Recent Patents on Drug Delivery & Formulation 2009, 3, 71-89
71
CNS Drug Delivery Systems: Novel Approaches
Shadab A. Pathan1, Zeenat Iqbal1, Syed M. A. Zaidi3, Sushma Talegaonkar1, Divya Vohra2, Gaurav
K. Jain1, Adnan Azeem1, Nitin Jain1, Jigar R. Lalani4, Roop K. Khar1 and Farhan J. Ahmad1,3*
1
Department of Pharmaceutics, Faculty of Pharmacy, 2Department of Pharmacology, Faculty of Pharmacy, 3Faculty of
Interdisciplinary Studies, Hamdard University, New Delhi-110062, India, 4Department of Pharmacy, Faculty of
Technology & Engineering, The M.S. University of Baroda, Vadodara-390001, Gujarat, India
Received: May 16, 2008; Accepted: November 22, 2008; Revised: November 28, 2008
Abstract: The brain is a delicate organ, and nature has very efficiently protected it. The brain is shielded against
potentially toxic substances by the presence of two barrier systems: the blood brain barrier (BBB) and the blood
cerebrospinal fluid barrier (BCSFB). Unfortunately, the same mechanisms that protect it against intrusive chemicals can
also frustrate therapeutic interventions. Despite aggressive research, patients suffering from fatal and/or debilitating
central nervous system (CNS) diseases, such as brain tumours, HIV encephalopathy, epilepsy, cerebrovascular diseases
and neurodegenerative disorders, far outnumber those dying of all types of systemic cancers or heart diseases. The
abysmally low number of potential therapeutics reaching commercial success is primarily due to the complexity of the
CNS drug development. The clinical failure of many probable candidates is often, ascribable to poor delivery methods
which do not pervade the unyielding BBB. It restricts the passive diffusion of many drugs into the brain and constitutes a
significant obstacle in the pharmacological treatment of central nervous system (CNS) disorders. General methods that
can enhance drug delivery to the brain are, therefore, of great pharmaceutical interest. Various strategies like non-invasive
methods, including drug manipulation encompassing transformation into lipophilic analogues, prodrugs, chemical drug
delivery, carrier-mediated drug delivery, receptor/vector mediated drug delivery and intranasal drug delivery, which
exploits the olfactory and trigeminal neuronal pathways to deliver drugs to the brain, are widely used. On the other hand
the invasive methods which primarily rely on disruption of the BBB integrity by osmotic or biochemical means, or direct
intracranial drug delivery by intracerebroventricular, intracerebral or intrathecal administration after creating reversible
openings in the head, are recognised. Extensive review pertaining specifically, to the patents relating to drug delivery
across the CNS is currently available. However, many patents e.g. US63722506, US2002183683 etc., have been
mentioned in a few articles. It is the objective of this article to expansively review drug delivery systems for CNS by
discussing the recent patents available.
Keywords: Patents, drug targeting, CNS, BBB, nanoparticles, liposomes, polymers.
1. INTRODUCTION
In 1998, the global market for CNS drugs was US $33
billion, which was roughly, half that of the global market for
cardiovascular drugs. This was when the global burden of
CNS affictions had risen remarkably and an expected US
$1.5 billion people around the world were likely to suffer
from one or the other brain diseases. The recent advances in
understanding the causes as well as treatment approaches to
CNS disorders have governed the pharmaceutical interest in
this field, which is evident from the rapid growth in the
global CNS drugs. Market which reached a US $55.5 billion
in 2005, and is further forecasted to expand to US $63.9
billion in 2010 [1]. In spite of an impressive increase in CNS
drug discovery leading to numerous molecules indicated in
neurological disorders the biggest impediment remains the
effective delivery of these agents across the BBB. Despite
aggressive research, patients suffering from fatal or
debilitating CNS diseases, such as brain tumours, HIV
encephalopathy, epilepsy, cerebrovascular diseases and
neurodegenerative disorders, far outnumber those dying of
*Address Correspondence to this author at the Department of
Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard (Hamdard
University), New Delhi-110062, India; Tel: +91-09810720387;
Fax: +91-11-26059663; E-mail: farhanja_2000@yahoo.com
1872-2113/09 $100.00+.00
all types of systemic cancers or heart diseases [2]. The blood
brain barrier (BBB) represents an insurmountable barrier for
the majority of drugs including anticancer agents, antibiotics,
peptides and other oligo- and macromolecular drugs [3-6].
The presence of BBB often turns out to be the sole reason for
the clinical failure of even a highly potent neurotherapeutic
agent.
2. BLOOD BRAIN BARRIER (BBB)
The brain is shielded against potentially toxic substances
by the presence of two barrier systems: the blood brain
barrier (BBB) and the blood cerebrospinal fluid barrier
(BCSFB) [7]. The term “blood brain barrier” was first coined
in 1900 by Lewandowsky, while studying the limited
penetration of potassium ferrocyanate into the brain [8]. The
structure of the BBB is subdivided into two components: the
endothelial or capillary barrier and the ependymal barrier.
The BBB is considered to be the major route for the uptake
of serum ligands since its surface area is approximately
5000-fold greater than that of BCSFB. The BBB is formed
by a complex cellular system of endothelial cells, astroglia,
pericytes, perivascular macrophages, and a basal lamina.
Compared to other tissues, brain endothelia have the most
intimate cell-to-cell connections: endothelial cells adhere
strongly to each other, forming structures specific to the
CNS called "tight junctions" or zonula occludens.
© 2009 Bentham Science Publishers Ltd.
72 Recent Patents on Drug Delivery & Formulation, 2009, Vol. 3, No. 1
They involve two opposing plasma membranes which
form a membrane fusion with cytoplasmic layer on either
side. These tight junctions prevent cell migration or cell
movement across endothelial cells. A continuous uniform
basement membrane surrounds the brain capillaries [9]. This
basal lamina encloses contractile cells called pericytes,
which form an intermittent layer and probably play some
role in phagocytosis and defence if the BBB is breached.
Astrocytic end feet, which cover the brain capillaries, build a
continuous sleeve and maintain the integrity of the BBB by
the synthesis and secretion of soluble growth factors (e. g.)
gamma-glutamyl transpeptidase) essential for the endothelial
cells to develop their BBB characteristics. The brain
capillary network has an average spacing of just 40 microns
in between the capillaries and is so dense that each brain cell
essentially has its own vessel for nutrient supply [10]. The
BBB, which consists of the endothelium of the brain vessels,
the basal membrane and neuroglial cells, acts to limit the
transport of substances into the brain [11]. Owing to its
stringent permeability, it allows only restricted entry of
promising drugs to the target brain tissues and is presumed to
be the key hurdle in developing CNS drugs. On the contrary,
this limitation is constructively used by the drug developers
to mitigate or remove CNS side-effects of drugs targeting
peripheral receptors which may also populate the CNS.
Many polar therapeutic agents are unable to reach the CNS
because of the absence of paracellular pathways in the BBB.
The presence of few endocytic vesicles in the CNS
capillaries further removes a transcellular route for free
diffusion of substances into the interstitium [12, 13]. Further,
Fig. (1). CNS drug delivery approaches.
Ahmad et al.
a large number of more lipophilic drugs are also subject to
the activity of efflux transporters (P-glycoproteins and MRP,
the multi-drug resistance-related proteins). As a result of this
difficulty of delivering drugs across the BBB, a significant
number of CNS diseases have poorly met therapy [14,15].
The parameters considered optimum for a compound to
transport across the BBB are:
•
Compound should be unionised.
•
Its log P value should be near to 2.
•
Its molecular weight should be less than 400 Da.
•
Cumulative number of hydrogen bonds should not go
beyond 8 to10 [16].
The factors which need profound understanding while
designing a delivery system for neurotherapeutic agents are
given in Table 1.
3. APPROACHES TO CNS DRUG DELIVERY
To overcome the multitude of barriers restricting CNS
drug delivery of potential therapeutic agents, numerous drug
delivery strategies have been developed. These strategies
generally fall into one or more of the following categories:
invasive, non-invasive or miscellaneous techniques [17-19].
The CNS drug delivery tree encompassing the various
possible strategies is given below in the Fig. (1).
3.1. Non-Invasive Approaches
A variety of non-invasive brain drug delivery methods
have been investigated, that make use of the brain blood
CNS Drug Delivery
Table 1.
Recent Patents on Drug Delivery & Formulation, 2009, Vol. 3, No. 1
73
Factors Affecting Drug Transport Across BBB [17-19]
Factors Affecting Drug Transport Across BBB
•
Concentration gradient of drug/polymer
•
Molecular charge
•
Molecular weight of the drug
•
Affinity for receptors or carriers
•
Lipophilicity of the drug
•
Cerebral blood flow
•
Sequestration by other cells
•
Systemic enzymatic stability
•
Affinity for efflux proteins (e.g. Pgp
•
Metabolism by other tissues
•
Pathological status
•
Clearance rate of drug/polymer
•
Flexibility, conformation of drug/polymer
•
Cellular enzymatic stability
vessel network to gain widespread drug distribution. Noninvasive techniques of delivery may be of a chemical or
biological nature. Such methods usually rely upon drug
manipulations which may include alterations as prodrugs,
lipophilic analogues, chemical drug delivery, carrier-mediated drug delivery, receptor/vector mediated drug delivery etc.
Intranasal drug delivery which primarily exploits the
olfactory and trigeminal neuronal pathways has also gained a
recent reappraisal as a potential non-invasive approach [20].
3.1.1. Chemical Methods
The main premise for the chemical methods remains the
use of prodrugs. An extension of the concept uses the
chemical transformation of drugs by changing the various
functionalities. The chemical change is usually designed to
improve some deficient physicochemical property such as
membrane permeability or solubility. For example, esterification or amidation of hydroxy-, amino-, or carboxylic acidcontaining drugs may greatly enhance the lipid solubility and
hence, entry into the brain. Generally, conversion to the
active form is realized via an enzymatic cleavage. Going to
the extremes of the lipophilic precursor scale, a possible
choice for CNS prodrugs is to link the drug to a lipid moiety,
such as a fatty acid, a glyceride or a phospholipid. Such
prodrug approaches were explored for a variety of acidcontaining drugs, like levodopa [21]. Problems associated
with prodrugs are: the poor selectivity and poor tissue
retention of some of these molecules. Besides, the lipidization strategy involves the addition of lipid-like molecules
through modification of the hydrophilic moieties in the drug
structure. Lipid-soluble molecules are believed to be
transported through the BBB by passive diffusion but the
lipidization of molecules generally increases the volume of
distribution, particularly due to to plasma protein-binding
which affects all other pharmacokinetic parameters. Furthermore, increasing lipophilicity tends to increase the rate of
oxidative metabolism by cytochrome P-450 and other enzymes. While increased lipophilicity may improve diffusion
across the BBB, it also tends to increase uptake into other
tissues, causing an increased tissue burden [22, 23].
