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ISSN: 2229-3787

Journal of Advanced Pharmaceutical Research. 2015, 6(4), 71 - 87 Review Article

RECENT APPROACHES ON CNS DRUG DELIVERY FOR IMPROVED THERAPEUTIC EFFECTIVENESS Mehendra Kumar Dewangan *, Durgeshnandani Sinha, Vijay Kumar Singh, S. Prakash Rao, Trilochan Satapathy, Amit Roy. Columbia Institute of Pharmacy, Tekari, Near Vidhansabha Raipur, C.G., 493111, India. Corresponding author: [email protected] Received: Dec-2015; Accepted: Dec-2015 ABSTRACT Nanoparticles (NP) are defined as particles with a diameter smaller than 100 nm, are increasingly used in different applications, including drug carrier systems and to pass organ barriers such as the blood-brain barrier. Because of their unique properties Nanocrystals, quantum dots and other nanoparticles (gold colloids, nanobars, dendrimers and nanoshells) have been receiving a lot of attention for potential use in Therapeutics, Bioengineering and therapeutics drug discovery. Several polymeric nanoparticulate systems have been prepared and characterized in recent years, based on both natural and synthetic polymers, each with its own advantages and drawbacks. Among the natural polymers, chitosan has been studied extensively for preparation of nanoparticles. Chitosan nanoparticles have been reported with different characteristics with respect to drug delivery. Chitosan nanoparticle have gained more attention as drug delivery carriers because of their better stability, low toxicity, simple and mild preparation method, and providing versatile routes of administration. In this review potential use of these Nanocrystals and Nanoparticles in various important areas has been discussed. Special properties of these nanoparticles may offer new advancement in drug discovery.

Keywords: Nanoparticles, types, applications Chitosan Nanoparticles, Drug delivery carriers, Polymers, Lipophilic drugs, Toxicity.

Introduction: Brain is one of the active and highly organised

parenchyma permeability.

cells)

also

act

as barriers to

drug

[1]

delicate organs of body. BBB in the cerebral endothelial

Drug targeting to specific organs and tissues has

cells and the blood- cerebrospinal fluid barrier are its

become one of the critical endeavours of the new century.

parts. Barrier is an interface between the organ and

The search for new drug delivery approaches and new

Blood. It consists of endothelial cells. It control/prevent

modes of action represent one of the frontier areas which

transport of any agent from the stream of blood into the

involves a multidisciplinary scientific approach to

cell (or from the cell to the blood). BBB prevents and

provide major advances in improving therapeutic index

create obstacles in the entry of most drugs to brain such

and bioavailability at site specific-delivery. These new

as antibiotics, anti-neoplastic, anti-Parkinson and many

systems can hinder solubility problems; protect the drug

other CNS acting drugs. Brain parenchymal cells (i.e.,

from the external environment such as photo degradation

neuroglia and neurons) exist within this highly regulated

and pH changes, while reducing dose dumping by

environment and function in coordination. Additionally

controlling the release profile. Biocompatibility is one of

they also have a significant impact on the general

the major pre-requisites for pharmaceutical use, and

pharmacokinetic/pharmacodynamics of drugs. The cell

designing a formulation to fit the physicochemical

membranes of astrocytes and microglia (both are

71

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[2]

ISSN: 2229-3787

therapeutic index, as measured by its pharmacological response and safety, relies in the access and specific

Most brain disease leads to be localized loss of

introduction of the drug with its candidate receptor,

neurons. At present most Brain and CNS disorders such

whilst minimizing its introduction with non target tissue.

as neurodegeneration, malignant brain is a delicate organ

[5]

.The brain is shielded against potentially toxic substances

This regulation of the brain homeostasis results

by the presence of two barrier system such as the blood

in the inability of some small and large therapeutic

brain barrier and cerebrospinal fluid barrier. BBB is a

compounds to cross the blood–brain barrier (BBB).

complex system of endothelial cells, astroglia, pericytes,

Therefore, various strategies have been developed to

perivascular macrophages and a basal lamina. Clinical

enhance the amount and concentration of therapeutic

failure of potentially effective therapeutics is often due to

compounds in the brain. The brain is shielded against

insufficient amount of delivery to brain. At the same time

potentially toxic substances by the presence of two barrier

people suffer by so many brain disorders such as

systems: the blood brain barrier (BBB) and the blood

ischemic stroke, glioma, Parkinson’s diseases and Alzhei-

cerebrospinal fluid barrier (BCSFB). It is estimated that

mer’s disease. To enhance bioavailability and targeting

more than 98% of small molecular weight drugs and

action of brain, pharma field people have recently focus

practically 100% of large molecular weight drugs (mainly

their faces on the development of new strategies to more

peptides and proteins) developed for CNS pathologies do

effectively deliver molecules to CNS.

[3]

not readily cross the BBB and discovery of new

The major problem in drug delivery to brain is

modalities allowing for effective delivery of drugs and

the presence of the BBB. Drugs that are effective against

bio macromolecules to the central nervous system (CNS)

diseases in the CNS and reach the brain via the blood

is of great need and importance for treatment of

compartment must pass the BBB. In order to develop

neurodegenerative

drugs which penetrate the BBB well to exhibit the

Epilepsy).

disorders

(Alzheimer’s

disease,

[6]

expected CNS therapeutic effects, it is of great importance to understand the mechanisms involved in uptake into and efflux from the brain. The function of the BBB is dynamically regulated by various cells present at the level of the BBB. [4] The Structural BBB is created by the cerebral

BARRIERS TO CNS DRUG DELIVERY: The failure of systemically delivered drugs to effectively treat many CNS diseases can be rationalized by considering a number of barriers that inhibit drug delivery to the CNS.

