**2. Drug delivery to brain: potential hurdles to overcome**

Mainly lipophilic drugs are used to treat CNS ailments and possess a molecular weight below 400 Da and log P between −0.5 and 6.0 [8, 9]. For drugs that are ionized at physiologic pH, it is their unionized fraction that determines the concentration gradient across the BBB for passive diffusion [2]. By considering these facts, a drug should be designed in such a manner that it has optimal lipid solubility so that it penetrates BBB and maintains a therapeutic concentration in the brain. But this is not that simple because only increasing the lipophilicity of the drug molecule via certain chemical modifications may not attain the desired pharmacokinetic effects as it may lead to decreased systemic solubility and bioavailability. It may also have increased protein binding and higher uptake by liver and reticuloendothelial system which ultimately leads to increased metabolism thus leading to diminished active drug concentration at the target site [2]. There are certain drug molecules that penetrate the BBB besides what their lipid solubility suggest. This penetration is attributed to the carrier-mediated transport of these polar compounds present at the tight junctions [10].

**119**

**Table 1.**

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

**3. Nanopharmaceuticals: an approach to achieve brain targeting**

Brain targeting is potentially difficult because of multiple barriers. Recent advances in nanotechnology present opportunities to overcome such limitations and to deliver the drug to the brain targets. Nanopharmaceuticals are the relatively newer field that employed "therapeutic containing nanomaterial" with unique physicochemical properties due to their small size (one to several 100 nm), high

**Route Brand Nanocarrier Indication Manufacturer** SC Copaxone Glatiramer acetate Multiple sclerosis TEVA

> Lymphomatous malignant meningitis

Local ablation in glioblastoma, prostate, and pancreatic cancer

Cryptococcal meningitis

Cryptococcal meningitis

Glioblastoma and Pediatric brain tumors

Malignant brain tumors imaging

Glioblastoma Phase II

Glioblastoma Phase II

tumors

Chronic pain Pacira

Glioblastoma Cell Therapeutics

Psychostimulant Pfizer/King

ADHD Novartis

ADHD Novartis

Multiple sclerosis Biogen

Leadiant Biosciences

Magforce

Pharma

Gilead Sciences,

Enzon Pharma

Under Phase I trial

Phase II Phase II

Phase I

Inc.

Pharmaceuticals

encapsulated in multivesicular liposomes (20 μm)

encapsulated in multivesicular liposomes (17–23 μm)

linked to SLN

nanocrystals

liposome

liposome

cholesterol, and DSPE-PEG2,000

Cationic liposome with anti-transferrin

with a fluorophore, PEG-coated

*SC, subcutaneous; IM, intramuscular; IV, intravenous; AHDH, attention deficit hyperactivity disorder; IFN, interferon;* 

cholesterol

antibody

*DSPE, distearoylphosphatidylethanolamine; EPC, egg phosphatidylcholine; PEG, polyethylene glycol.*

IV DaunoXome® Daunorubicin liposome Pediatric brain

superparamagnetic iron oxide (15 nm) nanoparticles

Dexmethylphenidate HCl nanocrystals

Methylphenidate HCl nanocrystals

conjugate (PEGylated IFN Beta-1a)

IM injection Invega Sustenna® Paliperidone Schizophrenia Janssen Pharms

DepoDur® Morphine sulfate

NanoTherm® Aminosilane-coated

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

IV DepoCyt® Cytarabine

IV Opaxio® Paclitaxel covalently

Oral Avinza® Morphine sulfate

SC injection Plegridy® Polymer-protein

IV AmBisome® Amphotericin B

IV Abelcet® Amphotericin B

IV Doxil®/Caelyx® Doxorubicin HSPC,

IV Myocet® Doxorubicin EPC and

— Cornell Dots Silica nanoparticles

(SynerGene Therapeutics)

*Marketed nanopharmaceuticals for brain disorders.*

Epidural space injection

Intratumoral Injection

Oral Focalin

Oral Ritalin

IV SGT-53

XR®

LA®

*Pharmaceutical Formulation Design - Recent Practices*

**1.1 Barriers in delivering drug to brain**

diffusion, specific transporters, and transcytosis [4].

*1.1.1 The blood-brain barrier (BBB)*

*1.1.2 Other barriers*

endothelial barrier [6].

of solutes between the blood and CSF [7].

**2. Drug delivery to brain: potential hurdles to overcome**

brain ailments. BBB serves as both physical and transport barrier and is present at the interface of blood and brain. It is a tight junction made of microvascular endothelial cells, astrocytes, and pericytes [3]. Therefore, the development of newer therapeutic

It is a tight physical junction present at the interface of CNS and blood circulation. It consists of endothelial cells that do not have fenestrations and thus restrict the influx of ions and other solutes into the brain from surrounding blood capillaries. Astrocytes and pericytes surround endothelial cells and thus make it almost an impermeable barrier. BBB allows paracellular transport of small lipophilic compounds (<400 Da) via passive diffusion. This barrier also offers active transport of some hydrophilic compounds by the means of transport proteins (e.g., P-glycoprotein) present at the junction. The transcellular pathway that is used by some compounds to enter the brain includes different mechanisms such as passive

Among the primary brain tumors, gliomas are considered the most common. These tumors make a barrier at their early stage termed as blood-brain tumor barrier (BBTB). Although BBTB is permeable at the core of glioblastomas, however, it closely resembles BBB at the peripheral regions. This combination of BBB and BBTB leads to an additional hindrance for drug delivery to reach the glioblastoma cells and thus requires newer drug development strategies to aid drug delivery to the tumor site [5].

Efflux pumps also serve as additional barriers in drug delivery to the brain that are present in endothelial cells lining. These efflux pumps are made up of protein complexes called adherens junctions primarily regulate the permeability of the

Blood-cerebrospinal fluid also acts as a barrier that limits the free movement of molecules and drug compounds across the brain by strictly regulating the transfer

Mainly lipophilic drugs are used to treat CNS ailments and possess a molecular weight below 400 Da and log P between −0.5 and 6.0 [8, 9]. For drugs that are ionized at physiologic pH, it is their unionized fraction that determines the concentration gradient across the BBB for passive diffusion [2]. By considering these facts, a drug should be designed in such a manner that it has optimal lipid solubility so that it penetrates BBB and maintains a therapeutic concentration in the brain. But this is not that simple because only increasing the lipophilicity of the drug molecule via certain chemical modifications may not attain the desired pharmacokinetic effects as it may lead to decreased systemic solubility and bioavailability. It may also have increased protein binding and higher uptake by liver and reticuloendothelial system which ultimately leads to increased metabolism thus leading to diminished active drug concentration at the target site [2]. There are certain drug molecules that penetrate the BBB besides what their lipid solubility suggest. This penetration is attributed to the carrier-medi-

ated transport of these polar compounds present at the tight junctions [10].

strategies is the need of the hour to overcome these transport hurdles.

**118**