Chemical approaches disclosed for delivering drugs to
the brain include lipophilic addition and modification of
hydrophilic drugs, (e.g., N-methylpyridinium-2-carbaldoxime chloride; 2-PA by Bodor et al. [24, 25]. Linkage of
prodrugs to biologically active compounds is yet another
strategy, e.g., phenylethylamine coupled to nicotinic acid has
been modified to form N-methylnicotinic acid esters and
amides by Bodor [26]. Derivatization of compounds to
centrally acting amines, e.g., dihydropyridinium quaternary
amine derivatives; has also been suggested by Bodor [27].
Caging compounds within glycosyl-, maltosyl-, diglucosyland dimaltosyl-derivatives of cyclodextrin is reported by
Bodor in US Patent 5017566 [28]. Loftsson in 1994
disclosed usage of cyclodextrin complexes [29]. Yaksh et al.
disclosed a patent enclosing compounds in cyclodextrin
caged complexes [30]. Robert Katz et al. described sitespecific biomolecular complexes comprising of a therapeutic, prophylactic and diagnostic agent. The complexes are
further covalently bonded with cationic carriers and
permeabilizer peptides for delivery across the BBB and with
targeting moieties for uptake by target brain cells. Invented
complexes are particularly useful for delivery of a biologically active agent to the glial tissue of the brain as well as
to the cortical, cholinergic and adrenergic neurons. The
mentioned therapeutic complexes or conjugates comprise of
an omega-3 fatty acid such as alpha-linolenic acid, eicosapentaenoic acid or docosahexaenoic acid and derivatives
thereof [31]. Christian and Samuel T. in US20060189547A1
disclosed hydrophilic N-linked pharmaceutical compositions,
methods of their preparation and use in neuraxial drug
delivery comprising of a glycosyl- CNS acting prodrug
compound covalently N-linked with a saccharide through an
amide or amine bond and a formulary consisting of an
additive, stabilizer, carrier, binder, buffer, an excipient, an
emollient, disintegrant, lubricating agent, an antimicrobial
agent , with the provision that the saccharide moiety is not a
cyclodextrin or a glucuronide. Compounds produced
according to the methods of invention find a variety of uses
in therapeutic methods for treating symptoms of various
neurologic dysfunctions [32]. Atlas; Daphne et al. in U.S.
patent application 20060211628A1, disclosed a method of
treating multiple sclerosis, using effective amount of a
compound having: (a) A combination of molecular weight
and membrane miscibility properties for permitting the
compound to cross the BBB of the organism; (b) A readily
oxidizable chemical group for exerting antioxidant
properties; and (c) A chemical make-up for permitting the
compound or its intracellular derivative to accumulate within
the cytoplasm of cells [33]. Chung et al. invented inositol
derivatives in accordance with the invention. The derivatives
are effective in significantly enhancing the transportation of
various therapeutic molecules across a biological membrane,
[34]. In US patent application 20070203080A1 Lipshutz;
Bruce H., described the synthesis of new ubiquinol
74 Recent Patents on Drug Delivery & Formulation, 2009, Vol. 3, No. 1
analogues as well as methods of using these compounds to
deliver drug moieties to the CNS [35].
3.1.2. Biological Methods
Biological approaches of CNS drug delivery primarily
emanate from the understanding of the physiological and
anatomical nuances of the BBB transportation. Of the many
available approaches, conjugation of a drug with antibodies
is an important mechanism. Other biological methods for
targeting exploit ligands in the form of sugar or lectins,
which can be directed to specific receptors found on cell
surfaces [36, 37]. The antibody-drug conjugate is directed
towards an antigen residing on or within the target tissues.
For example, the OX26 antibody, the 8D3 MAb or the R17217 MAb which are all antibodies to transferrin receptor
(TfR), were able to undergo receptor-mediated transcytosis
across the mouse BBB via the endogenous TfR. Unfortunately, it is difficult to find target tissues bearing specific
antigens that will provide a unique targeting effect. Demeule
Michel invented a non-invasive and flexible method, and a
carrier for transporting paclitaxel. The formula for the
invented compounds or conjugates is R-L-M, wherein R is
aprotinin or a fragment, L is a linker or a bond and M is the
drug. This invention is based on the discovery, that aprotinin
binds to and crosses the brain capillary endothelial wall in a
very effective manner. Aprotinin is known in the art to be a
basic polypeptide, that effectively inhibits a variety of serine
proteases, including trypsin, chymotrypsin, kallikrein and
pepsin. The transendothelial transport of aprotinin is
approximately 10-50 times higher than that of other proteins,
including transferrin or ceruloplasmin [38].
Antibodies are particularly well suited for targeting BBB
receptor-mediated transcytosis systems given their high
affinity and specificity for their ligands [39]. As examples,
appropriately-targeted antibodies that recognize extracellular
epitopes of the insulin and transferrin receptors can act as
artificial transporter substrates that are effectively
transported across the BBB and deposited into the brain
interstitium via the transendothelial route [40]. Shusta et al.
in WO2007143711 disclosed non-invasive transport of small
molecules such as methotrexate using anti-transferrin
receptor antibodies. Proteins such as nerve growth factor,
brain derived neurotrophic factor and basic fibroblast growth
factor were delivered to the brain after intravenous
administration by using an anti-transferrin receptor antibody.
This invention provides antibodies that bind to endothelial
cell receptors resulting in endocytosis of the receptor and
bound ligands. The invention comprises of an isolated
antibody fragment having the amino acid sequence linked to
a pharmaceutically active compound [41]. Megalin ligands
are carriers or vectors for the delivery of active agents via
transcytosis to brain and are patented by Starr et al. who
disclosed RAP (receptor-associated protein), which serves to
increase the transport of the therapeutic agent. In some
embodiments, the megalin ligand or megalin-binding
fragment of such a ligand may be modified as desired to
enhance its stability or pharmacokinetic properties (e. g.
PEGylation of the RAP (receptor-associated protein) moiety
of the conjugate, mutagenesis of the RAP moiety of the
conjugate) [42]. In another patent Neuwelt. disclosed
monoclonal antibody conjugated for the delivery of the drugs
Ahmad et al.
across the BBB [43]. Pardridge, disclosed the delivery of
radiopharmaceuticals across BBB with a monoclonal
antibody. [125I]-A1-40 was mono-bionylated and conjugated
to a BBB drug delivery system that comprised of a complex
of the 83-14 monoclonal antibody to the human insulin
receptor, which was tagged with Streptavidin. The effect to
produce a marked increase in Rhesus monkey brain uptake
of the [125I]-A1-40 at 3 hrs following the i.v. injection [44]. In
patent number WO2007036022 Abulrob et al. disclosed
subunits and multimers of subunits suitable for use in
inducing the transport of one or more cargo substances into a
cell and in some instances across a cell. The subunits may
have a targeting domain, such as an antibody or antibody
fragment; a multimerization domain, such as a verotoxin Bsubunit mutant scaffold, and a cargo molecule such as a drug
or imaging agent, which may be directly linked to the
subunit or may be packaged in a liposome, nanoparticle, or
the like.
In some instances, the targeting domain may have
affinity for a blood brain barrier antigen and may be capable
of inducing cell-mediated transcytosis to facilitate the
delivery of cargo molecule across the blood brain barrier. In
some instances, the targeting region may have affinity for a
cancer antigen and may be capable of inducing cell-mediated
endocytosis [45]. Tchistiakova et al. invented a polypeptide
comprising of at least one peptide following motif of
sequence identity number : Yl-Y2-X-Y3-X-Y4-X-Ys, where
Y1 is a positively charged amino acid; such as Arg or Lys;
Y2 is Val, Leu, Ile or Met; Y3 is negatively charged amino
acid such as Glu or Asp; Y4 is negatively charged amino
acid such as of Glu or Asp; Ys is Thr; X is any amino acid,
an analogue, or a derivative comprising of one or more
ligands in association with a carrier. The association of the
ligand and the carrier can be achieved by chemical, genetic
or physical linking of the ligand and the carrier, by mixing
the above components or by their co-administration [46].
Beliveau et al. in 2002 invented polypeptides derived
from aprotinin and aprotinin analogues as well as conjugates
and pharmaceutical compositions comprising of these
polypeptides for treating a patient of a neurological disease.
The invention also related to the use of these polypeptides
for transporting a compound or drug across the blood brain
barrier [47]. Further, US patent application 20060182684A1
Beliveau; Richard [48] and US patent application
20060189515A1 Beliveau et al. related to a non-invasive and
flexible method and carrier for transporting a compound or
drug across the blood brain barrier of an individual. This
comprised of the step of administering to the patient a
compound comprising of the agent attached to aprotinin, a
pharmaceutically acceptable salt of aprotinin, a fragment of
aprotinin or a pharma-ceutically acceptable salt of a
fragment of aprotinin [49]. Receptor-recognizing molecular
fragment(s) in the form of proteins like apolipoproteins
bonded to the particle surface for the delivery of drug to
specific tissue or CNS was described by Mueller et al. [50].
The use of molecular Trojan horses to ferry drugs or
genes across the BBB is described in U.S. Patent Nos.
4801575 and 6372250 [51, 52]. The linking of drugs to MAb
transport vectors is facilitated with the use of avidinbiotin
technology. In this approach, the drug or protein therapeutic
CNS Drug Delivery
is monobiotinylated and bound to a conjugate of the antibody
vector and avidin or streptavidin.