endothelial cells forming the capillaries of the brain and

Blood-Brain Barrier (BBB): It is now well established that the BBB is a

spinal cord. The endothelial cells at their adjacent

unique membranous barrier that tightly segregates the

margins form tight junctions (zona occludes – ZO),

brain from the circulating blood. Basal membrane and

produced by the interaction of several Tran’s membrane

brain cells, such as pericytes and astrocytes, surrounding

proteins that project into and seal the paracellular

the endothelial cells further form and maintain an

pathway. The molecular structure and function of the

enzymatic and physical barrier known as the blood–brain

BBB junctional proteins is beyond the scope of this

barrier (BBB). The CNS consist blood capillaries which

review, but several recent reviews exist. Targeted drug

are structurally different from the blood capillaries in

delivery seeks to concentrate the medication in the tissues

other tissue. These structural differences result in a

of interest while reducing the relative concentration of the

permeability barrier between the blood within brain

medication in the remaining tissues. This improves

capillaries and the extracellular fluid in brain tissue.

efficacy of the while reducing side effects. This improves efficacy of the while reducing side effects. The drug’s

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The capillary walls act as a continuous lipid bilayer and

to solutes, the epithelial cells of the choroid plexus and

prevent the entry of microscopic, large, polar or lipid

the tanycytes of other regions form tight junctions to

insoluble molecules into the brain except the exchange of

prevent transport from the abluminal extracellular fluid

gases (such as carbon dioxide, oxygen) and essential

(ECF) to the brain ECF. The BBB also has an additional

nutrients. The important morphological characteristics of

enzymatic aspect. Solutes crossing the cell membrane are

BBB include fenestrations and presence of tight

subsequently exposed to degrading enzymes present in

junctions. The tight junctions between endothelial cells

large numbers inside the endothelial cells that contain

results in a very high trans-endothelial electrical

large densities of mitochondria, metabolically highly

resistance of 1500-2000 Ω.cm2 compared to 3-33 Ω.cm2

active organelles. [8]

of other tissues which reduces the aqueous based

Transportation of glucose into the CNS occurs

paracellular diffusion that is observed in other organs.

through facilitative diffusion by a non-energy-dependent

BBB tight junctions are formed between endothelial cells

glucose transporter. The epithelial cells of BBB prohibit

in brain capillaries, thus preventing paracellular transport

paracellular diffusion of drugs by forming tight junctions.

of molecules into the brain. Micro-vessels small in

BBB enzymes also recognize and rapidly degrade most

diameter and thin walls compared to vessels in other

peptides, including naturally occurring neuropeptides.

organs make up an estimated 95% of the total surface

Finally, the BBB is further reinforced by a high

area of the BBB, and represent the principal route by

concentration of P-glycoprotein (Pgp), active –drug-

which chemicals enter the brain. In

brain

[7]

capillaries,

efflux-transporter protein in the luminal membranes of intercellular

cleft,

the cerebral capillary endothelium. [9]

pinocytosis, and fenestrate are virtually non-existent;

Therefore, only lipid-soluble solutes that can

exchange must pass trans-cellularly. Micro-vessels make

freely diffuse through the capillary endothelial membrane

up an estimated 95% of the total surface area of the BBB,

may passively cross the BBB. However, this barrier is not

and represent the principal route by which chemicals

considered as a main route for the uptake of drugs since

enter the brain. In brain capillaries, intercellular cleft,

its surface area is 5000-fold smaller than that of the BBB.

pinocytosis, and fenestrae are virtually non-existent;

The choroid plexus and the arachnoid membrane act

exchange must pass trans-cellular. Given the prevalence

together at the barriers between the blood and CSF. The

of brain diseases alone, this is a considerable problem.

arachnoid membrane is generally impermeable to

Practically all drugs currently used for disorders of the

hydrophilic substances, and its role is formation of the

brain are lipid-soluble and can readily cross the BBB

Blood-CSF barrier, is largely passive. [10]

following oral administration. Further, in spite of being well distributed into

Different routes of delivery to Brain: 

Rectal



Skin



Nasal

dizziness due to the displacement of g-amino butyric acid



Inhaled

(GABA) from the GABA receptor binding sites. On the



Buccal

various tissues, a lipophilic new quinolone antimicrobial agent, grepafloxacin, cannot enter the brain, resulting in the avoidance of CNS side effects such as headache and

other hand, benzodiazepines such as diazepam have been used as sedative-hypnotic agents, because these lipophilic drugs readily cross the BBB. Although levodopa, which is useful for treatment of Parkinson’s disease, is very

Direct delivery to brain : Possible Methodologies for direct delivery of CNS drugs to brain: [11]

