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Patent No. 7033598 Methods and apparatus for enhanced and controlled delivery of a biologically active agent into the central nervous system of a mammal (Lerner, Apr 25, 2006)
Abstract:
Disclosed are invasive and non-invasive central nervous system (CNS) drug delivery methods and devices for use in these methods that essentially circumvent the blood-brain barrier. More specifically, the disclosed methods and devices utilize 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)-programmable and controlled transport.
Notes:
FIELD
OF THE INVENTION
The present invention relates to delivery methods and devices for effectively
introducing a biologically active agent into deeper layers of the mammalian
central nervous system (CNS). More specifically the invention relates to both
invasive and non-invasive methods and devices for enhanced and controlled delivery
of said agents into the mammalian CNS while circumventing the blood-brain barrier
(BBB).
BACKGROUND OF THE INVENTION
A variety of approaches currently exist for delivering biologically active agents
to the CNS. These include, among possible others, oral administration, intravenous--,
intramuscular--and transcutaneous administration. All of the above drug delivery
approaches tend to be systemic. Meaning that the drug is delivered into the
systemic circulation, being carried to all internal organs and tissues and it
has to pass through the blood-brain barrier (BBB) in order to access the CNS.
Obviously, all other organs are being exposed to the drug, which may lead to
a high incidence of side effects, particularly with those medications toxic
to certain organs (e.g. nephrotoxic, hepatotoxic etc.). Most importantly, the
therapeutic efficacy of numerous highly effective biologically active agents
(e.g. large compounds, hydrophilic and charged substances such as peptides)
is restricted, because they cannot or poorly penetrate the BBB, resulting in
sub-therapeutic brain levels of these substances. High systemic levels have
to be generated, in order to create therapeutic concentrations in the CNS, but
for many therapeutic substances even this strategy is not always effective.
Therefore, there is a large interest in development of alternative drug delivery
methods for the central nervous system.
The above strategies are based on a pharmacological approach to solve the problem
of BBB transport. Another strategy often employed in brain delivery is the use
of invasive methods such as intraventricular infusion systems, intracerebral
(polymeric) implants, transplantation of genetically engineered protein-secreting
cells and cell implants. These methods are unfortunately only effective for
drug delivery to the surface of the brain or to cells immediately adjacent to
the depot or infusion site and can be used for example in the treatment of carcinomatous
infiltration of the meninges. However, these methods have many limitations because
effective drug concentrations in brain parenchyma cannot be achieved. There
are two reasons for the poor drug distribution in the brain following local
delivery from a depot or infusion site. At first the efficacy of diffusion decreases
with the square of the distance and at second, molecules that are highly diffusible
will be immediately transported out of the brain by means of transport across
local capillaries.
Diffusion in the brain is slow and it has been reported that the time required
to obtain 50% equilibration over distances of approximately 1 cm may take hours
to days. Administration directly into the cerebrospinal fluid (CSF) will result
in significant drug levels in only the outer few millimeters of the tissue adjacent
to the ventricular and subarachnoid spaces. Another disadvantage of intraventricular
infusion is the occurrence of drug distribution only to the ipsilateral brain,
because of the unidirectional flow of CSF within the brain. Intraventricular
administration can be compared with a slow, intravenous infusion causing the
drug to be rapidly eliminated out of the brain, because the CSF volume in humans
is completely recycled every four to five hours, the drug is thus readily distributed
into the peripheral blood stream.
Drug distribution from the matrix of a polymeric implant or catheter of a CNS
delivery device is based on passive diffusion, which is a slow process. During
diffusion the drug may be subjected to substantial metabolism and clearance.
As a result, the volume of tissue exposed to the drug is very small. The treatment
volume of a polymeric implant or intraventricular infusion has been determined
to be less than 1 mm and this is true for both small and large substances. The
limited migration distance has been demonstrated with small molecules and with
large molecules such as nerve growth factor (NGF). A consequence of the limited
diffusion distance is that cells immediately adjacent to the intracerebral implant
are being exposed to high and often toxic concentrations of the drug.