The use of avidin-biotin technology to facilitate linking
of drugs to antibody-based transport vectors is described in
US patent number 6287792 [53]. Fusion proteins have also
been used, where a drug is genetically fused with the MAb
transport vector. More particularly, the present invention
involves the development of "humanized" monoclonal
antibodies MAb that may be attached to pharmaceutical
agents to form compounds that are able to readily bind to the
human insulin receptor (HIR). The compounds are able to
cross the human BBB by way of insulin receptor-mediated
endocytosis, the receptors being located on the brain
capillary endothelium. Composition that is capable of
delivering a large enzyme across the BBB comprising: a
large enzyme; and a blood brain barrier targeting agent
linked via an avidin-biotin linkage [54].
In the field of peptide discovery for carrying drugs
through the blood brain barrier, Forni et al. invented a
peptide comprising of the sequence: H2N-Gly-Phe-D-ThrGly-Phe-Leu~Ser-CONH23, wherein the serine residue may
be functionalised with sugar residues; other amino acids can
replace the first two amino acids of the N-terminal portion,
The order of which can be reversed, and their number may
be different from two. The invention also relates to a
conjugate of said peptides with a pharmaceutically
acceptable polyester or polyamide polymer, nanoparticle
systems comprising said conjugates, and pharmaceutical
compositions comprising said nanoparticle systems to
prepare medicinal products designed to cross the blood brain
barrier. Wherein, the said medicinal products take the form
of nanoparticle systems [55]. Hochman Shawn in patent
application WO2005094497 provides methods for delivering
a neuroactive fusion molecule across the blood-brain or
blood-nerve barriers comprising: (a) administering by nonintramuscular means, a neuroactive fusion molecule
comprising a therapeutic polypeptide and a delivery
polypeptide to a subject, such that the bloodstream of the
said subject is capable of transporting said administered
neuroactive fusion molecule to a fenestrated capillary of the
said subject; and (b) wherein, said administered fusion
molecule is delivered across said fenestrated capillary and
into a neurone.
The neurone can be, for example, a central nervous
system neurone, a peripheral neurone, an enteric nervous
system neurone, or an autonomic nervous system neurone
[56]. Ferguson Ian A. in US2003083299 patented methods
for delivering polypeptides into central nervous system
(CNS) tissue in humans. It also relates to methods for
targeting the delivery of polypeptides to specific populations
or types of neurons that reside entirely within the brain or
spinal cord tissue. For that a genetic vector is used to
transfect one or more neurons which "straddle" the BBB,
such as sensory neurons, nocioceptive neurons, or lower
motor neurons. This is done by administering the vector in a
manner that causes it to contact neuronal projections that
extend outside the BBB. Once inside a peripheral projection
that belongs to a BBB-straddling neuron, the vectors will be
transported into the main cell body of the neuron through a
process called retrograde transport. Inside the main cell
Recent Patents on Drug Delivery & Formulation, 2009, Vol. 3, No. 1
75
body, at least one gene carried by the genetic vector will be
expressed to form polypeptides. Some of these polypeptides
(which can include leader sequences that will promote
anterograde transport and secretion by BBB-straddling
neurons) will be transported by the neurons to secretion sites
inside the BBB. The polypeptides will be secreted by
transfected neurons at locations inside the BBB, and will
then contact and exert their effects upon secondary "target"
neurons located entirely within the BBB. By using this
system, polypeptides that stimulate nerve growth or activity
can be used to treat neurodegenerative diseases, impaired
limbs in stroke victims, etc., and polypeptides that suppress
neuronal activity can be used to treat unwanted excessive
neuronal activity, such as neuropathic pain. This approach
also provides new methods for delivering endocrine and
paracrine polypeptides into the CNS, thereby allowing
improved medical and reproductive treatments in humans,
and improved ability to modulate growth, maturation,
reproduction or other endocrine-related functions among
livestock, endangered species, and other animals [57].
An invention that pertains to compositions for increasing
the permeability of the bloodbrain barrier in an animal is
patented by Kozarich et al. These compositions are
permeabilizers of the blood-brain barrier which are peptides
having a core sequence of amino acids or amino acid
analogues. In the core peptide, the sequence is arginineproline-hydroxyproline-glycine-thienylalanine-serineproline-4-Me-tyrosine-(CH2NH)-arginine [58].
In 2007, Daneman et al. discovered that the NgRHl cell
surface receptor, an antigen preferentially expressed in
endothelial cells, is involved in regulating blood-brain
barrier (BBB) permeability. Invention provides a method of
modulating BBB permeability comprising of the step of
administering an agent to a subject, wherein the said agent
targets a human NgRHl cell surface receptor that is present
in the brain. Non- limiting examples of the agents useful for
modulating BBB permeability via NgRHl include inorganic
molecules,
peptides,
peptide-mimetics,
antibodies,
liposomes, small interfering RNAs, antisense protiens,
aptamers and external guide sequences [59].
In US patent number 4801575 Pardridge, describes the
preparation of chimeric peptides by coupling or conjugating
the pharmaceutical agent to a transportable peptide. The
chimeric peptide purportedly passes across the barrier via
receptors for the transportable peptide. Trans-portable
peptides, or vectors, mentioned as suitable for coupling to
the pharmaceutical agent include insulin, transferrin, insulinlike growth factors I and II, basic albumin and prolactin [60].
U.S. patent number 4902505 to Pardridge et al. describes the
use of chimeric peptides for neuropeptide delivery through
the blood-brain barrier. A receptor-specific peptide is used to
carry a neuroactive hydrophilic peptide through the BBB.
The disclosed carrier proteins, which are capable of crossing
the BBB by receptor-mediated trans-cytosis, include histone,
insulin, transferrin, insulin-like growth factor I (IGF-I),
insulin-like growth factor II (IGF-II), basic albumin and
prolactin [61]. U.S. patent number 5442043 to Fukuta et al.
disclosed using an insulin fragment as a carrier in a chimeric
peptide for transporting a neuro-peptide across the bloodbrain barrier [62]. Bentley et al. in 2003 provided a method
76 Recent Patents on Drug Delivery & Formulation, 2009, Vol. 3, No. 1
for delivering a peptide into the brain of a human or other
animal through the blood-brain barrier. The peptide to be
delivered is bonded to a water soluble, non-peptidic polymer
to form a conjugate. The conjugate is then administered into
the blood circulation of an animal so that the conjugate
passes across the blood-brain barrier and into the brain. The
water-soluble non-peptidic polymer can be selected from the
group consisting of polyethylene glycol and copolymers of
polyethylene glycol and polypropylene glycol activated for
conjugation by covalent attachment to the peptide [63].
US Patent number 5833988 to Friden described a method
for delivering a neuropharmaceutical or diagnostic agent
across the blood-brain barrier employing an antibody against
the transferrin receptor. A nerve growth factor or a
neurotrophic factor is conjugated to a transferrin receptorspecific antibody. The resulting conjugate is administered to
an animal and is capable of crossing the BBB [64]. Another
method for delivering hydrophilic compounds into the brain
by receptor-mediated transcytosis is described by Pardridge
et al. A monoclonal antibody to the transferrin receptor
(OX26 MAb) modified with streptavidin is used to transport
the cationic protein, brain-derived neurotrophic factor
(BDNF) through the BBB. BDNF is first modified with
PEG.sup.2000-biotin to form BDNF-PEG.sup.2000-biotin,
which is then bound to the streptavidin-modified antibody
OX26 MAb. The resulting conjugate was shown to be able to
cross the BBB into the brain [65].
Temsamani et al. patented use of taxoid for brain
cancers, a compound consisting of at least one taxol
derivative bound to at least one vector peptide capable of
increasing the solubility of the said derivative and advantageously of allowing it to be transported across the blood
brain barrier. The invention also relates to the preparation of
these compounds and to the pharmaceutical compositions
containing them, useful for the treatment of cancers, most
particularly of brain cancers [66]. Temsamani et al. also
patented a compound consisting of at least an antibody or an
antibody fragment bound to at least a vector peptide capable
of transporting it across the BBB [67].
In US patent application 20070264351 Nelson et al.
invented a highly efficient artificial low-density lipoprotein
(LDL) carrier system for the targeted delivery of therapeutic
agents across the blood-brain barrier (BBB). In particular,
this invention relates to artificial LDL particles comprised of
three lipid elements: phosphatidyl choline, fatty-acylcholesterol esters and at least one apolipoprotein. The
present invention further relates to compositions, methods
and kits comprising of artificial LDL particles for targeting
drugs to and across the BBB for the prevention and treatment
of brain diseases [68].
3.1.3. CNS Drug Delivery Through Novel Carriers
3.1.3.1. Colloidal Drug Carriers
In general, colloidal drug carriers include micelles,
emulsions, liposomes and nanoparticles (nanospheres and
nanocapsules).It is noteworthy that only liposomes and
nanoparticles have been largely exploited for brain drug
delivery because the methods of preparation are generally
simple and easy to scale-up [69]. The aim of using colloidal
carriers is generally, to increase the specificity towards cells
Ahmad et al.
or tissues, to improve the bioavailability of drugs by
increasing their diffusion through biological membranes
and/or to protect them against enzyme inactivation. Moreover, the colloidal systems allow access of non-transportable
drugs across the BBB by masking their physicochemical
characteristics through their encapsulation in these systems.
The fate of colloidal particles after intravenous administration is determined by a combination of biological and
physicochemical events that need to be considered in the
design of efficient drug carrier systems. After intravenous
administration, all colloidal immunoglobulins, albumin, the
elements of the complement, fibronectin, etc may undergo a
process known as “opsonization” thus, colloidal particles
that present hydrophobic surface properties are efficiently
coated with plasma components (opsonins) and rapidly
removed from the circulation, since the macrophages of the
liver and the spleen own their specific receptors for these
opsonins. However, colloidal particles that are small and
hydrophilic enough can escape, at least partially, from the
opsonization process and consequently, remain in the
circulation for a relatively longer period of time.