hydrophilic, it can readily penetrate the BBB. Though in



CSF Delivery

the CVO brain regions the capillaries are more permeable



Drug Wafers

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

Seizure –activated drugs

disruption of the neuroprotective BBB by osmotic



Local perfusion

imbalance, ultrasound or vasoactive compounds (e.g.,



Nanoparticles

bradykinin or P-glycoprotein inhibitors), or physiological



Liposomes

strategies



Polymeric micelles

mechanisms. While the first method has the disadvantage



Cell encapsulation therapy

that those neurons may be damaged (semi)-permanently



Gene therapy

Blood-Tumor Barrier: Drug targeting to the brain tumour is more difficult. Intracranial drug delivery becomes even more challenging when the target is a CNS tumor. The presence of the BBB in the microvasculature of CNS tumors has clinical consequences. There may be disruption of BBB by brain tumours, locally and nonhomogeneously. An increase in tumour permeability results in potentially large increase in delivery of watersoluble drugs. At the same time, intra-capillary distance increases, leading to a greater diffusional requirement for drug delivery to neoplastic cells and due to high interstitial tumor pressure and the associated peri-tumoral edema leads to increase in hydrostatic pressure in the normal brain parenchyma adjacent to the tumor. [12] Permeability is a complex topic in context of brain tumour. Two major variables involve in it are tumour micro vessel populations and spatial distribution of the target capillaries. There are three different types of micro vessel populations are present in brain tumours. The first type consists of no fenestrated capillaries. Tumours with this type of micro vessel show no enhanced permeability to contrast agents used with CT or MRI. Second type of micro vessel population consists of fenestrated capillaries. Tumours consist of these micro vessels exhibit enhanced permeability to small molecules. Third type of micro vessel population consists of inter endothelial gaps. The gaps may be about 1μm large. These tumours do not exhibit selective permeability for large molecules. [13] APPROACHES TO CNS DRUG DELIVERY: Basically, two methods have been described in the literature to actively enhance drug delivery to the brain after systemic administration: either opening/

aiming

to

use

endogenous

transport

due to unwanted blood components entering the brain [14] TYPE OF NEW DRUG CARRIERS SYSTEMS: Micro-encapsulation has been important to the development of new therapeutics and has been used to produce microspheres containing both hydrophilic and hydrophobic drugs entrapped within biocompatible polymers. The purpose of using these carriers is to obtain a con-trolled release thus maintaining therapeutic drug levels over a specified time period while reducing systemic absorption. These systems have been used in food and cosmetic industry and drug and gene delivery. Micro particles are a generic term to mention microcapsules and microspheres which can be made of polymers or lipids (liposomes) with sizes ranging from 1 to 250 μm (ideally <125 μm and exceptionally 1000 μm). This technology is very important in drug delivery. Reduced doses due to higher absorption and pro- longed absorption time by using adhesion properties of microparticles have been envisioned. On the other hand, good in vitro/in vivo correlations have been observed. Biodegradable microparticles are easily cleared by physiological

systems

thus

avoiding

the

possible

cytotoxicity caused by accumulation in cells and tissues. Active substances may be either adsorbed at the surface of the polymer or encapsulated within the particle. Furthermore, controlled release can be achieved by pHsensitive (especially useful in intravenous delivery) and/ or thermo-sensitive microparticles. Microparticles have been used to encapsulate several peptides (e.g. calcitonin and insulin), aesthetics, anti-viral drugs, hypertension and anticancer drugs, among others. However, sub-micron size particles have shown to off- far mark advantages over microparticles. For example PLGA micro- and nanoparticles were compared for their uptake in caco-2 cells and revealed a higher up- take from nanoparticles

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(41% vs. 15%). Moreover, targeting to specific tissues

recombinant virus can improve transfection efficiency

such as inflamed and cancerous tissues may be limited

while evading degradation by lysosomes thus enhancing

only to nanoparticles. [15]

drug delivery. Various viruses have been tested and the most common used are lentivirus, retrovirus and

1. Microsponges: Microsponges are biologically porous inert particles that are made of synthetic polymers with the capacity to store a volume of an active agent up to their own weight. They can protect the drug from the

adenovirus. In contrast to these, nonviral vectors such as liposomes (virosomes) and nanoparticles have rapidly increased due to their low immune response and ease of synthesis. [19]

environment and pro- vide a controlled release. Market products are available such as Retin-A micro® for acne

5. Liposomes, Transferosomes, Ethosomes, Niosomes,

vulgaris and Carac® containing fluorouracil for actinic

Virosomes, Cochleate, Cubosomes: These are phosphor-

keratosis treatments. [16]

lipid based vehicles composed of a bilayer membrane that can be divided into small unilamellar vesicles (or SUV

2. Nanotechnology: The use of nanotechnology for drug delivery

rapidly

products

and

produced the

term

commercially

available

nanomedicine

emerged.

Nanomedicine is the application of nanometer scale materials in an innovative way to develop new approaches and therapies. At this scale, materials display different physicochemical properties due to their small size, surface structure and high surface area. Thus, nanotechnology has been adopted in several fields such as drug/gene delivery, imaging and diagnostics. [17] 3.Immunoconjugates:

Antibody drug-conjugates or

from 20 nm to 100 nm), large unilamellar vesicles (LUV from 100 to 500 nm) and multilamellar vesicles (MVL exceeding 500 nm). Liposomes can also act as a drug depot injected subcutaneously and intact vesicles were found after 96hr. However, liposomes are metastable systems and their pharmaceutical use may be limited due to content leakage with poor controlled release, low encapsulation efficiency and loading. Niosomes are a non-ionic

surfactant

vesicles

made

up

from

polyoxyethylene alkyl ethers, polyoxyethylene alkyl esters or saccharose diesters. [20]

immunoconjugates are recombinant antibodies covalently

These systems are specially designed for skin

bound through a linker to a drug. The idea behind this

delivery (ethanol is a known permeability enhancer) due

technology is to tar- get potent drugs to the specific site

to their facilitated fusion and malleability (transferosomes

by using the specificity of monoclonal antibodies (mAb)

are ultradeformable) with membranes and have shown

thus avoiding non- targeted organs toxicity. How- ever,

that they can be modulated from superficial skin (e.g.

initial works showed some limitations such as short half-

treatment of Herpes virus) to full dermal penetration (e.g.

lives, immunogenicity or even lack of efficient interact-

required for transdermal delivery of insulin) overcoming

tion. To avoid this limitation strategies such as PE-

limitation com- monly found in liposomes. They have

Gylation, conjugation with proteins such as albumin or

self-assembly cubic-like appearance, are biocompatible

the use of chimeric humanized and fully human mAbs

and show bio-adhesive properties ideal for oral adminis-

has been envisioned. Moreover, they can target hard-to-

tration. Example, the oral administration of cubosomes

target tissues such as blood-brain barrier (BBB) by target-

loaded with insulin resulted in a hypoglycaemic effect in

ing transferrin, insulin or glutathione receptors, triggering

rats. More recently, the problems associated with the use

their activation and consequent internalization. [18]

of ultrasound in liposomes was overcome and a new kind of liposomes named eLiposomes were produced. A