The maximal penetration of drug into brain parenchyma is <1 mm regardless
of the mode of administration (intracerebral implant, microdialysis within the
brain or intracerebroventricular infusion). This imposes a severe limitation
in clinical situations where much larger treatment regions may be required.
Delivery through a chronically implanted canula in the CNS is described by Hargraves
et al. and Yebenes et al. Harbaugh et al. described the use of implantable infusion
pumps.
U.S. Pat. No. 5,720,720 discloses a convection-enhanced delivery catheter and
method adapted to increase the migration distance of the infused drug by maintaining
a pressure gradient during interstitial infusion. Two to ten-fold larger treatment
volumes may be achieved following high-flow infusion for 12 hours using a microinfusion
rate of 3 mu.l/min than can be achieved with low-flow infusion delivering the
same mass using an infusion rate of 0.05 mu.l/min. Despite its large improvement
in delivery efficiency this method has also some disadvantages such as the long
infusion time, the risk of leakage of drug and the limited control of the distribution
pattern within anisotropic media such as the white matter.
As with all catheter devices for intracerebral drug delivery, insertion of a
device into a ventricle requires a risky surgical intervention that may cause
serious tissue damage.
The present invention overcomes the disadvantages such as limited penetration
depth of existing implantable delivery methods by using iontophoresis as a drug
delivery enhancement technique. Iontophoresis has been defined as the active
introduction of ionised molecules into tissues by means of an electric current.
The technique has been used to enhance drug delivery into tissues underlying
the donor electrode (e.g. skin) as well as to the general blood circulation,
thus providing systemic delivery of a drug to the entire body. Iontophoresis
devices require at least two electrodes, both being in electrical contact with
some portion of a biological membrane surface of the body. One electrode commonly
referred to as the "donor" or "active" electrode, is the electrode from which
the biologically active substance, such as a drug or prodrug, is delivered into
the body. Another electrode having an opposite polarity functions to complete
the electric circuit between the body and the electrical power source. This
electrode is commonly referred to as the "receptor" or "passive" electrode.
During iontophoresis, an electrical potential is applied over the electrodes,
in order to create an electrical current to pass through the drug solution and
the adjacent tissue.
Iontophoretic drug administration into body cavities by means of a catheter
type of electrode has been first disclosed about 95 years ago. The Russians
were in this field very productive and during the 1970's and 1980's a considerable
number of patents were issued (e.g. SU Nos 532,890; 843,999; 1,005796). Recently,
patents have been issued that disclose the treatment of blood-vessel related
disorders (e.g. restenosis), bladder, uterus, urethra and prostate disorders.
U.S. Pat. Nos. 6,219,557; 5,588,961; 5,843016; 5,486,160; 5,222,936; 5,232,441;
5,401,239 and 5,728,068 disclose different types of iontophoresis catheters
for insertion into hollow, tubular organs (bladder, urethra and prostate) or
into blood vessels. An implantable system for myocardial iontophoretic delivery
of drugs to the heart is disclosed in U.S. Pat. No. 5,087,243.
Reference may be made to U.S. Pat. No. 5,807,306, which describes an iontophoresis
catheter device for delivering a drug contained in a polymer matrix into internal
tissue. The disclosed catheter may thus be an ideal tool for selective and controlled
delivery to any body passageway or hollow organ. Because the drug is contained
in a polymeric matrix, the risk of leakage typically associated with catheter
devices is practically negligible. However, the disclosed device is not adapted
to be implanted in the brain and is not suitable for long-term treatment. Furthermore,
the device requires manual operation and it requires serious surgical intervention
for intracerebral installation of the catheter.
The parent U.S. patent application of this CIP, Ser. No. 09/197,133 relates
to a non-invasive 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 circumventing
the BBB. This method we have called transnasal iontophoretic delivery. The present
invention describes besides the non-invasive also invasive methods and devices
for enhanced and controlled delivery of a biologically active agent to the CNS
that also circumvents the BBB.