Additionally, the concept of “steric hindrance” has been
applied to avoid the deposition of plasma proteins either by
adsorbing some surfactant molecules (such as copolymers of
polyoxyethylene and polyoxypropylene) at the surface of the
colloids or by providing a sterical stability by the direct
chemical link of polyethyleneglycol (PEG) at the surface of
the particles. In addition, active targeting can be achieved by
the attachment of a specific ligand (such as a monoclonal
antibody) onto the surface of the colloidal particle,
preferentially at the end of the PEG molecules, since the
targeted colloidal particles will be much more efficient if
they are also sterically stabilized [70-72]. The fate of various
colloidal carriers after administration is illustrated in Fig. (2)
given below.
Polymeric Micelles and Microemulsions
Polymeric micelles as drug delivery systems are formed
by amphiphilic copolymers having an A-B diblock structure
with A, the hydrophilic (shell) and B, the hydrophobic (core)
polymers. The polymeric micelles are thermodynamically
and kinetically stable in aqueous media. They have a size
range of several tens of nanometers with a considerably
narrow distribution. This narrow size range is similar to that
of viruses and lipoproteins. Several reviews have analyzed in
great detail, the properties of the different copolymers used
in the preparation of the polymeric micelles, as well as the
physical chemistry of these systems, which may influence
their properties such as their size distribution, stability, drugloading capacity, drug release kinetics, blood circulation
time and biodistribution [73-75].
Earlier studies have shown that poloxamer (PluronicTM)
micelles conjugated with antibodies may improve brain
distribution of haloperidol, a neuroleptic agent. This
approach has resulted in a dramatic improvement of drug
efficacy. This result indicates that PluronicTM micelles
provide an effective transport of solubilized neuroleptic
agents across the BBB [76]. However, recent investigations
made by the same group demonstrated that only PluronicTM
unimers allowed cell penetration in bovine BMEC
monolayers of molecules such as rhodamine-123, digoxin or
CNS Drug Delivery
Recent Patents on Drug Delivery & Formulation, 2009, Vol. 3, No. 1
77
Fig. (2). Fate of various colloidal carriers after oral administration.
doxorubicin by inhibition of the P-gp-mediated drug-efflux
system. Other studies have shown an increased analgesic
effect when enkephalin, biphalin or morphine were administered as a cocktail with Pluronic P-85 at a concentration of
0.01%. It is noteworthy that the analgesia was lower with a
higher concentration of Pluronic P-85 (0.1%) due to micellar
trapping, which reduces the free drug concentration available
for transcellular flux [77-80]. Ringe et al. invented a method
of producing a delivery vehicle by the miniemulsion method,
comprising of nanoparticles made by the said method,
optionally also having a surface-modifying agent and a
pharmaceutical agent to cross one or more physio-logical
barriers, in particular the blood-brain-barrier. This
subsequently showed modified-release characteristics such
as sustained-release or prolonged-release of a pharmaceutical
agent in the target tissue [81].
Polymeric Nanoparticles
Therapeutic strategies to probe the CNS are limited by
the restrictive tight junctions at the endothelial cells of the
BBB. To overcome the impositions of the BBB, polymeric
biocompatible drug carriers, e.g., nanoparticles, liposomes
have been applied to the CNS for many applications such as
cancers. Nanoparticles mostly consist of polymers and are
about 10 to 200 nm in size. Some researchers managed to
produce efficient nanoparticles that ensure rapid transport of
drug-charged particles across the BBB. Nanoparticles from
polybutyl cyanoacrylate are able to transport drugs by encapsulating or binding them to the surface of the nanoparticles
[82]. However, these nanoparticles cannot be transported
directly across the BBB only by coating them with Polysorbate-80.
Nanoparticles consisting of polycyanoacrylate that were
coated with polyethylene glycol could only overcome the
BBB if, due to an infection of the brain, the BBB is defective
and has become more permeable [83]. Wang et al. found a
cationic polymer (polyethylenimine) with which the drug can
bypass the BBB and which uses an intramuscular injection in
the tongue to introduce drugs into the brain using retrograde
axonal transport. Rousselle et al. transported doxorubicin
across the BBB using a peptide vector. The drug to be
transported is covalently bound to D-penetrantin, a peptide,
and synB1, which facilitate transport across the BBB without
78 Recent Patents on Drug Delivery & Formulation, 2009, Vol. 3, No. 1
causing efflux by the P-glycoprotein. Other ways include
transporting nanoparticles via the transferrin receptor by
binding them to ligands. This system however has the
setback that the particles can be charged with a small
quantity of the substance to be transported only [84].
Compared with other colloidal carriers, polymeric
nanoparticles present a higher stability when in contact with
the biological fluids. Also, their polymeric nature permits the
attainment of the desired properties such as controlled- and
sustained-drug release. Ideal properties of nanoparticles to
cross the CNS are mentioned in Table 2. A number of
possibilities which can explain the mechanism of the
delivery of drugs by nanoparticles across the blood-brain
barrier are as follows:
1.
An increased retention of the nanoparticles in the brain
blood capillaries combined with an adsorption to the
capillary walls could create a higher concentration
gradient that would enhance the transport of drug across
the endothelial cell layer and as a result its delivery to
the brain.
2.
A general surfactant effect characterized by the
solubilization of endothelial cell membrane lipids that
would lead to membrane fluidisation and enhanced drug
permeability through the BBB.
3.
The nanoparticles could lead to an opening of the tight
junctions between the endothelial cells. The drug could
then permeate through the tight junctions either in free
form or together with the nanoparticles in bound form.
4.
The nanoparticles may be endocytosed by the
endothelial cells followed by the release of the drug
within these cells and its delivery to the brain.
5.
The nanoparticles with bound drugs could be transcytosed through the endothelial cell layer.
6.
The Polysorbate-80 used as the coating agent could
inhibit the efflux system, especially P-glycoprotein
(Pgp) [85].
Heppe et al. in US2006051423 patented a chitosan-based
transport system for overcoming the BBB. The transport
system contains at least one substance selected from the
group consisting of chitin, chitosan, chitosan oligosaccharides, glucosamine and derivatives thereof (molecular
weights ranging from 179 Da to 400 kDa), and optionally
one or more active agents and/or one or more markers and/or
one or more ligands [87]. Chen patent number CN1850032
Table 2.
Ahmad et al.
disclosed a nano prepa-ration of antimycotic amphotericin B
(AmB) using n-butyl polycyanoacrylate as carrier material
[88]. WO2004017945 discloses the use of nanoparticles for
the transfection of DNA into eukaryotic cells. It further
discloses the DNA administration to a target organ in the
human or animal body, for example, the brain in the case of
brain tumours. It also discloses the use of substances
(stabilizers) which act as enhancers of the bond between the
DNA
and
the
nano-particles.
Among
others,
Diethylaminoethyl-(DEAE)-dextran and dextran 70,000 are
listed as stabilizers [89].Kreuter et al. WO2007110152
invented a system for targeted-active substance delivery for
administering a pharma-cologically active substance to the
CNS of a mammal across the BBB, where the system for
targeted-drug delivery comprises of nanoparticles of
Poly(DL-lactide) and/or Poly(DL-lactide-co-glycolide and at
least one pharmacologically active substance which is
absorbed into the nanoparticles, adsorbed thereon or is
incorporated therein, and includes a coating of the surfaceactive substance Pluronic(TM) 188, which is deposited on the
nanoparticles loaded with active substance, and to methods
for producing the system for targeted active substance
delivery and the use of the system for targeted active
substance delivery for the treatment of a disease or an
impairment of the CNS [90]. Kreuter Jorg et al. US6117454
disclosed a novel method of delivering drugs and diagnostics
across the BBB. Drugs or diagnostic agents are incorporated
into nanoparticles which have been fabricated in
conventional ways. These nanoparticles are then coated with
additional surfactant and adminisrered to animals or humans.
This invention is based on the surprising finding that
treatment of nanoparticles having a drug absorbed, adsorbed
or incorporated therein with a sufficient coating of an
appropriate surfactant allows the adsorbed drug to traverse
the BBB. The basic drug targeting system is made by the
following process:
a.
Formation of a suspension of nanoparticles by
polymerization or dispersion,
b.
Sorption of an active ingredient to the nanoparticle, and
c.
Coating such nanoparticles with one or more layers of
an appropriate surfactant [91].
U.S. patent no. US6419949 invented by Gasco Maria
Rosa disclosed pharmaceutical compositions in the form of
nanoparticles suitable for passage through the intestinal
mucosa, the BBB and the BCFB. Said nanoparticles have a
size ranging from 40 to 150 nm, and are formed by one or
Ideal Properties of Nanoparticles For Crossing CNS [86]
Ideal Properties of Nanoparticles for Brain Drug Delivery
•
Nontoxic, biodegradable, and biocompatible
•
Scalable and cost-effective manufacturing process
•
Particle diameter between 10- 100 nm
•
Amenable to small molecules, peptides, proteinsor nucleic
acids
•
Formulation stability, minimal nanoparticle excipient-induced
drug alteration (chemical degradation/ alteration, protein
denaturation)
•
Controlled-drug release profiles
•
Physical stability in vivo and in vitro
•
Avoidance from RES (Reticulo-endothelial system) leads to
prolonged blood circulation time
•
CNS targeted delivery via receptor-mediated transcytosis across
brain capillary endothelial cells
CNS Drug Delivery
more lipids optionally in combination with a steric stabilizer
and by a drug. They are prepared dispersion in an aqueous
medium at 2-4°C, a hot prepared oil/water or water/oil/water
microemulsion comprising one or more lipids, a surfactant
agent, a cosurfactant and optionally a steric stabilizer [92].
Dennis et al. in US 7195780 invented a nanotube
comprising: a hollow tubular body comprising a first end and
a second end, wherein the first end is open; and a first end
cap positioned over the first open end, wherein the end cap is
attached to the hollow tubular body by a covalent bond and
the particle has a maximum dimension of less than 100 m.
