine

Vasoactive intestinal

90–100 nm

peptide (VIP)

Sumatriptan Zolmitriptan FITC labeled

23.1 ± 0.4 nm

23 nm

5 nm

**Drug** Coumarin

**Particle size** 100 to 600 nm

**Nano component**

methoxy-PEG-polycaprlactone

PEG-PLA nanoparticles (NP)

Miceller nanocarrier

Miceller nanocarrier

AuNP Transferrin anchored PEG

nanoparticles

Nanoparticles

PBCA NPs PEG modified Cellulose

(Cellax) NPs

Peptide modified Cationic

liposomes

Exosomes

Nanogels Magnetic NPs

NPs

FITC

—

—

**Active ligand**

—

**Indication** Enhanced brain

penetration

Protein translocation

[79]

across BBB

Migraine therapy

Migraine therapy

Brain specific delivery

Viral infection

Epilepsy Alzheimer's disease

Glioblastoma

Glioma Parkinsonism

Glioma Detection of amyloid

[88]

plexus in Alzheimer's

Glioblastoma Cerebral ischemia

Malignant glioma

[91]

[90]

[89]

[86]

[87]

[85]

[83]

[84]

[82]

[57]

[56]

**References**

[58]


**Table 2.**

 *Nanopharmaceuticals administration through various routes.* therapeutic efficacy and bioavailability. Thus, oral drug delivery failed to deliver the therapeutic moiety to the brain efficiently. In this regard, nanopharmaceuticals must possess the properties to bear harsh enzymatic environment, overcome first pass metabolism and efficiently permeate through the intestinal epithelial barrier to reach the systemic circulation.

Scientists developed lipid nanocore surrounded by poly (e-caprolactone) and orally administered to the mice. The concentration of the loaded drug, indomethacin, was successively increased in the brain and efficiently treat glioblastoma in the mice model without causing BBB vessel alteration. This could serve as a basis for safe and effective brain targeting via oral route [31].

Similarly, orally administered saquinavir-loaded nanoemulsion significantly delivers the drug across BBB. Nanoemulsion was stabilized by deoxycholic acid which overpasses first-pass elimination of the drug. The oily phase, polyunsaturated fatty acids (PUFA) facilitates rapid transport to the brain. It laid the foundation for effective brain targeting through oral route [32].

Researchers formulated poly (butyl cyanoacrylate) nanoparticles, double coated with Tween 80 and polyethylene glycol (PEG)-2000 for the oral delivery of the dalargin to the brain. Dalargin is a hexapeptide, anti-nociceptive agent which could not cross BBB. However, its nanoformulation showed promising analgesic effects in the mice model, which demonstrated the potential of the nanoformulation for brain targeting via oral route [33].

Orally administered Tween 80 coated PLGA deliver estradiol successfully to the brain. The therapeutic efficacy in elevating Alzheimer's disease was parallel to the nanoformulation administered intramuscularly [34]. In short, oral delivery of drug-loaded nanopharmaceuticals achieved preliminary success but still need to be further explored in the near future.

### **5.2 Intraperitoneal administration (IP)**

Intraperitoneal administration involved peritoneal cavity of the abdomen. The route is still under investigation. It has an advantage of delivering a larger amount of the drug and it is employed when a vein for the IV injection is not easily located. In addition, it can be employed when animals are not ready for oral administration. However, the route is currently limited to pre-clinical research in small animals and need to be scaled up [35].

Iron oxide nanoparticles were fabricated with the aim to target subcellular compartment of the brain cells. For this purpose, iron oxide nanoparticles with different shapes (round, biconcave, spindle, nanotube) were synthesized and coated with glucose derived fluorescent carbon layer. In-vivo administration through IP route indicated biconcave nanoparticles localized in the nuclei and nanotubeshaped nanoparticles located in the cytoplasm of the brain cells. While the carbon coated surface on iron oxide nanoparticles facilitated attachment of several therapeutic moieties on the nanoparticles for their delivery inside the brain cells [36]. Therefore, the IP route could serve as a major route to deliver the drug across the brain barriers.