In humans and primates, the olfactory epithelium or olfactory mucosa is located
at the top of the nasal cavity between the central nasal septum and the lateral
wall of each main nasal passage. This region of the nasal cavity, which is free
of airflow, lies just under the cribriform plate of the ethmoid bone that separates
the nasal and cranial cavities. In humans the olfactory epithelium covers an
area in the nose of approximately 2 cm.sup.2 to 10 cm.sup.2. The total olfactory
surface area varies with age and between individuals. The olfactory area can
be reached through the naris following the nasal septum in a superior and posterior
direction. The middle turbinate, which closely opposes the septum usually prevents
access to this region, fortunately, this obstruction is not surmountable.
In the last decade a number of articles were published that describe the delivery
of drugs into the brain by administering the drug in the olfactory area and
also a small number of patents have been issued that describe the use of the
olfactory pathways to the brain as possible alternative drug delivery methods.
For example, U.S. Pat. No. 5,624,898 issued by Frey W. H.; WO 033813A1 issued
by Frey W. H.; WO 09901229A1 issued by Gizurarson S. and WO 044350A1 issued
by Cevc et al. These patents all relate to the passive delivery of substances
to the brain using the olfactory pathways. The agent is administered in the
olfactory region and transport of the agent is based on passive diffusion through
the olfactory epithelium. However, compounds that are hydrophilic, charged and/or
larger than 300 Dalton may be not delivered in therapeutic effective amounts
by the methods described in the cited references. These compounds, but also
all other compounds may be delivered more rapidly and more effectively by means
of a physical enhancement technique such as electrotransport and/or phonophoresis
(sonophoresis). The use of an enhancement technique such as electrotransport
has the additional advantage that it can provide a dose- and rate-controlled
delivery of the biologically active agent and the dose can be pre-programmed
according to individual needs.
Literature provides examples of methods to treat the nasal (respiratory) mucosa
by means of iontophoresis, electrophoresis, and phonophoresis for allergy, rhinitis,
sinusitis etc., and there are also papers that describe the use of nasal iontophoresis
for systemic drug delivery. Already in 1937 Bailey L. et al. described the use
of intranasal zinc iontophoresis to treat hay fever. (Bailey L. D. and Shields
C.; Br. Med J. 1, 808, 1937). Other examples of nasal iontophoresis can be found
in literature as for instance in; Weir et al., J. Laryngol. Otol. 81 (10): 1143-1150
(1967), Dadiomova et al., Vestn. Dermatol. Venerol. 43(7):72-74 (1969), Dainiak
et al., Vestn. Otorinolaringol. May-June; (3): 26-34 (1979); Sokolova et al.,
Vestn. Otorinolaringol. November-December; (6):57-60 (1979); Krotkova et al.,
Zh. Vopr. Neirokhir. Im. N. N. Burdenko May-June; (3): 44-47 (1980); Buzek et
al., Cas. Lek. Cesk.; 120 (51): 1561-1565 (1981) and Gronfors et al., Med. Prog.
Technol.; 17 (2): 119-128 (1991). Examples of nasal iontophoresis electrodes
for systemic delivery or local delivery are described in the following patents:
U.S. Pat. No. 5,298,017 issued by Theeuwes et al., SU-992075 issued by Kens
et al. and U.S. Pat. No. 6,001,088 issued by Roberts et al. that describes a
method for delivery of a biologically active agent to the eye following iontophoresis
through the nasal epithelium.
Systemic nasal drug delivery implicates that drugs are delivered through the
respiratory epithelium of the nasal cavity. In contrast to the olfactory mucosa,
the respiratory epithelium is easy accessible by means of for example; nose
drops, nasal sprays and a possible iontophoresis or phonophoresis probe. However,
the major reason why respiratory epithelium is the target site of nasal drug
administration is its rich underlying vascular network, especially in the Kiesselbach's
area. These blood vessels can be accessed immediately following absorption and
blood flow distributes the drug throughout the rest of the body. The present
invention is based on enhanced delivery of a biologically active agent through
the olfactory epithelium of the nasal cavity. Vascularization in the olfactory
region is much less compared to the anterior part of the nasal cavity. The olfactory
epithelium has distinct anatomic differences with the respiratory epithelium
(Graziadei P. P. C. and Monti-Graziadei, 1985, Ann.NYacad.Sci, 457,127-145).