Alternatively, the nanocap can be held in place by
electrostatic forces, hydrogen bonding or other non-covalent
interactions. The present invention provides a method for the
in vivo delivery of a bioactive agent comprising of administering the bioactive agent contained within a nanotube to
target the CNS [93]. Sabel in US patent application
20020034474A1 disclosed a composition and method of
fabrication in which nanoparticles may be used as a tool to
deliver drugs to a specific target within or on a mammalian
body, specifically, by using stabilizers other than Dextran
70,000 during the polymerization process. In the present
invention, a drug is either incorporated into or adsorbed onto
the stabilized nanoparticles. This drug/nano-particle complex
is then administered to the organism through any route such
as by oral administration, injection or inhalation, whereupon
the drug exerts its effects at the desired site of pharmacological action. The present invention also discussed a
method of preparation of non-coated nanoparticles as drug
carriers for a wide range of drugs in order to allow the
targeting of drug to a specific site in the mammalian body,
specifically in order to enhance the penetration of drugs or
diagnostic agents across the BBB. The said method does not
require a coating procedure during the fabrication of
nanoparticles. Nanoparticles could be prepared by
polymerization, in a per se known manner, one or more
monomeric and/or oligomeric precursor(s) of said polymeric
material in the presence of said stabilizer(s); loading one or
more physiologically effective substance(s) to be delivered
[94]. Few patents also disclosed nanosizing of neurotherapeutic agents to improve their efficacy as by Gustow et
al. who envisaged a nanosized fromulation of the topiramate,
an antiepileptic agent, to improve its efficacy and reduce its
dose [95].
Solid lipid nanoparticles (SLN) were developed at the
beginning of the 1990s as an alternative carrier system to
emulsions, liposomes, and polymeric nanoparticles. SLN can
provide advantages including stabilization of incorporated
compounds, controlled release, and occluviseness. The solid
lipid nanoparticles by virtue of surface functionalization,
neutral lipid character and nanoscale particle sizecan
effectively transport a delivery package such as biologically
active agents, pharmaceutically active agents, magnetically
active agents, and/or imaging agents across the BBB and into
the brain tissue [96-98].
Shastri et al. in WO2006044660 discloses an invention
which relates to methods of delivering at least one
biologically, pharmaceutically or magnetically active agent,
or imaging agent across the BBB, cellular lipid bilayer and
into a cell, and to a subcellular structure with functionalized
solid lipid nanoparticles comprising a neutral lipid and
Recent Patents on Drug Delivery & Formulation, 2009, Vol. 3, No. 1
79
functionalized polymer comprising of at least one ionic or
ionizable moiety. The patent also discloses method of SLN
preparation, as lipids and pharmaceutically active agents for
preparing the solid lipid nanoparticles of the invention
compositions can be dissolved in a binary solvent system
comprising, for example, of dimethylformamide and acetone.
An aqueous solution of comprising functionalized polymer,
for example poly (acrylic acid), can then be added to the
binary solvent system. A system comprising a solid lipid
nanoparticle, a surface functionalized layer surrounding the
solid lipid nanoparticle and a pharmaceutically active agent
is then formed. The solvents can be removed, thereby
yielding a system for the delivery of a pharmaceutically
active agent across the blood brain barrier [99].
Liposomes for CNS Drug Delivery
It has also been suggested that liposomes can enhance
drug delivery to the brain across the BBB. Liposomes are
small vesicles (usually submicron-sized) comprising of one
or more concentric bilayers of phospholipids separated by
aqueous compartments. Although liposomes have been
reported to enhance the uptake of certain drugs into the brain
after intravenous injection [100].
US patent application 20020025313A1 Micklus et al.
disclosed immunoliposomes and pharmaceutical compositions capable of targeting pharmacological compounds to
the brain. Liposomes are coupled to an antibody binding
fragment such as Fab, F(ab').sub.2, Fab'or or a single chain
polypeptide antibody which binds to a receptor molecule
present on the vascular endothelial cells of the mammalian
BBB. Typically the antibody binding fragment is prepared
from a monoclonal antibody. The receptor is preferably of
the brain peptide transport system, such as the transferrin
receptor, or insulin receptor, IGF-I or IGF-2 receptor. The
antibody binding fragment is preferably coupled by a
covalent bond to the liposome [101]. CN1833633 Chen Ya
Li patented a liposome able to pass through blood brain
barrier contains the blood brain barrier anchor site (5-15 mol
%), the phosphatide with high phase-change temp,
cholesterol and fusion aid.
A composite medicine using said liposome as a carrier
for passing through the blood brain barrier for treating the
diseases of the central nerve system and its preparing process
are also disclosed [102]. Pardrige disclosed a non-invasive
gene targeting to brain by liposomes. Liposomes containing
therapeutic genes are conjugated to multiple brain barrier
and brain cell membrane targeting agents to provide
transport of the encapsulated gene across the BBB. After
crossing the BBB, the encapsulated gene expresses the
encoded therapeutic agent within the brain to provide
therapeutic effect and diagnosis of neurological disorders
[103]. Pardrige and Huwyler disclosed liposomes for
transporting the therapeutic agents across the CNS. Invention
discusses brain specific targeting vehicle for transporting
neuropharmacological agents across the BBB. Liposomes are
sterically stabilized by attaching ligands to the surface of the
liposomes [104]. As several patents disclosed the use of
liposomes as a potential delivery system for brain targeting,
many research papers also supported the use of liposomes for
CNS drug delivery as given in Table 3 below [105-111]:
80 Recent Patents on Drug Delivery & Formulation, 2009, Vol. 3, No. 1
3.2. Invasive Methods
Although, the ease and compliance of non-invasive
delivery methods is often not associated with direct or
invasive delivery of drugs to the brain, it often shows up as
the sole alternative wherein the drugs elicit right physicochemical properties. Generally, only low molecular
weight, lipid-soluble molecules and a few peptides and
nutrients can cross this barrier to any significant extent,
either by passive diffusion or using specific transport mechanisms [112]. So, for most drugs it is not possible to achieve
therapeutic levels within the brain tissue following
intravenous or oral administration. In addition, highly potent
drugs (e.g., anticancer drugs and neurotrophic factors) that
may be necessary to be delivered to the CNS, often cause
serious toxic side effects when administered systemically.
The drug can be administered directly into the brain tissue
[113]. Many ways are explored for direct intracranial drug
delivery by intracerebroventricular, intracerebral or
intrathecal administration after creating holes in head or
Disrupting the BBB integrity by osmotic blood brain barrier
disruption or biochemical BBB disruption and also by
employing controlled release biodegradable drug delivery
systems which are able to control the release rate of an
incorporated drug in a pre-determined manner over periods
of days to months [114-120].
3.2.1. Disruption of the BBB
One of the earliest techniques to circumvent the BBB for
therapeutic purpose and the first to be used in humans was
developed by Neuwelt (1989). The idea behind this approach
was to break down the barrier temporarily by injecting a
sugar solution (mannitol) into arteries in the neck. The
resulting high sugar concentration in brain capillaries sucks
water out of the endothelial cells, shrinking them thus
opening the tight junctions [121]. In current practice, the
effect lasts for 20-30 min, during which the drugs that would
not normally cross the BBB diffuse freely. This method
Table 3.
Ahmad et al.
allows the delivery of chemotherapeutic agents in patients
with malignant glioma, cerebral lymphoma and disseminated
CNS germ cell tumours, with a subsequent decrease in
morbidity and mortality compared with patients receiving
systemic chemotherapy alone. However, this approach also
causes several undesirable side effects in humans, including
physiological stress, transient increase in intracranial
pressure, and unwanted delivery of anticancer agents to
normal brain tissue. In addition, this technique requires
considerable expertise for administration. However,
disrupting the BBB even for brief periods leaves the brain
vulnerable to infection and damage from toxins. Even
substances that circulate harmlessly through the peripheral
bloodstream, such as albumin, can have deleterious effects if
they enter the brain [122]. Intrathecal injection allows
administration of agents directly into the brain ventricles and
spinal fluid by puncturing the membranes surrounding the
brain. Sustained-delivery of agents directly into the spinal
fluid can be attained by the use of infusion pumps that are
implanted surgically. These spinal fluid delivery techniques
are used to treat brain cancers, infections, inflammation and
pain. However, they do not penetrate deeply into the brain.
Clinicians prefer to avoid intrathecal injections because they
frequently are ineffective and can be dangerous. Substances
injected intrathecally are distributed unevenly, slowly and
incompletely in the brain. Since the volume of the spinal
fluid is small, increase in intracerebral pressure may occur
with repeated injections. Furthermore, improper needle or
catheter placement can result in seizure, bleeding,
encephalitis and a variety of other severe side effects [123].
In WO9807367 Jolesz discloses image guide methods and
apparatus for ultrasound delivery of compounds through the
blood brain barrier to selected locations in the brain, target a
selected location in the brain of a patient, and apply
ultrasound to affect the tissues and/or fluids, at that location,
a change detectable by imaging. At least a portion of the
brain in the vicinity of the selected location is imaged, e.g.,
Liposomes for Brain Targeting
Candidate Drug
Amphotericin B
Type of Liposome
Target CNS Disease
Route of Administration
Reference
Liposomes (commercial
Infection
Intravenously
[105]
Autoimmune
Intravenously
[106]
Brain Tumour
Intravenously
[107-108]
formulation Ambisone®,
Fujisawa, USA)
[3H]-Prednisolone
Pegylated liposomes
Encephalitis
Doxorubicin
Pegylated liposomes
(commercial formulation
Caelyx®)
IFN- gene plasmid
Cationic liposomes
Brain Tumour
Intratumoural
[109]
Antisense epidermal
growth factor
Cationic liposomes
Brain Tumour
Intratumoural
[110]
Doxorubicin
Polymeric nanoparticles
Glioblastoma
Intravenous
[3]
Quinoline derivatives
Polymeric nanoparticles
Alzheimer’s Disease
Intravenous
[111]
CNS Drug Delivery
via magnetic resonance imaging to confirm the location of
that change. A compound, e.g., a neuro-pharmaceutical in
the patient's bloodstream, is delivered to the confirmed
location by applying ultrasound to effect opening of the
blood brain barrier at that location, and thereby to induce
uptake of the compound there [124]. An another PCT
application entitled “ Parenteral delivery system” disclosed
hypertonic solution of sugar by different means of administration to open the BBB to permit the entry into the CNS of a
co-administered chemical compound such as nutrient or a
therapeutic or a diagnostic agent [125].