4. Virus: Viruses are potential vehicles for drug and gene

variety of commercially available products constituted

therapies due to their natural ability to infect specific cells

from liposomes are available such as Pevaryl® containing

and transport genomic material to the nucleus. Using

econazole which have been used to treat dermatomycosis,

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Diclac® for therapy of osteoarthritis and Daylong®

Some strategies are manipulatory drugs, disrupting the

containing UV filters for patients with high risk of actinic

BBB , finding alternative route for drug delivery,

keratosis.[21]

analogues of CNS, lack of ionization at physiological pH,

Blood-Cerebrospinal Fluid Barrier (BCB):

penetration is favored by low molecular weight,

BCB act as barrier to drugs entering the CNS. It

lipophilicity14 and others are transient osmotic opening

is formed by the plexus epithelial cells. The epithelial

of BBB , high dose chemotherapy, biodegradable

cells have an arrangement in such a manner that it

implants. [25]

prevents the entry of molecules6. There may be existence of substantial inconsistencies between the composition of interstitial fluid and CSF, which suggest the presence of a

RECENT APPROACHES Quantum Dots: A quantum dot is a semiconductor nanostructure

barrier called as CSF-brain barrier. [22]

that confines the motion of conduction band electrons, valence band holes, or exactions (bound pairs of

DRUG TRANSPORT MECHANISM :

conduction band electrons and valence band holes) in all Through BBB :

three spatial directions. The confinement can be due to

Most of research studies revealed that drugs are reaching brain by some diffusion mechanism such as transcytosis, endocytosis and passive diffusion, carrier mediated endocytosis. Passive diffusion of molecule is dependent

on

its

structural

and

physicochemical

properties such as molecular size, charge, hydrogen bonding

potential,

lipophilicity

generally

clathrin

mediated endocytosis was suggested to be predominant pathway for uptake of small particles below 200nm, whereas uptake of larger particles up to assize of 500nm seems to be caveolae mediated. Generally Nanoparticles cross the blood brain barrier by following aspects. [23] 1. An increased retention of nanoparticles in the brain blood capillaries creates higher concentration gradient which enhances the transport of drugs across endothelial cell layer. 2. Addition of surfactants for formulation of nanoparticles which fluidize the endothelial cell membrane and enhance drug permeability through BBB. 3. The nanoparticles lead to an opening of the tight junction between endothelial cells and permeate through this.

electrostatic potentials (generated by external electrodes, doping, strain, impurities), the presence of an interface between

different

semiconductor

materials

(e.g.

incoreshell nanocrystal systems), the presence of the semiconductor surface (e.g. semiconductor nanocrystal), or a combination of these. Quantum dots are particularly significant

for

optical

Application

due

to

their

theoretically high quantum yield. The ability to tune the size of quantum dots is advantageous for many applications and it is one of the most promising candidates for use in solid-state quantum computation and diagnosis , drug delivery, Tissue engineering, catalysis, filtration and also textiles technologies. [26] Transdermal Approach: Transdermal drug delivery system is topically administered medicaments in the form of patches that deliver drugs for systemic effects at a predetermined and controlled rate. A transdermal drug delivery device, which may be of an active or a passive design, is a device which provides an alternative route for administering medication. These devices allow for pharmaceuticals to be delivered across the skin barrier. In theory,

4. The polysorbate 80 used as the coating agent could inhibit the efflux system, especially P-glycoprotein. [24] STRATEGIES FOR ENHANCEMENT OF DRUG CONCENTRATION IN BRAIN: Numerous drug delivery strategies have been

transdermal patches work very simply. A drug is applied in a relatively high dosage to the inside of patch, which is worn on the skin for an extended period of time. Through a diffusion process, the drug enters the bloodstream directly through the skin. Since there is high concen-

developed as per invasive and non-invasive methods.

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tration on the patch and low concentration in the blood,

nanoparticles have no effect on BBB integrity, whereas

the drug will keep diffusing into the blood for a long

high concentrations of anionic nanoparticles and cationic

period of time, maintaining the constant concentration of

nanoparticles were toxic for the BBB. The extent of brain

drug in the blood flow.

[27]

uptake of anionic nanoparticles at lower concentrations was superior to neutral or cationic formulations at the

Folate Targeting: Folate targeting is a method utilized in

same concentrations. So, nanoparticle surface charges

biotechnology for drug delivery purposes. It involves the

must be considered for toxicity and brain distribution

attachment of the vitamin, folate (folic acid), to a

profiles. Especially coating of the nanoparticles with the

molecule/drug to form a "folate conjugate". Based on the

polysorbate (Tween) surfactants resulted in transport of

natural high affinity of folate for the folate receptor

drugs across the blood brain barrier. Investigations

protein (FR), which is commonly expressed on the

revealed the role of Apo lipoprotein-E for transport of

surface of many human cancers, folate-drug conjugates

drugs across the BBB .It is suggested that the recognition

also bind tightly tithe FR and trigger cellular uptake via

and interaction with lipoprotein receptors on brain

endocytosis. Molecules as diverse as small radio

capillary endothelial cells is responsible for the brain

diagnostic imaging agents to large DNA plasmid

uptake of the drug. Other routes for reaching the brain,

formulations have successfully been delivered inside FR-

circumventing the BBB, may be via migration along the

positive cells and tissues. FA also displays high affinity

olfactory or trigeminal nerve endings after deposition on

for the folate receptor (FR), glycosylphosphatidylinositol-

the olfactory mucosa in the nasal region. [30]

linked protein that captures its ligands from the extracellular milieu and transports them inside the cell via a non-destructive, recycling endosomal pathway. The FR