#### **5.3 Intravenous administration (IV)**

Systemic route including IV drug delivery to the brain involves the receptor-mediated and adsorptive mediated transcytosis. It is the most exploited route of administration for the nanoparticles because of the immediate action systemically and locally by targeted delivery. Polybutyl cyanoacrylate (PBCA) was first used for the synthesis of the NPs intended for the brain. Analgesic dalargin was incorporated in the PBCA NPs

**127**

**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

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

with Polysorbate 80 coating and a marked level of analgesia was seen in the animal studies after IV administration of the NPs [37]. PBCA NPs with doxorubicin coated with Polysorbate 80 were studied for their brain delivery in the rats and showed the promising result in 2–4 hours as compared to the uncoated NPs after IV drug delivery [38]. In a similar study, Polysorbate 80 coated PBCA NPs with a size of 280 nm were evaluated for the delivery of Loperamide across BBB following IV injection. Results were quite promising in the *in-vivo* nociceptive studies on mice [39]. Musumeci et al. prepared the docetaxel loaded nanospheres using PLGA and observed the biphasic release of drug following IV administration. An *in vitro* study using a biomembrane model made of dipalmitoylphosphatidylcholine (DPPC) was conducted and confirmed the significant release of the drug across the membrane, making it a potent drug delivery approach for crossing BBB [40]. An *in vitro* study was conducted on brain endothelial cell lines and glioma cells using nanocarrier system made with PLGA/PLA and a detailed sketch of cellular uptake, cytotoxicity and therapeutic efficiency were obtained. Furthermore, the animal studies confirmed the uptake of NPs in the brain following IV administration [41]. In one study, male Sprague Dawley rats were used for establishing the efficacy of curcumin as an anticancer drug with neuroprotective properties. The study group demonstrated that how the nanoparticles can increase the circulation time of curcumin in the body and penetration across the BBB, especially the distribution of NPs in the hippocampus. Half-life and mean residence time of curcumin increased after IV administration of NPs across the BBB [42]. Liu et al. demonstrated the effect of breviscapine loaded PLA NPs in rats after IV administration. NPs with an average particle size of 319 nm were distributed in the liver, spleen and brain. The prepared NPs had longer circulation life because they evaded the RES and crossed BBB [43]. Poly (alkyl cyanoacrylate) NPs can deliver several drugs like loperamide, doxorubicin, tubocurarine, etc., across the brain based on the principle of LDL receptor mediate endocytosis after injection of these NPs into the blood by IV administration. Prior to *in vivo* studies, these NPs were coated with surfactants like Poloxamers and Tween for the enhanced drug uptake by brain blood capillaries [44]. Some of the latest techniques of treating brain disorders include delivery of neurogenic genes, mRNA and siRNA. One such study was reported by Son et al. for the delivery of rabies virus glycoprotein (RVG) labeled disulfide containing polyethyleneimine (PEI) nanomaterial to the brain. *In vivo* studies revealed promising data after the infusion of RVG peptide linked nanomaterial in 6 weeks old male BALB/c mice. [45] MRI-driven targeting of the brain using iron oxide NPs of around 100 nm was reported by the group of researchers. Mice were injected with the NPs suspension and were kept in the magnetic field for 30 minutes. There was 5-folds increase in the accumulation of NPs in the glioma cells in the presence of a magnetic field as compared to undirected NPs following IV administration. This approach can be used as a non-invasive therapeutic and diagnostic tool in the various dimensions of health [46]. However, the associated issues like rapid body clearance through the reticuloendothelial system and unintended organ distribution must be overcome for appropriate brain-specific drug delivery.

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

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

*Pharmaceutical Formulation Design - Recent Practices*

safe and effective brain targeting via oral route [31].

tion for effective brain targeting through oral route [32].

reach the systemic circulation.

targeting via oral route [33].

need to be scaled up [35].

brain barriers.

further explored in the near future.

**5.2 Intraperitoneal administration (IP)**

**5.3 Intravenous administration (IV)**

therapeutic efficacy and bioavailability. Thus, oral drug delivery failed to deliver the therapeutic moiety to the brain efficiently. In this regard, nanopharmaceuticals must possess the properties to bear harsh enzymatic environment, overcome first pass metabolism and efficiently permeate through the intestinal epithelial barrier to

Scientists developed lipid nanocore surrounded by poly (e-caprolactone) and orally administered to the mice. The concentration of the loaded drug, indomethacin, was successively increased in the brain and efficiently treat glioblastoma in the mice model without causing BBB vessel alteration. This could serve as a basis for

Similarly, orally administered saquinavir-loaded nanoemulsion significantly delivers the drug across BBB. Nanoemulsion was stabilized by deoxycholic acid which overpasses first-pass elimination of the drug. The oily phase, polyunsaturated fatty acids (PUFA) facilitates rapid transport to the brain. It laid the founda-

Researchers formulated poly (butyl cyanoacrylate) nanoparticles, double coated

with Tween 80 and polyethylene glycol (PEG)-2000 for the oral delivery of the dalargin to the brain. Dalargin is a hexapeptide, anti-nociceptive agent which could not cross BBB. However, its nanoformulation showed promising analgesic effects in the mice model, which demonstrated the potential of the nanoformulation for brain