The olfactory epithelium being a sensitive neuroepithelium with poor regeneration
properties whereas the respiratory epithelium is an "ordinary" squamous mucosal
epithelium with good regeneration properties and having mucocilliary clearance.
Due to the differences between these two types of epithelium and especially
to the delicate nature of olfactory neuroepithelium compared to the respiratory
mucosa, nasal compositions for the respiratory nasal mucosa will not automatically
be appropriate for the olfactory mucosa. Also, iontophoresis parameters (e.g.
current strength, wave-form, frequency, duration) for enhanced olfactory drug
delivery will differ from enhanced transport through respiratory nasal mucosa
use of nasal iontophoresis according to the present invention requires specific
physicotechnical properties of the nasal electrode(s) that differ from the nasal
electrodes described for local and systemic delivery through the respiratory
epithelium. For example, the electrode must have such a shape to allow it to
be inserted into the olfactory region through the olfactory cleft and to make
an intimate contact with the olfactory mucosa.
An alternate BBB circumventing pathway to the brain is provided by the optic
nerve. The optic nerve, which is about 4 cm long, is directed backwards and
medially through the posterior part of the orbital cavity. It then runs through
the optic canal into cranial cavity and joins the optic chiasma. The optic nerve
is enclosed in three sheaths, which are continuous with the membranes of the
brain, and are prolonged as far as the back of the eyeball. Therefore, there
is a direct connection between the optic nerve and the brain structures. Itaya
and van Hoessen described transneuronal retrograde labeling of neurons in the
stratum griseum superficiale of the superior colliculus following intra-ocular
injection of wheat germ agglutinin-horseradish peroxidase. A study of the distribution
of wheat germ agglutinin-horseradish peroxidase in the visual system following
intra-ocular injections in the chick, rat and monkey confirmed early findings
of transneural transport of this conjugate in vivo. It is therefore envisioned
that a biologically active agent can be delivered direct to the CNS by a non-invasive
delivery method and apparatus that utilises the ocular pathway that circumvents
the BBB.
SUMMARY OF THE INVENTION
The present invention provides invasive and non-invasive methods and devices
for enhanced and controlled delivery of a biologically active agent directly
into the CNS, thereby circumventing essentially the blood-brain barrier. The
invasive methods involve a surgical intervention that is limited to a minimum
compared to existing methods, because the delivery system is installed at an
extracerebral location i.e. for example in the cranium, the epidural, or subdural
spaces, on the brain surface or intrabrain. The non-invasive methods and devices
utilise the olfactory or ocular pathway to the CNS and thus circumvent the BBB.
Both invasive and non-invasive methods allow for achievement of therapeutic
brain levels of a biologically active agent while effectively reducing the application
or infusion time of said agent compared to existing methods.
In view of the limitations of existing CNS delivery systems, it is an object
of the present invention to provide a method and device for enhanced and controlled
administration of a biologically active agent that allows for effective concentrations
of said agent in deeper tissue layers of the CNS while essentially circumventing
the systemic compartment and the blood-brain barrier.
It is an object of the present invention to provide a method and device for
enhanced and controlled CNS administration of a biologically active agent that
requires a minimum of surgical intervention and that allows for a high level
of safety with a minimum of local side effects.
It is a further object of the invention to provide a device of such design and
made of such materials, as well as such a method for administration of a biologically
active agent into the CNS that promotes high patient compliance and acceptance.
It is yet another object of the invention to provide a method and device for
controlled and enhanced delivery of a biologically active agent into the CNS
that is regulated by a feedback signal.
It is a further object of the present invention to thus treat CNS disorders.
These and other objects are accomplished by providing drug delivery methods
and devices that use iontophoresis for controlled and enhanced delivery of a
biologically active agent into the CNS. Phonophoresis may be chosen as an alternate
delivery technique for the non-invasive delivery methods and devices of the
present invention.