Advantages of using nanoparticles for CNS targeted drug delivery:

is also are cognized tumor antigen/biomarker. Because of The methods of preparation of particles are

this, diagnostic and therapeutic methods which exploit the

simple and easy to scale-up. Nanoparticles formed are

FR’s function are being developed for cancer. [28]

stable and easily freeze dried. Nanoparticles protect drugs

Brain targeted drug delivery system: The brain is a delicate organ, and evolution built very efficient ways to protect it. The delivery of drugs to centralnervous system (CNS) is a challenge in the treatment of neurological disorders. Drugs may be administered directly into the CNS or administered systematically (e.g., by intravenous injection) for targeted action in the CNS. The major challenge to CNS drug delivery is the blood-brain barrier (BBB), which limits the access of drugs to the brain substance. Advances in understanding of the cell biology of the BBB have opened new avenues and possibilities for improved drug

against chemical and enzymatic degradation. Are also able to reduce side effects of some active drugs. Nanoparticles were able to achieve with success tissue targeting of many drugs (antibiotics, cytostatic, peptides and

proteins,

acids,

etc.).

The

use

of

biodegradable materials for nanoparticle preparation, allows sustained drug release at the targeted site after injection over a period of days or even weeks. Controlled release and particle degradation characteristics can be readily modulated by the choice of matrix constituents. Site-specific targeting can be achieved by attaching targeting ligands to surface of particles or use of magnetic

delivery to the CNS. [29] USE OF NANOPARTICLES FOR CNS TARGETED

guidance. The system can be used for various routes of administration

DRUG DELIVERY: Nanoparticles

nucleic

with

different

surface

intraocular etc.

including

oral,

nasal,

parenteral,

[31]

characteristics when evaluated, it was found that neutral nanoparticles

and

low

concentrations

of

anionic

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Limitations of using nanoparticles for CNS targeted

poly (lactic-co-glycolic acid) copolymer, polylacticacid,

drug delivery:

polyglycolic acid, poly (alkyl cyanoacrylate), poly

Their small size and large surface area can lead

(methyl methacrylate), and poly (butyl) cyanoacrylate.

to particle-particle aggregation, making physical handling

This

of nanoparticles difficult in liquid and dry forms. In

immunogenicity, and limit the phagocytosis of nano-

addition, small particles size and large surface area

particles by their ticuloendothelial system, resulting in

[32]

increased blood levels of drug in the brain. Practically,

readily result in limited drug loading and burst release.

polymeric

coating

is

thought

to

reduce

large-scale production and manufacturing remains an Ideal properties of Nanoparticles for Brain Drug

issue with polymeric nanoparticles. [35]

Delivery: The

nanoparticles

should

be

nontoxic,

biodegradable, and biocompatible. Particle diameter 200

C). Solid lipid nanoparticles:

nm and should have a narrow particle size distribution.

They consist of a relatively rigid core consisting

Should be physically stable in blood (No aggregation).

of hydrophobic lipids that are solid at room and body

Nanoparticles

temperatures,

should

avoid

opsonisation,

thereby

surrounded

by

a

monolayer

of

prolonged blood circulation time. BBB-targeted and brain

phospholipids. These aggregates are further stabilized by

delivery (receptor-mediated transcytosis across brain

the inclusion of high levels of surfactants. Because of

capillary endothelial cells).Amenable to small molecules,

their ease of bio- degradation, they are less toxic than

peptides, proteins, or nucleic acids. Minimal nanoparticle

polymer or ceramic nanoparticles. They have controllable

excipient

pharmacokinetic parameters and can be engineered with

induced

drug

alteration

degradation/alteration, protein denaturation).

(chemical [33]

three types of hydrophobic core designs: a homogenous matrix, a drug-enriched shell, or a drug-enriched core.

Different types of nanoparticles used for CNS targeted drug delivery: A). Inorganic nanoparticles: Ceramic nanoparticles are typically composed of

SLNs can easily gain access to the blood compartment, through their small size and lipophilic nature. The detection of these particles by the reticuloendothelial system is a major disadvantage. [36]

inorganic compounds such as silica, alumina, metals, metal oxides, and metal sulphides can be used. Hollow silica nanoparticles have been prepared, such as calcium

D). Nanocrystals:

phosphate-based nanoshell, with surface pores leading to

Nanocrystals are aggregates of molecules that

a central reservoir. Inorganic nanoparticles may be

can be combined into a crystalline form of the drug

designed to escape the reticuloendothelial system by

surrounded

varying size and surface composition. Also provide a

nanocrystalline species may be prepared from a

physical encasement to protect an entrapped molecular

hydrophobic

payload from degradation or denaturisation. Their lack of

hydrophilic layer. The biological reaction to nanocrystals

biodegradation and slow dissolution may not be suitable

depends strongly on the chemical nature of this

for long term administration. [34]

hydrophilic coating. The limited carrier consisting of

by

a

thin

compound

coating

and

of

coated

surfactant.

with

a

A

thin

primarily the thin coating of surfactant may reduce B). Polymeric nanoparticles: Most polymeric nanoparticles are biodegradable and biocompatible and have been adopted as a desired method for nanomaterial drug delivery. Nanoparticle

potential toxicity. A drawback however, is that the stability of nanocrystals is limited. Moreover, this technique requires crystallization; some therapeutic compounds may not be easily crystallized. [37]

formulations include those made from gelatines, chitosan,

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6. Different methods used in the preparation of

Carbon nanotubes are used as carriers for drug

nanoparticles are:

[43]

or oligonucleotide delivery and represent the most investigated therapeutic strategies for intratumoral drug and gene therapy delivery. While they are potentially promising

for

pharmaceutical

applications,

human

tolerance of these compounds remains unknown, and toxicity reports are conflicting. Extensive research into the biocompatibility and toxicity of nanotubes remains ongoing. [38]

a.