3.2.2. Direct Drug Delivery
One strategy to overcome the BBB that has been used
extensively in clinical trials is the direct administration of
drugs by intraventricular and intracerebral routes. The drugs
can be infused intraventricularly using a plastic reservoir
(Ommaya reservoir) implanted subcutaneously in the scalp
and connected to the ventricles within the brain via an outlet
catheter.Unfortunately, there are several problems, apart
from the surgical intervention required. Firstly, in the human
brain the diffusion distances from cerebrospinal fluid (CSF)
to a drug target site may only be several centimeters, and for
drugs relying only on diffusion for penetration, insufficient
concentration of drug may reach the target site Secondly, the
microvessels of the brain secrete interstitial fluid at a low but
finite rate, generating a flow towards the CSF spaces, which
also works against diffusive drug penetration. Finally, the
high turnover rate of the CSF (total renewal every 5-6 hrs in
humans) means that injected drug is being continuously
cleared back into the blood. In practice, drug injection into
the CSF is a suitable strategy only for sites close to the
ventricles. For drugs that need to be at elevated levels for
long periods for an effective action, continuous or pulsatile
infusion may be necessary [126,127].
WO2004043334 disclosed an apparatus for delivering a
non steroidal anti -inflammatory drug (NSAID) supplied to
the body of a subject for delivery to at least a portion of a
CNS of the subject via the systemic blood circulation,
including a stimulator adapted to stimulate at least one site of
the subject, during at least a portion of the time when the
NSAID is present in the blood. The apparatus uses electrical,
chemical, mechanical and/or odorant stimulation [128].
Shalev and Gross invented an apparatus for modifying a
property of the brain of a patient, including electrodes
applied to the sphenopalatine ganglion (SPG) or a neural
tract originating in or leading to the SPG. A control unit
drives the electrodes to apply a current capable of inducing
(a) an increase in permeability of a BBB of the patient, (b) a
change in cerebral blood flow of the patient, and/or (c) an
inhibition of the parasympathetic activity of the SPG [129].
US Patent 5752 515 to Jolesz et al. describes an apparatus
for image-guided ultrasound delivery of compounds through
the BBB. At least a portion of the brain in the vicinity of the
selected location is imaged, e. g., via magnetic resonance
imaging, to confirm the location of that change. A compound, e.g., a nerotherapeutic, in the patient's bloodstream is
delivered to the confirmed location by applying ultrasound to
effect opening of the BBB at that location and, thereby, to
induce uptake of the compound there [130]. US Patent
6405079 describes a method for the suppression or
Recent Patents on Drug Delivery & Formulation, 2009, Vol. 3, No. 1
81
prevention of various medical conditions, including pain,
movement disorders, autonomic disorders and neuropsychiatric disorders. The method includes positioning an
electrode adjacent to or around a sinus, orfalx cerebri and
activating the electrode to apply an electrical signal to the
site. In a further embodiment for treating the same
conditions, the electrode dispenses a medication solution or
analgesic to the site. The patent also describes surgical
techniques for implanting the electrode [131]. Miller Landon
et al. provided a direct central nervous system catheter which
can be directly inserted into the ventricle space or spinal
canal to provide access which enables the sampling of the
CSF and/or monitoring of intracranial pressure while at the
same time facilitating the aseptic delivery of therapeutic
agents and/or drugs directly into the cerebrospinal fluid and
the management of CSF temperature. The direct CNS
catheter includes a catheter body defining at least one lumen
and having a drug delivery branch, a monitoring/sensing
branch, and optional branches if desired, each branch being
connected in fluid communication with the lumen [132].
US2006009450 Tobinick provides specific methods of using
and administering etanercept to improve cognitive function
in a human, for both the treatment and prevention of
cognitive impairment or, alternatively, to enhance cognitive
function. The methods of the present invention include not
only the perispinal administration of etanercept (which itself
can be accomplished in various ways, including transcutaneous, interspinous injection or catheter delivery into the
epidural or interspinous space) but also other novel methods
of localized administration, specifically including intranasal
adminis-tration.
Perispinal
administration
involves
anatomically localized delivery performed so as to place the
therapeutic molecule directly in the vicinity of the spine, and,
for the purposes of this patent, administration which is
outside of the intrathecal space [133]. In US patent
application 20070055214A1 Gilbert entitled “Method for
delivering drugs to tissue under microjet propulsion”
disclosed a new and useful device and method for the
needle-free delivery of drugs with minimal trauma to tissue
and that are suitable for delivering drugs in sensitive areas of
the body such as the eye, nasal passageways, brain, mouth
and other areas of the body [134].
US5720720 Laske et al. disclosed a method of high-flow
microinfusion which provides convection-enhanced delivery
of agents into the brain and other solid tissue structures. The
method involves positioning the tip of an infusion catheter
within a tissue structure and supplying an agent through the
catheter while maintaining a pressure gradient from the tip of
the catheter during infusion. Agent delivery rates of 0.5 to
15.0 l/min have been used experimentally with infusion
distances greater than 1 cm from the delivery source. The
method can be used to deliver various drugs, protein toxins,
antibodies for treatment or imaging, proteins in enzyme
replacement therapy, growth factors in the treatment of
various neurodegenerative disorders, viruses and in gene
therapy. An infusion catheter developed for the high-flow
microinfusion includes a plurality of elongated slits adjacent
to a tapered portion of the catheter which are parallel to the
axis of the catheter and spaced symmetrically about the
circumference thereof. The infusion catheter is used in a
convention-enhanced delivery system in which, after the
82 Recent Patents on Drug Delivery & Formulation, 2009, Vol. 3, No. 1
infusion catheter is positioned in a tissue situs, it is
connected to a pump which delivers a desired agent and
maintains a desired pressure gradient throughout delivery of
the agent [135].
Targeted-drug delivery into the brain desires precise
anatomically localized delivery of the drug to the desired
tissue and benefits from the differentiation or localization of
normal and abnormal tissues. Present systems of imageguided placement of intracranial probes, such as drug
delivery catheters, include framed and frameless technologies, which typically use images acquired preoperatively to
create a three-dimensional space on which the surgical
navigation is based. Framed systems use externally applied
frames to establish the fiducials for navigation, whereas
frameless systems use optical, electromagnetic or ultrasound
sensors and mechanical arms to track the position of surgical
tools and instruments during surgical procedures.
US6537232 Kucharczyk et al. disclosed a device and
method for monitoring intracranial pressure during magnetic
resonance (MR) image-guided neurosurgical procedures,
such as intracranial drug delivery procedures, wherein an
MR-compatible microsensor pressure transducer coupled to
a pressure sensing diaphragm located a) at the tip, b) on a
lateral side, and/or c) in multiple locations of an MRcompatible catheter is inserted into a lateral cerebral
ventricle, cerebral cistern, subarachnoid space, subdural or
extradural spaces, venous sinuses or intraparenchymal tissue
locations under MR imaging guidance, and is used to record
intracranial pressures over hours to days in patients undergoing diagnostic or therapeutic neurologic interventions
[136]. US 7241283 Putz disclosed a method of treating a
tissue region in the brain of a patient comprising: inserting
into the brain an outer catheter having a passageway
extending between a proximal end and at least one port, the
outer catheter guiding the inner catheter to the tissue region;
and transferring fluids between the tissue region and the
proximal end through the passageway [137].
3.2.3. Intracerebral Implants
Over the past few years, research in galenic pharmacy
has allowed the development of implantable polymer
systems which protect active substances against degradation
while at the same time allowing their controlled local release
decreasing the systemic side effects. The advantages of these
implantable polymer systems have recently prompted several
teams to study their use in central nervous system pathologies. Different CNS diseases principally brain tumours and
neurodegenerative disorders such as Parkinson’s and
Huntington’s diseases can be treated with intracranially
administered controlled drug delivery systems [138-140].
The efficiency of various devices has been investigated in
animal models and some systems have also been subjected to
clinical trials [141,142]. The first (and so far only)
pharmaceutical product that is available on the market based
on the principle of intracranial controlled drug delivery is
Gliadel®. It comprises of a disc-shaped wafer, consisting of
BCNU (1,3-bis(2- chloroethyl)-1-nitrosourea; carmustine) as
the drug (loading: 3.85%) and poly[bis(p-carboxyphenoxy)]
propane-sebacic acid (PCPP:SA) as the biodegradable
polymer. Gliadel® was developed in the early to mid 1990’s
by the group of Henry Brem and obtained Food and Drug
Ahmad et al.
Administration (FDA) approval in 1996 for the treatment of
recurrent glioblastoma multiforme [143-145]. A multiparticulate drug delivery system for the same type of treatment
has been proposed by the groups of Benoit and Menei 5fluorouracil (5-FU)-loaded poly (lactic-co-glycolic acid)
(PLGA)-based microparticles. These micro-particles have
the advantage that they can be administered by stereotaxic
means using standard syringes. Thus, both operable and
inoperable tumours can be treated [146]. The most widely
known device is the ALZETTM minipump, a reservoir-type
system which can continuously deliver a solution containing
a drug, for example, dopamine or a dopamine agonist, for up
to four weeks. The delivery is through a cannula which is
chronically implanted into the CNS. Drug delivery directly
to the brain interstitium using polymeric devices releases
unprecedented levels of drug directly to an intracranial target
in a sustained fashion for extended periods of time. The fate
of a drug delivered to the brain interstitium from the
biodegradable polymer was based on:
(1) Rates of drug transport via diffusion and fluid
convection,
(2) Rates of elimination from the brain via degradation,
metabolism and permeation through capillary networks,
and
(3) Rates of local binding and internalization [147].
Controlled-release polymers used to deliver drugs to the
CNS were first demonstrated in U.S. 4883666 [148]. A
method whereby a small controlled-delivery device
implanted into the CNS was used to deliver vasopressin to
the cerebrospinal fluid with zero-order kinetics was
described by Boer et al. [149], but zero-order release was not
obtained for a period beyond one week. In summary, only in
US 4883666 has a method been disclosed whereby
substances can be delivered to the CNS which is clinically
practicable and safe, and which is characterized by long-term
controlled release kinetics. The device is a matrix-system.
The term "matrix" as used herein is defined as a polymeric
carrier matrix that is biocompatible and sufficiently resistant
to chemical and/or physical destruction by the environment
of use such that the matrix remains essentially intact
throughout the release period. This type of release is
particularly desirable as a treatment for a variety of CNS
disorders since it allows targeting of drugs to the brain
without adverse effects arising from variations in delivery.