For the purpose of this invention, "iontophoresis" is defined as any form of
electrotransport of a substance through mammalian tissue induced or enhanced
by the application of an electrical potential. Thus, the term "iontophoresis"
as used herein includes without limitation previously defined terms such as
iontophoresis, electrotransport, iontokinesis and electroosmosis, and the combination
of thereof, which comprises the transport of a substance induced or enhanced
by the application of an electric potential.
"Olfactory region" or "olfactory area" of the human nose for the purpose of
the disclosed invention defines the area of nasal mucosa that covers the olfactory
cleft, as well as the septal mucosa of the superior and middle turbinates in
the posterior and middle thirds of the nose.
As used in conjunction with the disclosed invention, the term "biologically
active agent" as defined herein, is an agent, or its pharmaceutically acceptable
salt, or mixture of compounds, which has therapeutic, prophylactic, pharmacological,
physiological or diagnostic effects on a mammal and may also include one compound
or mixture of compounds that produce more than one of these effects. Suitable
therapeutic, pharmacological, physiological and/or prophylactic biologically
active agents can be selected from the following listed, and are given as examples
and without limitation: amino acids, anabolics, analgesics and antagonists,
anaesthetics, anti-adrenergic agents, anti-asthmatics, anti-atherosclerotics,
antibacterials, anticholesterolics, anti-coagulants, antidepressants, antidotes,
anti-emetics, anti-epileptic drugs, anti-fibrinolytics, anti-inflammatory agents,
antihypertensives, antimetabolites, antimigraine agents, antimycotics, antinauseants,
antineoplastics, anti-obesity agents, anti-Parkinson agents, antiprotozoals,
antipsychotics, antirheumatics, antiseptics, antivertigo agents, antivirals,
appetite stimulants, bacterial vaccines, bioflavonoids, calcium channel blockers,
capillary stabilizing agents, coagulants, corticosteroids, detoxifying agents
for cytostatic treatment, diagnostic agents (like contrast media, radiopaque
agents and radioisotopes), drugs for treatment of chronic alcoholism, electrolytes,
enzymes, enzyme inhibitors, ferments, ferment inhibitors, gangliosides and ganglioside
derivatives, hemostatics, hormones, hormone antagonists, hypnotics, immunomodulators,
immunostimulants, immunosuppressants, minerals, muscle relaxants, neuromodulators,
neurotransmitters and nootropics, osmotic diuretics, parasympatholytics, para-sympathomimetics,
peptides, proteins, psychostimulants, respiratory stimulants, sedatives, serum
lipid reducing agents, smooth muscle relaxants, sympatholytics, sympathomimetics,
vasodilators, vasoprotectives, vectors for gene therapy, viral vaccines, viruses,
vitamins, oligonucleotides and derivatives, and any therapeutic agent capable
of affecting the nervous system.
Examples of biologically active agents, which may be preferentially administered
using either the invasive or non-invasive methods disclosed here for enhanced
delivery directly into the CNS and thereby essentially avoiding the systemic
circulation include those biologically active agents degraded in the gastrointestinal
tract, metabolised in an internal organ or in the blood, rapidly excreted from
the bloodstream (e.g. through kidney clearance), and those with limited penetration
of the blood-brain barrier. Also, those agents with systemic side effects will
benefit from direct administration in the CNS avoiding the blood stream. Further
those biologically active agents that at least partly target the CNS although
the underlying disease may have systemic clinical manifestations (e.g. alpha-2-agonists
and hypertension). Also, those that target the neural components of the olfactory
pathway (e.g. therapeutics that promote regeneration of the olfactory bulb)
or those that target neural components of the ocular pathway. Iontophoresis
and/or phonophoresis provide thus a means for active transport of a biologically
active agent into and/or through the ocular pathway or into and/or through the
nasal mucosa, and into the olfactory pathways, and/or into the CNS. Also, iontophoresis
and/or phonophoresis provide an active transport means to rapidly and effectively
transport a biologically active agent out of the delivery device to the olfactory
area of nasal mucosa to be treated or into the underlying tissues.