Nano precipitation,

b.

Emulsion polymerization,

c.

Emulsion solvent evaporation,

d.

Supercritical fluid expansion method,

e.

Complex Coacervation,

f.

Salting out method,

g.

Denaturation.

7. Analytical methods for characterization of different

F). Dendrimers: Dendrimers are polymer-based macromolecules formed from monomeric or oligomeric units, such that

types of nanoparticles : A. Particle size:

each layer of branching units doubles or triples the Photon correlation spectroscopy: nanoparticles

number of peripheral groups. Dendrimers require further improvements

in

cytotoxicity

profiles

and

biocompatibility. [39]

are usually poly dispersion nature and polydispersity index (P.I.) gives a measure of size distribution of the nanoparticle population. (P.I. greater than 0.5 indicates a

G). Quantum dots:

very broad size distribution).Transmission electron

QDs are luminescent nanocrystals made of

microscopy form easuring both particle size as well as

semicon-ductors used for imaging in biological systems.

distribution Scanning electron microscopy Scanned probe

This interaction allows specific drugs such as protein,

microscopes

siRNA, genetic materials, and antisense oligonucleotides

scattering (PIDS) (measures the particle size as low to 40

to penetrate targeted cancer cells in the CNS. As

nm) X-ray diffraction helps in characterizing the

semicon-ductors are poisonous heavy metals, toxicity is a

crystalline nature of the compound. [44]

and

Polarization

intensity

differential

huge obstacle to clinical application of QDs for humans. B. Molecular weight:

[40]

Gel chromatography Atomic force microscopy (to determine the original unaltered shape and surface H). Gold nanoparticles: Gold nanoparticles (NPs) are made of a silica

properties of the particles) Static secondary-ion mass spectrometry (SSIMS). [45]

core coated with a thin gold shell. Gold NP scan be prepared with different geometries, such as nanospheres,

C. Surface element analysis: X-ray photoelectron spectroscopy for chemical

nanoshells, nanorods, and nanocages. [41] analysis I). Magnetic nanoparticles:

(ESCA)

Electrophoresis

Laser

Doppler

anaemomometry X-ray diffraction (XRD) Amplitude-

Magnetic NPs are iron oxide particles with a

weighted phase structure determination Differential

diameter of 10 nm. Many groups have tested these

scanning calorimetry (DSC) (yields information on

molecules as contrasting agents for MRI, through

melting behaviour and crystallization behaviour of solid

conjugation of iron oxide NPs with hydrophilic polymer

and liquid constituents of the particles). [46]

coatings of dextran or polyethylene glycol. [42]

79

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ISSN: 2229-3787

in the development of: Combined therapy and medical

D. Density: Helium compression pychnometry Contact angle

imaging, for example, nanoparticles for diagnosis and

measurement hydrophobic interaction chromatography H

manipulation during surgery (e.g. Thermotherapy with

NMR (mobility of molecules inside the solid lipid

magnetic particles);

nanoparticles).

[47]

j) Universal formulation schemes that can be used as intravenous, intramuscular or per oral drugs;

E. Molecular analysis: Infra-red analysis (structural property of lipids).

[48]

k) Cell and gene targeting systems; 8. Future prospects of nanoparticles on CNS targeted l) User-friendly lab-on-a-chip devices for point-of-care

drug delivery:

and disease prevention and control at home; There are many technological challenges to be met, in m) Devices for detecting changes in magnetic or physical

developing the following techniques: [49]

properties

after

specific

binding

of

ligands

on

a) Nano-drug delivery systems that deliver large but

paramagnetic nanoparticles that can correlate with the

highly localized quantities of drugs to specific areas to be

amount of ligand;

released in controlled ways; n) Better disease markers in terms of sensitivity and b) Controllable release profiles, especially for sensitive

specificity.

drugs; Drug Manipulations: c) Materials for nanoparticles those are biocompatible Lipophilic Analogs:

and biodegradable;

CNS penetration is favored by low molecular d) Architectures / structures, such as biomimetic

weight, lack of ionization at physiological pH, and

polymers, nanotubes;

lipophilicity. Delivery of poorly lipid-soluble compounds to the brain requires some way of getting past the BBB.

e) Technologies for self-assembly;

There are several possible strategies, such as transient

f) Functions (active drug targeting, on command delivery,

osmotic opening of the BBB, exploiting natural chemical

intelligent drug release devices/bio responsive triggered

transporters,

systems,

biodegradable implants. Heroin, a diacyl derivative of

self-regulated

delivery

systems,

systems

interacting with the body, smart delivery);

high

dose

chemotherapy,

or

even

morphine, is a notorious example that crosses the BBB about 100 times more easily than its parent drug just by

g) Nanoparticles to improve devices such as implantable

being more lipophilic. [50]

devices/Nano chips for nanoparticle release, or multi reservoir drug delivery-chips; Prodrugs: h) Nanoparticles for tissue engineering; e.g. for the

Brain uptake of drugs can be improved via

delivery of cytokines to control cellular growth and

prodrug formation. Prodrugs are pharmacologically

differentiation, and stimulate regeneration; or for coating

inactive compounds that result from transient chemical

implants with nanoparticles in biodegradable polymer

modifications of biologically active species. After

layers for sustained release;

administration, the prodrug, by virtue of its improved

i) Advanced polymeric carriers for the delivery of therapeutic peptide/proteins (bio pharmaceutics), and also

characteristics, is brought closer to the receptor site and is maintained there for longer periods of time. [51]