Nathalie et al. US Patent No. 6803052 describes invention
related to the use of biodegradable microspheres that release
a radiosensitizing anticancer agent for treating glioblastoma.
The use of said biodegradable microspheres according to the
invention results in a patient survival time of least 90 weeks,
a therapeutically effective concentration being maintained in
the parenchymatous area throughout this time. The
microspheres used preferably contain 5-fluorouracil put in to
the tumour by intratissular injection. The radiotherapy
targeting the tumorous mass is dosed at 60 Gy over
approximately 6 weeks. The invention also relates to a
method for producing the biodegradable microspheres by
emulsion-extraction, and to a suspension containing the
biodegradable microspheres obtained using this method
[150]. Sabel et al. disclosed a polymeric drug delivery
system for the delivery of any substance to the central
CNS Drug Delivery
nervous system. The delivery system is preferably implanted
in the central nervous system for delivery of the drug directly
to the central nervous system. These implantable devices can
be used, for example, to achieve continuous delivery of
dopamine, which cannot pass the blood brain barrier, directly
into the brain for an extended time period. The implantable
devices display controlled, "zero-order" release kinetics, a
life time of a minimum of several weeks or months even
when the devices contain water soluble, low molecular
weight compounds, biocom-patibility, and relative noninvasiveness. The polymeric devices are applicable in the
treatment of a variety of central nervous system disorders
[151]. Brem et al. invented a method and devices for
localized delivery of a chemo-therapeutic agent to solid
tumours. The devices consist of reservoirs which release
drug over an extended time period while at the same time
preserving the bioactivity and bioavailability of the agent. In
the most preferred embodiment, the device consists of
biodegradable polymeric matrixes, although reservoirs can
also be formulated from non-biodegradable polymers or
reservoirs connected to implanted infusion pumps. The
devices are implanted within or immediately adjacent to the
tumours to be treated or the site where they have been
surgically removed. The examples demonstrate the efficacy
of paclitaxel and camptothecin delivered in polymeric
implants prepared by compression molding of biodegradable
and non-biodegradable polymers, respectively. The results
are highly statistically significant. These methods can be
used to make micro-implants (micro-particles, microspheres
and microcapsules encapsulating drug to be released), slabs
or sheets, films, tubes, and other structures. A preferred form
for infusion or injection is micro-implants [152].
3.3. Alternative Route of Administration
An alternative route to CNS drug delivery is the
intranasal administration. Intranasal drug administration
offers rapid absorption to the systemic blood avoiding firstpass metabolism in the gut wall and the liver. This route of
administration has been shown to present a safe and
acceptable alternative to parenteral administration of various
drugs. Delivery of drugs into the brain by administering the
drug in the olfactory area and also a small number of patents
has been issued that describe the use of the olfactory
pathways to the brain as possible alternative drug delivery
methods. For example, US Patent No. 5624898 issued by
Frey [153]; WO033813A1 issued by Frey [154];
WO09901229A1 issued by Gizurarson [155] and
WO044350A1 issued by Cevc [156]. US Patent 5756071 to
Mattern et al. describes a method for nasally administering
aerosols of therapeutic agents to enhance penetration of the
blood brain barrier. The patent describes a metering spray
designed for pernasal application, the spray containing at
least one sex hormone or at least one metabolic precursor of
a sex hormone or at least one derivative of a sex hormone or
combinations of these, excepting the precursors of
testosterone, or at least one biogenic amine, with the
exception of catecholamines [157]. CA2560798 Parnell
Francis W. provided the non-invasive transnasal and
transocular drug delivery to the central nervous system using
eriodictyon fluid extract technology. By administration
through the olfactory nerve or the optical nerve, the delivery
of a biologically active substance of interest into the CNS
Recent Patents on Drug Delivery & Formulation, 2009, Vol. 3, No. 1
83
and CSF can be enhanced through bypassing the BBB. The
invention involves the use of eriodictyon fluid extract as an
excipient in compositions and systems for administering
drugs to the olfactory or optical nerve. An apparatus to
enhance the delivery of at least one delivery substance into
the central nervous system of a mammal, utilizing the
olfactory pathway(s) as a direct delivery route for the
substance from an exogenous source via the mammal's
olfactory area to a target site of the mammal's central
nervous system, bypassing the mammal's blood brain barrier
comprising: (a) a drug; (b) an excipient composition
comprising eriodictyon fluid extract; and (c) a pressurized
delivery device, configured to deliver the drug and excipient
to the olfactory nerve administered through nasal route
[158]. In CN1579407 Wu et al. discloses a nasal cavity
administration preparation which can resist the brain
infection of AIDS. It belongs to medicine preparation
technology field for anti-AIDS virus, and uses hydroxyl
inosine as pharmacologic active ingredient, adds in pH value
regulator, penetration advancing agent, thickener, equalpenetration regulator, antiseptic and produces them into a
preparation suitable for nose cavity, solves the problem that
the current medicine with oral, muscle injection or other
modes. The medicine can penetrate the vein blood brain
barrier to the brain, the release and absorption of the
preparation in the invention are quick, the medicine can
gather in the brain, the medicine density in brain is upgraded
prominently, at the same time, the invention has character
that the nasal cavity mucous coat and cilium toxin are small
[159]. Summary of various patents pertaining to intranasal
brain drug delivery is given in the Table 4 mentioned below
[160-199]. As nasal route of administration is found to be a
validated route of drug delivery to brain many scientists have
revealed that ocular route can be the next alternative for CNS
drug targeting. In this regard U.S. 7241283 Abdulrazik,
Muhammad entitled “Method for central nervous system
targeting through the ocular route of drug delivery”.
Surprisingly, the inventor of the present invention has found
that a conventional pharmaceutical agent, when administered
by ocular route of drug delivery, provides good CNS targeting. In the present invention, pharmaceutical composition is
a N-methyl-D-aspartate receptor antagonist. Preferably, the
N-methyl-D-aspartate receptor antagonist is memantine,
brimonidine. A study was conducted to examine for the first
time the neuro-ocular tissue distribution of brimonidine
following one single 50 l instillation of 3H-Alphagan
aqueous solution (0.2%) into the albino rabbit eye.
Both the eyes and the brain were dissected. Both side
specimens of aqueous humor, cornea, iris, lens, vitreous
humor, conjunctiva, sclera, ciliary body, choroid, retina,
optic nerve, optic tract, olfactory bulb, as well as corpus
callosum and blood samples were collected. The corpus
callosum was chosen as an indicator of general availability
of the drug in the brain. The olfactory bulbs were included to
rule out ocular-brain drug delivery through the nasal cavity
[200]. In US20070265203A1 Eriksson et al. disclosed a
method and compositions for modulating blood-neural
barrier (BNB) for the treatment of CNS conditions such as
oedema, and for increased drug delivery efficacy across the
BNB. The present invention further relates to improved tPA
84 Recent Patents on Drug Delivery & Formulation, 2009, Vol. 3, No. 1
Table 4.
Ahmad et al.
Patents Pertaining To Intranasal Brain Drug Delivery
Drug
Application
Delivery
Related Patent
Ref.
Frey II W H. US5624898 (1997)
[160]
Frey II, W H. W000033813 (2000)
[161]
System
Neurotrophic Agents
Brain Disorders
-
Frey II, W H. WO07947A1 (1991)
[162]
Frey II, WH. US20016180603 (2001)
[163-169]
Frey II, W. H. EP0504263B1 (1997)
Frey II, W. H. US20030215398A1 (2003)
Frey II, W. H. US20020072498A1 (2002)
Frey II, W. H. US20016313093 (2001)
Frey II, W. H. US20026342478 (2002)
Frey II, W. H. US20026407061 (2002)
Melanocortin-4
Receptor Agonist
Obesity,
-
Type II Diabetes
Xiao et al. US20030229025A1 (2003)
[170-172]
Xiao et al. US20070004743A1 (2007)
Xiao et al.WO03072056A2 (2003)
Nicotinic Antagonist
Nicotine Withdrawal
-
Houdi, A.A. US20006121289 (2000)
[173]
Folic Acid,
Cholinesterase
Alzheimer's Disease
-
Hussain et al.US20026369058 (2002)
[174]
Liquid, Gel, Powder
Quay, S.C. US20060003989A1 (2006)
[175]
Heller et al. US20060141029A1 (2006)
[176-178]
Galantamine
Catecholic Butane
(NDGA Compounds)
Obesity, Diabetes,
Hypertension
-
Heller et al. US20060141047A1 (2006)
Huang et al. US20060141025A1 (2006)
NMDA Receptor
Antagonist,
MAO Inhibitor
Parkinson's Disease,
Multiple Sclerosis,
Alzheimer's Disease
Extended Release
Dosage Form
Meyerson et al. US20050245617A1 (2005)
[179]
Went et al. US20060252788A1 (2006)
[180-182]
Meyerson et al. US20060240043A1 (2006)
Levin, B. H.: US20050281751A1 (2005)
Delta-9-THC
-
-
Hussain et al. US20036380175 (2003)
[183]
Clotrimazole
Huntington's Disease
-
Cummings et al. US20070037800A1 (2007)
[184]
Huperzine-A
Senile Dementia
-
Tao et al. CN1621039 (2005)
[185]
Neurotrophic Agents
Brain Disorders
Liposomes, Sustained
Release Matrix, Lipid
Based Micelles
Frey et al. WO000033814 (2000)
[186-189]
Frey II, W. H.: WO00033813A1 (2000)
Frey II, W. H.: US20030072793(2003)
Frey II, W. H.: EP1137401B1 (2005)
Proteosomes
Glatiramer
Neurodegenerative
Disorders
Nanoemulsion
Frenkel et al. US20060229233A1 (2006)
[190]
Diazepam
Epilepsy
Microemulsions
Choi et al. US20050002987A1 (2005)
[191,192]
Choi et al. WO04110403A1 (2004)
Benzodiazepines
Valproic Acid
Carbamazepines
Epilepsy
Nasoadhesive
Microemulsions
Ambikanandan et al. 1061/MUM (2005)
[193]
Sedatives
Insomnia
Nasoadhesive
Microemulsions
Ambikanandan et al.1124/MUM/ (2005)
[194]
Triptans, Caffeine
Migraine
Nasoadhesive
Microemulsions
Ambikanandan et al.1125/MUM/ (2005)
[195]
CNS Drug Delivery
Recent Patents on Drug Delivery & Formulation, 2009, Vol. 3, No. 1
85
(Table 4) Contd….