Orally administered Tween 80 coated PLGA deliver estradiol successfully to the brain. The therapeutic efficacy in elevating Alzheimer's disease was parallel to the nanoformulation administered intramuscularly [34]. In short, oral delivery of drug-loaded nanopharmaceuticals achieved preliminary success but still need to be

Intraperitoneal administration involved peritoneal cavity of the abdomen. The route is still under investigation. It has an advantage of delivering a larger amount of the drug and it is employed when a vein for the IV injection is not easily located. In addition, it can be employed when animals are not ready for oral administration. However, the route is currently limited to pre-clinical research in small animals and

Iron oxide nanoparticles were fabricated with the aim to target subcellular compartment of the brain cells. For this purpose, iron oxide nanoparticles with different shapes (round, biconcave, spindle, nanotube) were synthesized and coated with glucose derived fluorescent carbon layer. In-vivo administration through IP route indicated biconcave nanoparticles localized in the nuclei and nanotubeshaped nanoparticles located in the cytoplasm of the brain cells. While the carbon coated surface on iron oxide nanoparticles facilitated attachment of several therapeutic moieties on the nanoparticles for their delivery inside the brain cells [36]. Therefore, the IP route could serve as a major route to deliver the drug across the

Systemic route including IV drug delivery to the brain involves the receptor-mediated

and adsorptive mediated transcytosis. It is the most exploited route of administration for the nanoparticles because of the immediate action systemically and locally by targeted delivery. Polybutyl cyanoacrylate (PBCA) was first used for the synthesis of the NPs intended for the brain. Analgesic dalargin was incorporated in the PBCA NPs

**126**

with Polysorbate 80 coating and a marked level of analgesia was seen in the animal studies after IV administration of the NPs [37]. PBCA NPs with doxorubicin coated with Polysorbate 80 were studied for their brain delivery in the rats and showed the promising result in 2–4 hours as compared to the uncoated NPs after IV drug delivery [38]. In a similar study, Polysorbate 80 coated PBCA NPs with a size of 280 nm were evaluated for the delivery of Loperamide across BBB following IV injection. Results were quite promising in the *in-vivo* nociceptive studies on mice [39]. Musumeci et al. prepared the docetaxel loaded nanospheres using PLGA and observed the biphasic release of drug following IV administration. An *in vitro* study using a biomembrane model made of dipalmitoylphosphatidylcholine (DPPC) was conducted and confirmed the significant release of the drug across the membrane, making it a potent drug delivery approach for crossing BBB [40]. An *in vitro* study was conducted on brain endothelial cell lines and glioma cells using nanocarrier system made with PLGA/PLA and a detailed sketch of cellular uptake, cytotoxicity and therapeutic efficiency were obtained. Furthermore, the animal studies confirmed the uptake of NPs in the brain following IV administration [41]. In one study, male Sprague Dawley rats were used for establishing the efficacy of curcumin as an anticancer drug with neuroprotective properties. The study group demonstrated that how the nanoparticles can increase the circulation time of curcumin in the body and penetration across the BBB, especially the distribution of NPs in the hippocampus. Half-life and mean residence time of curcumin increased after IV administration of NPs across the BBB [42]. Liu et al. demonstrated the effect of breviscapine loaded PLA NPs in rats after IV administration. NPs with an average particle size of 319 nm were distributed in the liver, spleen and brain. The prepared NPs had longer circulation life because they evaded the RES and crossed BBB [43]. Poly (alkyl cyanoacrylate) NPs can deliver several drugs like loperamide, doxorubicin, tubocurarine, etc., across the brain based on the principle of LDL receptor mediate endocytosis after injection of these NPs into the blood by IV administration. Prior to *in vivo* studies, these NPs were coated with surfactants like Poloxamers and Tween for the enhanced drug uptake by brain blood capillaries [44]. Some of the latest techniques of treating brain disorders include delivery of neurogenic genes, mRNA and siRNA. One such study was reported by Son et al. for the delivery of rabies virus glycoprotein (RVG) labeled disulfide containing polyethyleneimine (PEI) nanomaterial to the brain. *In vivo* studies revealed promising data after the infusion of RVG peptide linked nanomaterial in 6 weeks old male BALB/c mice. [45] MRI-driven targeting of the brain using iron oxide NPs of around 100 nm was reported by the group of researchers. Mice were injected with the NPs suspension and were kept in the magnetic field for 30 minutes. There was 5-folds increase in the accumulation of NPs in the glioma cells in the presence of a magnetic field as compared to undirected NPs following IV administration. This approach can be used as a non-invasive therapeutic and diagnostic tool in the various dimensions of health [46]. However, the associated issues like rapid body clearance through the reticuloendothelial system and unintended organ distribution must be overcome for appropriate brain-specific drug delivery.