80

Available online at www.pharmresfoundation.com

(i) The nucleoside transport system for purine bases such

Chemical Drug Delivery: Chemical

drug

ISSN: 2229-3787

delivery

systems

(CDDS)

as adenine and guanine, but not pyrimidine bases, and

represent novel and systematic ways of targeting active

(j) The peptide transport system for small peptides such

biological molecules to specific target sites or organs

as encephalin, thyrotrophic-releasing hormone, arginine

based on predictable enzymatic activation. They are

vasopressin etc.

inactive chemical derivatives of a drug obtained by one or more chemical modifications so that the newly attached

Disturbing the Blood-Brain Barrier:

moieties are monomolecular units (generally comparable

Despite recent developments for enhanced CNS

in size to the original molecule) and provide a site-

penetration, the BBB remains a formidable obstacle that

specific or site enhanced delivery of the drug through

compromises successful treatment of many neurological

multi-step enzymatic and/or chemical transformations.

disorders. The second invasive strategy for enhanced

During the chemical manipulations, two types of bio-

CNS drug delivery involves the systemic administration

removable moieties are introduced to convert the drug

of drugs in conjunction with transient BBB disruption

into an inactive precursor form.

[52]

(BBBD). Theoretically, with the BBB weakened, systemically administered drugs can undergo enhanced

Carrier Mediated Drug Delivery:

extra vacation rates in the cerebral endothelium, leading

Carrier-mediated transport (CMT) and receptor-

to increased parenchyma drug concentrations. [54]

mediated transport (RMT) pathways are available for certain circulating nutrients or peptides. The availability

Novel Methods:

of these endogenous CMT or RMT pathways means that

The challenging domain of effective brain

portals of entry to the brain for circulating drugs are

delivery has led to a keen scientific pursuit and as a result

potentially available. In the brain capillary endothelial

many novel methods have been invented and patented. In

cells, which make up the BBB, there are several transport

these series, researchers have revealed the use of

systems for nutrients and endogenous compounds.

[53]

iontophoresis as an adjuvant for CNS drug delivery. Iontophoresis has been defined as the active introduction

They are;

of ionised molecules into tissues by means of an electric

(a) The hexose transport system for glucose and

current. The parent US patent method and device for

mannose,

delivery of a biologically active agent that is transported

(b) The neutral amino acid transport system for

by means of iontophoresis and/or phonophoresis directly

phenylalanine, leucine and other neutral amino acids,

to the CNS using the olfactory pathway to the brain and

(c) The acidic amino acid transport system for glutamate

thereby circum-venting the BBB and is known as

and aspartate,

transnasal iontophoretic delivery. [55]

(d) The basic amino acid transport system for arginine and lysine,

Molecular Trojan Horses:

(e) The b-amino acid transport system for b-alanine and taurine, (f) The monocarboxylic acid transport system for lactate and short-chain fatty acids such as acetate and propionate, (g) The choline transport system for choline and thiamine, (h) The amine transport system for mepyramine,

Endogenous ligands for specific BBB receptors, also known as Trojan horses, have the capacity to shuttle drugs into the brain. Vasoactive intestinal polypeptide (VIP) participates in the regulation of cerebral blood flow;

however,

in

vivo

studies

showed

no

neuropharmacological effect as a result of low transport of peptide to the brain, which is attributable to the presence of the BBB. [56]

81

Available online at www.pharmresfoundation.com

ISSN: 2229-3787

4. Skin Drug Delivery:

Pharmaceutical Applications:

Application to the skin desires two effects: 1. Brain Delivery: The

blood

transdermal and topical effects. The transdermal delivery brain

barrier

(BBB)

is

an

extraordinary gate- keeper toward exogenous substances being estimated that 98% of all drug never reach the brain in therapeutic concentrations. There have been several experimental strategies to address these problems and enhance brain bioavailability of existing therapeutics into the CNS. Since nanoparticles are small in size, they easily penetrate into small capillaries and through the physical restrictions presented by the brain interstitial space. However, nanoparticles cannot freely diffuse through the BBB and require receptor-mediated transporters. Hence, the use of the specific peptides for targeting the receptormediated transcytosis across BBB can be a successful strategy for improving drug delivery to the brain. In this way, promising results have been achieved by directly delivering drugs to the brain interstitium through the design of polymer-based drug delivery systems. [57]

has gained a significant importance for systemic treatment as it is able to avoid first-pass metabolism and major fluctuations of plasma levels typical of repeated oral administration. SLN, due to an initial burst release followed by water evaporation, proved to penetrate human and pig skin ex vivo more rapidly and to a higher extent

than

conventional

dosage

forms

and

a

nanoemulsion. Other drug carriers have been used in skin drug delivery. Example, transferosomes with ketoprofen (Diractin®) were applied as a transdermal system in a multicentre, randomized, double-blind trial and showed similar efficacy in relief of knee osteoarthritis compared to celecoxib. In addition, liposomes tend to fuse at the skin surface and marked changes can be induced in the horny layer depending on the phospholipids used as intercellular deposition can occur and destroy lipid membranes. [60]

2. Mucosal Drug Delivery:

5. Cancer Delivery:

The oral route is the most desirable route for the administration of drugs as it is simple and free from