Drug
Application
Delivery
Related Patent
Ref.
System
Maps
Immunomodulator
Dendrimer
Solomon, B.: US20060034855A1 (2006)
[196]
Lorazepam
Epilepsy
Spray
Wermeling, D.P. :US20016610271 (2001)
[197,198]
Wermeling, D.P. :US20010055571A1 (2001)
Zolpidem
Insomnia
Cyclodextrin / Chitosan
Sols
treatment of ischemic cerebrovascular and related diseases in
combination with antagonism of the PDGF signalling pathway. The inventive method and composition is particularly
suitable for conjunctive therapy of ischemic stroke using tPA
and an anti-PDGF-C antagonist or an anti-PDGFR-alpha
antagonist [201].
3.4. Novel Methods
The challenging domain of effective brain delivery has
led to a keen scientific pursuit and as a result many novel
methods have been invented and patented. In these series,
researchers have revealed the use of iontophoresis as an
adjuvant for CNS drug delivery. Iontophoresis has been
defined as the active introduction of ionised molecules into
tissues by means of an electric current. The parent US patent
application of this CIP, Ser. No. 09/197,133 relates to a noninvasive method and device for delivery of a biologically
active agent that is transported by means of iontophoresis
and/or phonophoresis directly to the CNS using the olfactory
pathway to the brain and thereby circum-venting the BBB
and is known as transnasal iontophoretic delivery. Besides
the non-invasive methods, the present invention also
describes the invasive methods and devices for enhanced and
controlled delivery of a biologically active agent to the CNS
that also circumvents the BBB. US Patent application
20020183683A1 Lerner disclosed invasive and non-invasive
CNS drug delivery methods and devices for use in these
methods that essentially circumvent the BBB utilizing
iontophoresis as delivery technique that allows for enhanced
delivery of a biologically active agent into the CNS of a
mammal as well as for (pre)-programm-able and controlled
transport [202]. In US application 20030191426A1, Lerner
et al. invented a device to enhance the delivery of a drug or
other substance of interest into a selected organ or tissue,
comprising of special electrodes, one of the electrodes
carrying a container with the selected drug or other substance
of interest, said electrodes being capable of being positioned
at preselected locations of said organ or tissue, wherein the
electrodes are all connected with a selected energy source
which generates and maintains an energy field before and
during the enhanced delivery of said substance, under the
influence of which delivery is accomplished in a direction
from the active to the passive electrode and into said organ
or tissue . The energy source may be selected from suitable
sources providing an electric field, a magnetic field,
ultrasonic waves, high energy waves like laser beams, or a
combination thereof. Further a method for the enhanced
delivery of said drug or other substance of interest to an
Castile. US20070140981A1 (2007)
[199]
internal organ or target tissue of an organism, for example
the brain, bypassing the BBB, is disclosed [203]. LeBowitz
US Patent application 20060121018A1 disclosed methods
and compositions for targeting therapeutic proteins to the
brain. Methods and compositions of the invention involve
associating an IGF moiety with a therapeutic protein in order
to target the therapeutic protein to the brain. Soluble fusion
proteins that include an IGF targeting moiety are transported
to neural tissue in the brain from blood. Methods and
compositions of the invention include therapeutic
applications for treating lysosomal storage diseases. The
invention also provides nucleic acids and cells for expressing
IGF fusion proteins [204]. Lamensdorf et al. US Patent
application 20060142227A1; “Amphiphilic peptide-PNA
conjugates for the delivery of PNA through the blood brain
barrier” The invention provides molecules comprising of a
nucleic acid, a hydrophobic moiety and a positively charged
moiety, useful in the delivery of a nucleic acid sequence
across a cellular membrane. The invention further relates to
the use of these molecules for the delivery of a nucleic acid
sequence to the brain across the blood brain barrier for
diagnostic and therapeutic applications [205].
4. CURRENT & FUTURE DEVELOPMENTS
A number of concrete examples where successful
delivery and sustained activity have been achieved were
provided. They clearly prove that, with adequate design, the
approach can provide substantially increased and prolonged
brain exposure of the drugs. From the discussion it was
found that many delivery systems like polymeric Nanoparticles and liposomes are the promising carriers to deliver
drugs beyond the BBB for the scrutiny of the central nervous
system. This is even more evident in light of the fact that
most of the potentially available drugs for CNS therapies are
large hydrophilic molecules, e.g., peptides, proteins and
oligonucleotides that do not cross the BBB. Among the
several strategies attempted in order to overcome this
problem, properly tailored NPs may have a great potential.
The large amount of evidence regarding brain drug delivery
by means of P80-coated NPs cannot be ignored or
considered as single evidence even though its action
mechanism is not completely understood. Lipid NPs, e.g.
SLN, NLC, LDC NPs, may represent, in fact, promising
carriers since their prevalence over other formulations in
terms of toxicity, production feasibility and scalability is
widely documented in the literature. The ability of
engineered liposomes to enter into brain tumours makes
86 Recent Patents on Drug Delivery & Formulation, 2009, Vol. 3, No. 1
Table 5.
Ahmad et al.
Patent Status of Therapeutics Used to Treat Various Brain Disorders
Brain Disorder
Molecules Patented Or Under Investigation*
Drugs
Peptides
Cerebral ischemia/
Stroke
Deferoxamine, Trientine, Ebselen, Heregulin, Cobalt,
Tetrathiomolybdate, Remacemide, Nicergoline, Hydergine,
Lubeluzole
Growth factors, Brain-derived neurotrophic factor, Interleukin1, Tumour necrosis factor-, Vasoactive intestinal peptide,
Leuenkephalin, pyruvate, N-acetyl cysteine amide, lactate
Brain Tumours
Procarbazine, Lomustine, Vincristine, Temozolomide,
Dexamethasone
Epidermal growth factor receptor antisense, RNA interference
Pain
Morphine, Frovatriptan, Cannabinoids, Oxycodone, Levallorphan,
Fentanyl, Alfentanil
Alzheimer’s
disease
Ambenonium, Edrophonium, Neostigmine, Tacrine, Rivastigmine,
Pyridostigmine, Galantamine
Peptide T, Interleukin-1
Parkinsonism
Selegiline, Rimantadine, Amantadine, Levodopa, Taolcapone,
Entacapone, Pramipexole, Ropinirole
Glial-derived neurotrophic factor, Interleukin-1,
Tyrosine hydroxylase
Obesity
Diltiazem, Phentermine, Sibutramine, Rimonabant, Melanocortin4 receptor agonist
Migraine
Frovatriptan, Ergotamine, Sumatriptan, Rizatriptan, Zolmitriptan,
Tumor necrosis factor antagonists
Botulinum toxin, Interleukin-1
AIDS
Zidovudine, Efavirenz, Tenofovir, Saquinavir
Human Immuno Virus coat protein, Interferon-, T-20 peptides
Epilepsy
Phenytoin, Ethosuximide, Topiramate, Gabapentin,
Carbamazepine, Lamotrigine
----
Anxiety
Flurazepam, Alprazolam, Diazepam, Lorazepam, Clonazepam,
Propranolol, Buspirone
----
Insomnia
Temazepam, Lorazepam, Flurazepam, Nitrazepam, Midazolam,
Diphenhydramine
----
Schizophrenia
Chlorpromazine, Clozapine, Risperidone, Olanzapine
----
Depression
Imipramine, Fluoxetine, Sertraline, Moclobemide, Phenelzine,
Bupropion
----
Narcotic Addiction
Dihydro--erythroidine,Mecamylamine, Pempidine,
Succinylcholine, Trimethaphean, Chlorisondamine,
Hexamethonium, Pentolinium, Methadone
----
Interleukin-1, Enkephalins, Botulinum toxin, Dynorphin, Endorphin
Leptin, -Melanocyte stimulating hormone
* No brain targeted delivery system available
them potential delivery systems for brain targeting.
Biodegradable polymers are also making their place in the
area of matrix type sustained-release of neurotherapeutics.
Every delivery system has some potential advantages over
each other along with some limitations but it’s a need of the
hour to design a developmental programme in such a way
that the delivery of the drugs across the BBB should be
looked simultaneously along with the discovery programmes. Patient compliance and risk-benefit ratio suggest the
use of non-invasive methods of drug delivery over invasive
methods. A technology of chimeric peptides which are
potential BBB transport vectors and have been applied to
several peptide pharmaceuticals, nucleic acid therapeutics,
and small molecules to make them CNS transportable. The
concept of Trozen Horses is looking promising for brain
targeting which will be amenable to all kinds of molecules,
genes, peptides etc. But the path of CNS drug development
and delivery is full of hurdles. There are challenges ahead of
us to resolve the question of delivery of the drugs to CNS.
More research is in progress to address such challenging
problems. It is clear that this failure is ascribable to a wrong
design in the drug discovery and development programs that
overlook the fundamental contribution of a well sustained
drug delivery program. A long way of optimization and
evaluation is still, however, needed before potential clinical
application. In the absence of an effective BBB technology,
the pharmaceutical industry cannot provide therapeutics for
the majority of patients with brain disorders. It is estimated
that the global CNS pharmaceutical market would have to
grow by more than 500% just to equal the cardiovascular
market. If BBB delivery solutions were in place for either
small or large molecules, then almost any pharmaceutical
could enter clinical drug development programs and
therapies could be developed for most CNS disorders. A
sound review of the patents dealing with CNS drug delivery
approaches has shown that scientific interest in the field has
CNS Drug Delivery
risen but a lot needs to be done. The poor status of potent
molecules available in customized formats produces a dismal
picture for a vast population waiting to be treated. Table 5
presented below summarizes the drugs available for brain
disorders along with their routes of administration.
ACKNOWLEDGEMENT
The authors are thankful to the Central Council for
Research in Unani Medicine (CCRUM) under the Ministry
of AYUSH, Government of India for providing generous
funding and support to the Department of Pharmaceutics,
Jamia Hamdard.
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