Cancer delivery presents a challenging obstacle

complications arising from more invasive methods. When

for every dosage forms. Targeting cancer cells while

designing such formulation, several parameters have to be

avoiding damage to other cells is the main endeavour of

ac- cessed as charges from the carrier system and content,

cancer therapy. Major clinical obstacles raised to

the solubility of the drug carrier, among others. It has

chemotherapeutic

been shown that they can protect protein and peptide

distributions, multidrug resistance mechanism (MDR),

drugs from enzymatic degradation and increase their low

poor absorption, increased metabolism and excretion

permeability

while having poor diffusion through the tumor mass

across

the

circumvent efflux processes.

intestinal

epithelium

and

[58]

agents

are

due

to

large

body

which constitutes the impaired delivery. Herein, the concept of enhanced permeability and retention (EPR) in the solid tumor and the microenvironment of the tumor

3. Pulmonary Drug Delivery: The pulmonary route requires a suitable design

(physiological drug resistance) plays a vital role to the enhancement of nanoparticles’ uptake. [61]

as the deposition of the nanoparticles differs according to the particle size. On the other hand, the mucus may re-

GENE TRANSFER:

strain the entry of nanoparticles. PSA-PEG nanoparticles were able to penetrate and diffuse in sputum expectorate from lungs of cystic fibrosis patients and this system could be used to improve drug therapies in various mucosal surfaces. [59]

Recombinant adenoassociated virus vectors have shown significant promise as vehicles for in vivo gene transfer, particularly for transduction of organs composed primarily on nondiluting cells (i.e., muscle, CNS and

82

Available online at www.pharmresfoundation.com

ISSN: 2229-3787

liver). Adeno-associated virus (AAV) vectors are derived

carriers since their prevalence over other formulations in

from non-pathogenic and defective human parvovirus.

terms of toxicity, production feasibility and scalability is

The recombinant AAV system has continued to attract

widely documented in the literature.

enormous interest primarily due to its unique features A technology of chimeric peptides which are

such as safety, high titres, broad host range, transduction of quiescent cells and vector integration. Recently rAAVmodified in vivo gene transfers have demonstrated efficient long term transduction from (3months to more than 15 years) and lack of toxicity and cellular immune response in the target tissues especially in CNS. Insertion of HS-tk into tumors and subsequent treatment with GCV has successfully eliminated tumors in experimental animal model. [62]

potential BBB transport vectors and have been applied to several

peptide

pharmaceuticals,

nucleic

acid

therapeutics, and small molecules to make them CNS transportable. As seen, the effort to produce these new drug carrier systems is clearly high. Undoubtedly, those carriers pro- vide the hope to treat and diagnose several diseases. Several technologies have advanced into clinical studies and are nowadays market products that have been shown favourable results. However, there are some issues

FUTURE PROSPECTIVE:

that need to be understood in order to ensure their safety and effectiveness. Nevertheless, in the future, new entities

It may be feasible to develop a number of systemically effective neuro-pharmaceuticals that will be effective

following systemic administration. Novel

strategies based mainly on exploitation of specific transport systems at the BBB are being planned and developed. The advancement for delivering drug or peptide across BBB requires the integration of antibody engineering, pharmacokinetics, and receptor-based drug

will become available and responsive and “clever” polymers will offer new perspectives for the treatment of diseases. Brain targeting drug delivery system has essential in management of CNS disorders. It can be concluded from this review that by means of the nanotechnology, nasal routes, disruption of BBB, prodrugs, etc. the drug can be delivered across the BBB efficiently.

design. The development of a successful BBB drug delivery system seems possible. Thus, there is need of development of CNS drug delivery.

Additional drug exposure to brain can be improved by utilizing modified colloidal particles and liposomes. Because it is assumed that they have prolong

CONCLUSION:

blood circulation, which helps in more interaction and

From the above discussion it is found that many

penetration into brain endothelial cells. Recent drug

delivery systems like polymeric Nanoparticles and

designs such as Liposomes, Nanoparticles, gene therapy,

liposomes are the promising carriers to deliver drugs

implants, enzymatic activation seizure activated drugs,

beyond the BBB for the scrutiny of the central nervous

encapsulation therapy are the promising strategies to

system. This is even more evident in light of the fact that

promote drug delivery to brain. Cell and gene therapies

most of the potentially available drugs for CNS therapies

will play on important role in the treatment of

are large hydrophilic molecules, e.g., peptides, proteins

neurological disorders in the future. It has crossed the

and oligonucleotides that do not cross the BBB. The large

infancy period and now touching height of growths from

amount of evidence regarding brain drug delivery by

the pharmacy point of view. Very difficult for a drug

means of P80-coated NPs cannot be ignored or

molecule to reach its destination in the complex cellular

considered as single evidence even though its action

network of an organism. Nanoparticles have shown great

mechanism is not completely understood. Lipid NPs, e.g.

application in specific targeted drug delivery systems.

SLN, NLC, LDC NPs, may represent, in fact, promising

83

Available online at www.pharmresfoundation.com So there is a wide scope to develop medicines in

March 2011, revised 04th May 2011, accepted

nanoparticles, which will specifically target the CNS. The blood-brain barrier (BBB) is the most important limiting

ISSN: 2229-3787

05th May 2011. 7.

Dikpati Amrita, Madgulkar AR, Kshirsagar J.

factor for the development of new drugs for the central

Sanjay, Bhalekar M R, Chahal Andeep Singh,

nervous system. It may possible that most of the future

Targeted

therapeutics against brain diseases can be delivered

Nanoparticles, Review Article eISSN 2249-5797

through nanovehicles. Targeted delivery of drugs, as the

Journal of Advanced Pharmaceutical Sciences.

name suggests, is to assist the drug molecule to reach

8.

Drug

Delivery

to

CNS

using

Singh Swatantra Bahadur, Novel Approaches for

preferably to the desired site. Manifestation of these

Brain

Drug

Delivery

System-Review,

strategies in clinical now seems possible in near future.

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